Patent Publication Number: US-2023142883-A1

Title: Compounds and uses thereof

Description:
SEQUENCE LISTING 
     This application contains a Sequence Listing which has been filed electronically in Extensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on Aug. 9, 2022, is named 51121-027006_Sequence_Listing_8_9_22 and is 638,338 bytes in size. 
     BACKGROUND 
     Disorders can be affected by the BAF complex. BRD9 is a component of the BAF complex. The present invention relates to useful compositions and methods for the treatment of BAF complex-related disorders, such as cancer and Infection. 
     SUMMARY 
     Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain-containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Accordingly, agents that reduce the levels and/or activity of BRD9 may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that depleting BRD9 in cells results in the depletion of the SS18-SSX fusion protein in those cells. The SS18-SSX fusion protein has been detected in more than 95% of synovial sarcoma tumors and is often the only cytogenetic abnormality in synovial sarcoma. Additionally, evidence suggests that the BAF complex is involved in cellular antiviral activities. Thus, agents that degrade BRD9 (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to BAF, BRD9, and/or SS18-SSX. 
     The present disclosure features compounds and methods useful for treating BAF-related disorders (e.g., cancer or infection). 
     In an aspect, the disclosure features a compound having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     where 
     A is a BRD9 binding moiety; 
     B is a degradation moiety; and 
     L has the structure of Formula II: 
     
       
         
         
             
             
         
       
     
     where 
     A 1  is a bond between the linker and A; 
     A 2  is a bond between B and the linker; 
     each of m, n, o1, o2, and p is, independently, 0 or 1; 
     each of E 1  and E 2  is, independently, O, S, NR N , optionally substituted C 1-10  alkylene, optionally substituted C 2-10  alkenylene, optionally substituted C 2-10  alkynylene, optionally substituted C 2 -C 10  polyethylene glycol, or optionally substituted C 1-10  heteroalkylene; 
     E 3  is optionally substituted C 1 -C 6  alkylene, optionally substituted C 1 -C 6  heteroalkylene, O, SNR N ; 
     each R N  is, independently, H, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 6-12  aryl, or optionally substituted C 1-7  heteroalkyl; 
     C 3  is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and 
     each of F 1 , F 2 , and F 3  is, independently, optionally substituted C 3 -C 10  carbocyclylene, optionally substituted C 2-10  heterocyclylene, optionally substituted C 6 -C 10  arylene, or optionally substituted C 2 -C 9  heteroarylene, 
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the linker has the structure of Formula IIa: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IIb: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IIc: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IId: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IIe: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IIf: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of Formula IIg: 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of E 1  and E 2  is, independently, NR N , optionally substituted C 1-10  alkylene, optionally substituted C 2 -C 10  polyethylene glycolene, or optionally substituted C 1-19  heteroalkylene. 
     In some embodiments, E 3  is optionally substituted C 1 -C 6  alkylene, O, S, or NR N ; 
     In some embodiments, E 3  is optionally substituted C 1 -C 6  alkylene. In some embodiments, E 3  is optionally substituted C 1 -C 3  alkylene. In some embodiments, E 3  is O, S, or NR N . 
     In some embodiments, E 3  is C 1 -C 6  alkylene. In some embodiments, E 3  is C 1 -C 3  alkylene. In some embodiments, E 3  is O. 
     In some embodiments, E 3  is 
     
       
         
         
             
             
         
       
     
     where a is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, E 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R N  is, independently, H or optionally substituted C 1-4  alkyl. 
     In some embodiments, each R N  is, independently, H or methyl. 
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     where a is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     where a is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where 
     b is 0, 1, 2, 3, 4, 5, or 6; 
     R a  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 8  carbocyclyl; 
     R b  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 8  carbocyclyl; and 
     R c  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 8  carbocyclyl. 
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R a  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R b  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R c  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, R a  is H or methyl. In some embodiments, R c  is H or methyl. In some embodiments, R c  is H or methyl. 
     In some embodiments, b is 0, 1, 2, or 3. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. 
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 2  is H NR w , 
     
       
         
         
             
             
         
       
     
     wherein 
     c is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
     d is 0, 1, 2, or 3; 
     e is 0, 1, 2, 3, 4, 5, or 6; 
     f is 0, 1, 2, 3, or 4; 
     R d  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 6  carbocyclyl; 
     R 8  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 6  carbocyclyl; 
     R f  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 6  carbocyclyl; 
     R g  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 6  carbocyclyl; and 
     W is O or NR w , wherein R w  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, E 2  is O, NR w   
     
       
         
         
             
             
         
       
     
     In some embodiments, R d  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 8  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 1  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R d  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R w  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, R d  is H or methyl. In some embodiments, R f  is H or methyl. In some embodiments, R f  is H or methyl. In some embodiments, R g  is H or methyl. In some embodiments, R w  is H or methyl. 
     In some embodiments, E 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, E 2  is O, 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of F 1 , F 2 , or F 3  is, independently, optionally substituted C 3 -C 10  carbocyclylene. 
     In some embodiments, the C 3 -C 10  carbocyclylene is monocyclic. In some embodiments, the C 3 -C 10  carbocyclylene is polycyclic. 
     In some embodiments, the C 3 -C 10  carbocyclylene is bicyclic. 
     In some embodiments, the C 3 -C 10  carbocyclylene is bridged. In some embodiments, the C 3 -C 10  carbocyclylene is fused. In some embodiments, the C 3 -C 10  carbocyclylene is spirocyclic. 
     In some embodiments, the C 3 -C 10  carbocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 3 -C 10  carbocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of F 1 , F 2 , or P is, independently, optionally substituted C 2 -C 9  heterocyclylene. 
     In some embodiments, the C 2 -C 9  heterocyclylene is monocyclic. In some embodiments, the C 2 -C 9  heterocyclylene is polycyclic. 
     In some embodiments, the C 2 -C 9  heterocyclylene is bicyclic. 
     In some embodiments, the C 2 -C 9  heterocyclylene is bridged. In some embodiments, the C 2 -C 9  heterocyclylene is fused. In some embodiments, the C 2 -C 9  heterocyclylene is spirocyclic. 
     In some embodiments, the C 2 -C 9  heterocyclylene includes a quaternary amine. 
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where 
     q1 is 0, 1, 2, 3, or 4; 
     q2 is 0, 1, 2, 3, 4, 5, or 6; 
     q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
     each R h  is, independently,  2 H, halogen, optionally substituted C 1 -C 6  alkyl, OR i2 , or NR i3 R i4 ; or two R h  groups, together with the carbon atom to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl; or two R h  groups, together with the carbon atoms to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl; 
     R i1  is H or optionally substituted C 1 -C 6  alkyl; 
     R i2  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 8  carbocyclyl; 
     R i3  is H or optionally substituted C 1 -C 6  alkyl; and 
     R i4  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, each R h  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, OR i2 , or NR i3 R i4 . In some embodiments. R i1  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R i2  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R i3  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R i4  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, each R h  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, OR i2 , or NR i3 R i4 . In some embodiments, each R h  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, or NR i3 R i4 . 
     In some embodiments, each R h  is, independently,  2 H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, OR i2 , or NR i3 R i4 . In some embodiments, two R h  groups, together with the carbon atom to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl. In some embodiments, two R h  groups, together with the carbon atoms to which each is attached, combine to form optionally substituted C 3 -C 10  carbocyclyl or optionally substituted C 2 -C 9  heterocyclyl. 
     In some embodiments, each R h  is, independently,  2 H, F, methyl, 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R h  is, independently, F, methyl, or NR i3 R i4 . 
     In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. 
     In some embodiments, q2 is 0, 1, or 2. In some embodiments, q2 is 0. In some embodiments, q2 is 1. In some embodiments, q2 is 2. 
     In some embodiments, q3 is 0, 1, or 2. In some embodiments, q3 is 0. In some embodiments, q3 is 1. In some embodiments, q3 is 2. 
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R i1  is H or methyl. In some embodiments, R i2  is H or methyl. In some embodiments, R i3  is H or methyl. In some embodiments, R 4  is H or methyl. 
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocycyl is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocyclyl is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocycyl is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the C 2 -C 9  heterocycyl is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of F 1 , F 2 , or P is, independently, optionally substituted C 8 -C 10  arylene. 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of F 1 , F 2 , or P is, independently, optionally substituted C 2 -C 9  heteroarylene. 
     In some embodiments, the C 2 -C 9  heteroarylene is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, F 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, C 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, C 3  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, m is 1. In some embodiments, p is 1. 
     In some embodiments, the linker has the structure of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the linker is absent. 
     In some embodiments, the linker is optionally substituted C 3 -C 10  carbocyclylene, optionally substituted C 2-10  heterocyclylene, optionally substituted C 6 -C 10  arylene, or optionally substituted C 2 -C 9  heteroarylene. 
     In some embodiments, the linker is optionally substituted C 3 -C 10  carbocyclylene or optionally substituted C 2-10  heterocyclylene. In some embodiments, the linker is optionally substituted C 6 -C 10  arylene or optionally substituted C 2 -C 9  heteroarylene. 
     In some embodiments, the linker is optionally substituted C 2-10  heterocyclylene. 
     In some embodiments, the C 2 -C 9  heterocyclylene is monocyclic. In some embodiments, the C 2 -C 9  heterocyclylene is polycyclic. 
     In some embodiments, the C 2 -C 9  heterocyclylene is bicyclic. 
     In some embodiments, the C 2 -C 9  heterocyclylene is bridged. In some embodiments, the C 2 -C 9  heterocyclylene is fused. In some embodiments, the C 2 -C 9  heterocyclylene is spirocyclic. 
     In some embodiments, the linker has the structure of 
     
       
         
         
             
             
         
       
     
     In some embodiments, the linker has the structure of 
     
       
         
         
             
             
         
       
     
     In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety. 
     In some embodiments, the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Landau (VHL) ligands, or derivatives or analogs thereof. 
     In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety. 
     In some embodiments, the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof. 
     In some embodiments, the degradation moiety includes the structure of Formula Y: 
     
       
         
         
             
             
         
       
     
     where 
     A 2  is a bond between the degradation moiety and the linker; 
     v1 is 0, 1, 2, 3, 4, or 5; 
     u1 is 1, 2, or 3; 
     T 1  is a bond or 
     
       
         
         
             
             
         
       
     
     T 2  is, 
     
       
         
         
             
             
         
       
     
     R 5  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     each R J1  is, independently, halogen, optionally substituted C 1 -C 9  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     J A  is absent, O, optionally substituted amino, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 5  heteroalkyl; and 
     J is absent, optionally substituted C 3 -C 10  carbocyclylene, optionally substituted C 6 -C 10  arylene, optionally substituted C 2 -C 9  heterocyclylene, or optionally substituted C 2 -C 9  heteroarylene, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula Y has the structure of Formula Y1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, T 1  is a bond. In some embodiments, T 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula Y has the structure of Formula Y2: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula Y has the structure of Formula Z: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, u1 is 1. In some embodiments, u1 is 2. In some embodiments u1 is 3. 
     In some embodiments, the structure of Formula Z has the structure of Formula AA0: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula Z has the structure of Formula AB: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula Z has the structure of Formula AC: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, J A  is absent. In some embodiments, J A  is optionally substituted C 1 -C 6  alkyl. In some embodiments, J A  is optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, J A  is O or optionally substituted amino. 
     In some embodiments, J A  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula AA0 has the structure of Formula AA0: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3. 
     In some embodiments, the structure of Formula AA has the structure of Formula AA1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula AB has the structure of Formula AB1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula AC has the structure of Formula AC1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, J is absent. In some embodiments, J is optionally substituted C 3 -C 10  carbocyclylene or optionally substituted C 6 -C 10  arylene. In some embodiments, J is optionally substituted C 2 -C 9  heterocyclylene or optionally substituted C 2 -C 9  heteroarylene. 
     In some embodiments, J is optionally substituted heterocyclylene. In some embodiments, J is optionally substituted C 6 -C 10  arylene. 
     In some embodiments, J is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula AA has the structure of Formula AA2: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula AA has the structure of Formula AA3: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula AA has the structure of Formula AA4: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, R A5  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R A5  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R A5  is H or methyl. In some embodiments, R A5  is H. In some embodiments, R A5  is methyl. In some embodiments, R A5  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula AA has the structure of Formula A: 
     
       
         
         
             
             
         
       
     
     where 
     Y 1  is 
     
       
         
         
             
             
         
       
     
     R A5  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     R A6  is H or optionally substituted C 1 -C 6  alkyl; and R A1  is H or optionally substituted C 1 -C 6  alkyl; or 
     R A6  and R A1 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6  carbocycyl or optionally substituted C 2 -C 5  heterocyclyl; or R A6  and R A1 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6  carbocyclyl or optionally substituted C 2 -C 6  heterocyclyl; 
     R A8  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     each of R A1 , R A2 , R A3 , and R A4  is, independently, H, A 2 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 6  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 6  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, optionally substituted —O—C 3 -C 6  carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1  and R A2 , R A2  and R A3 , and/or R A3  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     is optionally substituted C 6 -C 10  aryl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 6  heteroaryl, or C 2 -C 9  heterocyclyl, any of which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A1  is A 2 , or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, each of R A1 , R A2 , R A3 , and R A4  is, independently, H, A 2 , halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 9  heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or R A1  and R A2 , R A2  and R A3 , and/or R A3  and R A1 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     is optionally substituted C 6 -C 10  aryl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heteroaryl, or C 2 -C 9  heterocyclyl, any of which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A1  is A 2 , or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, each of R A1 , R A2 , R A3 , and R A4  is, H, A 2 , halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted —O—C 3 -C 6  carbocyclyl, hydroxyl, optionally substituted amino; or R A1  and R A2 , R A2  and R A3 , or R A3  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     is optionally substituted C 2 -C 9  heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A1  is A 2  or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 . 
     In some embodiments, each of R A1 , R A2 , R A3 , and R A4  is, independently, H, A 2 , F, 
     
       
         
         
             
             
         
       
     
     or R A1 , and R A2 , and R A3 , or R A4  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     is optionally substituted C 2 -C 9  heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4  is A 2 , or 
     
       
         
         
             
             
         
       
     
     s substituted with A 2 . 
     In some embodiments, R A1  is A 2 . In some embodiments, R A2  is A 2 . In some embodiments, R A3  is A 2 . In some embodiments, R A1  is A 2 . In some embodiments, R A5  is A 2 . 
     In some embodiments, R A5  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, R A5  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R A5  is H. In some embodiments, R A5  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of R A6  and R A7  is, independently, H, F, 
     
       
         
         
             
             
         
       
     
     or R A6  and R A7 , together with the carbon atom to which each is bound, combine to form 
     
       
         
         
             
             
         
       
     
     In some embodiments, R A6  is H and R A7  is H. 
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, Y 1  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula A has the structure of Formula A1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A2: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A3: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A4: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable sail thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A5: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A6: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable sail thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A7: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A8: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A9: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula A has the structure of Formula A10: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, wherein the structure of Formula A is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, the structure of Formula A is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula A is 
     
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     where R A9  is H, A 2 , optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, the structure of Formula A is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, R A9  is H, A 2 , or optionally substituted C 1 -C 6  alkyl. In some embodiments, R A9  is H, A 2 , or methyl. In some embodiments, R 9A  is H. In some embodiments, R 9A  is methyl. In some embodiments, R A9  is A 2 . 
     In some embodiments, the structure of Formula A is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula AA has the structure of Formula B: 
     
       
         
         
             
             
         
       
     
     where 
     R A5  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     each of R A1 , R A2 , R A3 , and R A1  is, independently, H, A 2 , halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, optionally substituted —O—C 3 -C 6  carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1  and R A2 , R A2  and R A3 , and/or R A3  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     and is optionally substituted C 6 -C 10  aryl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heteroaryl, or C 2 -C 9  heterocyclyl, any of which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4  is A 2 , or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, each of R A1 , R A2 , R A3 , and RU is, H, A 2 , halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted —O—C 3 -C 6  carbocyclyl, hydroxyl, optionally substituted amino; or R A1  and R A2 , R A2  and R A3 , or R A3  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     is optionally substituted C 2 -C 9  heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4  is A 2  or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 . 
     In some embodiments, each of R A1 , R A2 , R A3 , and R A4  is, independently, H, A 2 , F, 
     
       
         
         
             
             
         
       
     
     or R A1  and R A2 , R A2  and R A3 , or R A3  and R A4 , together with the carbon atoms to which each is attached, combine to form 
     
       
         
         
             
             
         
       
     
     and is optionally substituted C 2 -C 9  heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4  is A 2 , or 
     
       
         
         
             
             
         
       
     
     is substituted with A 2 . 
     In some embodiments, R A1  is A 2 . In some embodiments, R A2  is A 2 . In some embodiments, R A3  is A 2 . In some embodiments, R A4  is A 2 . In some embodiments, R A5  is A 2 . 
     In some embodiments, R A5  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, R A5  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R A5  is H. In some embodiments, R A5  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula B has the structure of Formula B1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable sail thereof. 
     In some embodiments, the structure of Formula B has the structure of Formula B2: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula B has the structure of Formula B3: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable sail thereof. 
     In some embodiments, the structure of Formula B has the structure of Formula B4: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula B is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula B is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula B is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the ubiquitin ligase binding moiety comprises a von Hippel-Landau ligand. 
     In some embodiments, the von Hippel-Lindau ligand has the structure of 
     
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, the degradation moiety includes the structure of Formula C: 
     
       
         
         
             
             
         
       
     
     where 
     R B1  is H, A 2 m optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     R B2  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     R B3  is A 2 , optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 3 -C 10  aryl, optionally substituted C 1 -C 6  alkyl C 3 -C 10  carbocyclyl, or optionally substituted C 1 -C 6  alkyl C 6 -C 10  aryl; 
     R B4  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 1 -C 6  alkyl C 3 -C 10  carbocyclyl, or optionally substituted C 1 -C 6  alkyl C 6 -C 10  aryl; 
     R B5  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     v2 is 0, 1, 2, 3, or 4; 
     each R B6  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocycyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 
     each of R B7  and R B6  is, independently, H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl, where one of R B1  and R B1  is A 2 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula C is 
     
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, the structure of Formula C is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the degrader moiety includes the structure of Formula D: 
     
       
         
         
             
             
         
       
     
     where 
     A 2  is a bond between B and the linker; 
     each of R C1 , R C2 , and R C7  is, independently, H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     R C3  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 1 -C 6  alkyl C 3 -C 10  carbocyclyl, or optionally substituted C 1 -C 6  alkyl C 6 -C 10  aryl; 
     R C5  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 8 -C 10  aryl, optionally substituted C 1 -C 6  alkyl C 3 -C 10  carbocyclyl, or optionally substituted C 1 -C 6  alkyl C 8 -C 10  aryl; 
     v3 is 0, 1, 2, 3, or 4; 
     each R C8  is, independently, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 8  alkenyl, optionally substituted C 2 -C 8  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     v4 is 0, 1, 2, 3, or 4; and 
     each R C9  is, independently, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 8  heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula D is 
     
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, the degrader moiety includes the structure of Formula E: 
     
       
         
         
             
             
         
       
     
     where 
     A 2  is a bond between B and the linker; 
     each of R C10  and R C11  is, independently, H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 1 -C 6  alkyl C 3 -C 10  carbocyclyl, or optionally substituted C 1 -C 6  alkyl C 6 -C 10  aryl; 
     v5 is 0, 1, 2, 3, or 4; 
     each R C12  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; vets 0, 1, 2, 3, or 4; and 
     each R 21  is, independently, halogen, optionally substituted C 1 -C 6  al yl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula E is 
     
       
         
         
             
             
         
       
     
     or derivative or analog thereof. 
     In some embodiments, the degradation moiety includes the structure of Formula FA: 
     
       
         
         
             
             
         
       
     
     where 
     
       
         
         
             
             
         
       
     
     or a bicyclic moiety which is substituted with A 2  and substituted with one or more groups independently selected from H, R FF1 , and oxo; 
       is a single bond or a double bond; 
     u2 is 0, 1, 2, or 3; 
     A 2  is a bond between the degrader and the linker; 
     Y Fa  is CR Fb R Fc , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ; 
     Y Fb  is NH, NR FF1 , CH 2 , CHR FF1 , C(R FF1 ) 2 , O, or S; 
     Y FA  is CR Fb R Fc , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 . 
     each of R Fb , R Fc , R Fd , and R Fe  is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl 2 ; 
     or R Fb  and R Fc , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and 0; 
     or R Fd  and R Fe , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; and 
     or R Fd  and R Fb , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; 
     each of Y Fd  and Y Ff  is, independently, CH 2 , CHR FF2 , C(R FF2 ) 2 , C(O), N, NH, NR FF3 , O, S, or S(O); 
     Y Fe  is a bond or a divalent moiety attached to Y Fd , and Y Ff  that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring,
         wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom;   wherein one of the ring atoms is substituted with A 2  and the others are substituted with one or more groups independently selected from H and R FF1 ; and   wherein the contiguous atoms of re can be attached through a single or double bond,       

     each R FF1  is, independently, H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl; 
     each R FF2  is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including alkyl)(aliphatic including alkyl), —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(aryl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and 
     R FF3  is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, 
     wherein if Y Fd  or Y Ff  is substituted with A 2 , then Y Fe  is a bond, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the compound of Formula FA has the structure of Formula FA1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the degradation moiety includes the structure of Formula FB: 
     
       
         
         
             
             
         
       
     
     where 
     
       
         
         
             
             
         
       
     
     or a bicyclic moiety which is substituted with A 2  and substituted with one or more groups independently selected from H, R FF1 , and oxo; 
     A 2  is a bond between the degrader and the linker; 
     Y Fa  is CR Fb R Fc , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ; 
     each of Y Fb  and Y Fc  is, independently, NH, NR FF1 , CH 2 , CHR FF1 , C(R FF1 ) 2 , O, or S; 
     Y Fc  is CR Fd R Fe , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 . P(O)alkyl, P(O)OH, P(O)NH 2 ; 
     each of R Fb , R Fc , R Fd , R Fe , R Ff , and R Fg  is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl 2 ; 
     or R Fb  and R Fc , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and 0; 
     or R Fd  and R Fe , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; 
     or R Ff  and R Fg , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; 
     or R Fd  and R Fb , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; 
     or R Fd  and R Ff , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; 
     or R Fb  and R Fg  together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; 
     each of Y Fd  and Y Ff  is independently, CH 2 , CHR FF2 , C(R FF2 ) 2 , C(O), N, NH, NR FF3 , O, S, or S(O); 
     Y Fe  is a bond or a divalent moiety attached to Y Fd  and Y Ff  that contains 1 to 5 contiguous carbon atoms that form a 3 to β-membered ring,
         wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom;   wherein one of the ring atoms is substituted with and the others are substituted with one or more groups independently selected from H and R FF1 ; and   wherein the contiguous atoms of re can be attached through a single or double bond,       

     each R FF1  is independently, H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl; 
     each R FF2  is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including alkyl)(aliphatic including alkyl), —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and 
     R FF1  is alkyl, alkenyl, alkynyl, —C(O)N, —C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, 
     wherein if Y Fc  or Y Ff  is substituted with A 2 , then Y Fe  is a bond, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the compound of Formula FB has the structure of Formula FB1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the degradation moiety includes the structure of Formula F1: 
     
       
         
         
             
             
         
       
     
     where A 2  is a bond between the degrader and the linker; and R F1  is absent or O, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, R F1  is absent. In some embodiments, R F1  is O. 
     In some embodiments, the structure of Formula F1 is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the degradation moiety Includes the structure Formula F2: 
     
       
         
         
             
             
         
       
     
     where A 2  is a bond between the degrader and the linker; and Y 2  is CH 2  or NH, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, Y 2  is NH. In some embodiments, Y 2  is CH 2 . 
     In some embodiments, structure of Formula F2 is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the degradation moiety includes the structure Formula G: 
     
       
         
         
             
             
         
       
     
     where A 2  is a bond between the degrader and the linker; and Y 3  is CH 2  or NH, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, Y 3  is NH. In some embodiments, Y 3  is CH 2 . 
     In some embodiments, structure of Formula G is 
     
       
         
         
             
             
         
       
     
     The degradation moiety may also include structures found in, e.g., WO2017/197036; WO2019/204354, WO2019/236483, WO02020/010177; and WO2020/010227, the structures of which are herein incorporated by reference. 
     In some embodiments, A test the structure of Formula III: 
     
       
         
         
             
             
         
       
     
     where 
     R 4  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl, Z 1  is N or CR 5 ; 
     Z 2  is N or CR 6a ; 
     Z 3  is N or CR 6b ; 
     R 5  is H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, or optionally substituted C 6 -C 10  aryl; 
     R 6a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocycyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; R 6B  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; or R 6a  and R 6b , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10  aryl or optionally substituted C 2 -C 9  heteroaryl; 
     s is 0, 1, 2, 3, or 4: 
     each R 9  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 
     A 1  is a bond between A and the linker, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, Z 1  is N. In some embodiments, Z 1  is CR 5 . 
     In some embodiments, Z 2  is N. In some embodiments, Z 2  is CR 6a . 
     In some embodiments, Z 3  is N. In some embodiments, Z 3  is CR 6b . 
     In some embodiments, Z 1  is CR 5 , Z 2  is CR 6a , and Z 3  is CR 6b . In some embodiments, Z 1  is N, Z 2  is CR 5a , and Z 2  is CR 5b . In some embodiments, Z 1  is CR 5 , Z 2  is N, and Z 3  is CR 6b . In some embodiments, Z 1  is N, V is CR 6a , and Z 3  is N. In some embodiments, Z 1  is N, Z 2  is N, and Z 3  is CR 6b . In some embodiments, Z 1  is CR 5 , Z 2  is N, and Z 3  is N. 
     In some embodiments, R 4  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 4  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, or optionally substituted C 3 -C 10  carbocyclyl. 
     In some embodiments, R 4  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 3 -C 10  carbocyclyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 4  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 4  is H. In some embodiments, R 4  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl. In some embodiments, R 5  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 5  is H, optionally substituted C 1 -C 3  alkyl, or optionally substituted C 3 -C 10  carbocyclyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 5  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is H. In some embodiments, R 5  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino. 
     In some embodiments, R 6a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 6a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, R 6a  is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 6a  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 6a  is H, F, cyano 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  is H. In some embodiments, R 6a  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6b  is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino. 
     In some embodiments, R 6b  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 6b  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, R 6b  is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 6b  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 6b  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6b  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6b  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6b  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6b  is H. In some embodiments, R 6b  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 6a  and R 6b , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10  aryl or optionally substituted C 2 -C 9  heteroaryl. 
     In some embodiments, s is 0, 1, or 2. In some embodiments, s is 1 or 2. In some embodiments, s is 2. 
     In some embodiments, each R 9  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, each R 9  is, independently, optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 9  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 9  is, independently, halogen, 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 9  is, independently, F, Cl, 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula III has the structure of Formula IIIa: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIb: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIc: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIId: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIe: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIf: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIg: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIh: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IIIi: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula III has the structure of Formula IV: 
     
       
         
         
             
             
         
       
     
     where 
     R 7  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl; 
     R 8  is H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, or optionally substituted C 6 -C 10  aryl; 
     s is 0, 1, 2, 3, or 4: 
     each R 9  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocycyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     X 1  is N or CR 10a ; 
     X 2  is N or CR 10b ; 
     X 3  is N or CR 10c ; 
     X 4  is N or CR 10d ; 
     each of R 10a , R 10b , R 10c , and R 10d  is, independently, H, halogen, hydroxy, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 
     A 1  is a bond between A and the linker, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, X 1  is N. In some embodiments, X 1  is CR 10 a. In some embodiments, X 2  is N. In some embodiments, X 2  is CR 10b . In some embodiments, X 3  is N. In some embodiments, X 3  is CR 10c . In some embodiments, X 4  is N. In some embodiments, X 1  is CR 10d . 
     In some embodiments, X 1  is CR 10a , X 2  is CR 10b , X 3  is CR 10c , and X 4  is CR 10d . In some embodiments, X 1  is N, X 2  is CR 10b , X 3  is CR 10c , and X 4  is CR 10d . In some embodiments, X 1  is CR 10a , X 2  is N. X 3  is CR 10c , and X 4  is CR 10d . In some embodiments, X 1  is CR 10a , X 2  is CR 10b , X 3  is N, and X 4  is CR 10d . In some embodiments, X 1  is CR 10a , X 2  is CR 10b , X 3  is CR 10c , and X 4  is N. In some embodiments, X 1  is N, X 2  is N, X 3  is CR 10c , and X 4  is CR 10d . In some embodiments, X 1  is N, X 2  is CR 10b , X 3  is N, and X 4  is CR 10c . In some embodiments, X 1  is N, X 2  is CR 10b , X 3  is CR 10c , and X 4  is N. In some embodiments, X 1  is CR 10a , X 2  is N, X 3  is N, and X 1  is CR 10d . In some embodiments, X 1  is CR 10a , X 2  is N, X 3  is CR 10c , and X 4  is N. In some embodiments, X 1  is CR 10a , X 2  is CR 10b , X 3  is N, and X 4  is N. 
     In some embodiments, R 7  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 7  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 7  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 3 -C 10  carbocyclyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 7  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 7  is H. In some embodiments, R 7  is H. 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 8  is H, optionally substituted C 1 -C 3  alkyl, or optionally substituted C 6 -C 10  aryl. In some embodiments, R 8  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted G-C 8  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 8  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 8  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 8  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 8  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 8  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 8  is H. In some embodiments, R 8  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, s is 0, 1, or 2. In some embodiments, s is 1 or 2. In some embodiments, s is 2. In some embodiments, s is 1. 
     In some embodiments, each R 9  is, independently, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, each R 9  is, independently, optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 9  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 9  is, independently, halogen, 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 9  is, independently, F, Cl, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 10a  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -Cis heteroalkyl. In some embodiments, R 10a  is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments. R 10a  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 10a  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10a  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10a  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10a  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10a  is H. In some embodiments, R 10a  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 10b  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, R 10b , is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 10b  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 10b  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is H 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10b  is H. In some embodiments, R 10b  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is H, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 10c  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, R 10c  is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 10c  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 10c  is H. F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is H 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10c  is H. In some embodiments, R 10c is   
     
       
         
         
             
             
         
       
     
     In some embodiments. R 10d  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 10d  is H, halogen, cyano, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, R 10d  is H, halogen, cyano, or optionally substituted C 1 -C 6  alkyl. In some embodiments. R 10d  is optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, R 10d  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10d  is H, F, cyano, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10d  is H, F, cyano, or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10d  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10d  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 10d  is H. In some embodiments, R 10d  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each of R 10a , R 10b , R 10c , and R 10d  is, independently, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted amino. 
     In some embodiments, each of R 10a , R 10b , R 10c , and R 10d  is, independently, —NH 2 , 
     
       
         
         
             
             
         
       
     
     In some embodiments, A includes the structure of Formula IVa: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVb: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVc: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVd. 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVe: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A Includes the structure of Formula IVf: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVg: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A Includes the structure of Formula IVh: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVi: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVj: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVk: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVm: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IVn: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of any one of 
     
       
         
         
             
             
         
       
     
     In some embodiments, A Includes the structure of Formula V 
     
       
         
         
             
             
         
       
     
     where 
     each R 11  and R 16  is, independently, H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     t is 0, 1, 2, 3, or 4; 
     each R 12  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     u is 0, 1, 2, 3, or 4; 
     each R 13  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     each R 14  and R 15  is, independently, selected form the group consisting of H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     G is optionally substituted C 1 -C 6  alkylene, optionally substituted C 6 -C 10  arylene, or optionally substituted C 3 -C 6  carbocyclylene; and 
     A 1  is a bond between A and the linker, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula VI: 
     
       
         
         
             
             
         
       
     
     where 
     Y 2  is CR 17  or N; 
     R 16  is A 1 , optionally substituted C 6 -C 10  aryl or C 2 -C 9  heteroaryl; 
     R 19  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     R 20  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     each R 17 , R 21 , and R 22  is, independently, H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 1 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     R 23  is H or —NR 24 R 25 ; and 
     each of R 24  and R 25  is, independently, H, A 1 , optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl, or R 24  and R 28  combine to form optionally substituted C 2 -C 9  heterocyclyl, 
     where one of R 18 , R 24 , or R 25  is A 1 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula VII: 
     
       
         
         
             
             
         
       
     
     where 
     each R 26a , R 26b , and R 26c  is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6  amyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     each R 27a  and R 27b  is, independently, H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     R 19  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     R 20  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 0 -C 10  aryl; 
     each R 17 , R 21 , and R 22  is, independently, H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 
     each of R 24  and R 25  is, independently, H, A 1 , optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl, or R 24  and R 25  combine to form optionally substituted C 2 -C 9  heterocyclyl, 
     where one of R 26a , R 26b , R 26c , R 24 , or R 25  is A 1 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula VIII: 
     
       
         
         
             
             
         
       
     
     where 
     v is 0, 1, 2, 3, or 4, 
     each R 28  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 8  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; 
     R 29  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     R 31  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     each R 30 , R 32 , and R 33  is, independently, H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; and 
     A 1  is a bond between A and the linker, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of Formula IX: 
     
       
         
         
             
             
         
       
     
     where 
     
       
         
         
             
             
         
       
     
     Z 4  is N or CR 38 ; 
     Z 5  is N or CR 39 ; 
     R 34  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 9  alkenyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl; 
     R 35  is H, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 6  carbocyclyl, or optionally substituted C 6 -C 10  aryl; 
     R 37  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl; 
     R 38  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     R 39  is H, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl; 
     w is 0, 1, 2, 3, or 4; 
     each R 38  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocyclyl, optionally substituted C 6 -C 10  aryl, optionally substituted C 2 -C 9  heteroaryl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 
     A 1  is a bond between A and the linker, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, Z 1  is N. In some embodiments, Z 1  is R 38 . In some embodiments, Z 5  is N. In some embodiments, Z 5  is R. 
     In some embodiments, Z 1  is N and Z 5  is R 39 . In some embodiments, Z 4  is R 39  and Z 5  is N. In some embodiments, Z 4  is R 39  and Z 5  is R 39 . 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments. 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 37  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 37  is H 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 38  is H or optionally substituted C 1 -C 6  alkyl. In some embodiments, R 38  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 39  is H or optionally substituted C 1 -C 6  alkyl.
 
In some embodiments, R 39  is H or
 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 34  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 2 -C 6  alkenyl, or optionally substituted C 3 -C 10 , carbocyclyl. In some embodiments, R 34  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 3 -C 10  carbocycyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 34  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 34  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 3  is H. In some embodiments, R 34  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 35  is H, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 6 -C 10  aryl. In some embodiments, R 35  is H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 35  is H, optionally substituted C 1 -C 3  alkyl, or optionally substituted C 3 -C 10  carbocyclyl. In some embodiments, R 35  is H or optionally substituted C 1 -C 6  alkyl. 
     In some embodiments, optionally substituted C 1 -C 6  alkyl is C 1 -C 6  perfluoroalkyl. 
     In some embodiments, R 35  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 35  is H, 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 35  is H or 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 35  is H. In some embodiments, R 35  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, w is 0, 1, or 2. In some embodiments, w is 1 or 2. In some embodiments, w is 2. 
     In some embodiments, each R 36  is, independently, halogen, optionally substituted C 1 -C 6  alkyl, or optionally substituted C 1 -C 6  heteroalkyl. In some embodiments, each R 36  is, independently, optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl. 
     In some embodiments, each R 36  is, independently, 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 36  is, independently, 
     
       
         
         
             
             
         
       
     
     In some embodiments, independently, F, Cl, 
     
       
         
         
             
             
         
       
     
     In some embodiments, the structure of Formula IX has the structure of Formula IXa: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXb: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXc: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXd: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXe: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXf: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXg: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXh: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the structure of Formula IX has the structure of Formula IXi: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, A includes the structure of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where A 1  is a bond between A and the linker, or derivative or analog thereof. 
     In some embodiments, the compound has the structure of any one of compounds D1-D177 in Table 1A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D178-D371 in Table 1B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D372-D476 in Table 1 D, or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the compound has the structure of any one of compounds D1, D3, D6, D9-D20, D23, D33, D33-D35, D37-D40, D42, D44-D47, D50-D53, D56-D60, D67, D69, D71-D73, D75, D76, D80, D81, D89, D92, D100, D108, D113, D122-D124, D128-D132, D143, D152, D157, D167, D168, D170, D171, D173, and D176 in Table 1A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D178, D180, D184-D189, D191, D194, D197-D199, D201-D208, D211, D213-D230, D235-D244, D246, D247, D250-D263, D268, D269, D271-D275, D277, D279, D280, D287-D291, D297-D299, D300-D302, D304, D306-D308, D310, D312, D313, D315, D316, D318-D333, D335-D341, D343-D349, D353, D354, D356-D363, and D366-D371 in Table 1B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds D372-D379, D381, D382, D384-D388, D395-D428, D430, D431, D433, D434, D436, D438-D444, D448, D450, D453-D460, D462, D463, D465, D466, D471, and D476 in Table 1 D, or a pharmaceutically acceptable salt thereof. 
     In an aspect, the disclosure features a compound having the structure of any one of compounds D1-D177 in Table 1A, or a pharmaceutically acceptable salt thereof. 
     In another aspect, the disclosure features a compound having the structure of any one of compounds D178-D371 in Table 1B, or a pharmaceutically acceptable salt thereof. 
     In another aspect, the disclosure features a compound having the structure of any one of compounds D372-D476 in Table 1 D, or a pharmaceutically acceptable salt thereof. 
     In another aspect, the disclosure features a compound having the structure of any one of compounds DD1-DD10 in Table 1C, or a pharmaceutically acceptable salt thereof. 
     In another aspect, the disclosure features a compound having the structure of any one of compounds DD11-DD16 in Table 1E, or a pharmaceutically acceptable salt thereof. 
     
       
         
           
               
             
               
                 TABLE 1A 
               
             
            
               
                   
               
               
                 Compounds D1-D177 of the Disclosure 
               
            
           
           
               
               
            
               
                 Com- 
                   
               
               
                 pound  
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
               
                 D1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D4  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D14  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D24  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D34  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D44  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D54  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D64  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D74  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D84  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D94  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D104  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D114  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D124  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D134  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D144  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D154  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D164  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D174  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1B 
               
             
            
               
                   
               
               
                 Compounds D178-D371 of the Disclosure 
               
            
           
           
               
               
            
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
               
                 D178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D179 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D180 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D181 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D184 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D185 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D188 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D191 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D192 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D193 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D194 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D195 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D196 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D197 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D198 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D199 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D200 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D201 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D202 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D203 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D204 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D205 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D206 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D207 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D208 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D209 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D210 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D211 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D212 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D213 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D214 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D215 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D216 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D217 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D218 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D223 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D224 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1C 
               
             
            
               
                   
               
               
                 Compounds DD1-DD10 of the Disclosure 
               
            
           
           
               
               
            
               
                 Com- 
                   
               
               
                 pound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
               
                 DD1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1D 
               
             
            
               
                   
               
               
                 Compounds D372-D477 of the disclosure 
               
            
           
           
               
               
            
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
               
                 D372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D378 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D379 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D380 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D381 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D382 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D383 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D404 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D421 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D422 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D423 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D424 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D425 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D431  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D432 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D436 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D438 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D439 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D440 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D441 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D443 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D444 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D447 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D448 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D449 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D452 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D453 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D456 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D460 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D461 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D463 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1E 
               
             
            
               
                   
               
               
                 Compounds DD11-DD16 of the disclosure 
               
            
           
           
               
               
            
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
               
                 DD11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 DD16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. 
     In an aspect, the disclosure features a method of inhibiting the level and/or activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. 
     In another aspect, the disclosure features a method of reducing the level and/or activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. 
     In some embodiments, the cell is a cancer cell. 
     In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing&#39;s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epitheloid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. 
     In an aspect, the disclosure features a method of treating a BAF complex-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the BAF complex-related disorder is cancer. In some embodiments, the BAF complex-related disorder is infection. 
     In another aspect, the disclosure features a method of treating an SS18-SSX fusion protein-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the SS18-SSX fusion protein-related disorder is cancer. In some embodiments, the SS18-SSX fusion protein-related disorder is infection. In some embodiments of any of the foregoing methods, the SS18-SSX fusion protein is a SS18-SSX1 fusion protein, a SS18-SSX2 fusion protein, or a SS18-SSX4 fusion protein. 
     In yet another aspect, the disclosure features a method of treating a BRD9-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the BRD9-related disorder is cancer. In some embodiments, the BRD9-related disorder is infection. 
     In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt&#39;s lymphoma and Non-Hodgkin&#39;s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing&#39;s sarcoma, hemangiosarcoma, Kaposi&#39;s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neuroblastomas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin&#39;s disease, Wilms&#39; tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, lumina B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epitheloid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin&#39;s lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor. Paget&#39;s disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma. B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma/leukemla, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 
     In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing&#39;s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. 
     In some embodiments, the infection is viral infection (e.g., an infection with a virus of the Retroviridae family such as the lentiviruses (e.g. Human Immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitis B virus (HBV)); Flaviviridae family (e.g. hepatitis C virus (HCV)); Adenoviridae family (e.g. Human Adenovirus); Herpesviridae family (e.g. Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus); Papillomaviridae family (e.g. Human Papillomavirus (HPV, HPV E1)); Parvoviridae family (e.g. Parvovirus B19); Polyomaviridae family (e.g. JC virus and BK virus); Paramyxoviridae family (e.g. Measles virus); or Togavirkdae family (e.g. Rubella virus)). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2 Schwannomatosis), or Multiple Meningioma. In an aspect, the disclosure features a method of treating a cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. 
     In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt&#39;s lymphoma and Non-Hodgkin&#39;s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing&#39;s sarcoma, hemangiosarcoma, Kaposi&#39;s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningliomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin&#39;s disease, Wilms&#39; tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, lumina) A breast cancer, lumina) B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin&#39;s lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor. Paget&#39;s disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL). T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma. T cell histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+×DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+×large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 
     In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing&#39;s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing&#39;s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. 
     In another aspect, the disclosure features a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g. Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitis B virus (HBV)), Flaviviridae family (e.g. hepatitis C virus (HCV)), Adenoviridae family (e.g. Human Adenovirus). Herpesviridae family (e.g. Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus). Papillomaviridae family (e.g. Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g. Parvovirus B19), Polyomaviridae family (e.g. JC virus and BK virus), Paramyxoviridae family (e.g. Measles virus). Togaviridae family (e.g. Rubella virus). 
     In another embodiment of any of the foregoing methods, the method further includes administering to the subject an additional anticancer therapy (e.g., chemotherapeutic or cytotoxic agent or radiotherapy). 
     In particular embodiments, the additional anticancer therapy is: a chemotherapeutic or cytotoxic agent (e.g., doxorubicin or ifosfamide), a differentiation-inducing agent (e.g., retinoic acid, vitamin D, cytokines), a hormonal agent, an immunological agent, or an anti-angiogenic agent. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gil man&#39;s The Pharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, New York, N.Y. 
     In particular embodiments, the compound of the invention and the additional anticancer therapy and any of the foregoing compounds or pharmaceutical compositions are administered within 28 days of each other (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in an amount that together are effective to treat the subject. 
     Chemical Terms 
     The terinmology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. 
     For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C 2  alkyl group has the formula —CH 2 CH 3 . When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogensulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring. 
     Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. 
     The term “aliphatic,” as used herein, refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , or C 1 -C 6 . The specified ranges as used herein Indicate an aliphatic group having each member of the range described as an independent species. For example, the term C 1 -C 6  aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an Independent species. For example, the term C 1 -C 4  aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. 
     The term “heteroaliphatic.” as used herein, refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. “Heteroaliphatic” is intended herein to Include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, —O-alkyl-O-alkyl, and alkyl-O-haloalkyl. 
     The term “acyl,” as used herein, represents a hydrogen or an alkyl group that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbons. 
     The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms). An “alkylene” is a divalent alkyl group. 
     The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms. 2 to 6, or 2 carbon atoms). An “alkenylene” is a divalent alkenyl group. 
     The term “alkynyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). An “alkynylene” is a divalent alkynyl group. 
     The term “amino,” as used herein, represents —N(RN 1 ) 2 , wherein each R N1  is, independently, H, OH, NO 2 , N(R N2 ) 2 , SO 2 OR N2 , SO 2 R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R N1  groups can be optionally substituted; or two R N1  combine to form an alkylene or heteroalkylene, and wherein each RN 2  is, independently, H, alkyl, or aryl. The amino groups of the compounds described herein can be an unsubstituted amino (i.e., —NH 2 ) or a substituted amino (i.e., —N(R N1 ) 2 ). 
     The term “aryl,” as used herein, refers to an aromatic mono- or polycarboxylic radical of, e.g., 6 to 12, carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. 
     The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6  alkyl C 6 -C 10  aryl, C 1 -C 10  alkyl C 6 -C 10  aryl, or C 1 -C 20  alkyl C 6 -C 10  aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. 
     The term “azido,” as used herein, represents a —N 3  group. 
     The term “bridged cyclyl,” as used herein, refers to a bridged polycyclic group of 5 to 20 atoms, containing from 1 to 3 bridges. Bridged cyclyl includes bridged carbocyclyl (e.g., norbornyl) and bridged heterocyclyl (e.g., 1,4-diazabicyclo[2.2.2]octane). 
     The term “cyano,” as used herein, represents a —CN group. 
     The term “carbocyclyl,” as used herein, refers to a non-aromatic C 3 -C 12 , monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups (e.g., cyclohexyl) and unsaturated carbocyclyl radicals (e.g., cyclohexenyl). Polycyclic carbocyclyl includes spirocyclic carbocyclyl, bridged carbocyclyl, and fused carbocyclyl. A “carbocyclylene” is a divalent carbocyclyl group. 
     The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, monovalent mono- or polycarboxylic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. 
     The terms “halo” or “halogen,” as used herein, mean a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. 
     The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers to alkyl-O— (e.g., methoxy and ethoxy), and an “alkylamino” which, as used herein, refers to —N(alkyl)R Na , where R Na  is H or alkyl (e.g., methylamino). A “heteroalkylene” is a divalent heteroalkyl group. 
     The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers to alkenyl-O—. A “heteroalkenylene” is a divalent heteroalkenyl group. 
     The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers to alkynyl-O—. A “heteroalkynylene” is a divalent heteroalkynyl group. 
     The term “heteroaryl,” as used herein, refers to an aromatic monocyclic or polycyclic structure of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazoyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl. A “heteroarylene” is a divalent heteroaryl group. 
     The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6  alkyl C 2 -C 9  heteroaryl, C 1 -C 10  alkyl C 2 -C 9  heteroaryl, or C 1 -C 20  alkyl C 2 -C 9  heteroaryl). In some embodiments, the alkyl and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. 
     The term “heterocyclyl,” as used herein, refers a monocyclic or polycyclic radical (e.g., bicyclic or tricyclic) having 3 to 12 atoms having at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and no aromatic ring containing any N, O, or S atoms. Polycyclic heterocyclyl includes spirocyclic heterocyclyl, bridged heterocyclyl, and fused heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A “heterocyclylene” is a divalent heterocyclyl group. 
     The term “heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocycylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6  alkyl C 2 -C 9  heterocyclyl, C 1 -C 10  alkyl C 2 -C 9  heterocyclyl, or C 1 -C 20  alkyl C 2 -C 9  heterocyclyl). In some embodiments, the alkyl and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. 
     The term “hydroxyalkyl,” as used herein, represents alkyl group substituted with an —OH group. 
     The term “hydroxyl,” as used herein, represents an —OH group. 
     The term “imine,” as used herein, represents ═NR N  group, where R N  is, e.g., H or alkyl. 
     The term “N-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene. “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley &amp; Sons, New York, 1999). N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-choroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). 
     The term “nitro,” as used herein, represents an —NO 2  group. 
     The term “oxo,” as used herein, represents an ═O group. 
     The term “thiol,” as used herein, represents an —SH group. 
     The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH 2  or mono- or dialkyl amino), azido, cyano, nitro, oxo, sulfonyl, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)). 
     Compounds described herein (e.g., compounds of the invention) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. “Racemate” or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “R,” “S,” “S”,” “R”, “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein (e.g., the compounds of the invention) may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary) resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. 
     Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. 
     Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as  2 H,  3 H,  11 C,  13 C,  14 C,  13 N,  15 N,  15 O,  17 O,  18 O,  32 P,  31 P,  35 S,  18 F,  38 Cl,  121 I and  125 I, isotopically-labeled compounds (e.g., those labeled with  3 H and  14 C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,  3 H) and carbon-14 (i.e.,  14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., Increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by  2H  or  3 H, or one or more carbon atoms are replaced by  13 C- or  14 C-enriched carbon. Positron emitting isotopes such as  15 O,  13 N,  11 C, and  18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. 
     As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. 
     Definitions 
     In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean ‘at least one’; (ii) the term “or” may be understood to mean “and/or”; and (iii) the terms ‘including’ and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. 
     As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM. 
     As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal. 
     As used herein, the term “adult soft tissue sarcoma” refers to a sarcoma that develops in the soft tissues of the body, typically in adolescent and adult subjects (e.g., subjects who are at least 10 years old, 11 years oil, 12 years oil, 13 years old, 14 years old, 15 years old, 18 years old, 17 years oil, 18 years old, or 19 years old). Non-limiting examples of adult soft tissue sarcoma include, but are not limited to, synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, lelomyosarcoma, hemangiosarcoma, Kaposi&#39;s sarcoma, lymphangiosarcoma, malignant peripheral nerve sheath tumor/neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, and extraskeletal mesenchymal. 
     The term “antisense,” as used herein, refers to a nucleic acid comprising a polynucleotide that is sufficiently complementary to all or a portion of a gene, primary transcript, or processed mRNA, so as to interfere with expression of the endogenous gene (e.g., BRD9). “Complementary” polynucleotides are those that are capable of base pairing according to the standard Watson-Crick complementarity rules. Specifically, purines will base pair with pyrimidines to form a combination of guanine paired with cytosine (G:C) and adenine paired with either thymine (A:T) in the case of DNA, or adenine paired with uracil (A:U) in the case of RNA. It is understood that two polynucleotides may hybridize to each other even if they are not completely complementary to each other, provided that each has at least one region that is substantially complementary to the other. 
     The term “antisense nucleic acid” includes single-stranded RNA as well as double-stranded DNA expression cassettes that can be transcribed to produce an antisense RNA. ‘Active’ antisense nucleic acids are antisense RNA molecules that are capable of selectively hybridizing with a primary transcript or mRNA encoding a polypeptide having at least 80% sequence identity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) with the targeted polypeptide sequence (e.g., a BRD9 polypeptide sequence). The antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof. In some embodiments, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence. The term “coding region” refers to the region of the nucleotide sequence comprising codons that are translated into amino acid residues. In some embodiments, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence. The term “noncoding region” refers to 5′ and 3′ sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions). The antisense nucleic acid molecule can be complementary to the entire coding region of mRNA, or can be antisense to only a portion of the coding or noncoding region of an mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length. 
     As used herein, the term “BAF complex” refers to the BRG1- or HRBM-associated factors complex in a human cell. 
     As used herein, the term “BAF complex” related disorder refers to a disorder that is caused or affected by the level and/or activity of a BAF complex. 
     As used herein, the terms “GBAF complex” and “GBAF” refer to a SW/SNF ATPase chromatin remodeling complex in a human cell. GBAF complex subunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2, SMARCD3, and SS18. The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. 
     As used herein, the term “BRD9” refers to bromodomain-containing protein 9, a component of the BAF (BRG1- or BRM-associated factors) complex, a SW/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene, the nucleic acid sequence of which is set forth in SEQ ID NO: 1. The term “BRD9” also refers to natural variants of the wild-type BRD9 protein, such as proteins having at least 85% Identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type BRD9, which is set forth in SEQ ID NO: 2. 
     As used herein, the term “BRD9-related disorder” refers to a disorder that is caused or affected by the level and/or activity of BRD9. The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. 
     As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally. 
     A “compound of the present invention” and similar terms as used herein, whether explicitly noted or not, refers to compounds useful for treating BAF-related disorders (e.g., cancer or infection) described herein, including, e.g., compounds of Formula I (e.g., compounds of Table 1A, Table 1B, and Table 1D) and compounds of Table 1C and 1E, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof. Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, and tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise Indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination. Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins. C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-Imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion. 
     As used herein, the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., BRD9) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject. 
     As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., BRD9. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., BRD9. 
     By “determining the level of a protein” is meant the detection of a protein, or an mRNA encoding the protein, by methods known in the art either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunopredpitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, micro cytometry, microscopy, fluorescence activated cell sorting (FAGS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure mRNA levels are known in the art. 
     As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and/or activity of BRD9 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and/or activity of BRD9 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and/or activity of BRD9. The amount of a given agent that reduces the level and/or activity of BRD9 described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and/or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and/or activity of BRD9 of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and/or activity of BRD9 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response. 
     As used herein, the term “inhibitor” refers to any agent which reduces the level and/or activity of a protein (e.g., BRD9). Non-limiting examples of inhibitors include small molecule Inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA). 
     The term “inhibitory RNA agent” refers to an RNA, or analog thereof, having sufficient sequence complementarity to a target RNA to direct RNA interference. Examples also include a DNA that can be used to make the RNA. RNA interference (RNAi) refers to a sequence-specific or selective process by which a target molecule (e.g., a target gene, protein, or RNA) is down-regulated. Generally, an interfering RNA (“iRNA”) is a double-stranded short-interfering RNA (siRNA), short hairpin RNA (shRNA), or single-stranded micro-RNA (miRNA) that results in catalytic degradation of specific mRNAs, and also can be used to lower or inhibit gene expression. 
     By lever is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an Increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass/vol (e.g., g/dL, mg/mL, μg/mL, ng/mL) or percentage relative to total protein or mRNA in a sample. 
     The terms “miRNA” and “microRNA” refer to an RNA agent, preferably a single-stranded agent, of about 10-50 nucleotides in length, preferably between about 15-25 nucleotides in length, which is capable of directing or mediating RNA interference. Naturally-occurring miRNAs are generated from stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer. The term “Dicer” as used herein, includes Dicer as well as any Dicer ortholog or homolog capable of processing dsRNA structures into siRNAs, miRNAs, siRNA-like or miRNA-like molecules. The term microRNA (“miRNA”) is used interchangeably with the term “small temporal RNA” (“stRNA”) based on the fact that naturally-occurring miRNAs have been found to be expressed in a temporal fashion (e.g., during development). 
     By “modulating the activity of a BAF complex,” is meant altering the level of an activity related to a BAF complex (e.g., GBAF), or a related downstream effect. The activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al, Cell 153:71 85 (2013), the methods of which are herein incorporated by reference. 
     “Percent (%) sequence identity” with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence Identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identify can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows: 
       100 multiplied by (the fraction X/Y) 
     where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program&#39;s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A. 
     A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. 
     As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid. 
     The compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic adds or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, sucinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. 
     The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation. 
     By “reducing the activity of BRD9,” is meant decreasing the level of an activity related to an BRD9, or a related downstream effect. A non-limiting example of inhibition of an activity of BRD9 is decreasing the level of a BAF complex (e.g., GBAF) in a cell. The activity level of BRD9 may be measured using any method known in the art. In some embodiments, an agent which reduces the activity of BRD9 is a small molecule BRD9 inhibitor. In some embodiments, an agent which reduces the activity of BRD9 is a small molecule BRD9 degrader. 
     By “reducing the level of BRD9,” is meant decreasing the level of BRD9 in a cell or subject. The level of BRD9 may be measured using any method known in the art. 
     By a “reference” is meant any useful reference used to compare protein or mRNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference. 
     The terms “short interfering RNA” and “sIRNA” (also known as “small interfering RNAs”) refer to an RNA agent, preferably a double-stranded agent, of about 10-50 nucleotides in length, the strands optionally having overhanging ends comprising, for example 1, 2 or 3 overhanging nucleotides (or nucleotide analogs), which is capable of directing or mediating RNA interference. Naturally-occurring siRNAs are generated from longer dsRNA molecules (e.g., &gt;25 nucleotides in length) by a cell&#39;s RNAi machinery (e.g., Dicer or a homolog thereof). 
     The term “shRNA”, as used herein, refers to an RNA agent having a stem-loop structure, comprising a first and second region of complementary sequence, the degree of complementarity and orientation of the regions being sufficient such that base pairing occurs between the regions, the first and second regions being joined by a loop region, the loop resulting from a lack of base pairing between nucleotides (or nucleotide analogs) within the loop region. 
     As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition. 
     As used herein, the term “SS18-SSX fusion protein-related disorder” refers to a disorder that is caused or affected by the level and/or activity of SS18-SSX fusion protein. 
     As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment Includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. 
     As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material. 
     The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a series of graphs illustrating the effect of specific guide RNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovial sarcoma cell growth. The Y-axis indicated the dropout ratio. The X-axis indicates the nucleotide position of the BRD9 gene. The grey box indicates the range of the negative control sgRNAs in the screen. The SYO1 cell line carries SS18-SSX2 fusion protein. The breakpoint joining the N-terminal region of SS18 to the C-terminal region of SSX2 are indicated by the black lines in their respective panel. The linear protein sequence is show with BRD9 PFAM domains annotated from the PFAM database. 
         FIG.  2    is an Image illustrating dose dependent depletion of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrader. 
         FIG.  3    is an Image illustrating sustained suppression of BRD9 levels in a synovial sarcoma cell line (SYO1) In the presence of a BRD9 degrader over 72 hours. 
         FIG.  4    is an image illustrating sustained suppression of BRD9 levels in two cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5 days. 
         FIG.  5    is an image illustrating sustained suppression of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9 degrader over 7 days compared to the levels in cells treated with CRISPR reagents. 
         FIG.  6    is an image Illustrating the effect on cell growth of six cell lines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 2931) in the presence of a BRD9 degrader and a BRD9 inhibitor. 
         FIG.  7    is an image Illustrating the effect on cell growth of two cell lines (SYO1 and G401) in the presence of a BRD9 degrader. 
         FIG.  8    is an Image illustrating the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder. 
         FIG.  9    is an image illustrating the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder. 
         FIG.  10    is a graph illustrating the percentage of SYO1 in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, or Compound 1 at 1 μM for 8 or 13 days. 
         FIG.  11    is a series of contour plots illustrating the percentage of SYO1 cells in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for 8 days. Numerical values corresponding to each contour plot are found in the table below. 
         FIG.  12    is a series of contour plots illustrating the percentage of SYO1 ceps in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 NM, or lenalidomide at 200 nM for 13 days. Numerical values corresponding to each contour plot are found in the table below. 
         FIG.  13    is a series of contour plots illustrating the percentage of early- and late-apoptotic SYO1 cells following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 NM, or lenalidomide at 200 nM for 8 days. Numerical values corresponding to each contour plot are found in the table below. 
         FIG.  14    is a graph illustrating the proteins present in BAF complexes including the SS18-SSX fusion protein. 
     
    
    
     DETAILED DESCRIPTION 
     The present disclosure features compositions and methods useful for the treatment of BAF-related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and/or activity of BRD9, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof. 
     Compounds 
     Compounds described herein reduce the level of an activity related to BRD9, or a related downstream effect, or reduce the level of BRD9 in a cell or subject. Exemplary compounds described herein have the structure according to Formula I. 
     Formula I is 
     
       
         
         
             
             
         
       
     
     where 
     A is a BRD9 binding moiety; 
     B is a degradation moiety; and 
     L has the structure of Formula II: 
     
       
         
         
             
             
         
       
     
      wherein 
     A 1  is a bond between the linker and A; 
     A 2  is a bond between B and the linker; 
     each of m, n, o1, o2, and p is, independently, 0 or 1; 
     each of E 1  and E 2  is, independently, O, S, NR N , optionally substituted C 1-10  alkyl, optionally substituted C 2-10  alkenyl, optionally substituted C 2-10  alkynyl, optionally substituted C 2 -C 10  polyethylene glycol, or optionally substituted C 1-10  heteroalkyl; 
     E 3  is O, S, or NR N ; 
     each R N  is, independently, H, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, optionally substituted C 2-10  heterocyclyl, optionally substituted C 6-12  aryl, or optionally substituted C 1-7  heteroalkyl; 
     C 3  is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and 
     each of F 1 , F 2 , and F 3  is, independently, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted C 2 -C 9  heterocycyl, optionally substituted C 6 -C 10  aryl, or optionally substituted C 2 -C 9  heteroaryl, or a pharmaceutically acceptable salt thereof. 
     Pharmaceutical Uses 
     The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of a BAF complex, e.g., by inhibiting the activity or level of the BRD9 protein in a cell within the BAF complex in a mammal. 
     An aspect of the present invention relates to methods of treating disorders related to BRD9 such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. 
     Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor. 
     Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×). 
     Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2×, 10×50×). 
     Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. 
     Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. 
     Combination Therapies 
     A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al.,  Neurology  85:S3-S8 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect. 
     In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroids, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredepa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic add; aceglatone; aldophosphamide glycoside; ammolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al.,  Proc. Am. Soc. On. Oncol.  18:233a (1999), and Douillard et al.,  Lancet  355(9209):1041-1047 (2000). 
     In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-I-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. 
     The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue. 
     The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. 
     In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascltes, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005. 
     In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. 
     Pharmaceutical Compositions 
     The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. 
     The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. 
     A compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixers, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington&#39;s Pharmaceutical Sciences (2012.22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use Include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochiorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm Intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature. 
     The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. 
     Dosages 
     The dosage of the compounds described herein, and/or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. 
     Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-100 mg/kg (e.g., 0.1-50 mg/kg (e.g., 0.25-25 mg/kg)). In exemplary, non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg). 
     Kits 
     The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, and (b) a package Insert with Instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein. 
     EXAMPLES 
     Example 1—High Density Tiling sgRNA Screen Against Human BAF Complex Subunits in Synovial Sarcoma Cell Line SYO1 
     the following example shows that BRD9 sgRNA inhibits cell growth in synovial sarcoma cells. 
     Procedure: To perform high density sgRNA tiling screen, an sgRNA library against BAF complex subunits was custom synthesized at Cellecta (Mountain View, Calif.). Sequences of DNA encoding the BRD9-targeting sgRNAs used in this screen are listed in Table 2. Negative and positive control sgRNA were Included in the library. Negative controls consisted of 200 sgRNAs that do not target human genome. The positive controls are sgRNAs targeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA, POLR2L, RPL9, and SF3A3). DNA sequences encoding all positive and negative control sgRNAs are listed in Table 3. Procedures for virus production, cell infection, and performing the sgRNA screen were previously described (Tshemiak et al,  Cell  170:564-576 (2017); Munoz et al, Cancer Discovery 6:900-913 (2016)). For each sgRNA, 50 counts were added to the sequencing counts and for each time point the resulting counts were normalized to the total number of counts. The log 2 of the ratio between the counts (defined as dropout ratio) at day 24 and day 1 post-infection was calculated. For negative control sgRNAs, the 2.5 and 97.5 percentile of the log 2 dropout ratio of all non-targeting sgRNAs was calculated and considered as background (grey box in the graph). Protein domains were obtained from PFAM regions defined for the UNIPROT Identifier: Q9H8M2. 
     Results: As shown in  FIG.  1   , targeted inhibition of the GBAF complex component BRD9 by sgRNA resulted in growth inhibition of the SYO1 synovial sarcoma cell line, sgRNAs against other components of the BAF complexes resulted in increased proliferation of cells, inhibition of cell growth had no effect on SYO1 cells. These data show that targeting various subunits of the GBAF complex represents a therapeutic strategy for the treatment of synovial sarcoma. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 BRD9 sgRNA Library 
               
            
           
           
               
               
               
               
            
               
                 SEQ 
                   
                 SEQ 
                   
               
               
                 ID 
                 Nucleic 
                 ID 
                 Nucleic 
               
               
                 NO 
                 Acid Sequence 
                 NO 
                 Acid Sequence 
               
               
                   
               
               
                 203 
                 CAAGAAGCACAAGAAGCACA 
                 319 
                 GCTCTACAGCGTGGTCAACA 
               
               
                   
               
               
                 204 
                 CTTGTGCTTCTTGCCCATGG 
                 320 
                 CGGGAGCCTGCTCTACAGCG 
               
               
                   
               
               
                 205 
                 CTTCTTGTGCTTCTTGCCCA 
                 321 
                 CGTGGTCAACACGGCCGAGC 
               
               
                   
               
               
                 206 
                 ACAAGAAGCACAAGGCCGAG 
                 322 
                 CCCACCATCAGCGTCCGGCT 
               
               
                   
               
               
                 207 
                 CTCGTAGGACGAGCGCCACT 
                 323 
                 ACGGCCGAGCCGGACGCTGA 
               
               
                   
               
               
                 208 
                 CGAGTGGCGCTCGTCCTACG 
                 324 
                 GGGCACCCACCATCAGCGTC 
               
               
                   
               
               
                 209 
                 GAGTGGCGCTCGTCCTACGA 
                 325 
                 GCCGAGCCGGACGCTGATGG 
               
               
                   
               
               
                 210 
                 AGGCTTCTCCAGGGGCTTGT 
                 326 
                 CCATGTCCGTGTTGCAGAGG 
               
               
                   
               
               
                 211 
                 AGATTATGCCGACAAGCCCC 
                 327 
                 CCGAGCCGGACGCTGATGGT 
               
               
                   
               
               
                 212 
                 ACCTTCAGGACTAGCTTTAG 
                 328 
                 CGAGCTCAAGTCCACCGGGT 
               
               
                   
               
               
                 213 
                 AGCTTTAGAGGCTTCTCCAG 
                 329 
                 GCGAGCTCAAGTCCACCGGG 
               
               
                   
               
               
                 214 
                 CTAGCTTTAGAGGCTTCTCC 
                 330 
                 AGAGCGAGCTCAAGTCCACC 
               
               
                   
               
               
                 215 
                 TAGCTTTAGAGGCTTCTCCA 
                 331 
                 GAGAGCGAGCTCAAGTCCAC 
               
               
                   
               
               
                 216 
                 CTAAAGCTAGTCCTGAAGGT 
                 332 
                 GAAGCCTGGGAGTAGCTTAC 
               
               
                   
               
               
                 217 
                 GCCTCTAAAGCTAGTCCTGA 
                 333 
                 CTCTCCAGTAAGCTACTCCC 
               
               
                   
               
               
                 218 
                 CTTCACTTCCTCCGACCTTC 
                 334 
                 AGCCCAGCGTGGTGAAGCCT 
               
               
                   
               
               
                 219 
                 AAGCTAGTCCTGAAGGTCGG 
                 335 
                 AAGCCCAGCGTGGTGAAGCC 
               
               
                   
               
               
                 220 
                 AGTGAAGTGACTGAACTCTC 
                 336 
                 ACTCCCAGGCTTCACCACGC 
               
               
                   
               
               
                 221 
                 GTGACTGAACTCTCAGGATC 
                 337 
                 CTCCCAGGCTTCACCACGCT 
               
               
                   
               
               
                 222 
                 ATAGTAACTGGAGTCGTGGC 
                 338 
                 CTCGTCTTTGAAGCCCAGCG 
               
               
                   
               
               
                 223 
                 CATCATAGTAACTGGAGTCG 
                 339 
                 CACTGGAGAGAAAGGTGACT 
               
               
                   
               
               
                 224 
                 TGACCTGTCATCATAGTAAC 
                 340 
                 GCACTGGAGAGAAAGGTGAC 
               
               
                   
               
               
                 225 
                 ACTCCAGTTACTATGATGAC 
                 341 
                 AGTAGTGGCACTGGAGAGAA 
               
               
                   
               
               
                 226 
                 CTTTGTGCCTCTCTCGCTCA 
                 342 
                 CGAAAGCGCAGTAGTGGCAC 
               
               
                   
               
               
                 227 
                 GGTCAGACCATGAGCGAGAG 
                 343 
                 CTGCATCGAAAGCGCAGTAG 
               
               
                   
               
               
                 228 
                 GAAGAAGAAGAAGTCCGAGA 
                 344 
                 ATGCAGAATAATTCAGTATT 
               
               
                   
               
               
                 229 
                 GTCCAGATGCTTCTCCTTCT 
                 345 
                 AGTATTTGGCGACTTGAAGT 
               
               
                   
               
               
                 230 
                 GTCCGAGAAGGAGAAGCATC 
                 346 
                 CGACTTGAAGTCGGACGAGA 
               
               
                   
               
               
                 231 
                 GGAGAAGCATCTGGACGATG 
                 347 
                 GAGCTGCTCTACTCAGCCTA 
               
               
                   
               
               
                 232 
                 TGAGGAAAGAAGGAAGCGAA 
                 348 
                 CACGCCTGTCTCATCTCCGT 
               
               
                   
               
               
                 233 
                 ATCTGGACGATGAGGAAAGA 
                 349 
                 TCAGCCTACGGAGATGAGAC 
               
               
                   
               
               
                 234 
                 AGAAGAAGCGGAAGCGAGAG 
                 350 
                 CAGGCGTGCAGTGTGCGCTG 
               
               
                   
               
               
                 235 
                 GAAGAAGCGGAAGCGAGAGA 
                 351 
                 CCGCGGCCCCTCTAGCCTGC 
               
               
                   
               
               
                 236 
                 CCGCCCAGGAAGAGAAGAAG 
                 352 
                 CATCCTTCACAAACTCCTGC 
               
               
                   
               
               
                 237 
                 AGAGAGGGAGCACTGTGACA 
                 353 
                 TAGCCTGCAGGAGTTTGTGA 
               
               
                   
               
               
                 238 
                 AGGGAGCACTGTGACACGGA 
                 354 
                 CAGGAGTTTGTGAAGGATGC 
               
               
                   
               
               
                 239 
                 GAGGGAGCACTGTGACACGG 
                 355 
                 AGGAGTTTGTGAAGGATGCT 
               
               
                   
               
               
                 240 
                 GCACTGTGACACGGAGGGAG 
                 356 
                 TGGGAGCTACAGCAAGAAAG 
               
               
                   
               
               
                 241 
                 GAGGCTGACGACTTTGATCC 
                 357 
                 GAGCTACAGCAAGAAAGTGG 
               
               
                   
               
               
                 242 
                 AGGCTGACGACTTTGATCCT 
                 358 
                 GAAAGTGGTGGACGACCTCC 
               
               
                   
               
               
                 243 
                 TCCACCTCCACCTTCTTCCC 
                 359 
                 CGCCTGTGATCTGGTCCAGG 
               
               
                   
               
               
                 244 
                 CGACTTTGATCCTGGGAAGA 
                 360 
                 CTCCGCCTGTGATCTGGTCC 
               
               
                   
               
               
                 245 
                 CTTTGATCCTGGGAAGAAGG 
                 361 
                 GACCTCCTGGACCAGATCAC 
               
               
                   
               
               
                 246 
                 TGATCCTGGGAAGAAGGTGG 
                 362 
                 CTCCTGGACCAGATCACAGG 
               
               
                   
               
               
                 247 
                 TCCTGGGAAGAAGGTGGAGG 
                 363 
                 GCTGGAAGAGCGTCCTAGAG 
               
               
                   
               
               
                 248 
                 CGGACTGGCCGATCTGGGGG 
                 364 
                 TGCAGCCCACCTGCTTCAGC 
               
               
                   
               
               
                 249 
                 ACGCTCGGACTGGCCGATCT 
                 365 
                 GACGCTCTTCCAGCTGAAGC 
               
               
                   
               
               
                 250 
                 AGGTGGAGCCGCCCCCAGAT 
                 366 
                 CTCTTCCAGCTGAAGCAGGT 
               
               
                   
               
               
                 251 
                 CGCTCGGACTGGCCGATCTG 
                 367 
                 GCTCTTCCAGCTGAAGCAGG 
               
               
                   
               
               
                 252 
                 GCTCGGACTGGCCGATCTGG 
                 368 
                 CCTCCAGATGAAGCCAAGGT 
               
               
                   
               
               
                 253 
                 CACGCTCGGACTGGCCGATC 
                 369 
                 GCTTCATCTGGAGGCTTCAT 
               
               
                   
               
               
                 254 
                 TGTGTCCGGCACGCTCGGAC 
                 370 
                 GGCTTCATCTGGAGGCTTCA 
               
               
                   
               
               
                 255 
                 CTGGCTGTGTCCGGCACGCT 
                 371 
                 CTTACCTTGGCTTCATCTGG 
               
               
                   
               
               
                 256 
                 ATCGGCCAGTCCGAGCGTGC 
                 372 
                 AAACTTACCTTGGCTTCATC 
               
               
                   
               
               
                 257 
                 CACCCTTGCCTGGCTGTGTC 
                 373 
                 GAAGCCTCCAGATGAAGCCA 
               
               
                   
               
               
                 258 
                 CGAGCGTGCCGGACACAGCC 
                 374 
                 TCCTAGGGTGTCCCCAACCT 
               
               
                   
               
               
                 259 
                 TGTTCCAGGAGTTGCTGAAT 
                 375 
                 CCTAGGGTGTCCCCAACCTG 
               
               
                   
               
               
                 260 
                 CACACCTATTCAGCAACTCC 
                 376 
                 GTGTCTGTCTCCACAGGTTG 
               
               
                   
               
               
                 261 
                 GCTGGCGGAGGAAGTGTTCC 
                 377 
                 TGTGTCTGTCTCCACAGGTT 
               
               
                   
               
               
                 262 
                 TTTACCTCTGAAGCTGGCGG 
                 378 
                 CCACAGGTTGGGGACACCCT 
               
               
                   
               
               
                 263 
                 CCCCGGTTTACCTCTGAAGC 
                 379 
                 AGAGCTGCTGCTGTCTCCTA 
               
               
                   
               
               
                 264 
                 ACTTCCTCCGCCAGCTTCAG 
                 380 
                 CAGAGCTGCTGCTGTCTCCT 
               
               
                   
               
               
                 265 
                 CAGGAAAAGCAAAAAATGCA 
                 381 
                 AGACAGCAGCAGCTCTGTTC 
               
               
                   
               
               
                 266 
                 GCTTTCAGAAAAGATCCCCA 
                 382 
                 ATCCACAGAAACGTCGGGAT 
               
               
                   
               
               
                 267 
                 AGGAAAAGCAAAAAATCCAT 
                 383 
                 GAGATATCCACAGAAACGTC 
               
               
                   
               
               
                 268 
                 GGAAAAGCAAAAAATCCATG 
                 384 
                 GGAGATATCCACAGAAACGT 
               
               
                   
               
               
                 269 
                 GGAGCAATTGCATCCGTGAC 
                 385 
                 GTCCTATCCCGACGTTTCTG 
               
               
                   
               
               
                 270 
                 GTCACGGATGCAATTGCTCC 
                 386 
                 TCTCCATGCTCAGCTCTCTG 
               
               
                   
               
               
                 271 
                 TTTATTATCATTGAATATCC 
                 387 
                 CTCACCCAGAGAGCTGAGCA 
               
               
                   
               
               
                 272 
                 AATGATAATAAAACATCCCA 
                 388 
                 ATCTCCATGCTCAGCTCTCT 
               
               
                   
               
               
                 273 
                 ATAAAACATCCCATGGATTT 
                 389 
                 TATCTCCATGCTCAGCTCTC 
               
               
                   
               
               
                 274 
                 TTCATGGTGCCAAAATCCAT 
                 390 
                 ATGTCCTGTTTACACAGGGA 
               
               
                   
               
               
                 275 
                 TTTCATGGTGCCAAAATCCA 
                 391 
                 TTACACAGGGAAGGTGAAGA 
               
               
                   
               
               
                 276 
                 TAATGAATACAAGTCAGTTA 
                 392 
                 AGTTCAAATGGCTGTCGTCA 
               
               
                   
               
               
                 277 
                 CAAGTCAGTTACGGAATTTA 
                 393 
                 TGACGACAGCCATTTGAACT 
               
               
                   
               
               
                 278 
                 ATAATGCAATGACATACAAT 
                 394 
                 AAGTTCAAATGGCTGTCGTC 
               
               
                   
               
               
                 279 
                 AACTTGTAGTACACGGTATC 
                 395 
                 TCGTCTCATCCAAGTTCAAA 
               
               
                   
               
               
                 280 
                 CTTCGCCAACTTGTAGTACA 
                 396 
                 TGAGACGACGAAGCTCCTGC 
               
               
                   
               
               
                 281 
                 AGATACCGTGTACTACAAGT 
                 397 
                 GTGCTTCGTGCAGGTCCTGC 
               
               
                   
               
               
                 282 
                 GCGAAGAAGATCCTTCACGC 
                 398 
                 GCAGGACCTGCACGAAGCAC 
               
               
                   
               
               
                 283 
                 TCATCTTAAAGCCTGCGTGA 
                 399 
                 GCTCCGCCTGTGCTTCGTGC 
               
               
                   
               
               
                 284 
                 TTCTCAGCAGGCAGCTCTTT 
                 400 
                 GGACCTGCACGAAGCACAGG 
               
               
                   
               
               
                 285 
                 CAATGAAGATACAGCTGTTG 
                 401 
                 CACGAAGCACAGGCGGAGCG 
               
               
                   
               
               
                 286 
                 ACTGGTACAACTTCAGGGAC 
                 402 
                 AGGCGGAGCGCGGCGGCTCT 
               
               
                   
               
               
                 287 
                 CTTGTACTGGTACAACTTCA 
                 403 
                 AGGGAGCTGAGGTTGGACGA 
               
               
                   
               
               
                 288 
                 ACTTGTACTGGTACAACTTC 
                 404 
                 GTTGGACAGGGAGCTGAGGT 
               
               
                   
               
               
                 289 
                 TTGGCAGTTTCTACTTGTAC 
                 405 
                 AGGCGTTGGACAGGGAGCTG 
               
               
                   
               
               
                 290 
                 TACCTGATAACTTCTCTACT 
                 406 
                 CCCTCTCGGAGGCGTTGGAC 
               
               
                   
               
               
                 291 
                 AGCCGAGTAGAGAAGTTATC 
                 407 
                 CCTCTCGGAGGCGTTGGACA 
               
               
                   
               
               
                 292 
                 AGCTGCATGTTTGAGCCTGA 
                 408 
                 CTGGTCCCTCTCGGAGGCGT 
               
               
                   
               
               
                 293 
                 GCTGCATGTTTGAGCCTGAA 
                 409 
                 CCCTGTCCAACGCCTCCGAG 
               
               
                   
               
               
                 294 
                 AAGCTGCAGGCATTCCCTTC 
                 410 
                 CCTGTCCAACGCCTCCGAGA 
               
               
                   
               
               
                 295 
                 GGTACTGTCCGTCAAGCTGC 
                 411 
                 GTGGTGCTGGTCCCTCTCGG 
               
               
                   
               
               
                 296 
                 AGGGAATGCCTGCAGCTTGA 
                 412 
                 CAGGTGGTGCTGGTCCCTCT 
               
               
                   
               
               
                 297 
                 CTTGACGGACAGTACCGCAG 
                 413 
                 GCATCTCACCCAGGTGGTGC 
               
               
                   
               
               
                 298 
                 CGCCAGCACGTGCTCCTCTG 
                 414 
                 CGAGAGGGACCAGCACCACC 
               
               
                   
               
               
                 299 
                 TACCGCAGAGGAGCACGTGC 
                 415 
                 GAGAGGGACCAGCACCACCT 
               
               
                   
               
               
                 300 
                 AGAGGAGCACGTGCTGGCGC 
                 416 
                 GTGGGGGCATCTCACCCAGG 
               
               
                   
               
               
                 301 
                 GGAGCACGTGCTGGCGCTGG 
                 417 
                 CCCCGACACTCAGGCGAGAA 
               
               
                   
               
               
                 302 
                 AGCACGCAGCTGACGAAGCT 
                 418 
                 TCCCCGACACTCAGGCGAGA 
               
               
                   
               
               
                 303 
                 GCACGCAGCTGACGAAGCTC 
                 419 
                 AGCCCTTCTCGCCTGAGTGT 
               
               
                   
               
               
                 304 
                 CAGCTGACGAAGCTCGGGAC 
                 420 
                 CTGGCTGCTCCCCGACACTC 
               
               
                   
               
               
                 305 
                 AAGCTCGGGACAGGATCAAC 
                 421 
                 CCCTTCTCGCCTGAGTGTCG 
               
               
                   
               
               
                 306 
                 CCTTGCCGCCTGGGAGGAAC 
                 422 
                 GCCCTTCTCGCCTGAGTGTC 
               
               
                   
               
               
                 307 
                 AGGATCAACCGGTTCCTCCC 
                 423 
                 TAGGGGTCGTGGGTGACGTC 
               
               
                   
               
               
                 308 
                 ATCAACCGGTTCCTCCCAGG 
                 424 
                 AAGAAACTCATAGGGGTCGT 
               
               
                   
               
               
                 309 
                 GCACTACCTTGCCGCCTGGG 
                 425 
                 GAAGAAACTCATAGGGGTCG 
               
               
                   
               
               
                 310 
                 AGAGCACTACCTTGCCGCCT 
                 426 
                 GAGACTGAAGAAACTCATAG 
               
               
                   
               
               
                 311 
                 CCGGTTCCTCCCAGGCGGCA 
                 427 
                 GGAGACTGAAGAAACTCATA 
               
               
                   
               
               
                 312 
                 TCCTCTTCAGATAGCCCATC 
                 428 
                 TGGAGACTGAAGAAACTCAT 
               
               
                   
               
               
                 313 
                 ATGGGCTATCTGAAGAGGAA 
                 429 
                 TCTTCAGTCTCCAGAGCCTG 
               
               
                   
               
               
                 314 
                 GGGCTATCTGAAGAGGAACG 
                 430 
                 TTGGCAGAGGCCGCAGGCTC 
               
               
                   
               
               
                 315 
                 TGGGCTATCTGAAGAGGAAC 
                 431 
                 TAGGTCTTGGCAGAGGCCGC 
               
               
                   
               
               
                 316 
                 TATCTGAAGAGGAACGGGGA 
                 432 
                 CTAGAGTTAGGTCTTGGCAG 
               
               
                   
               
               
                 317 
                 ATCTGAAGAGGAACGGGGAC 
                 433 
                 GGTGGTCTAGAGTTAGGTOT 
               
               
                   
               
               
                 318 
                 TGTTGACCACGCTGTAGAGC 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Control sgRNA Library 
               
            
           
           
               
               
               
               
            
               
                 SEQ 
                   
                   
                   
               
               
                 ID 
                   
                   
                   
               
               
                 NO. 
                 gRNA Label 
                 Gene 
                 Nucleic Acid Sequence 
               
               
                   
               
               
                 434 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTAGCGAACGTGTCCGGCGT 
               
               
                   
                 0001|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 435 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GACCGGAACGATCTCGCGTA 
               
               
                   
                 0002|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 436 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGCAGTCGTTCGGTTGATAT 
               
               
                   
                 0003|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 437 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCTTGAGCACATACGCGAAT 
               
               
                   
                 0004|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 438 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGGTAGAATAACGTATTAC 
               
               
                   
                 0005|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 439 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCATACATGGATAAGGCTA 
               
               
                   
                 0006|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 440 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GATACACGAAGCATCACTAG 
               
               
                   
                 0007|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 441 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAACGTTGGCACTACTTCAC 
               
               
                   
                 0008|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 442 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GATCCATGTAATGCGTTCGA 
               
               
                   
                 0009|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 443 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGTGAAGTGCATTCGATC 
               
               
                   
                 0010|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 444 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTTCGACTCGCGTGACCGTA 
               
               
                   
                 0011|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 445 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAATCTACCGCAGCGGTTCG 
               
               
                   
                 0012|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 446 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAAGTGACGTCGATTCGATA 
               
               
                   
                 0013|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 447 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGGTGTATGACAACCGCCG 
               
               
                   
                 0014|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 448 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACCGCGCCTGAAGTTCGC 
               
               
                   
                 0015|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 449 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCAGCTCGTGTGTCGTACTC 
               
               
                   
                 0016|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 450 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGCCTTAAGAGTACTCATC 
               
               
                   
                 0017|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 451 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGTGTCGTCGTTGCTCCTA 
               
               
                   
                 0018|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 452 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCAGCTCGACCTCAAGCCGT 
               
               
                   
                 0019|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 453 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTATCCTGACCTACGCGCTG 
               
               
                   
                 0020|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 454 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGTATCTCAGCACGCTAAC 
               
               
                   
                 0021|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 455 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGTCATACAACGGCAACG 
               
               
                   
                 0022|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 456 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGTGCGCTTCCGGCGGTA 
               
               
                   
                 0023|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 457 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGGTCCTCAGTAAGCGCGT 
               
               
                   
                 0024|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 458 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCTCTGCTGCGGAAGGATTC 
               
               
                   
                 0025|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 459 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCATGGAGGAGCGTCGCAGA 
               
               
                   
                 0026|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 460 
                 1|sg_Non_Targeting_Human 
                 Non_Targeting_Human 
                 GTAGCGCGCGTAGGAGTGGC 
               
               
                   
                 0027|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 461 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GATCACCTGCATTCGTACAC 
               
               
                   
                 0028|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 462 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCACACCTAGATATCGAATG 
               
               
                   
                 0029|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 463 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTTGATCAACGCGCTTCGCG 
               
               
                   
                 0030|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 464 
                 1|sg_Non_Tagreting_Human_ 
                 Non_Targeting_Human 
                 GCGTCTCACTCACTCCATCG 
               
               
                   
                 0031|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 465 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCCGACCAACGTCAGCGGTA 
               
               
                   
                 0032|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 466 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGATACGGTGCGTCAATCTA 
               
               
                   
                 0033|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 467 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAATCCAGTGGCGGCGACAA 
               
               
                   
                 0034|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 468 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCACTGTCAGTGCAACGATA 
               
               
                   
                 0035|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 469 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGATCCTCAAGTATGCTCA 
               
               
                   
                 0036|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 470 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCTAATATCGACACGGCCGC 
               
               
                   
                 0037|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 471 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGAGATGCATCGAAGTCGAT 
               
               
                   
                 0038|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 472 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGATGCACTCCATCTCGTCT 
               
               
                   
                 0039|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 473 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGCCGAGTAATAACGCGAG 
               
               
                   
                 0040|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 474 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGATTCCGATGTAACGTAC 
               
               
                   
                 0041|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 475 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGTCACGAGCAGGATTGC 
               
               
                   
                 0042|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 476 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGTTAGTCACTTAGCTCGA 
               
               
                   
                 0043|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 477 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTTCACACGGTGTCGGATAG 
               
               
                   
                 0044|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 478 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGATAGGTGACCTTAGTACG 
               
               
                   
                 0045|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 479 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTATGAGTCAAGCTAATGCG 
               
               
                   
                 0046|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 480 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCAACTATTGGAATACGTGA 
               
               
                   
                 0047|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 481 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTTACCTTCGCTCGTCTATA 
               
               
                   
                 0048|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 482 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACCGAGCACCACAGGCCG 
               
               
                   
                 0049|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 483 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCAGCCATCGGATAGAGAT 
               
               
                   
                 0050|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 484 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACGGCACTCCTAGCCGCT 
               
               
                   
                 0051|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 485 
                 1|sg|Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTCCTGTCGTATGCTTGCA 
               
               
                   
                 0052|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 486 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCCGCAATATATGCGGTAAG 
               
               
                   
                 0053|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 487 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGCACGTATAATCCTGCGT 
               
               
                   
                 0054|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 488 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGCACAACACGATCCACGA 
               
               
                   
                 0055|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 489 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCACAATGTTGACGTAAGTG 
               
               
                   
                 0056|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 490 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTAAGATGCTGCTCACCGTG 
               
               
                   
                 0057|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 491 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGGTGATCCAACGTATCG 
               
               
                   
                 0058|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 492 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGCTAGTAGGACGCAAGAC 
               
               
                   
                 0059|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 493 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACGTGGAAGCTTGTGGCC 
               
               
                   
                 0060|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 494 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGAACTGCCAGTTCTCGAT 
               
               
                   
                 0061|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 495 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCCATTCGGCGCGGCACTTC 
               
               
                   
                 0062|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 496 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCACACGACCAATCCGCTTC 
               
               
                   
                 0063|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 497 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGGTGATCGATTAAGTACA 
               
               
                   
                 0064|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 498 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCACTCGCAGACGCCTAAC 
               
               
                   
                 0065|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 499 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGCTACGGAATCATACGTT 
               
               
                   
                 0066|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 500 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTAGGACCTCACGGCGCGC 
               
               
                   
                 0067|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 501 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GA.ACTGCATCTTGTTGTAGT 
               
               
                   
                 0068|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 502 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GATCCTGATCCGGCGGCGCG 
               
               
                   
                 0069|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 503 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTATGCGCGATCCTGAGTT 
               
               
                   
                 0070|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 504 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGGAGCTAGAGAGCGGTCA 
               
               
                   
                 0071|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 505 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAATGGCAATTACGGCTGAT 
               
               
                   
                 0072|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 506 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTATGGTGAGTAGTCGCTTG 
               
               
                   
                 0073|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 507 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGTAATTGCGTCTAGTCGG 
               
               
                   
                 0074|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 508 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTCCTGGCGAGGAGCCTTG 
               
               
                   
                 0075|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 509 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAAGATAAGTCGCTGTCTCG 
               
               
                   
                 0076|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 510 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGGCGTTCTGTTGTGACT 
               
               
                   
                 0077|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 511 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAGGCAAGCCGTTAGGTGTA 
               
               
                   
                 0078|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 512 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGGATCCAGATCTCATTCG 
               
               
                   
                 0079|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 513 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGAACATAGGAGCACGTAGT 
               
               
                   
                 0080|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 514 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCATCATTATGGCGTAAGG 
               
               
                   
                 0081|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 515 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGACTAGCGCCATGAGCGG 
               
               
                   
                 0082|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 516 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGCGAAGTTCGACATGACAC 
               
               
                   
                 0083|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 517 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCTGTCGTGTGGAGGCTATG 
               
               
                   
                 0084|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 518 
                 1|sg_Non_Targeting_Human 
                 Non_Targeting_Human 
                 GCGGAGAGCATTGACCTCAT 
               
               
                   
                 0085|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 519 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GACTAATGGACCAAGTCAGT 
               
               
                   
                 0086|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 520 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGGATTAGAGGTAATGCGG 
               
               
                   
                 0087|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 521 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCCGACGGCAATCAGTACGC 
               
               
                   
                 0088|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 522 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTAACCTCTCGAGCGATAGA 
               
               
                   
                 0089|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 523 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GACTTGTATGTGGCTTACGG 
               
               
                   
                 0090|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 524 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCACTGTGGTCGAACATGT 
               
               
                   
                 0091|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 525 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACTCCAATCCGCGATGAC 
               
               
                   
                 0092|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 526 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGTTGGCACGATGTTACGG 
               
               
                   
                 0093|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 527 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAACCAGCCGGCTAGTATGA 
               
               
                   
                 0094|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 528 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTATACTAGCTAACCACACG 
               
               
                   
                 0095|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 529 
                 11sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAATCGGAATAGTTGATTCG 
               
               
                   
                 0096|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 530 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting.Human 
                 GAGCACTTGCATGAGGCGGT 
               
               
                   
                 0097|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 531 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAACGGCGATGAAGCCAGCC 
               
               
                   
                 0098|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 532 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCAACCGAGATGAGAGGTTC 
               
               
                   
                 0099|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 533 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCAAGATCAATATGCGTGAT 
               
               
                   
                 0100|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 534 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACGGAGGCTAAGCGTCGCAA 
               
               
                   
                 A0101|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 535 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCTTCCGCGGCCCGTTCAA 
               
               
                   
                 0102|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 536 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ATCGTTTCCGCTTAACGGCG 
               
               
                   
                 0103|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 537 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTAGGCGCGCCGCTCTCTAC 
               
               
                   
                 0104|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 538 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CCATATCGGGGCGAGACATG 
               
               
                   
                 0105|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 539 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TACTAACGCCGCTCCTACAG 
               
               
                   
                 0106|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 540 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TGAGGATCATGTCGAGCGCC 
               
               
                   
                 0107|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 541 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGGCCCGCATAGGATATCGC 
               
               
                   
                 0108|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 542 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TAGACAACCGCGGAGAATGC 
               
               
                   
                 0109|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 543 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACGGGCGGCTATCGCTGACT 
               
               
                   
                 0110|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 544 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCGGAAATTTTACCGACGA 
               
               
                   
                 0111|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 545 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTTACAATCGTCGGTCCAAT 
               
               
                   
                 0112|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 546 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCGTGCGTCCCGGGTTACCC 
               
               
                   
                 0113|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 547 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGGAGTAACAAGCGGACGGA 
               
               
                   
                 0114|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 548 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGAGTGTTATACGCACCGTT 
               
               
                   
                 0115|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 549 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGACTAACCGGAAACTTTTT 
               
               
                   
                 0116|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 550 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CAACGGGTTCTCCCGGCTAC 
               
               
                   
                 0117|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 551 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CAGGAGTCGCCGATACGCGT 
               
               
                   
                 0118|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 552 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TTCACGTCGTCTCGCGACCA 
               
               
                   
                 0119|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 553 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGTCGGATTCCGCCGCTTA 
               
               
                   
                 0120|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 554 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CACGAACTCACACCGCGCGA 
               
               
                   
                 GA_0121|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 555 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCTAGTACGCTCCTCTATA 
               
               
                   
                 GA_0122|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 556 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCGCGCTTGGGTTATACGCT 
               
               
                   
                 GA_0123|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 557 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTATCTCGAGTGGTAATGCG 
               
               
                   
                 GA_0124|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 558 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AATCGACTCGAACTTCGTGT 
               
               
                   
                 GA_0125|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 559 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CCCGATGGACTATACCGAAC 
               
               
                   
                 GA_0126|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 560 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACGTTCGAGTACGACCAGCT 
               
               
                   
                 GA_0127|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 561 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCGACGACTCAACCTAGTC 
               
               
                   
                 GA_0128|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 562 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTCACCGATCGAGAGCTAG 
               
               
                   
                 GA_0129|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 563 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTCAACCGACCGTATGGTCA 
               
               
                   
                 GA_0130|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 564 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGTATTCGACTCTCAACGCG 
               
               
                   
                 GA_0131|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 565 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTAGCCGCCCAGATCGAGCC 
               
               
                   
                 GA_0132|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 566 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GAATCGACCGACACTAATGT 
               
               
                   
                 GA_0133|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 567 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACTTCAGTTCGGCGTAGTCA 
               
               
                   
                 GA_0134|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 568 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTGCGATGTCGCTTCAACGT 
               
               
                   
                 GA_0135|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 569 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCCTAATTTCCGGATCAAT 
               
               
                   
                 GA_0136|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 570 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGTGGCCGGAACCGTCATAG 
               
               
                   
                 GA_0137|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 571 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACCCTCCGAATCGTAACGGA 
               
               
                   
                 GA_0138|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 572 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AAACGGTACGACAGCGTGTG 
               
               
                   
                 GA_0139|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 573 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACATAGTCGACGGCTCGATT 
               
               
                   
                 GA_0140|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 574 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GATGGCGCTTCAGTCGTCGG 
               
               
                   
                 GA_0141|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 575 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ATAATCCGGAAACGCTCGAC 
               
               
                   
                 GA_0142|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 576 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCCGGGCTGACAATTAACG 
               
               
                   
                 GA_0143|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 577 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGTCGCCATATGCCGGTGGC 
               
               
                   
                 GA_0144|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 578 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGGGCCTATAACACCATCGA 
               
               
                   
                 GA_0145|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 579 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCCGTTCCGAGATACTTGA 
               
               
                   
                 GA_0146|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 580 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGGGACGTCGCGAAAATGTA 
               
               
                   
                 GA_0147|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 581 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCGGCATACGGGACACACGC 
               
               
                   
                 GA_0148|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 582 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AGCTCCATCGCCGCGATAAT 
               
               
                   
                 GA_0149|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 583 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ATCGTATCATCAGCTAGCGC 
               
               
                   
                 GA_0150|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 584 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCGATCGAGGTTGCATTCGG 
               
               
                   
                 GA_0151|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 585 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTCGACAGTTCGTCCCGAGC 
               
               
                   
                 GA_0152|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 586 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGGTAGTATTAATCGCTGAC 
               
               
                   
                 GA_0153|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 587 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TGAACGCGTGTTTCCTTGCA 
               
               
                   
                 GA_0154|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 588 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGACGCTAGGTAACGTAGAG 
               
               
                   
                 GA_0155|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 589 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CATTGTTGAGCGGGCGCGCT 
               
               
                   
                 GA_0156|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 590 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CCGCTATTGAAACCGCCCAC 
               
               
                   
                 GA_0157|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 591 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AGACACGTCACCGGTCAAAA 
               
               
                   
                 GA_0158|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 592 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TTTACGATCTAGCGGCGTAG 
               
               
                   
                 GA_0159|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 593 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TTCGCACGATTGCACCTTGG 
               
               
                   
                 GA_0160|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 594 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GGTTAGAGACTAGGCGCGCG 
               
               
                   
                 GA_0161|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 595 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CCTCCGTGCTAACGCGGACG 
               
               
                   
                 GA_0162|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 596 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TTATCGCGTAGTGCTGACGT 
               
               
                   
                 GA_0163|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 597 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TACGCTTGCGTTTAGCGTCC 
               
               
                   
                 GA_0164|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 598 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCGGCCCACGCGTCATCGC 
               
               
                   
                 GA_0165|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 599 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AGCTCGCCATGTCGGTTCTC 
               
               
                   
                 GA_0166|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 600 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AACTAGCCCGAGCAGCTTCG 
               
               
                   
                 GA_0167|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 601 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCAAGGTGTCGGTAACCCT 
               
               
                   
                 GA_0168|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 602 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CTTCGACGCCATCGTGCTCA 
               
               
                   
                 GA_0169|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 603 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCCTGGATACCGCGTGGTTA 
               
               
                   
                 GA_0170|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 604 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ATAGCCGCCGCTCATTACTT 
               
               
                   
                 GA_0171|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 605 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTCGTCCGGGATTACAAAAT 
               
               
                   
                 GA_0172|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 606 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TAATGCTGCACACGCCGAAT 
               
               
                   
                 GA_0173|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 607 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TATCGCTTCCGATTAGTCCG 
               
               
                   
                 GA_0174|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 608 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACCATACCGCGTACCCTT 
               
               
                   
                 GA_0175|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 609 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TAAGATCCGCGGGTGGCAAC 
               
               
                   
                 GA_0176|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 610 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTAGACGTCGTGAGCTTCAC 
               
               
                   
                 GA_0177|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 611 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCGCGGACATAGGGCTCTAA 
               
               
                   
                 GA_0178|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 612 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AGCGCAGATAGCGCGTATCA 
               
               
                   
                 GA_0179|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 613 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTTCGCTTCGTAACGAGGAA 
               
               
                   
                 GA_0180|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 614 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GACCCCCGATAACTTTTGAC 
               
               
                   
                 GA_0181|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 615 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACGTCCATACTGTCGGCTAC 
               
               
                   
                 GA_0182|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 616 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACCATTGCCGGCTCCCTA 
               
               
                   
                 GA_0183|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 617 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TGGTTCCGTAGGTCGGTATA 
               
               
                   
                 GA_0184|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 618 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCTGGCTTGACACGACCGTT 
               
               
                   
                 GA_0185|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 619 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGCTAGGTCCGGTAAGTGCG 
               
               
                   
                 GA_0186|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 620 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AGCACGTAATGTCCGTGGAT 
               
               
                   
                 GA_0187|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 621 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AAGGCGCGCGAATGTGGCAG 
               
               
                   
                 GA_0188|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 622 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ACTGCGGAGCGCCCAATATC 
               
               
                   
                 GA_0189|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 623 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGTCGAGTGCTCGAACTCCA 
               
               
                   
                 GA_0190|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 624 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TCGCAGCGGCGTGGGATCGG 
               
               
                   
                 GA_0191|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 625 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 ATCTGTCCTAATTCGGATCG 
               
               
                   
                 GA_0192|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 626 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TGCGGCGTAATGCTTGAAAG 
               
               
                   
                 GA_0193|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 627 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CGAACTTAATCCCGTGGCAA 
               
               
                   
                 GA_0194|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 628 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GCCGTGTTGCTGGATACGCC 
               
               
                   
                 GA_0195|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 629 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 TACCCTCCGGATACGGACTG 
               
               
                   
                 GA_0196|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 630 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 CCGTTGGACTATGGCGGGTC 
               
               
                   
                 GA_0197|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 631 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 GTACGGGGCGATCATCCACA 
               
               
                   
                 GA_0198|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 632 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AAGAGTAGTAGACGCCCGGG 
               
               
                   
                 GA_0199|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 633 
                 1|sg_Non_Targeting_Human_ 
                 Non_Targeting_Human 
                 AAGAGCGAATCGATTTCGTG 
               
               
                   
                 GA_0200|Non_Targeting_Human 
                   
                   
               
               
                   
               
               
                 634 
                 3|sg_hCDC16_CC_1|CDC16 
                 CDC16 
                 TCAACACCAGTGCCTGACGG 
               
               
                   
               
               
                 635 
                 3|sg_hCDC16_CC_2|CDC16 
                 CDC16 
                 AAAGTAGCTTCACTCTCTCG 
               
               
                   
               
               
                 636 
                 3|sg_hCDC16_CC_3|CDC16 
                 CDC16 
                 GAGCCAACCAATAGATGTCC 
               
               
                   
               
               
                 637 
                 3|sg_hCDC16_CC_4|CDC16 
                 CDC16 
                 GCGCCGCCATGAACCTAGAG 
               
               
                   
               
               
                 638 
                 3|sg_hGTF2B_CC_1|GTF2B 
                 GTF2B 
                 ACAAAGGTTGGAACAGAACC 
               
               
                   
               
               
                 639 
                 3|sg_hGTF2B_CC_2|GTF2B 
                 GTF2B 
                 GGTGACCGGGTTATTGATGT 
               
               
                   
               
               
                 640 
                 3|sg_hGTF2B_CC_3|GTF2B 
                 GTF2B 
                 TTAGTGGAGGACTACAGAGC 
               
               
                   
               
               
                 641 
                 3|sg_hGTF2B_CC_4|GTF2B 
                 GTF2B 
                 ACATATAGCCCGTAAAGCTG 
               
               
                   
               
               
                 642 
                 3|sg_hHSPA5_CC_1|HSPA5 
                 HSPA5 
                 CGTTGGCGATGATCTCCACG 
               
               
                   
               
               
                 643 
                 3|sg_hHSPA5_CC_2|HSPA5 
                 HSPA5 
                 TGGCCTTTTCTACCTCGCGC 
               
               
                   
               
               
                 644 
                 3|sg_hHSPA5_CC_3|HSPA5 
                 HSPA5 
                 AATGGAGATACTCATCTGGG 
               
               
                   
               
               
                 645 
                 3|sg_hHSPA5_CC_4|HSPA5 
                 HSPA5 
                 GAAGCCCGTCCAGAAAGTGT 
               
               
                   
               
               
                 646 
                 3|sg_hHSPA9_CC_1|HSPA9 
                 HSPA9 
                 CAATCTGAGGAACTCCACGA 
               
               
                   
               
               
                 647 
                 3|sg_hHSPA9_CC_2|HSPA9 
                 HSPA9 
                 AGGCTGCGGCGCCCACGAGA 
               
               
                   
               
               
                 648 
                 3|sg_hHSPA9_CC_3|HSPA9 
                 HSPA9 
                 ACTTTGACCAGGCCTTGCTA 
               
               
                   
               
               
                 649 
                 3|sg_hHSPA9_CC_4|HSPA9 
                 HSPA9 
                 ACCTTCCATAACTGCCACGC 
               
               
                   
               
               
                 650 
                 3|sg_hPAFAH1B1_CC_1_PAFA 
                 PAFAH1B1 
                 CGAGGCGTACATACCCAAGG 
               
               
                   
                 H1B1 
                   
                   
               
               
                   
               
               
                 651 
                 3|sg_hPAFAH1B1_CC_2_PAFA 
                 PAFAH1B1 
                 ATGGTACGGCCAAATCAAGA 
               
               
                   
                 H1B1 
                   
                   
               
               
                   
               
               
                 652 
                 3|sg_hPAFAH1B1_CC_3_PAFA 
                 PAFAH1B1 
                 TCTTGTAATCCCATACGCGT 
               
               
                   
                 H1B1 
                   
                   
               
               
                   
               
               
                 653 
                 3|sg_hPAFAH1B1_CC_4_PAFA 
                 PAFAH1B1 
                 ATTCACAGGACACAGAGAAT 
               
               
                   
                 H1B1 
                   
                   
               
               
                   
               
               
                 654 
                 3|sg_hPCNA_CC_1|PCNA 
                 PCNA 
                 CCAGGGCTCCATCCTCAAGA 
               
               
                   
               
               
                 655 
                 3|sg_hPCNA_CC_2|PCNA 
                 PCNA 
                 TGAGCTGCACCAAAGAGACG 
               
               
                   
               
               
                 656 
                 3|sg_hPCNA_CC_3|PCNA 
                 PCNA 
                 ATGTCTGCAGATGTACCCCT 
               
               
                   
               
               
                 657 
                 3|sg_hPCNA_CC_4|PCNA 
                 PCNA 
                 CGAAGATAACGCGGATACCT 
               
               
                   
               
               
                 658 
                 3|sg_hPOLR2L_CC_1|POLR2L 
                 POLR2L 
                 GCTGCAGGCCGAGTACACCG 
               
               
                   
               
               
                 659 
                 3|sg_hPOLR2L_CC_2|POLR2L 
                 POLR2L 
                 ACAAGTGGGAGGCTTACCTG 
               
               
                   
               
               
                 660 
                 3|sg_hPOLR2L_CC_3|POLR2L 
                 POLR2L 
                 GCAGCGTACAGGGATGATCA 
               
               
                   
               
               
                 661 
                 3|sg_hPOLR2L_CC_4|POLR2L 
                 POLR2L 
                 GCAGTAGCGCTTCAGGCCCA 
               
               
                   
               
               
                 662 
                 3|sg_hRPL9_CC_1|RPL9 
                 RPL9 
                 CAAATGGTGGGGTAACAGAA 
               
               
                   
               
               
                 663 
                 3|sg_hRPL9_CC_2|RPL9 
                 RPL9 
                 GAAAGGAACTGGCTACCGTT 
               
               
                   
               
               
                 664 
                 3|sg_hRPL9_CC_3|RPL9 
                 RPL9 
                 AGGGCTTCCGTTACAAGATG 
               
               
                   
               
               
                 665 
                 3|sg_hRPL9_CC_4|RPL9 
                 RPL9 
                 GAACAAGCAACACCTAAAAG 
               
               
                   
               
               
                 666 
                 3|sg_hSF3A3_CC_1|SF3A3 
                 SF3A3 
                 TGAGGAGAAGGAACGGCTCA 
               
               
                   
               
               
                 667 
                 3|sg_hSF3A3_CC_2|SF3A3 
                 SF3A3 
                 GGAAGAATGCAGAGTATAAG 
               
               
                   
               
               
                 668 
                 3|sg_hSF3A3_CC_3|SF3A3 
                 SF3A3 
                 GGAATTTGAGGAACTCCTGA 
               
               
                   
               
               
                 669 
                 3|sg_hSF3A3_CC_4|SF3A3 
                 SF3A3 
                 GCTCACCGGCCATCCAGGAA 
               
               
                   
               
               
                 670 
                 3|sg_hSF383_CC_1|SF3B3 
                 SF3B3 
                 ACTGGCCAGGAACGATGCGA 
               
               
                   
               
               
                 671 
                 3|sg_hSF3B3_CC_2|SF3B3 
                 SF3B3 
                 GCAGCTCCAAGATCTTCCCA 
               
               
                   
               
               
                 672 
                 3|sg_hSF3B3_CC_3|SF3B3 
                 SF3B3 
                 GAATGAGTACACAGAACGGA 
               
               
                   
               
               
                 673 
                 3|sg_hSF383_CC_4|SF3B3 
                 SF3B3 
                 GGAGCAGGACAAGGTCGGGG 
               
               
                   
               
            
           
         
       
     
     Example 2—BRD9 Degrader Depletes BRD9 Protein 
     The following example demonstrates the depletion of the BRD9 protein in synovial sarcoma cells treated with a BRD9 degrader. 
     Procedure: Cells were treated with DMSO or the BRD9 degrader, Compound 1 (also known as dBRD9, see Remillard et al, Angew. Chem. Mt. Ed. Engl. 56(21):5738-5743 (2017); see structure of Compound 1 below), for indicated doses and timepoints. 
     
       
         
         
             
             
         
       
     
     Whole cell extracts were fractionated by SDS-PAGE and transferred to a polyvinylidene difluoride membrane using a transfer apparatus according to the manufacturer&#39;s protocols (Bio-Rad). After incubation with 5% nonfat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for 60 minutes, the membrane was incubated with antibodies against BRD9 (1:1,000, Bethyl laboratory A303-781A), GAPDH (1:5,000, Cell Signaling Technology), and/or MBP (1:1,000, BioRad) overnight at 4° C. Membranes were washed three times for 10 min and Incubated with anti-mouse or anti-rabbit antibodies conjugated with either horseradish peroxidase (HRP,  FIGS.  2 - 3   ) or IRDye ( FIG.  4   , 1:20,000, LI-COR) for at least 1 h. Blots were washed with TBST three times and developed with either the ECL system according to the manufacturer&#39;s protocols ( FIGS.  2 - 3   ) or scanned on an Odyssey CLx Imaging system ( FIG.  4   ). 
     Results: Treatment of SYO1 synovial sarcoma cells with the BRD9 degrader Compound 1 results in dose dependent ( FIG.  2   ) and time dependent ( FIG.  3   ) depletion of BRD9 in the cells. Further, as shown in  FIG.  4   , the depletion of BRD9 by Compound 1 is replicated in a non-synovial sarcoma cell line (293T) and may be sustained for at least 5 days. 
     Example 3—Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitors and BRD9 Degraders 
     The following example demonstrates that BRD9 degraders and Inhibitors selectively Inhibit growth of synovial sarcoma cells. 
     Procedures: 
     Cells were treated with DMSO or the BRD9 degrader, Compound 1, at indicated concentrations, and proliferation was monitored from day 7 to day 14 by measuring confluency over time using an IncuCyte live cell analysis system ( FIG.  5   ). Growth medium and compounds were refreshed every 3-4 days. 
     Cells were seeded into 12-well plates and treated with DMSO, 1 μM BRD9 inhibitor, Compound 2 (also known as BI-7273, see Martin et al, J Med Chem. 59(10):4462-4475 (2016); see structure of Compound 2 below), or 1 μM BRD9 degrader, Compound 1. 
     
       
         
         
             
             
         
       
     
     The number of cells was optimized for each cell line. Growth medium and compounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T and HS-SY-II cells were fixed and stained at day 11. ASKA cells were fixed and stained at day 23. Staining was done by incubation with crystal violet solution (0.5 g Crystal Violet, 27 ml 37% Formaldehyde, 100 mL 10×PBS, 10 mL Methanol, 863 dH 2 O to 1 L) for 30 min followed by 3×washes with water and drying the plates for at least 24 h at room temperature. Subsequently plates were scanned on an Odyssey CLx Imaging system ( FIG.  6   ). 
     Cells were seeded into 96-well ultra low cluster plate (Costar, #7007) in 200 μL complete media and treated at day 2 with DMSO, Staurosporin, or BRD9 degarder, Compound 1, at indicated doses (FIG. 7). Media and compounds were changed every 5 d and cell colonies were imaged at day 14. 
     Results: As shown in  FIGS.  5 ,  6 , and  7   , treatment of synovial sarcoma cell lines (SYO1, Yamato, HS-SY-II, and ASKA) with a BRD9 inhibitor, Compound 2, or a BRD9 degrader, Compound 1, results in inhibition of the growth of the cells, but does not result in inhibition of the growth of non-synovial control cancer cell lines (293T, A549, G401). 
     Example 4—Selective Inhibition of Growth of Synovial Cell Lines by BRD9 Degraders and BRD9 Binders 
     The following example demonstrates that BRD9 degraders and binders selectively inhibit growth of synovial sarcoma cells. 
     Procedure: Cells were seeded into 6-well or 12-well plates and were treated daily with a BRD9 degrader (Compound 1), a bromo-domain BRD9 binder (Compound 2), E3 ligase binder (lenalidomide), DMSO, or staurosporin (positive control for cell killing), at indicated concentrations. The number of cells was optimized for each cell line. Growth media was refreshed every 5 days. By day 14, medium was removed, cells were washed with PBS, and stained using 500 μL of 0.005% (w/v) crystal violet solution in 25% (v/v) methanol for at least 1 hour at room temperature. Subsequently plates were scanned on an Odyssey CLx Imaging system. 
     Results: As shown in  FIGS.  8  and  9   , treatment of synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) with Compound 1 or Compound 2 resulted in inhibition of the growth of the cells, but did not result in inhibition of the growth of non-synovial control cancer cell lines (RD, HCT116, and Calu6). Overall, Compound 1 showed most significant growth inhibition in all synovial cell lines. 
     Example 5—Inhibition of Cell Growth in Synovial Sarcoma Cells 
     The following example shows that BRD9 degraders inhibit cell growth and Induce apoptosis in synovial sarcoma cells. 
     Procedure: SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9 degrader (Compound 1) at 200 nM or 1 μM, or an E3 ligase binder (lenalidomide) at 200 nM. Compounds were refreshed every 5 days. Cell cycle analysis was performed using the Click-T™ Plus EdU Flow Cytometry Assay (Invitrogen). The apoptosis assay was performed using the Annexin V-FITC Apoptosis Detection Kit (Sigma A9210). Assays were performed according to the manufacturer&#39;s protocol. 
     Results: As shown in  FIGS.  10 - 13   , treatment with Compound 1 for 8 or 13 days resulted in reduced numbers of cells in the S-phase of the cell cycle as compared to DMSO and lenalidomide. Treatment with Compound 1 for 8 days also resulted in increased numbers of early- and late-apoptotic cells as compared to DMSO controls. 
     Example 6—Composition for SSI8-SSX1-BAF 
     The following example shows the identification of BRD9 as a component of SS18-SSX containing BAF complexes. 
     Procedure: A stable 293T cell line expressing HA-SS18SSX1 was generated using lentiviral integration. SS18-SSX1 containing BAF complexes were subject to affinity purification and subsequent mass spectrometry analysis revealed SS18-SSX1 interacting proteins. 
     Results: As shown in  FIG.  14   , BAF complexes including the SS18-SSX fusion protein also included BRD9. More than 5 unique peptides were identified for ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1 isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides). 
     Example 7—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide formic acid (Compound D1 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 4-[(8-aminooctyl)amino]-2-(2,6-diooxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione trifluoroacetic acid salt (50 mg, 0.097 mmol, 1 equiv) and 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid trifluoroacetic acid salt (50.87 mg, 0.097 mmol, 1 equiv) in DCM (2 mL, 31.460 mmol, 323.73 equiv) was added DIEA (37.68 mg, 0.292 mmol, 3 equiv) and PyBOP (75.88 mg, 0.148 mmol, 1.5 equiv). The mixture was stirred for 2 hours at room temperature, and then it was concentrated under vacuum. The residue was purified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (25% Phase B up to 45% in 8 minutes); Detector, UV). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide formic acid (4 mg, 4.81%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.54 (s, 1H), 7.76 (s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.60-7.51 (m, 1H), 7.04 (d, J=7.8 Hz, 2H), 6.83 (s, 2H), 5.07 (dd, J=12.5, 5.5 Hz, 1H), 4.31 (s, 2H), 4.05 (s, 4H), 3.94 (s, 6H), 3.71 (s, 3H), 3.52-3.45 (s, 2H), 3.22 (t, J=7.0 Hz, 2H), 2.91-2.66 (m, 4H), 2.14-2.11 (m, 1H), 1.67 (q, J=7.3 Hz, 2H), 1.54 (d, J=7.3 Hz, 2H), 1.45-1.38 (m, 8H). LCMS (ESI) m/z: [M+H] + =792.38. 
     Example 8—Preparation of 4-(2-[1-[2-([[2,6-dimethoxy-4-(2-methyl-l-xo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetyl]-[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (Compound D2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)(amino)acetic acid (i9.99 mg, 0.050 mmol, 1 equiv) and DIPEA (19.50 mg, 0.151 mmol, 3 equiv) in DMF (3 mL) was added PyBOP (28.68 mg, 0.075 mmol, 1.5 equiv) and 4-(2-[[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione trifluoroacetic acid salt (30 mg, 0.050 mmol, 1 equiv). The solution was stirred for 2 hours at room temperature. The resulting mixture was purified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA). Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 30% B in 8 minutes; 254 nm; R t : 7.56 minutes) to afford 4-(2-[1-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetyl]-[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i9 mg, 43.83%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.53 (d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (s, 0.3H), 7.76 (s, 2H), 7.64 (d, J=5.7 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.80 (s, 2H), 5.14 (t, J=15.7 Hz, 3H), 4.60-4.43 (m, 3H), 4.02 (d, J=13.6 Hz, 4H), 3.91 (s, 6H), 3.71 (s, 3H), 3.58 (s, 2H), 3.15-2.59 (m, 6H), 2.53 (s, 3H), 2.15 (s, 1H), 1.85-1.67 (m, 4H), 1.41-1.16 (m, 6H). LCMS (ESI) m/z: [M+H]+=862. 
     Example 9—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl) azetidine-3-carboxamide (Compound D3) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid trifluoroacetic acid salt (55.40 mg, 0.106 mmol, 1 equiv) and 4-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione; trifluoroacetic acid salt (50 mg, 0.106 mmol, 1 equiv) in DCM (2 mL) was added DIEA (41.04 mg, 0.318 mmol, 3 equiv) and PyBOP (82.62 mg, 0.159 mmol, 1.5 equiv). The mixture was stirred for 2 hours at room temperature, and then it was concentrated under vacuum. The residue was purified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (15% Phase B up to 35% in 8 minutes); Detector, UV). This resulted in 6 mg (6.98%) of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl) azetidine-3-carboxamide formate as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.53 (s, 1H), 7.76 (s, 1H), 7.65-7.51 (m, 2H), 7.05 (dd, J=7.8, 6.0 Hz, 2H), 6.83 (s, 2H), 5.11-5.02 (m, 1H), 4.57 (s, 1H), 4.36 (s, 2H), 4.10 (s, 4H), 3.95 (s, 6H), 3.71 (s, 3H), 3.36-3.26 (m, 3H), 2.91-2.68 (m, 3H), 2.12 (d, J=10.0 Hz, 1H), 1.76-1.67 (m, 2H), 1.60 (q, J=7.3, 6.8 Hz, 2H), 1.49 (d, J=7.1 Hz, 2H). LCMS (ESI) m/z: [M+H] + =750.32. 
     Example 10—Preparation of N-[8-[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)formamido]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide formic acid (Compound D4 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid; trifluoroacetic acid salt (68.57 mg, 0.131 mmol, 1.50 equiv) and N-(8-aminooctyl)-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide trifluoroacetic acid salt (50.00 mg, 0.087 mmol, 1.00 equiv) in DCM (2.00 mL) was added DIEA (67.72 mg, 0.524 mmol, 6.00 equiv) and PyBOP (68.17 mg, 0.131 mmol, 1.50 equiv). The mixture was stirred for 2 hours at room temperature, and then it was concentrated under vacuum. The residue was purified by Prep-HPLC (conditions: X Bridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (20% Phase B up to 32% in 7 minutes); Detector, UV). This resulted in N-[8-[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)formamido]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide formic acid (i2 mg, 14.77%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.65 (d, J=5.8 Hz, 1H), 7.87-7.78 (m, 1H), 7.75 (s, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 6.80 (s, 2H), 5.15 (dd, J=12.6, 5.3 Hz, 1H), 4.76 (s, 2H), 4.14 (s, 2H), 3.92 (s, 6H), 3.80 (s, 4H), 3.71 (s, 3H), 3.20 (t, J=7.0 Hz, 2H), 2.94-2.71 (m, 6H), 2.15 (s, 1H), 1.58 (d, J=7.9 Hz, 2H), 1.51 (s, 2H), 1.35 (s, 8H). LCMS (ESI) m/z: [M+H] + =850.37. 
     Example 11—Preparation of N-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanamide (Compound D5) 
     
       
         
         
             
             
         
       
     
     To a solution of 6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanoic acid (50.00 mg, 0.129 mmol, 1.00 eq.) and DIEA (49.92 mg, 0.386 mmol, 3 eq.) in DCM (2.00 mL, 31.460 mmol, 244.37 eq.) was added PyBOP (100.49 mg, 0.193 mmol, 1.5 eq.) and 4-[4-[(3-aminoazetidin-1-yl)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (48.98 mg, 0.129 mmol, 1 eq.). The resulting solution was stirred at room temperature for 1 hour. The crude product (50 mg) was purified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10% B to 30% B in 8 minutes; 254 nm; R t : 6.57 minutes) to afford N-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanamide (14.8 mg, 15.31%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 7.82-7.73 (m, 2H), 7.65-7.58 (m, 1H), 7.44 (dd, J=7.9, 3.2 Hz, 2H), 6.83 (s, 2H), 5.10 (dd, J=12.4, 5.4 Hz, 1H), 4.60-4.47 (m, 1H), 4.34 (s, 2H), 4.25 (1, J=6.1 Hz, 2H), 4.18 (s, 2H), 3.94 (s, 8H), 3.71 (s, 3H), 2.87-2.64 (m, 3H), 2.30 (t, J=7.3 Hz, 2H), 2.17-2.09 (m, 1H), 1.90 (p, J=6.4 Hz, 2H), 1.75 (p, J=7.4 Hz, 2H), 1.61 (q, J=8.0 Hz, 2H). LCMS (ESI) m/z: [M+H]+=751.25. 
     Example 12—Preparation of 4-[2-[1-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carbonyl)-[4,4-bipiperidin]-1-yl]-2-oxoethoxy]-2-(2,6-dioxo piperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione formic acid (Compound D6 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid trifluoroacetic acid salt (26.32 mg, 0.050 mmol, 1.50 equiv) and 4-(2-[[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetic acid salt (20.00 mg, 0.034 mmol, 1.00 equiv) in DCM (2 mL) was added DIEA (26.00 mg, 0.201 mmol, 6.00 equiv) and PyBOP (26.17 mg, 0.050 mmol, 1.50 equiv). The mixture was stirred for 2 hours at room temperature, and then it was concentrated under vacuum. The residue was purified was purified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (8% Phase B up to 22% in 8 minutes); Detector, UV). This resulted in 4-[2-[1-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carbonyl)-[4,4-bipiperidin]-1-yl]-2-oxoethoxy]-2-(2,6-dioxo piperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione formic acid (3.5 mg, 10.89%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (d, J=0.8 Hz, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.58 (s, 1H), 7.84-7.72 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 6.81 (s, 2H), 5.31-4.98 (m, 3H), 4.68-4.44 (m, 2H), 4.16 (s, 2H), 3.93 (s, 10H), 3.79-3.56 (m, 5H), 3.09-2.93 (m, 2H), 2.93-2.61 (m, 6H), 2.15 (d, J=10.4 Hz, 1H), 1.86-1.67 (m, 4H), 1.50-1.25 (m, 3H), 1.23-1.04 (m, 2H). LCMS (ESI) m/z: [M+H] + =874.37. 
     Example 13—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino] ethoxy)ethoxy]ethyl]azetidine-3-carboxamide formic acid (Compound D7 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid trifluoroacetic acid salt (75.73 mg, 0.145 mmol, 1.5 equiv) and 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione trifluoroacetic acid salt (50 mg, 0.096 mmol, 1 equiv) in DCM (2 mL) was added DIEA (74.79 mg, 0.579 mmol, 6 equiv) and PyBOP (75.28 mg, 0.145 mmol, 1.5 equiv). The mixture was stirred for 2 hours at room temperature, and then it was concentrated under vacuum. The residue was purified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (10% Phase B up to 32% in 8 minutes): Detector, UV). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-carboxamide formic acid (13.2 mg, 15.77%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.56 (s, 1H), 7.75 (s, 1H), 7.62 (d, J=5.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd, J=11.7, 7.8 Hz, 2H), 6.80 (s, 2H), 5.07 (dd, J=12.4, 5.5 Hz, 1H), 4.20 (s, 2H), 3.92 (s, 10H), 3.78-3.57 (m, 9H), 3.61-3.43 (m, 4H), 3.41 (td, J=5.2, 1.6 Hz, 2H), 2.88 (ddd, J=19.0, 14.0, 5.0 Hz, 1H), 2.80-2.64 (m, 3H), 2.17-2.08 (m, 1H). LCMS (ESI) m/z: [M+H] + =796.25. 
     Example 14—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide formic acid (Compound D8 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i14-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (500 mg, 1.810 mmol, 1 equiv) in DMF (10 mL) was added CH 3 I (385.39 mg, 2.715 mmol, 1.5 equiv) and K 2 CO 3  (750.51 mg, 5.430 mmol, 3 equiv). The resulting solution was stirred for overnight at 25° C. The solids were filtered out. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (480 mg, 91.38%) as a white solid. LCMS (ESI) m/z: [M−H]+=291. 
     Step 2: Preparation of tert-butyl N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (i14-3) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (480 mg, 1.654 mmol, 1 equiv) and tert-butyl N-(8-aminooctyl)carbamate (404.14 mg, 1.654 mmol, 1 equiv) in NMP (10 mL) was added DIEA (641.21 mg, 4.961 mmol, 3 equiv). The resulting solution was stirred for 6 hours at 90° C. The resulting solution was diluted with 20 mL of water and extracted with ethyl acetate (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in tert-butyl N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (480 mg, 58.40%) as a green solid. LCMS (ESI) m/z: [M−H]+=515. 
     Step 3: Preparation of 4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i14-4) 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate (150 mg, 0.291 mmol, 1 equiv) and 4 M HCl in 1,4-dioxane (5 mL) was stirred for 1 hour at 25° C. The resulting mixture was concentrated. This resulted in 4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i00 mg, 82.77%) as a white solid, that was used directly without further purification. LCMS (ESI) m/z: [M−H]+=415. 
     Step 4: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H4-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide formic acid (Compound D8 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (80 mg, 0.193 mmol, 1 equiv) and 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid (79.02 mg, 0.193 mmol, 1 equiv) in DMF (3 mL) was added HATU (110.08 mg, 0.290 mmol, 1.5 equiv) and DIEA (49.89 mg, 0.388 mmol, 2 equiv). The resulting solution was stirred for 2 hours at 25° C. The crude product was purified by Prep-HPLC (conditions: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN; Detector, UV 254 nm). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (15 mg, 9.64%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.54 (s, 1.2H, FA), 7.77 (s, 1H), 7.65-7.52 (m, 2H), 7.10-7.01 (m, 2H), 6.84 (s, 2H), 5.10 (dd, J=12.9, 5.4 Hz, 1H), 4.39 (s, 2H), 4.14 (d, J=8.2 Hz, 3H), 3.95 (s, 6H), 3.71 (s, 3H), 3.54 (d, J=8.1 Hz, 1H), 3.22 (t, J=7.0 Hz, 2H), 3.17 (d, J=3.1 Hz, 1H), 3.15 (s, 3H), 2.99 (s, 1H), 2.98-2.86 (m, 2H), 2.69 (dt, J=12.7, 6.3 Hz, 2H), 2.15-2.05 (m, 1H), 1.68 (p, J=7.1 Hz, 2H), 1.52 (q, J=7.1 Hz, 2H), 1.38 (s, 8H). LCMS (ESI) m/z: [M−H]+=806.40. 
     Example 15—Preparation of 2-(1-[[2,6-dimethoxy-4-(2-ethyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamide formic acid (Compound D9 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)acetic acid (i10 mg, 0.260 mmol, 1 equiv) in DMF (3 mL) was added 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i04.03 mg, 0.260 mmol, 1.00 equiv), PyBOP (202.77 mg, 0.390 mmol, 1.50 equiv), and DIEA (167.86 mg, 1.299 mmol, 5.00 equiv). The resulting mixture was stirred at room temperature for 16 hours. Without workup, the crude product was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 27% B to 34% B in 8 minutes; 254 nm; R t : 6.28 minutes) to afford 2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamide formic acid (26.7 mg) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (s, 0.8H, FA), 7.76 (s, 1H), 7.61 (d, J=5.7 Hz, 1H), 7.54 (dd, J=8.5, 7.1 Hz, 1H), 7.03 (dd, J=7.8, 3.5 Hz, 2H), 6.85 (s, 2H), 5.06 (dd, J=12.4, 5.4 Hz, 1H), 4.43 (s, 2H), 4.18 (t, J=9.5 Hz, 2H), 4.02-3.90 (m, 7H), 3.70 (s, 3H), 3.30 (d, J=6.8 Hz, 2H), 3.17 (t, J=7.1 Hz, 3H), 2.97-2.62 (m, 3H), 2.58 (d, J=7.4 Hz, 2H), 2.19-2.05 (m, 1H), 1.65 (q, J=7.0 Hz, 2H), 1.57-1.37 (m, 10H). LCMS (ESI) m/z: [M+H] + =806.25. 
     Example 16—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl) azetidine-3-carboxamide (D10) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of (R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid (40.9 mg, 0.100 mmol, 1 equiv), DIEA (64.55 mg, 0.499 mmol, 5 equiv), and PyBOP (155.95 mg, 0.300 mmol, 3 equiv) in DMF (1 mL) was added 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride (43.65 mg, 0.100 mmol, 1 equiv) at ambient atmosphere. The mixture was stirred for 1 hour at room (conditions: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 18% B to 35% B in 12 minutes; 254/220 nm; R t : 11.74 minutes) to afford (R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (25 mg, 31.60%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.54 (dd, J=8.5, 7.1 Hz, 1H), 7.01 (t, J=7.8 Hz, 2H), 6.78 (s, 2H), 5.06 (dd, J=12.3, 5.5 Hz, 1H), 4.17 (s, 2H), 3.93 (s, 6H), 3.97-3.82 (m, 1H), 3.74 (s, 2H), 3.69 (s, 3H), 3.31-3.09 (m, 4H), 2.97-2.62 (m, 3H), 2.50 (d, J=9.2 Hz, 1H), 2.32-2.20 (m, 1H), 2.19-2.09 (m, 1H), 1.57 (q, J=6.9 Hz, 2H), 1.45-1.30 (m, 10H). LCMS (ESI) m/z: [M+H]+=792.20. 
     Example 17—Preparation of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide (Compound D11) 
     
       
         
         
             
             
         
       
     
     To a solution of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylic acid (50.00 mg, 0.122 mmol, 1.00 equiv) and 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1-1H-isoindole-1,3-dione (48.91 mg, 0.122 mmol, 1.00 equiv) In DMF (2.00 mL) was added PyBOP (127.10 mg, 0.244 mmol, 2.00 equiv) and DIEA (47.35 mg, 0.388 mmol, 3.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The crude product was purified by preparative HPLC (condition: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B In 8 minutes; 254 nm; R t : 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford (2S)-1-[[2,8-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide (35 mg, 35.47%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.65 (d, J=5.7 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=5.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.00 (dd, J=10.6, 7.8 Hz, 2H), 6.75 (s, 2H), 5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.59 (s, 9H), 3.69 (s, 3H), 3.30 (s, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.94-2.64 (m, 3H), 2.35 (d, J=9.5 Hz, 1H), 2.186-2.00 (m, 1H), 1.58 (t, J=7.1 Hz, 2H), 1.40 (d, J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z: [M+H]+=792.60. 
     Example 18—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (Compound D12) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)sulfamoyl]azetidine-1-carboxylate (i18-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i00.00 mg, 0.250 mmol, 1.00 equiv) in DCM (2.00 mL) was added tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (95.78 mg, 0.375 mmol, 1.50 equiv) and TEA (50.53 mg, 0.499 mmol, 2.00 equiv) at 0° C. The resulting solution was stirred for 2 hours at 25° C. The reaction was then quenched by the addition of 5 mL of MeOH. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl DCM/MeOH (20:1). This resulted in 110 mg (71.08%) of tert-butyl 3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl) sulfamoyl]azetidine-1-carboxylate as a yellow solid. LCMS (ESI) m/z: [M+H]+=620. 
     Step 2: Preparation of N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (i18-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl) sulfamoyl]azetidine-1-carboxylate (110.00 mg, 0.177 mmol, 1.00 equiv) in TFA (2.00 mL) and CH 2 Cl 2  (2.00 mL) was stirred at 0° C. for 1 hour. The resulting mixture was concentrated under reduced pressure to afford N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (85 mg, 92.16%) as a yellow solid, which was used directly without further purification. LCMS (ESI) m/z: [M+H]+=520. 
     Step 3: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (Compound D12) 
     
       
         
         
             
             
         
       
     
     To a solution of N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (85.00 mg, 0.164 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (53.06 mg, 0.164 mmol, 1.00 equiv) in MeOH (2.00 mL) was added NaBH 3 CN (20.58 mg, 0.327 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The crude product was purified by preparative HPLC Column (condition: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minutes; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R t : 7.12 minutes). Fractions containing the desired compound were evaporated to dryness to afford 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide (50 mg, 36.92%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (d, J=0.9 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.53 (s, 0.47H, FA), 7.74 (s, 1H), 7.63 (dd, J=5.8, 0.9 Hz, 1H), 7.55 (dd, J=8.5, 7.1 Hz, 1H), 7.03 (dd, J=7.8, 4.8 Hz, 2H), 6.77 (s, 2H), 5.06 (dd, J=12.5, 5.5 Hz, 1H), 4.03 (p, J=8.2, 7.8 Hz, 1H), 3.91 (d, J=4.1 Hz, 2H), 3.89 (s, 6H), 3.78-3.68 (m, 8H), 3.30 (d, J=6.8 Hz, 1H), 3.03 (t, J=7.0 Hz, 2H), 2.94-2.80 (m, 1H), 2.80-2.68 (m, 2H), 2.17-2.08 (m, 1H), 1.70-1.62 (m, 2H), 1.51 (d, J=6.9 Hz, 2H), 1.44-1.37 (m, 8H). LCMS (ESI) m/z: [M+H]+=828.35. 
     Example 19—Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-3-methylazetidine-3-carboxamide (Compound D13) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of methyl 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-3-methylazetidine-3-carboxylate (i19-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (200 mg, 0.617 mmol, 1 equiv) and methyl 3-methylazetidine-3-carboxylate (79.65 mg, 0.617 mmol, 1.00 equiv) in MeOH (2 mL) was added NaBH 3 CN (77.50 mg, 1.233 mmol, 2 equiv). The resulting solution was stirred at 25° C. for 1 hour. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (9:1) to afford methyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl) phenyl] methyl]-3-methylazetidine-3-carboxylate (247 mg, 91.56%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=438. 
     Step 2: Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-3-methylazetidine-3-carboxylic acid (i19-3) 
     
       
         
         
             
             
         
       
     
     A solution of methyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazetidine-3-carboxylate (235 mg, 0.537 mmol, 1 equiv) in HCl (12 M, 5 mL) was stirred at 25° C. for 40 minutes. The mixture was concentrated under reduced pressure afford 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazeti-dione-3-carboxylic acid (i85 mg, 81.33%) as a brown solid, that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=424. 
     Step 3: Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-3-methylazetidine-3-carboxamide (Compound D13) 
     
       
         
         
             
             
         
       
     
     To a solution of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazetidine-3-carboxylic acid (50 mg, 0.118 mmol, 1 equiv), 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (94.57 mg, 0.236 mmol, 2 equiv) and Et 3 N (119.48 mg, 1.181 mmol, 10.00 equiv) in DMF (3 mL), was added EDCI (27.16 mg, 0.142 mmol, 1.2 equiv) and HOBT (19.15 mg, 0.142 mmol, 1.2 equiv), the resulting solution was stirred at 25° C. for 24 hours. The crude product was purified by Prep-HPLC with the following conditions (condition: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN; Detector. UV) to give 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-3-methylazetidine-3-carboxamide (21.7 mg, 22.80%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.59-7.49 (m, 1H), 7.07-6.98 (m, 2H), 6.81 (s, 2H), 5.06 (dd, J=12.3, 5.4 Hz, 1H), 4.19 (s, 2H), 4.06 (s, 2H), 3.93 (s, 6H), 3.71 (s, 5H), 3.32-3.16 (m, 1H), 2.92-2.66 (m, 4H), 2.15-2.06 (m, 1H), 1.64 (d, J=7.4 Hz, 2H), 1.55 (s, 5H), 1.39-1.32 (m, 8H). LCMS (ESI) m/z: [M+H]+=806.50. 
     Example 20—Preparation of 1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamide (Compound D14) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]carbamate (i20-2) 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl N-(8-aminooctyl)carbamate (1.00 g, 4.092 mol, 1.00 equiv) and phthalic anhydride (606.10 mg, 4.092 mmol, 1.00 equiv) in toluene (20.00 mL) was stirred for 2 hours at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]carbamate (1.7 g, 95.41%) as a white solid. LCMS (ESI) m/z: [M+H]+=375. 
     Step 2: Preparation of tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate (i20-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-[8-(1,3-dioxisoindol-2-yl)octyl]carbamate (1.24 g, 3.311 mmol, 1.00 equiv) in DMF (1.00 mL) was added NaH (0.16 g, 6.622 mmol, 2 equiv) in portions at 0° C. under nitrogen atmosphere. Then CH 3 I (1.88 g, 13.245 mmol, 4 equiv) was added. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (12:1)) t afford tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate (800 mg, 62.19%) as a colorless liquid. LCMS (ESI) m/z: [M+H]+=389. 
     Step 3: Preparation of tert-butyl N-(8-aminooctyl)-N-methylcarbamate (i20-4) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate (700.00 mg, 1.802 mmol, 1.00 equiv) and NH 2 NH 2  (259.84 mg, 3.604 mmol, 2 equiv) in EtOH (5.00 mL) was stirred for 1 hour at 90° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with PE/EtOAc (12:1) to afford tert-butyl N-(8-aminooctyl)-N-methylcarbamate (580 mg, 94.68%) as a colorless liquid. LCMS (ESI) m/z: [M+H]+=259. 
     Step 4: Preparation of tert-butyl N-(8-[[(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate (i20-5) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro isoindole-1,3-dione (520.00 mg, 1.883 mmol, 1.00 equiv) and tert-butyl N-(8-aminooctyl)-N-methylcarbamate (486.46 mg, 1.883 mmol, 1 equiv) in DMF (5.00 mL) was added DIPEA (1216.53 mg, 9.413 mmol, 5 equiv). The solution was stirred for 1 hour at 90° C. under nitrogen atmosphere, then it was cooled down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 CM/MeOH (12:1) to afford tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate (260 mg, 26.84%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=515. 
     Step 5: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-[[8-(methylamino)octyl]amino]isoindole-1,3-dione (i20-6) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate (220.00 mg, 0.427 mmol, 1.00 equiv) in 4 M HCl in dioxane (6.00 mL) was stirred for 2 hours at room temperature. The solvent was evaporated and the residue was purified by reverse flash chromatography (condition: C18 silica gel column; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to afford 2-(2,6-dioxopiperidin-3-yl)-4-[[8-(methylamino)octyl]amino]isoindole-1,3-dione (170 mg, 95.94%) as a dark yellow oil. LCMS (ESI) m/z: [M+H]+=415. 
     Step 6: Preparation of 1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydo-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamide (Compound D14) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid (30 mg, 0.073 mmol, 1 equiv) in DMF (0.5 mL), was added DIPEA (47.35 mg, 0.368 mmol, 5 equiv), HATU (55.72 mg, 0.147 mmol, 2 equiv), and 2-(2,6-dioxopiperidin-3-yl)-4-[[(8-(methylamino)octyl]amino]-2,3-dihydro-1H-isoindole-1,3-dione (30.37 mg, 0.073 mmol, 1 equiv). The reaction was stirred at ambient atmosphere for 1 hour. The mixture was purified directly by Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minutes; Gradient: 24% B to 38% B in 8 minutes; 254 nm; R t : 7.9 minutes) to afford 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamide formate (25 mg, 40.05%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.52 (dd, J=4.5, 0.9 Hz, 1H), 8.68 (dd, J=5.8, 2.5 Hz, 1H), 8.56 (s, 0.5H, FA), 7.75 (d, J=2.0 Hz, 1H), 7.67-7.58 (m, 1H), 7.53 (ddd, J=8.5, 7.1, 4.7 Hz, 1H), 7.07-6.95 (m, 2H), 6.81 (d, J=1.8 Hz, 2H), 5.06 (ddd, J=12.1, 5.4, 2.5 Hz, 1H), 4.21 (d, J=4.7 Hz, 2H), 4.00 (dd, J=17.1, 8.8 Hz, 4H), 3.93 (s, 6H), 3.80 (t, J=8.2 Hz, 1H), 3.70 (d, J=3.3 Hz, 3H), 3.45-3.19 (m, 2H), 2.94 (d, J=4.3 Hz, 3H), 2.91-2.68 (m, 3H), 2.12 (s, 1H), 1.67 (s, 2H), 1.57 (d, J=6.9 Hz, 2H), 1.41-1.33 (m, 8H). LCMS (ESI) m/z: [M+H]+=808.35. 
     Example 21—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)-N-methylazetidine-3-carboxamide formic acid (Compound D15 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[[5-(methylamino)pentyl]amino]-2,3-dihydro-1H-isoindole-1,3-dione (60.00 mg, 0.161 mmol, 1.00 equiv), 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid (65.96 mg, 0.161 mmol, 1.00 equiv), and DIEA (41.64 mg, 0.322 mmol, 2.00 equiv) in DMF (2.00 mL, 25.844 mmol, 160.41 equiv) was added HATU (91.89 mg, 0.242 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for 16 hours. Without workup, the crude product was purified by Prep-HPLC (condition: XBridge Shield RP18 OBD Column 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 40 mL/minute; Gradient: 18% B to 18% B In 2 minutes; 254/220 nm; R t : 11.43 minutes) to afford 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)-N-methylazetidine-3-carboxamide; formic acid (25.1 mg) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (dd, J=5.4, 0.9 Hz, 1H), 8.68 (dd, J=5.8, 1.2 Hz, 1H), 8.58 (s, 0.53H, FA), 7.79-7.73 (m, 1H), 7.67-7.50 (m, 2H), 7.09-6.99 (m, 2H), 6.80 (d, J=3.2 Hz, 2H), 5.06 (ddd, J=12.3, 5.4, 2.8 Hz, 1H), 4.17 (s, 2H), 3.92-3.90 (m, 10H), 3.78 (q, J=9.0, 8.5 Hz, 1H), 3.71 (d, J=2.2 Hz, 3H), 3.48-3.35 (m, 2H), 3.27 (t, J=7.5 Hz, 1H), 2.98-2.85 (m, 3H), 2.89-2.64 (m, 4H), 2.22-2.08 (m, 1H), 1.75-1.62 (m, 4H), 1.43 (s, 2H). LCMS (ESI) m/z: [M+H] + =764.45. 
     Example 22—Preparation of 2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diol formic acid (Compound D16 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (i22-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 5-bromo-1,3-dimethylpyridin-2-one (1.00 g, 4.949 mmol, 1.00 equiv) and bis(pinacolato)diboron (1508.17 mg, 5.939 mmol, 1.20 equiv) in dioxane (10.00 mL) was added KOAc (971.46 mg, 9.898 mmol, 2.00 equiv) and Pd(dppf)Cl 2 CH 2 Cl 2  (404.18 mg, 0.495 mmol, 0.10 equiv). After stirring for 2 hours at 90° C. under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =250. 
     Step 2: Preparation of 4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (i22-3) 
     
       
         
         
             
             
         
       
     
     To a solution of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (1.20 g, 4.817 mmol, 1.00 equiv) and 4-bromo-2,6-dimethoxybenzaldehyde (1.18 g, 4.817 mmol, 1.00 equiv) in 1,4-dioxane (40.00 mL) and H 2 O (4.00 mL) was added CS 2 CO 3  (3.14 g, 9.634 mmol, 2.00 equiv) and Pd(dppf)Cl 2  (0.35 g, 0.482 mmol, 0.10 equiv). After stirring for 2 hours at 80° C. under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (18:1) to afford 4-(1,5-dimethyl-8-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (1.43 g, 87.83%) as a brown syrup. LCMS (ESI) m/z: [M+H] + =288. 
     Step 3: Preparation of methyl 1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate (i22-4) 
     
       
         
         
             
             
         
       
     
     To a solution of methyl azetidine-3-carboxylate hydrochloride (1.13 g, 7.488 mmol, 1.50 equiv) in MeOH (10.00 mL) was added Et 3 N to pH 7-8. Then 4-(1,5-dimethyl-8-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (1.43 g, 4.977 mmol, 1.00 equiv) was added. After stirring for 5-10 minutes, NaBH 3 CN (0.63 g, 9.954 mmol, 2.00 equiv) was added in portions at ambient atmosphere. The resulting mixture was concentrated after stirring for 1 hour at room temperature. The residue was purified by silica gel column chromatography, eluted with CH 2 C 2 /MeOH (20:1) to afford methyl 1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate (1.06 g, 52.36%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =387. 
     Step 4: Preparation of 1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylic acid (i22-5) 
     
       
         
         
             
             
         
       
     
     A mixture of methyl 1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate (203.00 mg, 0.525 mmol, 1.00 equiv) in HCl (12 N, 2.00 mL) was stirred for 2 hours at 90° C. The resulting mixture was concentrated under reduced pressure to give 1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylic acid (i50 mg, 71.31%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=373. 
     Step 4: Preparation of 2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diol formic acid (Compound D16 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 1-[[4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylic acid trifluoroacetic acid (50 mg, 0.103 mmol, 1 equiv) and 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride (44.91 mg, 0.103 mmol, 1 equiv) in DCM (2 mL) was added DIEA (53.57 mg, 0.415 mmol, 4 equiv). After stirring for 10 minutes, PyBOP (80.89 mg, 0.155 mmol, 1.5 equiv) was added. The resulting mixture was concentrated under reduced pressure, and then the residue was purified by Prep-HPLC (conditions: Sun Fire C18 OBD Prep Column, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (23% Phase B up to 33% in 8 min, hold 33% in 1 minutes); Detector, UV). This resulted in 2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diol formic acid (2.4 mg, 2.73%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 8.58 (s, 2H, FA), 7.96 (s, 1H), 7.83 (s, 1H), 7.61-7.50 (m, 1H), 7.04 (d, J=7.7 Hz, 2H), 6.88 (s, 2H), 4.62 (s, 1H), 4.32 (s, 2H), 4.09 (d, J=7.9 Hz, 4H), 3.98 (s, 6H), 3.68 (s, 3H), 3.55-3.44 (m, 2H), 3.21 (t, J=7.0 Hz, 2H), 2.91-2.68 (m, 4H), 2.22 (s, 3H), 2.12 (s, 1H), 1.68 (s, 2H), 1.64-1.39 (m, 10H). LCMS (ESI) m/z: [M+H] + =373.17. 
     Example 23—Preparation of 3-amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (Compound D17) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 1-tert-Butyl 3-ethyl-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate (i23-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (120 mg, 0.491 mmol, 1 equiv) and 2,5-dioxopyrrolidin-1-yl (9H-fluoren-9-yl)methyl carbonate (182.3 mg, 0.540 mmol, 1.1 equiv) In DCM (1 mL) was added TEA (149.1 mg, 1.474 mmol, 3 equiv). The resulting solution was stirred at room temperature for 1 hour. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 1-tert-butyl 3-ethyl 3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate (120 mg, 48%) as a white solid. LCMS (ESI) m/z: [M+H] + =467. 
     Step 2: Preparation of ethyl 3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate (i23-3) 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 3-ethyl 3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate (120.00 mg, 0.257 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford ethyl 3-([(9H-fluoren-9-yl)methoxy]carbonylamino)azetidine-3-carboxylate (120 mg, 89%) as a white solid that was used directly without further purification. LCMS (ESI) m/z: [M+H] + =387. 
     Step 3: Preparation of Ethyl 1-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate (123-4) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (127.5 mg, 0.393 mmol, 1.20 equiv) and ethyl 3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate (120 mg, 0.327 mmol, 1 equiv) in MeOH (1 mL) was added NaBH 3 CN (41.2 mg, 0.655 mmol, 2 equiv). The resulting solution was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and the residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH 12:1) to afford ethyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate (100 mg, 45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=675. 
     Step 4: Preparation of Ethyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylic acid (i23-5) 
     
       
         
         
             
             
         
       
     
     A solution of ethyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate (100 mg, 0.148 mmol, 1 equiv) in concentrated HCl (2 mL) was stirred at 90° C. for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylic acid (100 mg, 94%) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=647.3 
     Step 5: Preparation of (9H-fluoren-9-yl)methyl N-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate (i23-7) 
     
       
         
         
             
             
         
       
     
     To a solution of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylic acid (100 mg, 0.155 mmol, 1 equiv) and 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (74.3 mg, 0.186 mmol, 1.2 equiv) In DMF (1 mL) was added DIEA (60.0 mg, 0.464 mmol, 3 equiv) and HATU (88.2 mg, 0.232 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and the residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH 12:1) to afford (9H-fluoren-9-yl)methyl N-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate (90 mg, 51%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=1029. 
     Step 6: Preparation of 3-Amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (Compound D17) 
     
       
         
         
             
             
         
       
     
     A solution of (9H-fluoren-9-yl)methyl N-(1-[[2,6-dimethoxy-4-(2-methyl 1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-[(8-[[2-(2,8-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate (90 mg, 0.087 mmol, 1.00 equiv) in piperidine (1 mL) and DMF (4 mL) was stirred at room temperature for 1 hour. The crude solution was purified by Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN: Flow rate: 25 mL/minute; Gradient: 28% B to 28% B in 2 minutes; 254 nm; R t : 6.9 minutes) to afford 3-amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (3.8 mg, 5.2%) as a yellow solid.  1 H NMR (300 MHz, Acetontrile-d3) δ 9.52 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.26 (s, 0.53H, FA), 7.78-7.42 (m, 4H), 7.02 (dd, J=7.8, 4.2 Hz, 2H), 6.75 (s, 2H), 6.30 (t, J=5.9 Hz, 1H), 4.95 (dd, J=12.4, 5.2 Hz, 1H), 4.10 (s, 2H), 3.95 (d, J=8.8 Hz, 2H), 3.87 (s, 6H), 3.50 (s, 3H), 3.24 (dq, J=23.4, 6.6 Hz, 4H), 2.83-2.59 (m, 3H), 1.63 (s, 2H), 1.49 (s, 2H), 1.32 (d, J=13.1 Hz, 10H). LCMS (ESI) m/z: [M+H]+=807.40. 
     Example 24—Preparation of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide (Compound D18) 
     
       
         
         
             
             
         
       
     
     Compound D11 was further separated by chiral HPLC to afford (2S)-1-((2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl)methyl)-N-(8-((2-((R)-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl) azetidine-2-carboxamide (10 mg, 10.34%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.00 (dd, J=10.6, 7.8 Hz, 2H), 6.75 (s, 2H), 5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.89 (s, 9H), 3.69 (s, 3H), 3.30 (s, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.94-2.64 (m, 3H), 2.35 (d, J=9.5 Hz, 1H), 2.16-2.00 (m, 1H), 1.58 (t, J=7.1 Hz, 2H), 1.40 (d, J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z: [M+H]+=792.60. 
     Example 25—Preparation of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide (Compound D19) 
     
       
         
         
             
             
         
       
     
     Compound D11 was further separated by chiral HPLC to afford (2S)-1-((2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl)methyl)-N-(8-((2-((S)-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl) azetidine-2-carboxamide (10 mg, 10.34%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.00 (dd, J=10.6, 7.8 Hz, 2H), 6.75 (s, 2H), 5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.89 (s, 9H), 3.69 (s, 3H), 3.30 (s, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.94-2.64 (m, 3H), 2.35 (d, J=9.5 Hz, 1H), 2.16-2.00 (m, 1H), 1.58 (t, J=7.1 Hz, 2H), 1.40 (d, J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z: [M+H]+=792.60 
     Example 26—Preparation of 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,5a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide (Compound D20) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of methyl 2-azaspiro[3.3]heptane-6-carboxylate trifluoroacetic acid (i26-2) 
     
       
         
         
             
             
         
       
     
     A mixture of 2-tert-butyl 6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate (127.60 mg, 0.500 mmol, 1.00 equiv) and TFA (1 mL) in DCM (3.00 mL) was stirred for 2 hours at room temperature. Then, the solvent was evaporated, and the resulting residue was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=156. 
     Step 2: Preparation of methyl-2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate (i26-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of methyl 2-azaspiro[3.3]heptane-6-carboxylate trifluoroacetic acid (77.60 mg, 0.288 mmol, 1.00 equiv), Et 3 N (116.67 mg, 1.153 mmol, 4 equiv), and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (93.49 mg, 0.288 mmol, 1 equiv) in MeOH (2.00 mL) was added NaBH 3 CN (36.23 mg, 0.576 mmol, 2 equiv) in portions at room temperature. After the solvent was evaporated, the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (12:1) to afford methyl 2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate (156 mg, 96.91%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=464. 
     Step 3: Preparation of 2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylic acid (i26-5) 
     
       
         
         
             
             
         
       
     
     A solution of methyl 2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate (156.00 mg, 0.347 mmol, 1.00 equiv) and LIOH (83.28 mg, 3.47 mmol, 10.0 equiv) in mixed THF (2.00 mL) and H 2 O (1.00 mL) was stirred for 1 hour at room temperature. Then solvent was evaporated, and the resulting solution was purified by Prep-HPLC (0-100% ACN/water, with 0.1% TFA) to afford 2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3] heptane-6-carboxylic acid (114.7 mg, 75.89%) as a dark yellow oil. LCMS (ESI) m/z: [M+H]+=450. 
     Step 4: Preparation of 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide (Compound D20) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]spiro[3.3]heptane-2-carboxylic acid (45 mg, 0.100 mmol, 1 equiv) and 4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (40.00 mg, 0.100 mmol, 1 equiv) in DMF (0.5 mL), was added DIEA (64.54 mg, 0.499 mmol, 5 equiv) and PyBOP (103.95 mg, 0.200 mmol, 2 equiv) at room temperature. The mixture was stirred for 1 h and directly purified by Prep-HPLC with the following conditions (conditions: SunFire C18 OBD Prep Column, 19 mm×250 mm: Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 29% B to 32% B in 8 minutes; 254 nm; R t : 6.55 minutes) to afford 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide (14.1 mg, 14.24%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.78 (s, 1H), 7.65-7.50 (m, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.88 (s, 2H), 5.05 (dd, J=12.6, 5.7 Hz, 1H), 4.63 (s, 2H), 4.44 (s, 2H), 4.18 (s, 3H), 3.97 (s, 6H), 3.88 (s, 1H), 3.71 (s, 3H), 3.34-3.11 (m, 3H), 3.10-2.67 (m, 5H), 2.61-2.37 (m, 4H), 2.27-2.13 (m, 1H), 1.67 (q, J=7.0 Hz, 2H), 1.59-1.26 (m, 10H). LCMS (ESI) m/z: [M+H]+=832.5. 
     Example 27—Preparation of 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexyl)spiro[3.3]heptane-2-carboxamide (Compound D21) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl) carbamate (i27-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of pomalidomide (150.30 mg, 0.550 mmol, 1.00 equiv) and tert butyl N-(6-bromohexyl)carbamate (154.13 mg, 0.550 mmol, 1 equiv) in DMF (1.00 mL) was added K 2 CO 3  (152.04 mg, 1.100 mmol, 2 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature, and then it was concentrated and purified by silica gel column chromatography, eluting with PE/EtOAc (10:1) to afford tert-butyl N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl) carbamate (293 mg, 95.82%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=473. 
     Step 2: Preparation of 4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetic acid (i27-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl) carbamate (293.00 mg, 0.620 mmol, 1.00 equiv) and TFA (2.0 mL) in DCM (5.00 mL) was stirred for 1 h at room temperature. The mixture was then concentrated to afford 4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (243 mg, 80.56%) as a yellow semi-solid, that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=373. 
     Step 3: Preparation of 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-terrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexyl) spiro[3.3]heptane-2-carboxamide (Compound D21) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 8-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]spiro[3.3]heptane-2-carboxylic acid (30 mg, 0.067 mmol, 1 equiv) in DMF (0.5 mL) was added DIEA (43.03 mg, 0.333 mmol, 5 equiv), PyBOP (69.30 mg, 0.133 mmol, 2 equiv), and 4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (24.80 mg, 0.067 mmol, 1 equiv). The reaction was stirred at ambient atmosphere for 1 hour. The mixture was purified directly by Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12% B to 38% B in 8 minutes; 254 nm; R t : 7.58 minutes), to afford 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexy)spiro[3.3]heptane-2-carboxamide (11.2 mg, 20.90%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=5.8 Hz, 1H), 7.50-7.39 (m, 1H), 7.01 (dd, J=17.7, 7.7 Hz, 2H), 6.85 (s, 2H), 5.09 (dd, J=12.9, 5.5 Hz, 1H), 4.42 (s, 2H), 4.16 (d, J=3.1 Hz, 4H), 3.96 (s, 6H), 3.78 (t, J=7.4 Hz, 2H), 3.71 (s, 3H), 3.50 (q, J=7.3 Hz, 1H), 3.20 (qd, J=7.3, 5.4 Hz, 9H), 2.99-2.87 (m, 2H), 2.91-2.83 (m, 1H), 2.75-2.61 (m, 1H), 2.53 (s, 2H), 2.53-2.47 (m, 1H), 2.47-2.37 (m, 2H), 2.22-2.09 (m, 2H), 1.94 (s, 2H), 1.93 (s, 6H), 1.61 (s, 1H), 1.51 (tt, J=15.1, 8.0 Hz, 4H), 1.46-1.26 (m, 23H), 1.12 (t, J=7.3 Hz, 10H), 0.91 (q, J=9.7, 7.9 Hz, 3H). LCMS (ESI) m/z: [M+H]+=804.40. 
     Example 28—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-1-yl]amino]butyl) azetidine-3-sulfonamide formic acid (Compound D22 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate (i28-2) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 5-[(4-aminobutyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (60.00 mg, 0.174 mmol, 1.00 equiv) and tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (111.38 mg, 0.436 mmol, 2.50 equiv) in DCM (2.00 mL) was added TEA (52.89 mg, 0.523 mmol, 3.00 equiv). After stirring for 1.5 hours at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 /EtOAc (1:2)) to afford tert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate (78 mg, 73.87%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =564.20. 
     Step 2: Preparation of N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)azetidine-3-sulfonamide (i28-3) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of tert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate (78.00 mg, 0.138 mmol, 1.00 equiv) in DCM (2.00 mL, 0.012 mmol, 0.10 equiv) was added TFA (0.40 mL, 5.385 mmol, 38.91 equiv). After stirring for 1 hour at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =464.15. 
     Step 3: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamide formic acid (Compound D38 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A mixture of N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl) azetidine-3-sulfonamide (64.17 mg, 0.138 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (44.90 mg, 0.138 mmol, 1.00 equiv) in DMF (2 mL) was stirred at room temperature, then adjusted to pH 8-9 by addition of TEA. The above mixture was added NaBH 3 CN (26.10 mg, 0.415 mmol, 3.00 equiv) in portions, the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure, the residue was purified by Prep-HPLC (condition: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (15% Phase B up to 30% in 14 minutes); Detector, UV). This resulted in 15 mg (12.59%) of 1-[[2,8-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]buty)azetidine-3-sulfonamide formic acid as a yellow solid.  1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.45 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.14 (s, 0.5H, FA), 7.87 (s, 1H), 7.59-7.52 (m, 2H), 7.13 (s, 1H), 6.94 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.78 (s, 2H), 6.55 (s, 1H), 5.03 (dd, J=12.9, 5.4 Hz, 1H), 3.84 (s, 7H), 3.60 (s, 4H), 3.28-3.20 (m, 3H), 3.16 (d, J=6.3 Hz, 3H), 2.97 (d, J=6.5 Hz, 2H), 2.92-2.81 (m, 1H), 2.61-2.53 (m, 3H), 2.03-1.95 (m, 1H), 1.55 (s, 4H). LCMS (ESI) m/z: [M+H] + =772.30. 
     Example 29—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-6-yl]amino]pentyl) azetidine-3-sulfonamide formic acid (Compound D23 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl-3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl) sulfamoyl]azetidine-1-carboxylate (128-2) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 5-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (100.00 mg, 0.279 mmol, 1.00 equiv) and tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (178.37 mg, 0.698 mmol, 2.50 equiv) In DCM (2.00 mL) was added TEA (84.70 mg, 0.837 mmol, 3.00 equiv). After stirring for 1.5 hours at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 /EA (1:2)) to afford tert-butyl-3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl)sulfamoyl]azetidine-1-carboxylate (58.7 mg, 33.87%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =578. 
     Step 2: Preparation of N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)azetidine-3-sulfonamide (i28-3) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of tert-butyl 3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl)sulfamoyl]azetidine-1-carboxylate (58.70 mg, 0.102 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (0.40 mL, 5.385 mmol, 52.99 equiv). After stirring for 1 hour at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =478.17. 
     Step 3: Preparation of 1-[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamide formic acid (Compound D22 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A mixture of N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl) azetidine-3-sulfonamide (48.54 mg, 0.102 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (39.56 mg, 0.122 mmol, 1.20 equiv) in THF (2 mL) was stirred at room temperature, then adjusted to pH 8-˜9 with TEA. To the above mixture was added NaBH 3 CN (12.78 mg, 0.203 mmol, 2.00 equiv) in portions, and the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (conditions: Sun Fire C18 OBD Prep Column, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (hold 3% Phase B in 2 minutes, up to 15% In 8 minutes); Detector, UV). This resulted in 7.4 mg (8.31%) of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamide formic acid as a yellow solid.  1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.44 (s, 1H), 8.72 (d, J=5.7 Hz, 1H), 7.86 (s, 1H), 7.59-7.52 (m, 2H), 7.21 (s, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 6.83 (dd, J=8.3, 1.7 Hz, 1H), 6.76 (s, 2H), 6.55 (s, 1H), 5.03 (dd, J=13.0, 5.4 Hz, 1H), 4.02 (s, 1H), 3.83 (s, 6H), 3.60 (s, 4H), 3.29-3.20 (m, 2H), 3.19-3.08 (m, 3H), 3.01-2.78 (m, 4H), 2.61-2.51 (m, 3H), 2.06-1.93 (t, J=12.7 Hz, 1H), 1.60-1.51 (m, 2H), 1.50-1.42 (m, 2H), 1.42-1.32 (m, 2H). LCMS (ESI) m/z: [M+H]+=786.28. 
     Example 30—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide formic acid (Compound D24 Formic Acid) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-(2-[4-[2-(2,6-dioxopiperdin-3-yl)-1,3-dioxisoindol-5-yl]piperazin-1-yl]ethyl)carbamide (i30-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430 mmol, 1.00 equiv) and tert-butyl N-[2-(piperazin-1-yl)ethyl]carbamate (1.49 g, 6.516 mmol, 1.20 equiv) In NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 6 hours at 90° C. under nitrogen atmosphere. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN In water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in tert-butyl NV-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)carbamate (2 g, 75.85%) as a green oil. LCMS (ESI) m/z: [M+H]+=486. 
     Step 2: Preparation of 5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i30-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl) carbamate (2.00 g, 4.119 mmol, 1.00 equiv) and TFA (2.00 mL, 26.926 mmol, 6.54 equiv) in DCM (5.00 mL, 78.650 mmol, 19.09 equiv) was stirred for 1 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1.5 g, 94.48%) as a green solid. LCMS (ESI) m/z: [M+H]+=388. 
     Step 3: Preparation of tert-butyl 3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxisoindol-5-yl]piperazin-1-yl]ethyl)sulfamoyl]azetidine-1-carboxylate (i30-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (400.00 mg, 1.038 mmol, 1.00 equiv) and tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (318.46 mg, 1.245 mmol, 1.20 equiv) in DCM (10.00 mL) was added TEA (210.03 mg, 2.076 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/EtOAc (1:1) to afford tert-butyl 3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)sulfamoyl]azetidine-1-carboxylate (500 mg, 79.68%) as a green solid. LCMS (ESI) m/z: [M+H] + =605. 
     Step 4: Preparation of N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (i30-5) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl) sulfamoyl]azetidine-1-carboxylate (500.00 mg, 0.827 mmol, 1.00 equiv) and TFA (3.00 mL) in DCM (5.00 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. This resulted in N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (400 mg, 95.87%) as a green solid. LCMS (ESI) m/z: [M+H]+=505. 
     Step 5: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl-N-(2-[4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide formic acid (Compound D24 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A solution of N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (60.00 mg, 0.119 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (46.28 mg, 0.143 mmol, 1.20 equiv) in DMF (1.50 mL) was stirred for 20 minutes at room temperature. Then NaBH 3 CN (14.95 mg, 0.238 mmol, 2.00 equiv) was added to the reaction mixture. The resulting mixture was stirred for 1 hour at room temperature. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (9.4 mg, 9.72%) as a green solid.  1 H NMR (400 MHz, DMSO-d6) δ 12.79 (brs, 0.8H, FA(COOH)), 11.08 (s, 1H), 9.44 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.14 (s, 0.8H, FA), 7.86 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=5.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.24 (dd, J=8.8, 2.3 Hz, 1H), 7.11 (s, 1H), 6.73 (s, 2H), 5.07 (dd, J=13.0, 5.4 Hz, 1H), 4.08-4.02 (m, 1H), 3.82 (s, 7H), 3.69-3.62 (m, 2H), 3.60 (s, 3H), 3.50-3.39 (m, 8H), 3.12-3.05 (m, 2H), 2.95-2.83 (m, 1H), 2.63-2.55 (m, 3H), 2.55 (s, 2H), 2.47-2.39 (m, 3H), 2.07-1.98 (m, 1H). LCMS (ESI) m/z: [M+H] + =813.30. 
     Example 31—Preparation of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethyl)(methyl)amino]ethyl]azetidine-2-carboxamide (Compound D25) 
     
       
         
         
             
             
         
       
     
     To a solution of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylic acid (80 mg, 0.195 mmol, 1.00 equiv) and DIEA (75.8 mg, 0.586 mmol, 3.00 equiv) in DMF (1.50 mL) was added HATU (111.4 mg, 0.293 mmol, 1.50 equiv), and the resulting solution was stirred at room temperature for 1 hour. The crude mixture was directly purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 7% B to 22% B in 8 minutes; 254 nm; R t : 7.75 minutes) to afford (2S)-1-[-[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethyl)(methyl)amino]ethyl]azetidine-2-carboxamide (5.5 mg, 3.5%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.45 (d, J=1.1 Hz, 1H), 8.67 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=5.9 Hz, 1H), 7.54-7.42 (m, 1H), 6.99 (d, J=7.1 Hz, 1H), 6.91 (dd, J=8.5, 3.1 Hz, 1H), 6.71 (d, J=0.9 Hz, 2H), 5.13-5.02 (m, 1H), 3.86 (s, 8H), 3.66 (d, J=1.0 Hz, 5H), 3.28 (s, 5H), 2.76-2.66 (m, 6H), 2.53-2.42 (m, 2H), 2.34 (s, 3H), 2.30-2.19 (m, 1H), 2.15-1.94 (m, 2H). LCMS (ESI) m/z: [M+H]+=765.30. 
     Example 32—Preparation of N-[2-[(2-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]formamido]ethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide (Compound D26) 
     
       
         
         
             
             
         
       
     
     To a solution of (2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylic acid (30 mg, 0.073 mmol, 1.00 equiv) and DIEA (28.4 mg, 0.220 mmol, 3.00 equiv) in DMF (1.00 mL) was added HATU (41.8 mg, 0.110 mmol, 1.50 equiv) and N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide (31.61 mg, 0.073 mmol, 1.00 equiv). The resulting solution was stirred at room temperature for 1 hour. The crude mixture was directly purified by Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 5% B in 2 minutes; 254 nm; R t : 9.88 minutes) to afford N-[2-[(2-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]formamido]ethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide (4.8 mg, 7.5%) as a yellow solid.  1 H NMR (300 MHz, Acetontrile-d3) δ 9.52 (s, 1H), 9.11 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.20-8.02 (m, 1H), 7.79 (t, J=6.5 Hz, 2H), 7.57 (d, J=5.0 Hz, 2H), 7.45-7.23 (m, 2H), 6.73 (s, 2H), 4.99 (dd, J=12.1, 5.3 Hz, 1H), 4.63 (s, 2H), 4.38 (s, 1H), 4.11 (s, 2H), 3.87 (s, 6H), 3.72-3.60 (m, 5H), 3.59-3.49 (m, 2H), 3.45 (d, J=5.6 Hz, 2H), 3.01 (dt, J=11.1, 5.7 Hz, 4H), 2.83-2.72 (m, 2H), 2.72-2.60 (m, 5H), 2.13 (ddd, J=10.6, 5.5, 3.1 Hz, 2H). LCMS (ESI) m/z: [M+H]+=823.45. 
     Example 33—Preparation of 4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D27) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl (2S)-2-((2,2,2-trifluoroacetamido)methyl)azetidine-1-carboxylate (i33-2) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (2S)-2-(aminomethyl)azetidine-1-carboxylate (900.00 mg, 4.832 mmol, 1.00 equiv) and trifluoroacetic anhydride (1522.33 mg, 7.248 mmol, 1.5 equiv) in THF (9.00 mL) was added TEA (977.92 mg, 9.664 mmol, 2 equiv). The mixture was stirred at 25° C. for 12 hours. The resulting solution was diluted with EA. Then washed with water (3×50 mL). The residue was applied onto a silica gel column with ethyl EA/PE (15/85). The resulting mixture were evaporated to dryness to afford tert-butyl (2S)-2-[(2,2,2-trifluoroacetamido) methyl]azetidine-1-carboxylate (1270 mg, 93.11%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=283. 
     Step 2: Preparation of tert-butyl (2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate (i33-3) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (2S)-2-[(2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (1270.00 mg, 4.499 mmol, 1.00 equiv) and dimethyl sulfate (681.00 mg, 5.399 mmol, 1.2 equiv) in acetone (15.00 ml) was added K 2 CO 3  (621.83 mg, 4.499 mmol, 1 equiv). The mixture was stirred at 25° C. for 12 hours. The resulting mixture were evaporated to dryness to afford tert-butyl (2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate (1640 mg, 123.02%) as a yellow oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=297. 
     Step 3: Preparation of N-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (i33-4) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl (2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate (1.64 g, 5.535 mmol, 1.00 equiv) and TFA (3.50 mL, 47.121 mmol, 8.51 equiv) in DCM (16.00 mL) was stirred for 1 hour at 25° C. The mixture was concentrated to give N-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (2.08 g) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=197. 
     Step 4: Preparation of N-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide (i33-5) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (552.00 mg, 1.702 mmol, 1.00 equiv) and N-[(2S)-azetidin-2-yl]methyl-2,2,2-trifluoro-N-methylacetamide (500.81 mg, 2.553 mmol, 1.50 equiv) in DMF (6.00 mL) was added NaBH(OAc) 3  (721.42 mg, 3.404 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product that was purified by chromatography on silica gel eluted with MeOH/DCM (5:95) to give N-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide (275 mg, 32.03%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=505. 
     Step 5: Preparation of(S)-4-(3,5-dimethoxy-4-((2-((methylamino)methyl)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i33-6) 
     
       
         
         
             
             
         
       
     
     A solution of N-[[(2R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide (230 mg, 0.458 mmol, 1.00 equiv) and NH 3 .H 2 O (1 mL, 0.008 mmol, 0.05 equiv) in DMF (2.50 mL) was stirred at 25° C. for 1 hour. The resulting mixture were evaporated to dryness to afford 4-(3,5-dimethoxy-4-[[(2R)-2-[(methylamino) methyl]azetidin-1-yl]methyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (219 mg) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=409. 
     Step 6: Preparation of 4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D27) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(3,5-dimethoxy-4-[[(2R)-2-[(methylamino)methyl]azetidin-1-yl]methyl]phenyl)-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (150.00 mg, 0.367 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carbaldehyde (105.11 mg, 0.367 mmol, 1.00 equiv) in MeOH (2.00 mL) was added NaBH 3 CN (115.38 mg, 1.836 mmol, 5 equiv). The mixture was stirred at 25° C. for 1 hour. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 3% B to 3% B in 2 minutes; 254 nm; R t : 14.55 minutes) to give 4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8.0 mg, 3.01%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.67 (d, J=5.7 Hz, 1H), 8.57 (s, 0.4H, FA), 7.91-7.86 (m, 1H), 7.84 (d, J=6.0 Hz, 2H), 7.74 (d, J=6.5 Hz, 1H), 7.57 (t, J=6.3 Hz, 1H), 6.84 (d, J=5.4 Hz, 2H), 5.20-5.08 (m, 1H), 4.72-4.31 (m, 3H), 4.15-3.98 (m, 3H), 3.92 (d, J=11.5 Hz, 6H), 3.71 (d, J=1.8 Hz, 3H), 2.99-2.80 (m, 3H), 2.80-2.49 (m, 4H), 2.38-1.98 (m, 5H). LCMS (ESI) m/z: [M+H]+=679.30. 
     Example 34—Preparation of 4-(((1-(2,6-dimethoxy-4(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D28) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl (1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)carbamate (134-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl) benzaldehyde (250.00 mg, 0.772 mmol, 1.00 equiv) and tert-butyl azetidin-3-yl(methyl) carbamate hydrochloride (171.38 mg, 0.772 mmol, 1.00 equiv), was added Et 3 N (77.97 mg, 0.772 mmol, 1.00 equiv) and NaBH 3 CN (97.27 mg, 1.544 mmol, 2.00 equiv). The resulting mixture was stirred overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA in PE from 0% to 40% to afford tert-butyl (1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl) carbamate (170 mg, 0.344 mmol, 44.62%) as a white solid. LCMS (ESI) m/z: [M+H] + =495. 
     Step 2: Preparation of 4-(3,5-dimethoxy-4-((3-(methylamino)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i34-3) 
     
       
         
         
             
             
         
       
     
     Tert-butyl(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) azetidin-3-yl) (methyl) carbamate (170 mg, 0.344 mmol, 1.00 equiv) was dissolved in 4 N HCl in 1,4-dioxane (5 mL, 20 mmol, 58.13 equiv). The resulting solution was stirred for one hour at room temperature. The resulting mixture was concentrated to afford 4-(3,5-dimethoxy-4-((3-(methylamino)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (180 mg, crude) as a white solid, that was used directly without further purification. LCMS (ESI) m/z: [M+H] + =395. 
     Step 3: Preparation of 4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D28) 
     
       
         
         
             
             
         
       
     
     To a mixture of 4-(3,5-dimethoxy-4-[[3-(methylamino)azetidin-1-yl]methyl]phenyl)-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (30.00 mg, 0.076 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carbaldehyde (21.77 mg, 0.076 mmol, 1.00 equiv) in MeOH (2.00 mL) was added AcOH (0.05 mg, 0.001 mmol, 0.01 equiv). The mixture was stirred for 1 hour. NaBH 3 CN (9.56 mg, 0.152 mmol, 2.00 equiv) was added. The resulting mixture was stirred for 1 hour. The crude product was purified by preparative HPLC (condition: SunFire C16 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 5% B in 2 minutes; 254 nm; R t : 12.63 minutes. This afforded 4-[[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl))(methyl)amino]methyl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i8.90 mg, 0.028 mmol, 36.53%) as a light yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.60 (s, 1H), 8.70 (d, J=6.3 Hz, 1H), 8.00 (s, 1H), 7.96-7.82 (m, 4H), 6.88 (s, 2H), 5.17 (dd, J=12.4, 5.4 Hz, 1H), 4.58 (s, 2H), 4.33 (t, J=7.2 Hz, 4H), 4.10 (d, J=13.2 Hz, 1H), 4.02 (d, J=13.2 Hz, 1H), 3.97 (s, 6H), 3.75 (s, 4H), 2.95-2.83 (m, 1H), 2.81-2.67 (m, 2H), 2.29 (s, 3H), 2.21-2.11 (m, 1H). LCMS (ESI) m/z: [M+H] + =685.30. 
     Example 35—Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide (Compound D29) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methyl)isoindoline-1,3-dione (i35-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-carbaldehyde (70.00 mg, 0.245 mmol, 1.00 equiv) in DMF (3.00 mL) was added methanamine hydrochloride (24.77 mg, 0.367 mmol, 1.50 equiv). The resulting mixture was stirred overnight at room temperature. Then NaBH(OAc) 3  (103.88 mg, 0.490 mmol, 2.00 equiv) was added. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was purified by reverse phase column with ACN in water from (0% to 50%) to afford 2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methylisoindoline-1,3-dione (30 mg, 41.10%) as a white solid. LCMS (ESI) m/z: [M+H] + =302. 
     Step 2: Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide (Compound D29) 
     
       
         
         
             
             
         
       
     
     To a mixture of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzylazetidine-3-carboxylic acid (40.77 mg, 0.100 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU (94.65 mg, 0.250 mmol, 2.50 equiv) and DIEA (38.61 mg, 0.300 mmol, 3.00 equiv). The resulting mixture was stirred for 2 hours at room temperature. Then 2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methyl)isoindoline-1,3-dione (30.00 mg, 0.100 mmol, 1.00 equiv) was added. The resulting mixture was stirred for 1 hour. The crude product was purified by preparative HPLC (conditions: XSelect CSH Prep Cia OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12% B to 12% B in 2 minutes; 254/220 nm; R t : 13.57 min Fractions containing the desired compound were evaporated to dryness to afford 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide (17.10 mg, 24.25%) as a light yellow solid.  1 H-NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.69 (t, J=7.8 Hz, 1H), 7.98-7.87 (m, 2H), 7.85-7.77 (m, 2H), 7.72-7.64 (m, 1H), 6.89 (d, J=8.2 Hz, 2H), 5.22-5.01 (m, 3H), 4.65-4.36 (m, 5H), 4.34-4.21 (m, 1H), 4.20-4.07 (m, 1H), 4.01-3.92 (m, 6H), 3.74 (s, 3H), 3.02 (s, 3H), 2.96-2.84 (m, 1H), 2.80-2.71 (m, 2H), 2.24-2.12 (m, 1H). LCMS (ESI) m/z: [M+H] + =693.35. 
     Example 36—Preparation of 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(2(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-yl)amino)ethyl)sulfonyl)ethyl)azetidine-3-carboxamide (Compound D30) 
     
       
         
         
             
             
         
       
     
     Into a stirred mixture of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylic acid (53.00 mg, 0.129 mmol, 1.00 equiv) and DIEA (N,N-diisopropylamine) (50.19 mg, 0.388 mmol, 3.00 equiv) in DMF (dimethylformamide) (1.00 mL) was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (73.83 mg, 0.194 mmol, 1.50 equiv) at 0° C. After 10 minutes, to the above mixture was added 4-[[2-(2-aminoethanesulfonyl) ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (63.44 mg, 0.155 mmol, 1.20 equiv). Then the reaction was stirred at room temperature for 2 hours under N 2  atmosphere. The crude product was purified by Prep-HPLC (conditions: Sunfire C18 OBD Prep Column, 5 μm, 19 mm*250 mm; Mobile Phase A: Water (0.05% TFA, trifluoroacetic acid), Mobile Phase B: acetonitrile (MeCN or ACN); Flow rate: 25 mL/minute; Gradient: 3% B to 3% B in 2 minutes; 254 nm; R t : 13.98 minutes). This resulted in 1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)sulfonyl)ethyl)azetidine-3-carboxamide 18.4 mg (16.47%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.52 (d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (br s, 0.5H, FA), 7.77 (s, 1H), 7.67-7.55 (m, 2H), 7.13 (t, J=7.6 Hz, 2H), 6.83 (s, 2H), 5.06 (dd, J=12.3, 5.4 Hz, 1H), 4.37 (s, 2H), 4.23-4.06 (m, 4H), 3.95 (s, 6H), 3.89 (t, J=6.3 Hz, 2H), 3.77-3.69 (m, 2H), 3.71 (s, 3H), 3.52 (q, J=6.9, 6.3 Hz, 3H), 3.38 (t, J=6.3 Hz, 2H), 2.62-2.93 (m, 3H), 2.07-2.17 (m, 1H). LCMS (ESI) m/z: [M+H] + =800.35. 
     Example 37—Preparation of 5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D31 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 3-((2-(2,6-dioxopiperdin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate (137-2) 
     
       
         
         
             
             
         
       
     
     To a mixture of tert-butyl 3-bromoazetidine-1-carboxylate (2.00 g, 8.511 mmol, 1.00 equiv) and 2-(2,8-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (2.33 g, 8.511 mmol, 1.00 equiv) in DMF (30.00 mL) was added Cs 2 CO 3  (5.53 g, 17.022 mmol, 2.00 equiv). The resulting mixture was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA in PE from 0% to 50% to afford tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate (400 mg, 10.96%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=430. 
     Step 2: Preparation of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i37-3) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate (400.00 mg, 0.932 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added HCl (4 N in 1,4-dioxane) (5 mL, 20.000 mmol, 21.46 equiv). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum to afford 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (440.00 mg, crude) as a white solid. LCMS (ESI) m/z: [M+H] + =330. 
     Step 3: Preparation of tert-butyl (3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) zetkdin-1-yl)propyl)carbamate (i37-4) 
     
       
         
         
             
             
         
       
     
     A mixture of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-ylisoindoline-1,3-dione (200.00 mg, 0.608 mmol, 1.00 equiv) and tert-butyl (3-oxopropyl)carbamate (105.18 mg, 0.608 mmol, 1.00 equiv) in MeOH (5.00 mL) was stirred for 1.5 hours at room temperature. Then NaBH 3 CN (75.39 mg, 1.216 mmol, 2.00 equiv) was added. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA in PE from 0% to 50% to afford tert-butyl (3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)zetidin-1-yl)propyl)carbamate (100.00 mg, 33.89%) as a white solid. LCMS (ESI) m/z: [M+H] + =487. 
     Step 4: Preparation of 5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (i37-5) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) azetidin-1-yl)propyl)carbamate (100.00 mg, 0.206 mmol, 1.00 equiv) in DCM (4.00 mL) was added TFA (4.00 mL, 53.860 mmol, 261.46 equiv). The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum to afford 5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (120 mg, crude). LCMS (ESI) m/z: [M+H]+=387. 
     Step 5: Preparation of 5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D31 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60.00 mg, 0.155 mmol, 1.00 equiv) in MeOH (5.00 mL, 123.495 mmol, 795.32 equiv) was added 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (50.38 mg, 0.155 mmol, 1 equiv). The resulting mixture was stirred for 1 hour. Then NaBH 3 CN (19.52 mg, 0.311 mmol, 2 equiv) was added. The resulting mixture was stirred for 1 hour. The resulting mixture was filtered, and the filtrate was purified by prep-HPLC (conditions: SunFire C 18  OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 5% B in 2 minutes; 254 nm; R t : 9.75 minutes) to afford 5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; formate (14.4 mg, 12.52%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.67 (d, J=5.7 Hz, 1H), 8.26 (br s, 0.65H, FA), 7.82-7.75 (m, 2H), 7.60 (dd, J=5.8, 0.9 Hz, 1H), 7.21 (dq, J=4.6, 2.3 Hz, 2H), 6.88 (s, 2H), 5.13-5.00 (m, 2H), 4.38 (s, 2H), 3.99 (s, 6H), 3.93-3.89 (m, 2H), 3.71 (s, 3H), 3.44 (d, J=8.2 Hz, 2H), 3.22 (t, J=6.7 Hz, 2H), 2.95-2.82 (m, 3H), 2.82-2.62 (m, 2H), 2.21-2.05 (m, 1H), 1.89-1.81 (m, 2H). LCMS (ESI) m/z: [M+H] + =695.40. 
     Example 38—Preparation of 4-(4(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D32) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 8-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyldin-4-yl)benzyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (i38-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (700.00 mg, 2.158 mmol, 1.00 equiv) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00 equiv) in DMF (10.00 mL, 129.218 mmol, 59.87 equiv) was added NaBH(OAc) 3  (914.85 mg, 4.317 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product that was purified by chromatography on silica gel eluted with MeOH/DCM (6:94) to give tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3] heptane-2-carboxylate (808 mg, 73.90%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=507. 
     Step 2: Preparation of 4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i38-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (708.00 mg, 1.398 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 14.45 equiv) in DCM (7.00 mL, 110.110 mmol, 78.79 equiv) was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (696 mg) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=407. 
     Step 3: Preparation of 4-(4-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D32) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (40.00 mg, 0.098 mmol, 1.00 equiv) and 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid (35.46 mg, 0.098 mmol, 1.00 equiv) in DMF (1.0 mL) was added HATU (56.12 mg, 0.148 mmol, 1.5 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions: Kinetex EVO C18 Column 21.2*150, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 16% B to 26% B in 8 minutes; 254/220 nm; R t : 7.03 minutes) to afford 4-[4-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i2 mg, 16.29%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.70 (d, J=5.8 Hz, 1H), 7.79 (dd, J=8.5, 7.4 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.46 (dd, J=14.7, 7.9 Hz, 2H), 6.86 (s, 2H), 5.13 (dd, J=12.5, 5.4 Hz, 1H), 4.60 (s, 1H), 4.40 (d, J=13.7 Hz, 4H), 4.32-4.19 (m, 6H), 4.14 (s, 2H), 3.96 (s, 6H), 3.71 (s, 3H), 2.95-2.68 (m, 3H), 2.53-2.34 (m, 2H), 2.20-2.10 (m, 3H). LCMS (ESI) m/z: [M+H]+=749.40. 
     Example 39—Preparation of 4-(4-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D33) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (50.00 mg, 0.127 mmol, 1.00 equiv) and 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid (45.67 mg, 0.127 mmol, 1.00 equiv) in DMF (2.00 mL) was added DIEA (163.82 mg, 1.268 mmol, 10.00 equiv) and HATU (96.39 mg, 0.254 mmol, 2.00 equiv) at 0° C. The above mixture was stirred for 3 hours at room temperature. Then the crude product was purified by preparative HPLC (conditions: XBridge Shield RP18 OBD Column, 5 μm, 19*250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12% B to 26% B in 8 minutes; 254 nm; R t : 7.91 minutes). This resulted in 4-(4-(4-(2,8-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.60 mg, 5.54%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.85-7.73 (m, 2H), 7.63 (d, J=5.7 Hz, 1H), 7.52-7.43 (m, 2H), 6.79 (s, 2H), 5.11 (dd, J=12.2, 5.4 Hz, 1H), 4.30 (t, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.90 (s, 6H), 3.81-3.65 (m, 7H), 2.98-2.81 (m, 6H), 2.79-2.67 (m, 3H), 2.24-2.07 (m, 3H), vLCMS (ESI) m/z: [M+H] + =737.40. 
     Example 40—Preparation of 4-((5-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D34) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (i40-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (700.00 mg, 2.158 mmol, 1.00 equiv) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00 equiv) in DMF (10.00 ml, 129.218 mmol, 59.87 equiv) was added NaBH(OAc) 3  (914.85 mg, 4.317 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product that was purified by chromatography on silica gel eluted with MeOH]/DCM (6:94) to give tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (808 mg, 73.90%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=507. 
     Step 2: Preparation of 4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i40-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (708.00 mg, 1.398 mmol, 1.00 equiv) and TFA (1.50 ml, 20.195 mmol, 14.45 equiv) in DCM (7 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (696 mg) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=407. 
     Step 3: Preparation of 4-((5-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D34) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (40.00 mg, 0.098 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (36.84 mg, 0.098 mmol, 1 equiv) in DMF (1 ml) was added HATU (56.12 mg, 0.148 mmol, 1.5 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 12% B to 22% B In 12 minutes; 254/220 nm; R t : 10.52 minutes) to afford 4-[[5-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i0.1 mg, 13.46%) as a light yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.73-8.67 (m, 1H), 7.92 (d, J=6.9 Hz, 1H), 7.84-7.76 (m, 1H), 7.47 (t, J=8.1 Hz, 2H), 6.89 (d, J=3.5 Hz, 2H), 5.17-5.07 (m, 1H), 4.51 (d, J=3.0 Hz, 2H), 4.45-4.31 (m, 6H), 4.27 (t, J=5.5 Hz, 2H), 4.19 (s, 1H), 4.12 (s, 1H), 3.98 (d, J=3.4 Hz, 6H), 3.74 (d, J=1.7 Hz, 3H), 2.96-2.65 (m, 3H), 2.34-2.30 (m, 2H), 2.19-2.12 (m, 1H), 1.96-1.89 (m, 2H), 1.88-1.80 (m, 2H). LCMS (ESI) m/z: [M+H]+=763.40. 
     Example 41—Preparation of 4-((5-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D35 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (50.0 mg, 0.127 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (47.5 mg, 0.127 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA (163.8 mg, 1.268 mmol, 10.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 10 min at room temperature. To the above mixture was added HATU (96.4 mg, 0.254 mmol, 2.00 equiv). The resulting mixture was stirred for additional 2 hours at room temperature. The residue was purified by reverse flash chromatography (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 9 B to 27 B in 10 minutes; 254 nm; R T : 10.12) to afford 4-[[5-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (6.6 mg, 6.7%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.45 (br s, 0.13H. FA), 7.81-7.73 (m, 2H), 7.64 (dd, J=5.8, 0.9 Hz, 1H), 7.45 (dd, J=7.9, 6.2 Hz, 2H), 6.79 (s, 2H), 5.11 (dd, J=12.5, 5.5 Hz, 1H), 4.28 (t, J=5.7 Hz, 2H), 3.97 (s, 2H), 3.90 (s, 6H), 3.74-3.62 (m, 7H), 2.95-2.81 (m, 3H), 2.80-2.65 (m, 4H), 2.60 (t, J=7.4 Hz, 2H), 2.17-2.07 (m, 1H), 1.99-1.83 (m, 4H). LCMS (ESI) m/z: [M+H]+=751.40 
     Example 42—Preparation of 4-(2-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D36 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (i42-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (700.00 mg, 2.158 mmol, 1.00 equiv) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00 equiv) in DMF (10 mL) was added NaBH(OAc) 3  (914.85 mg, 4.317 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product that was purified by chromatography on silica gel eluted with MeOH]/DCM (6:94) to give tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (808 mg, 73.90%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=507. 
     Step 2: Preparation of 4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i42-3) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (708.00 mg, 1.398 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 14.45 equiv) in DCM (7 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (696 mg) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=407. 
     Step 3: Preparation of 4-(2-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione formic acid (Compound D35 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (40.00 mg, 0.098 mmol, 1.00 equiv) and [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid (32.70 mg, 0.098 mmol, 1.00 equiv) In DMF (1 mL) was added HATU (58.12 mg, 0.148 mmol, 1.50 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions: SunFire Prep C18 OBD Column 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 8% B to 21% B in 10 minutes; 254/220 nm; R t : 8.20 minutes) to afford 4-[2-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (6.2 mg, 8.74%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.55 (br s, 0.46H, FA), 7.80 (s, 1H), 7.69 (t, J=8.1 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.44 (dd, J=11.8, 7.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.87 (s, 2H), 5.19-5.10 (m, 1H), 4.69-4.51 (m, 6H), 4.39 (s, 2H), 4.34-4.26 (m, 2H), 4.22 (s, 2H), 3.97 (s, 6H), 3.69 (s, 3H), 2.95-2.68 (m, 3H), 2.20-2.09 (m, 1H). LCMS (ESI) m/z: [M+H]+=721.35. 
     Example 43—Preparation of 4-(2-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D37 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl)-2,7-naphthyridin-1-one (50.0 mg, 0.127 mmol, 1.00 equiv) and [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid (42.1 mg, 0.127 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA (163.8 mg, 1.268 mmol, 10.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 10 minutes at room temperature. To the above mixture was added HATU (96.4 mg, 0.254 mmol, 2.00 equiv). The resulting mixture was stirred for additional 2 hours at room temperature. The residue was purified by reverse flash chromatography (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 9 B to 27 B in 10 minutes; 254 nm; R T : 10.12 minutes) to afford 4-[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (12.2 mg, 13.6%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.34 (br s, 0.28H, FA), 7.83-7.73 (m, 2H), 7.67-7.61 (m, 1H), 7.52 (d, J=7.1 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 6.81 (s, 2H), 5.15-5.09 (m, 3H), 4.08 (s, 2H), 3.92 (s, 6H), 3.83-3.73 (m, 4H), 3.72 (s, 3H), 3.05-2.96 (m, 2H), 2.96-2.80 (m, 3H), 2.77-2.69 (m, 2H), 2.17-2.11 (m, 1H). LCMS (ESI) m/z: [M+H]+=709.35. 
     Example 44—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamide formic acid (Compound D38 Formic Acid) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]carbamate (i44-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,8-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-indole-1,3-dione (1.0 g, 3.620 mmol, 1.00 equiv) in NMP (15.00 mL) was added DIEA (940.47 mg, 7.277 mmol, 2.01 equiv) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (988.89 mg, 3.982 mmol, 1.10 equiv) in portions at room temperature. The resulting solution was stirred for 12 hours at 90° C. The resulting mixture was washed with water (3×100 mL). The resulting solution was extracted with ethyl acetate (3×200 mL). The organic layers combined and concentrated. This resulted in tert-butyl N-[2-[2-(2-[[2-(2,8-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]carbaminate (1.2 g, 65.70%) as light yellow oil. LCMS (ESI) m/z: [M+H]+=505. 
     Step 2: Preparation of 4-[(2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (i44-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4yl]amino]ethoxy)ethoxy]ethyl]carbamate (1.2 g, 2.378 mmol, 1.00 equiv) in DCM (40 mL) was added TFA (10 mL) in portions at room temperature. The resulting solution was stirred for 4 hours at room temperature. The resulting mixture was concentrated. This resulted in 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (0.8 g, 83.17%) as light yellow oil. LCMS (ESI) m/z: [M+H]+=405. 
     Step 3: Preparation of tert-butyl 3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]sulfamoyl)azetidine-1-carboxylate (i44-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (238.00 mg, 0.588 mmol, 1.00 equiv) in DCM was added TEA (120.00 mg, 1.186 mmol, 2.02 equiv) in portions at room temperature. To the above mixture was added tert-butyl 3-(chlorosulfonyl) azetidine-1-carboxylate (150.00 mg, 0.587 mmol, 1.00 equiv) in portions. The resulting mixture was stirred for additional 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /EtOAc (1:1) to afford tert-butyl 3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy] ethyl]sulfamoyl)azetidine-1-carboxylate (130 mg, 35.42%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=624. 
     Step 4: Preparation of N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethox-y)ethyl)azetidine-3-sulfonamide (i44-5) 
     
       
         
         
             
             
         
       
     
     To a stirred solution/mixture of tert-butyl 3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]sulfamoyl)azetidine-1-carboxylate (120.00 mg, 0.192 mmol, 1.00 equiv) in DCM (4 mL) was added TFA (1 mL) in portions at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product 130 mg was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=524. 
     Step 5: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamide formic acid (Compound D38 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy) ethoxy]ethyl]azetidine-3-sulfonamide (60.00 mg, 0.115 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (74.34 mg, 0.229 mmol, 2.00 equiv) in MeOH was added NaBH(OAc) 3  (97.15 mg, 0.458 mmol, 4.00 equiv) in portions at room temperature. The resulting mixture was stirred for 12 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: SunFire Prep C18 OBD Column, 19*150 mm 5 μm 10 nm; mobile phase, Water (0.1% FA) and ACN (10% Phase B up to 27% In 8 minutes); Detector, UV). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamide formic acid (8.1 mg, 8.05%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.49 (d, J=0.9 Hz, 1H), 8.66 (d, J=5.8 Hz, 1H), 8.45 (br s, 1H, FA), 7.74 (s, 1H), 7.62 (dd, J=5.8, 0.9 Hz, 1H), 7.50 (dd, J=8.5, 7.1 Hz, 1H), 7.02 (dd, J=7.8, 5.3 Hz, 2H), 6.79 (s, 2H), 5.07 (dd, J=12.4, 5.4 Hz, 1H), 4.61 (s, 1H), 4.36-4.23 (m, 1H), 4.20 (s, 2H), 4.13-3.99 (m, 4H), 3.92 (s, 6H), 3.73-3.64 (m, 9H), 3.55 (t, J=5.1 Hz, 2H), 3.50-3.41 (m, 2H), 3.28 (t, J=5.1 Hz, 2H), 2.96-2.61 (m, 3H), 2.18-2.04 (m, 1H). LCMS (ESI) m/z: [M+H]+=832.45. 
     Example 45—Preparation of 4-[4-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5.1]undecan-4-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione. (Compound D39) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (20.00 mg, 0.043 mmol, 1.00 equiv) and 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid (i5.00 mg, 0.042 mmol, 0.97 equiv) In DMF was added HATU (25.00 mg, 0.066 mmol, 1.53 equiv) and DIEA (60.00 mg, 0.464 mmol, 10.78 equiv) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: Gemini-NX C18 AXAI Packed, 21.2*150 mm 5 μm; mobile phase, Water (0.1% FA) and ACN (14% Phase B up to 19% in 10 minutes); Detector, UV). This resulted in 4-14-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl)-1-oxa-4,9-diaza spiro[5.5]undecan-4-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5.1 mg, 14.68%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.70 (d, J=5.6 Hz, 1H), 7.85-7.75 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.57-7.43 (m, 2H), 6.87 (d, J=5.2 Hz, 2H), 5.12 (d, J=11.8 Hz, 1H), 4.41 (s, 2H), 4.37-4.27 (m, 2H), 3.96 (d, J=8.2 Hz, 6H), 3.84-3.60 (m, 9H), 3.58-3.45 (m, 3H), 2.92-2.69 (m, 5H), 2.26-2.04 (m, 6H), 1.85-1.60 (m, 2H). LCMS (ESI) m/z: [M+H]+=807.40. 
     Example 46—Preparation of 4-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D40 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (30.00 mg, 0.065 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (24.17 mg, 0.065 mmol, 1 equiv) In DMF (1.00 mL) was added DIEA (83.48 mg, 0.648 mmol, 10.00 equiv) and HATU (36.83 mg, 0.097 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 1 hour. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 9% B to 25% B in 10 minutes; 254 nm; R t : 10.95 minutes) to give (4-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (8.6 mg, 15.25%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.53 (br s, 1H, FA), 7.85-7.74 (m, 2H), 7.62 (dd, J=5.9, 0.9 Hz, 1H), 7.46 (dd, J=7.8, 2.3 Hz, 2H), 6.86 (d, J=5.7 Hz, 2H), 5.12 (dd, J=12.3, 5.4 Hz, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 3H), 3.96 (s, 6H), 3.83-3.74 (m, 2H), 3.72 (s, 3H), 3.67-3.61 (m, 2H), 3.55-3.50 (m, 3H), 3.00-2.51 (m, 6H), 2.20-1.71 (m, 10H). LCMS (ESI) m/z: [M+H]+=821.45. 
     Example 47—Preparation of 4-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D41 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (30.00 mg, 0.065 mmol, 1.00 equiv) and [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid (21.48 mg, 0.065 mmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA (83.46 mg, 0.646 mmol, 10.00 equiv) and HATU (36.83 mg, 0.097 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 1 hour. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: Phenomenex Gemini C6-Phenyl, 21.2*250 mm, 5 μm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 7 B to 26 B in 15 minutes; 254 nm; R T : 14.62 minutes) to give 4-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (3.7 mg, 6.80%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (d, J=0.8 Hz, 1H), 8.70 (d, J=5.8 Hz, 1H), 8.56 (br s, 1H, FA), 7.86-7.75 (m, 2H), 7.63 (dd, J=5.8, 0.9 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 6.86 (s, 2H), 5.17-5.07 (m, 3H), 4.30 (s, 2H), 3.95 (s, 6H), 3.87-3.75 (m, 2H), 3.72 (s, 3H), 3.68-3.62 (m, 2H), 3.54 (s, 2H), 3.23-3.17 (m, 4H), 2.91-2.65 (m, 3H), 2.22-2.02 (m, 3H), 1.80 (s, 2H). LCMS (ESI) m/z: [M+H]+=779.40. 
     Example 48—Preparation of 5-(4-(2-(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D42 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (i42-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,8-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.38 g, 4.996 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (930.52 mg, 4.996 mmol, 1.00 equiv) in NMP (20 mL) was added DIPEA (1937.08 mg, 14.988 mmol, 3 equiv). The mixture was stirred at 90° C. for 2 hours (under nitrogen atmosphere). The reaction was monitored by LC-MS. The resulting mixture was diluted with water (70 mL) and then extracted with EA (3×25 mL). The combined organic layers were washed with water (2×25 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, 0.5% FA in water, 10% to 90% gradient in 25 minutes; detector, UV 220 nm). The fractions were concentrated under reduced pressure afford tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (700 mg, 31.67%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=443. 
     Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (i42-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate (500.00 mg, 1.130 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 17.87 equiv) in DCM (5.00 mL) was stirred at 25° C. for 1 hour. The resulting mixture were evaporated to dryness to afford 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (350 mg, 90.47%) as a brown solid. LCMS (ESI) m/z: [M+H]+=343 
     Step 3: Preparation of tert-butyl 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (i42-5) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (200.00 mg, 0.584 mmol, 1.00 equiv) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (132.79 mg, 0.584 mmol, 1 equiv) in DMF (3.00 mL) was added NaBH(OAc) 3  (247.63 mg, 1.168 mmol, 2 equiv). The resulting solution was stirred at 25° C. for 1 hour. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to give tert-butyl 4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate (197.5 mg, 61.06%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=554. 
     Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-1-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione (i42-6) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate (197.00 mg, 0.356 mmol, 1.00 equiv) and TFA (0.50 ml, 6.732 mmol, 18.92 equiv) in DCM (2.00 ml) was stirred at 25° C. for 1 hour. The mixture was concentrated to give crude product 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione (320 mg) as a yellow oil, that was used directly without further purification. LCMS (ESI) m/z: [M+H]+=454. 
     Step 5: Preparation of 5-(4-(2-(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D42 Formic Add) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione (100.68 mg, 0.222 mmol, 1.20 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (60.00 mg, 0.185 mmol, 1.00 equiv) in DMF (1.5 mL) was added NaBH(OAc) 3  (78.42 mg, 0.370 mmol, 2 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10 B to 12 B In 10 minutes; 254 nm; R T : 8.7 minutes) to afford 5-[4-[2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (24 mg, 17.03%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.55 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.15 (br s, 0.2H. FA), 7.80-7.71 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J=9.2 Hz, 1H), 6.89 (s, 2H), 5.10 (dd, J=12.3, 5.4 Hz, 1H), 4.41 (s, 2H), 3.98 (s, 6H), 3.72 (s, 3H), 3.67-3.55 (m, 6H), 3.17 (d, J=12.9 Hz, 2H), 3.05-2.92 (m, 4H), 2.90-2.70 (m, 5H), 2.17-2.00 (m, 3H), 1.81-1.51 (m, 5H). LCMS (ESI) m/z: [M+H]+=762.45. 
     Example 49—Preparation of 5-[2-(6-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D43 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (60.00 mg, 0.190 mmol, 1.00 equiv) and 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (77.12 mg, 0.190 mmol, 1 equiv) in DMF (1.00 mL) was added NaBH(OAc) 3  (80.42 mg, 0.379 mmol, 2 equiv). The resulting solution was stirred at room temperature for 1 hour. The crude product (60 mg) was purified by Prep-HPLC (conditions: SunFire Prep C18 OBD Column 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 7% B to 10% B in 12 minutes; 254/220 nm; R t : 9.65 minutes) to afford 5-[2-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (i4.3 mg, 9.82%) as a light yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.14 (br s, 0.2H, FA), 7.76 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.62-7.54 (m, 1H), 7.19 (d, J=2.2 Hz, 1H), 7.13 (dd, J=8.2, 2.2 Hz, 1H), 6.86 (s, 2H), 5.16 (dd, J=12.8, 5.4 Hz, 1H), 4.47 (s, 2H), 4.34 (s, 4H), 3.98 (s, 6H), 3.95-3.87 (m, 2H), 3.80 (s, 4H), 3.71 (s, 3H), 3.00-2.85 (m, 4H), 2.81-2.63 (m, 1H), 2.20-2.05 (m, 1H). LCMS (ESI) m/z: [M+H]+=707.5. 
     Example 50—Preparation of 5-((5-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D44 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: 5-(4-(1,3-dioxolan-2-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i50-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (400.0 mg, 1.459 mmol, 1.00 equiv) and 2-(4-bromobutyl)-1,3-dioxolane (305.0 mg, 1.459 mmol, 1.00 equiv) in DMF was added cesium carbonate (475.3 mg, 1.459 mmol, 1.00 equiv) at room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (40 mg, 6.5%) as an off-white oil. LCMS (ESI) m/z: [M+H]+=403. 
     Step 2: Preparation of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal (i50-3) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (40.0 mg, 0.099 mmol, 1.00 equiv) in water (1.50 mL) was added HCl in 1,4-dioxane (4 M, 3.00 mL) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (8 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=359. 
     Step 3: Preparation of N-(6-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamide formic acid (Compound D44 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution/mixture of 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (20 mg, 0.056 mmol, 1.00 equiv) in DMF (1 mL) was added 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (22.0 mg, 0.058 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. To the above mixture was added NaBH(OAc) 3  (23.7 mg, 0.112 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for additional 2 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10 B to 25 B in 8 minutes; 254/220 nm; R T : 6.53 minutes) to afford 5-[[5-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; formic acid (5 mg, 10.9%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.52 (br s, 0.3H, FA), 7.82 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.62 (dd, J=5.8, 0.9 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.33 (dd, J=8.3, 2.3 Hz, 1H), 6.82 (s, 2H), 5.12 (dd, J=12.5, 5.4 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 4.10 (s, 2H), 3.93 (s, 6H), 3.72 (s, 3H), 3.12-2.59 (m, 13H), 2.19-2.10 (m, 1H), 1.97-1.86 (m, 2H), 1.72-1.54 (m, 4H). LCMS (ESI) m/z: [M+H]+=737.40. 
     Example 51—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (Compound D45) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy) ethyl]sulfamoyl]azetidine-1-carboxylate (i51-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (200.00 mg, 0.555 mmol, 1.00 equiv) and TEA (168.48 mg, 1.665 mmol, 3.00 equiv) in DCM (2 mL) was added tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (170.30 mg, 0.666 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (7:1) to afford tert-butyl 3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]sulfamoyl]azetidine-1-carboxylate (150 mg, 46.63%) as a yellow solid. LCMS (ESI) m/z: [M−H]+=580.20. 
     Step 2: Preparation of N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (i51-3) 
     
       
         
         
             
             
         
       
     
     A solution of ter-butyl 3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl] sulfamoyl]azetidine-1-carboxylate (100.00 mg, 0.173 mmol, 1.00 equiv) and TFA (1.00 mL) in DCM was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. This resulted in N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (75 mg, 90.66%) as a red oil. LCMS (ESI) m/z: [M−H]+=480.15. 
     Step 3: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (Compound D45) 
     
       
         
         
             
             
         
       
     
     A solution of N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (30.00 mg, 0.063 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (26.38 mg, 0.081 mmol, 1.30 equiv) in DMF (2.00 mL) was stirred for 20 minutes at room temperature. Then NaBH(OAc) 3  (39.78 mg, 0.188 mmol, 3.00 equiv) was added to the reaction mixture. The resulting mixture was stirred for 1 hour at room temperature. The crude product was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; mobile phase. Water (0.1% FA) and ACN (11% Phase B up to 18% in 20 min, hold 18% in 3 minutes); Detector. UV). This resulted in 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide (7.9 mg, 16.03%) as a green solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.67 (d, J=5.8 Hz, 1H), 8.35 (br s, 0.3H, FA), 7.75 (s, 1H), 7.61 (dd, J=5.7, 0.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd, J=16.6, 7.8 Hz, 2H), 6.81 (s, 2H), 5.07 (d, J=12.3 Hz, 1H), 4.60 (s, 2H), 4.36 (s, 3H), 4.23 (d, J=7.7 Hz, 4H), 3.93 (s, 6H), 3.75 (t, J=5.2 Hz, 2H), 3.71 (s, 3H), 3.59 (t, J=5.2 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H), 2.92-2.66 (m, 3H), 2.12 (ddd, J=12.7, 6.9, 3.9 Hz, 1H). LCMS (ESI) m/z: [M−H]+=788.26. 
     Example 52—Preparation of 5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D46 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione (i52-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-[2-(piperazin-1-yl)ethoxy]ethan-1-ol (315.4 mg, 1.810 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (500.0 mg, 1.810 mmol, 1.00 equiv) in NMP (5 ml) was added DIEA (467.9 mg, 3.620 mmol, 2.00 equiv). The resulting mixture was stirred for 3 hours at 90° C. Without any additional work-up, the mixture was purified by reverse phase column, elution gradient 0% to 50% ACN in water to afford 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione (700.0 mg, 89.8%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =431. 
     Step 2: Preparation of 2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl))ethoxy)acetaldehyde (i52-3) 
     
       
         
         
             
             
         
       
     
     A solution of DMSO (54.5 mg, 0.697 mmol, 1.00 equiv) in DCM (6.00 mL) was added slowly to a stirred solution of oxalyl chloride (176.9 mg, 1.394 mmol, 2.00 equiv) in DCM (6.00 mL) at −78° C. under nitrogen atmosphere. After 30 minutes 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]isoindole-1,3-dione (300.0 mg, 0.697 mmol, 1.00 equiv) in DCM (6.00 mL) was added slowly. The resulting mixture was stirred for 2 hours at −78° C. and 1.5 hours at −55° C. Et 3 N (0.48 mL, 4.787 mmol, 5.00 equiv) was added slowly at −60° C. After stirring for an additional 10 minutes, the reaction was allowed to warm to room temperature. The resulting mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (EtOAc/PE=1:1) to afford 2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetaldehyde (30.0 mg, 5.7%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =429. 
     Step 3: Preparation of 5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D46 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a mixture of 2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]eth oxy)acetaldehyde (30.0 mg, 0.070 mmol, 1.00 equiv) in DMF (2.00 mL) was added 4-[3,5-dim ethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one (23.7 mg, 0.070 mmol, 1.00 equiv). The resulting mixture was stirred for 1 hour at room temperature, STAB (29.6 mg, 0.140 mmol, 2.00 equiv) was added. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture, without any additional wok-up, was purified by prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5% B to 30% B In 10 minutes; 254 nm; R t : 8.82 minutes) to afford 5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; formate (6.2 mg, 15.6%) as a light yellow solid. LCMS (ESI) m/z: [M+H] + =752.15.  1 H NMR (300 MHz, Methanol-d4) δ 9.47 (s, 1H), 8.64 (d, J=5.8 Hz, 1H), 8.57 (br s, 0.7H), 7.75 (s, 1H), 7.62 (dd, J=12.9, 7.1 Hz, 2H), 7.28 (d, J=2.3 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.89 (s, 2H), 5.07 (dd, J=12.3, 5.4 Hz, 1H), 4.53 (s, 2H), 3.99 (s, 6H), 3.91 (t, J=4.7 Hz, 2H), 3.76 (t, J=5.1 Hz, 2H), 3.67 (s, 3H), 3.53-3.40 (m, 6H), 2.91 (s, 4H), 2.81-2.67 (m, 8H), 2.18-2.05 (m, 1H). 
     Example 53—Preparation of 5-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D47 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A solution of 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (25 mg, 0.070 mmol, 1.00 equiv) and 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (32.4 mg, 0.070 mmol, 1.00 equiv) in DMF (0.8 mL) was stirred for 30 minutes at room temperature. NaBH(OAC) 3  (29.57 mg, 0.140 mmol, 2.00 equiv) was then added and the resulting mixture was stirred for 1 hour at room temperature. Without any additional work-up, the mixture was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA). Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 7% B to 20% B in 12 minutes; 254 nm; R t : 11.57 minutes) to afford 5-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (7.9 mg, 13%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.50 (br s, 1H, FA), 7.86-7.75 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.32 (dd, J=8.3, 2.3 Hz, 1H), 6.88 (s, 2H), 5.11 (dd, J=12.3, 5.4 Hz, 1H), 4.42 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.98 (s, 6H), 3.76 (t, J=4.9 Hz, 2H), 3.72 (s, 3H), 3.44-3.35 (3H), 2.93-2.67 (m, 3H), 2.53-2.10 (m, 10H), 1.98-1.51 (m, 8H). LCMS (ESI) m/z: [M+H]+=807.50. 
     Example 54—Preparation of N-(6-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl) acetamide formic acid (Compound D48 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (i54-2) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2.0 g, 9.467 mmol, 1.00 equiv) and ethyl-2-(triphenyl-lambda5-phosphanylidene)acetate (3.63 g, 10.414 mmol, 1.10 equiv) In toluene was stirred for 4 hours at 80° C. under nitrogen atmosphere. The resulting mixture was washed with water (3×30 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (2.51 g, 94.09%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=282. 
     Step 2: Preparation of tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-3) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (2506.00 mg, 8.907 mmol, 1.00 equiv) in MeOH (25 mL) was added Pd/C (10%, 1 g) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 day under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure afford tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2100.00 mg, 81.4%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=284. 
     Step 3: Preparation of tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl 6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 3.529 mmol, 1.00 equiv) in THF (20 ml) was added LAH (267.88 mg, 7.058 mmol, 2 equiv) in portions at 0° C. under nitrogen atmosphere. The reaction was quenched with Na 2 SO 4 .10H 2 O at room temperature. The resulting mixture was filtered. The filter cake was washed with MeOH (3×20 mL). 
     The filtrate was concentrated under reduced pressure. The crude product (537.00 mg, 63.0%) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=242. 
     Step 4: Preparation of tert-butyl 6-(2-((methylsulfonyl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-5) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (537.00 mg, 2.225 mmol, 1.00 equiv), Et 3 N (450.33 mg, 4.450 mmol, 2.00 equiv), and MsCl (280.38 mg, 2.448 mmol, 1.10 equiv) in DCM (5 mL) was stirred for 3 hours at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (1×20 mL). The combined organic layers were washed with water (3×10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (0% to 18%) to afford tert-butyl 6-[2-(methanesulfonyloxy)ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (593 mg, 83.43%) as a white solid. LCMS (ESI) m/z: [M+H]+=320. 
     Step 5: Preparation of tert-butyl 6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-6) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-[2-(methanesulfonyloxy)ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (320.00 mg, 1.002 mmol, 1.00 equiv), Cs 2 CO 3  (652.82 mg, 2.004 mmol, 2.00 equiv), and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (274.73 mg, 1.002 mmol, 1.00 equiv) in DMF (3 mL) was stirred for 15 hours at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (1×100 mL). The combined organic layers was washed with water (3×100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (265.0 0 mg, 53.2%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=498. 
     Step 6: Preparation of 5-(2-(2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (u54-7) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxyl]ethyl)-2-azaspiro[3.3] heptane-2-carboxylate (265.00 mg, 0.533 mmol, 1.00 equiv) and TFA (2.5 mL) in DCM (5.0 ml) was stirred for 1.5 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 C 2 /EtOAc 1:1) to afford 5-(2-[2-azaspiro[3.3]heptan-6-yl]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (200 mg, 94.48%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=398. 
     Step 7: Preparation of 5-(2-(2-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl) benzyl)-2-azaspiro[3.3] heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D48 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A solution of 5-(2-[2-azaspiro[3.3]heptan-6-yl]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (51.00 mg, 0.128 mmol, 1.00 equiv) in MeOH (1 mL) was treated with 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (41.62 mg, 0.128 mmol, 1.00 equiv) for 20 minutes at room temperature under nitrogen atmosphere followed by the addition of NaBH 3 CN (16.13 mg, 0.257 mmol, 2.00 equiv) in portions at room temperature. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes: detector, UV 254 nm). This resulted in 5-(2-(2-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (2.4 mg, 2.2%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.56 (brs, 1.1H, FA), 7.77 (s, 1H), 7.68-7.56 (m, 2H), 7.13 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.2.2.2 Hz, 1H), 6.85 (s, 2H), 5.10 (dd, J=12.9, 5.5 Hz, 1H), 4.40 (s, 2H), 4.21-4.12 (m, 2H), 4.05 (s, 2H), 3.96 (s, 6H), 3.79-3.70 (m, 5H), 2.95-2.84 (m, 2H), 2.75-2.59 (m, 1H), 2.49-2.36 (m, 2H), 2.27-2.06 (m, 2H), 2.05-1.92 (m, 2H), 1.72-1.54 (m, 2H). LCMS (ESI) m/z: [M+H]+=706.50. 
     Example 55—Preparation of 5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound D49) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 5-(2,2-Diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i55-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (500.00 mg, 1.823 mmol, 1.00 equiv) and Cs 2 CO 3  (980.20 mg, 3.008 mmol, 3 equiv) in DMF (10.00 mL) was added 2-bromo-1,1-diethoxyethane (538.97 mg, 2.735 mmol, 1.5 equiv). The mixture was stirred at 80° C. for 16 hours. The mixture was acidified to pH 6 with HCl (aq.). The mixture was diluted with water (40 mL) and extracted with EtOAc/DCM (60 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 5-(2,2-diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (110 mg, 15.45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=391. 
     Step 2: Preparation of 2-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (i55-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 5-(2,2-diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (100.00 mg, 0.256 mmol, 1.00 equiv) in THF (2.00 mL) was added HCl (4 M) (2.00 mL). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc/DCM (30 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. This resulted in 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (95 mg, crude) as a white solid. LCMS (ESI) m/z: [M+H]+=317. 
     Step 3: Preparation of 5-[2-(9-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperdin-3-yl)isoindole-1,3-dione (Compound D49) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (60.00 mg, 0.190 mmol, 1.00 equiv) and 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (88.13 mg, 0.190 mmol, 1.00 equiv) in DMF (1.50 mL) was added NaBH(OAc) 3  (80.42 mg, 0.379 mmol, 2.00 equiv). The mixture was stirred at room temperature for 2 hours. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: Xcelect CSH F-phenyl OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 11 B to 19 B in 12 minutes; 254/220 nm; R T :10.70 minutes) to give 5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (8.2 mg, 5.5 2%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.71 (s, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.82 (d, J=11.3 Hz, 1H), 7.71 (t, J=8.8 Hz, 1H), 7.24-7.05 (m, 2H), 6.85 (d, J=18.8 Hz, 2H), 5.32-5.16 (m, 1H), 4.43 (s, 2H), 4.20 (s, 2H), 3.97 (s, 7H), 3.90 (s, 1H), 3.75 (s, 3H), 3.59-3.38 (m, 4H), 3.31-3.12 (m, 5H), 3.05-2.86 (m, 2H), 2.82-2.63 (m, 1H), 2.47-1.84 (m, 5H). LCMS (ESI) m/z: [M+H]+=765.45. 
     Example 56—Preparation of 5-(4-(9-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D50) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i56-2) 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (500.00 mg, 1.823 mmol, 1.00 equiv) and 4-chloro-1,1-dimethoxybutane (278.27 mg, 1.823 mmol, 1 equiv) in DMF (7.00 mL) was added K 2 CO 3  (755.96 mg, 5.470 mmol, 3 equiv). The resulting solution was stirred at 80° C. for 12 hours. The resulting mixture was extracted with EA (50 mL×2). The combined organic layers were washed with saturated NaCl (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (100:0) to afford 5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (43.6 mg, 6.13%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=391. 
     Step 2: Preparation of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butanal (156-3) 
     
       
         
         
             
             
         
       
     
     A solution of 5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (43.60 mg, 0.112 mmol, 1.00 equiv) and HCl (1.00 mL, 4M) in THF (1.00 mL) was stirred at 25° C. for 1 hour. The resulting mixture was extracted with EA (50 mL×2). The combined organic layers were washed with saturated NaCl (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal (34.6 mg, 89.98%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=345. 
     Step 3: Preparation of 5-(4-(9-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthydrin-4-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D50) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal (34.00 mg, 0.099 mmol, 1.00 equiv) and 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (45.87 mg, 0.099 mmol, 1 equiv) in DMF (1.00 mL) was added NaBH(OAc) 3  (41.86 mg, 0.197 mmol, 2 equiv). The resulting solution was stirred at 25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions: Xselect CSH F-Phenyl OBD Column 19*150 mm 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10 B to 19 B In 15 minutes; 254/220 nm; R T : 14.53 minutes) to afford 5-[4-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i4 mg, 17.88%) as an off-white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.57 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=7.7 Hz, 2H), 7.27-7.14 (m, 2H), 6.89 (s, 2H), 5.16 (dd, J=12.8, 5.5 Hz, 1H), 4.45 (s, 2H), 4.09-4.01 (m, 2H), 3.98 (s, 6H), 3.89 (t, J=6.4 Hz, 2H), 3.73 (s, 3H), 3.57-3.48 (m, 2H), 3.28-3.17 (m, 4H), 2.98-2.87 (m, 2H), 2.85-2.59 (m, 2H), 2.41-2.25 (m, 1H), 2.23-2.07 (m, 2H), 2.05-1.90 (m, 2H), 1.89-1.59 (m, 5H). LCMS (ESI) m/z: [M+H]+=793.3. 
     Example 57—Preparation of 5-[2-[4-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; formic acid (Compound D51 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (30.00 mg, 0.092 mmol, 1.00 equiv) and 5-[2-(4-aminopiperidin-1-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (37.04 mg, 0.092 mmol, 1.00 equiv) in MeOH (1 mL) was stirred for 3 hours at room temperature under nitrogen atmosphere. To the above mixture was added NaBH 3 CN (11.63 mg, 0.185 mmol, 2.00 equiv), and the reaction was stirred for additional 1 hour at room temperature. To the above mixture was added HCHO (27.77 mg, 0.925 mmol, 10.00 equiv), and the reaction was stirred for 1 hour at room temperature under nitrogen atmosphere. Then NaBH 3 CN (11.63 mg, 0.185 mmol, 2.00 equiv) was added. The mixture was stirred for overnight at room temperature under nitrogen atmosphere. The crude product (40 mg) was purified by Prep-HPLC (conditions: Gemini-NX C18 AXAI Packed column, 21.2*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5 B to 17 B in 9 minutes; 254-220 nm; R T : 8.30 minutes) to afford 5-[2-[4-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)iso indole-1,3-dione formic acid (7.8 mg) as a white solid.  1 H NMR (300 MHz, DMSO-d6) δ 1.55 (2H, d), 1.77 (2H, d), 2.03 (3H, d), 2.16 (3H, s), 2.44 (3H, d), 2.73 (2H, s), 2.88-3.08 (3H, m), 3.61 (5H, s), 3.80 (6H, s), 4.30 (2H, s), 5.12 (1H, m), 6.72 (2H, s), 7.38 (1H, m), 7.48 (1H, d), 7.57 (1H, d), 7.80-7.90 (2H, m), 8.23 (1H, s), 8.72 (1H, d), 9.45 (1H, s), 11.12 (1H, s). LCMS (ESI) m/z: [M+H]+=723.40. 
     Example 58—Preparation of 5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) (methyl)amino) propyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D52 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step Preparation of tert-butyl 4-((2-(2,6dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidine-1-carboxylate (i58-2) 
     
       
         
         
             
             
         
       
     
     A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (1.00 g, 3.647 mmol, 1.00 equiv), tert-butyl 4-bromopiperidine-1-carboxylate (0.96 g, 3.634 mmol, 1.00 equiv) and Cs 2 CO 3  (2.38 g, 7.293 mmol, 2.00 equiv) In DMF (20.00 mL) was stirred for overnight at 90° C. under air atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (hexane/EtOAc 1:1) to afford tert-butyl 4-[[2-(2,6-dioxopiperidin-3-yn-1,3-dioxoisoindol-5-yl]oxy]piperidine-1-carboxylate (280 mg, 11.19%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=458.19. 
     Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione (i58-3) 
     
       
         
         
             
             
         
       
     
     A solution of TFA (1.00 mL) and tert-butyl 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidine-1-carboxylate (200.00 mg, 0.437 mmol, 1.00 equiv) in DCM (4.00 mL) was stirred for 2 hours at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure to afford 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy) isoindole-1,3-dione (120 mg, 76.81%) as a brown solid. LCMS (ESI) m/z: [M+H]+=358.14. 
     Step 3: Preparation of tert-butyl(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)propyl)(methyl) carbamate (i58-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindole-1,3-dione (i20.00 mg, 0.336 mmol, 1.00 equiv) and tert-butyl N-methyl-N-(3-oxopropyl)carbamate (62.87 mg, 0.336 mmol, 1.00 equiv) in MeOH (1.50 mL) was added NaBH 3 CN (42.20 mg, 0.672 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH 10:1) to afford tert-butyl N-[3-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidin-1-yl)propyl]-N-methylcarbamate (88.00 mg, 49.57%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=529.26. 
     Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(methylamino)propyl)piperidin-4-yl)oxy)isoindoline-1,3-dione (i58-5) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl N-[3-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidin-1-yl)propyl]-N-methyl carbamate (88.00 mg, 0.166 mmol, 1.00 equiv) and TFA (1.00 mL) in DCM (4.00 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(methylamino) propy)piperidin-4-yl)oxy)isoindoline-1,3-dione (70 mg, 98.50%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=429.21. 
     Step 5: Preparation of 5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benz yl)(methyl)amino)propyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D52 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A solution of 2-(2,6-dioxopiperidin-3-yl)-5-([1-[3-(methylamino)propyl]piperidin-4-yl]oxy)isoindole-1,3-dione (70.00 mg, 0.163 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (52.99 mg, 0.163 mmol, 1.00 equiv) in DMF (3.00 mL) was stirred for 30 minutes at room temperature. To the above mixture was added NaBH(AcO) 3  (69.25 mg, 0.327 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 days at 50° C. The mixture was allowed to cool down to room temperature. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes; detector. UV 254 nm). The crude product (75 mg) was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (hold 7% Phase B in 0 min, up to 12% in 10 minutes); Detector, UV 254/220 nm) to afford 5-([1-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)propyl]piperidin-4-yl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (7.8 mg, 6.48%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.42 (brs, 1.4H, FA), 7.83-7.74 (m, 2H), 7.63 (d, J=5.6 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.36-7.28 (m, 1H), 6.91 (s, 2H), 5.12 (dd, J=12.5, 5.4 Hz, 1H), 4.76 (s, 1H), 4.45 (s, 2H), 4.01 (s, 6H), 3.70 (s, 3H), 3.37 (s, 2H), 3.00 (s, 2H), 2.95-2.84 (m, 4H), 2.82-2.63 (m, 6H), 2.22-2.07 (m, 5H), 1.88 (s, 2H). LCMS (ESI) m/z: [M+H]+=737.40. 
     Example 59—Preparation of 5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl) propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound D53) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (i59-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) benzaldehyde (200.00 mg, 0.617 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (173.00 mg, 0.929 mmol, 1.51 equiv) in MeOH was added NaBH(OAc) 3  (527.00 mg, 2.487 mmol, 4.03 equiv) in portions at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10:1) to afford tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (204 mg, 68.89%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=495. 
     Step 2: Preparation of 4-(3,5-dimethoxy-4-(piperazin-1-ylethyl) phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i59-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl] methyl] piperazine-1-carboxylate (204.00 mg, 0.412 mmol, 1.00 equiv) in DCM was added TFA (1.00 mL) dropwise at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. The 4-(3,5-dimethoxy-4-(piperazin-1-ylmethyl) phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (210 mg crude) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=395. 
     Step 3: Preparation of 4-(4-((4-(3-hydroxypropyl) piperazin-1-yl) methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i59-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (200.00 mg, 0.507 mmol, 1.00 equiv) and 3-bromopropanol (140.94 mg, 1.014 mmol, 2.00 equiv) in acetone was added Cs 2 CO 3  (330.38 mg, 1.014 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=453. 
     Step 4: Preparation of 3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl]methyl]piperazin-1-yl)propyl methanesulfonate (i59-5) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(4-[[4-(3-hydroxypropyl) piperazin-1-yl] methyl]-3,5-dimethoxyphenyl-2-methyl-2,7-naphthyridin-1-one (200.00 mg, 0.442 mmol, 1.00 equiv) and Cs 2 CO 3  (287.98 mg, 0.884 mmol, 2.00 equiv) in acetone was added MsCl (101.25 mg, 0.884 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10:1) to afford 3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propyl methanesulfonate (92 mg, 39.23%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=531. 
     Step 5: Preparation of 5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthydrin-4-yl)phenyl]methyl]piperazin-1-yl) propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound d53) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propyl methanesulfonate (90.00 mg, 0.170 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (47.00 mg, 0.171 mmol, 1.01 equiv) in DMF was added Na 2 CO 3  (36.00 mg, 0.340 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 hours at 80° C. The crude product was purified by Prep-HPLC (conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; mobile phase, Water (0.05% TFA) and ACN (hold 5% Phase B in 2 min, up to 22% in 13 minutes); Detector, UV). This resulted in 5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (28.1 mg, 23.38%) as an off-white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.84 (t, J=7.6 Hz, 2H), 7.45 (d, J=2.1 Hz, 1H), 7.35 (dd, J=8.3, 2.2 Hz, 1H), 6.89 (s, 2H), 5.12 (dd, J=12.4, 5.4 Hz, 1H), 4.49 (s, 2H), 4.30 (t, J=5.7 Hz, 2H), 3.97 (s, 6H), 3.75 (s, 3H), 3.57 (s, 4H), 3.16 (s, 2H), 3.45-3.34 (m, 4H), 2.99-2.65 (m, 3H), 2.25 (s, 2H), 2.19-2.09 (m, 1H). LCMS (ESI) m/z: [M+H]+=709.35. 
     Example 60—Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dione formic acid (Compound D54 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 7-hydroxy-2-methylisoquinolin-1-one (i60-2) 
     
       
         
         
             
             
         
       
     
     To a mixture of 7-bromo-2-methylisoquinolin-1-one (500 mg, 2.100 mmol, 1.00 equiv), Pd 2 (dba) 3  (96.2 mg, 0.105 mmol, 0.05 equiv), tert-BuBrettPhos (101.8 mg, 0.210 mmol, 0.10 equiv), and KOH (353.5 mg, 6.300 mmol, 3.00 equiv) was added dioxane (15 mL) and water (5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 85° C. The mixture was acidified pH 4 with 1 M HCl (aq.) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1 to 3:1) to afford 7-hydroxy-2-methylisoquinolin-1-one (312 mg, 85%) as a grey solid. LCMS (ESI) m/z: [M+H]+=176. 
     Step 2: Preparation of 2-methyl-1-oxoisoquinolin-7-yl acetate (60-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution/mixture of 7-hydroxy-2-methylisoquinolin-1-one (272 mg, 1.553 mmol, 1.00 equiv) and pyridine (614 mg, 7.763 mmol, 5.00 equiv) in DCM (6 mL) was added DMAP (10 mg, 0.082 mmol, 0.05 equiv) and Ac 2 O (46.6 mg, 0.457 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 2-methyl-1-oxoisoquinolin-7-yl acetate (335 mg, 99%) as a light brown solid. LCMS (ESI) m/z: [M+H]+=218. 
     Step 3: Preparation of 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate (i60-4) 
     To a stirred solution/mixture of 2-methyl-1-oxoisoquinolin-7-yl acetate (325 mg, 1.498 mmol, 1.00 equiv) in ACN (10 mL) was added NBS (292.9 mg, 1.648 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was diluted with DCM (30 mL) and washed with 10 mL of water and 10 mL of brine. The organic layer was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was suspended in EtOAc (3 mL), then filtered and the light grey solid was collected as 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate (297 mg, 67%). LCMS (ESI) m/z: [M+H]+=296. 
     Step 4: Preparation of 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde (i60-5) 
     
       
         
         
             
             
         
       
     
     To a mixture of 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate (217 mg, 0.733 mmol, 1.00 equiv), 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (321.1 mg, 1.099 mmol, 1.50 equiv), Pd(dppf)Cl 2 .CH 2 Cl 2  (59.8 mg, 0.073 mmol, 0.10 equiv), and Cs 2 CO 3  (716.3 mg, 2.198 mmol, 3.00 equiv) was added dioxane (4 mL) and water (1 mL) at room temperature under N 2  atmosphere. The resulting mixture was stirred overnight at 80° C. The resulting mixture was diluted with sat. NH 4 Cl solution (10 mL) and extracted with DCM/i-PrOH (3/1) (5×20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (100:1 to 20:1) to afford 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde (248 mg, quant.) as a light brown solid. LCMS (ESI) m/z: [M+H]+=340. 
     Step 5: Preparation of tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (i60-6) 
     
       
         
         
             
             
         
       
     
     A solution of 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde (100 mg, 0.295 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (83.1 mg, 0.324 mmol, 1.1 equiv) in MeOH (1.5 mL) was stirred for 30 minutes at room temperature. Then NaBH 3 CN (125 mg, 1.989 mmol, 6.75 equiv) was added. The resulting mixture was stirred for 2 hours at room temperature. The reaction solution was purified by Prep-TLC (DCM/MeOH 20:1) to afford tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (134 mg, 78%) as a light brown foam. LCMS (ESI) m/z: [M+H]+=580. 
     Step 6: Preparation of 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one (i60-7) 
     
       
         
         
             
             
         
       
     
     To a stirred solution/mixture of tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxy phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (134 mg, 0.231 mmol, 1.00 equiv) in DCM (3 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. The mixture was concentrated to dryness to give 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one (135 mg, TFA salt, quant.) as a light brown solid. LCMS (ESI) m/z: [M+H]+=480. 
     Step 7: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[ 4 -(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dione formic acid (Compound D54 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid (33.8 mg, 0.094 mmol, 0.90 equiv) in DMF (1 mL) was added EDCI (40.0 mg, 0.209 mmol, 2.00 equiv) and HOBt (28.2 mg, 0.209 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 20 minutes followed by addition of 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one (50.0 mg, 0.104 mmol, 1.00 equiv) and DIEA (67.4 mg, 0.521 mmol, 5.00 equiv). After stirring for 3 hours at room temperature, the reaction mixture was purified by Prep-HPLC (conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 15 B to 24 B in 12 minutes; 254/220 nm; R T :11.28 minutes) to afford 2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5] undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dione formic acid (11.5 mg, 13%) as an off-white solid.  1 H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 0.5H, FA), 7.84-7.75 (m, 2H), 7.56 (dd, J=8.8, 3.3 Hz, 1H), 7.47 (dd, J=7.6, 2.7 Hz, 2H), 7.31-7.19 (m, 2H), 6.82 (d, J=8.8 Hz, 2H), 5.12 (dd, J=12.5, 5.6 Hz, 1H), 4.40-4.20 (m, 4H), 3.93 (d, J=12.4 Hz, 6H), 3.78-3.62 (m, 7H), 3.58-3.48 (m, 2H), 3.30-3.17 (m, 4H), 2.97-2.53 (m, 5H), 2.24-1.99 (m, 5H), 1.95-1.71 (s, 2H). LCMS (ESI) m/z: [M+H]+=822.40. 
     Example 61—Preparation of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide (Compound D55) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of methyl 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate (i61-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one (264.00 mg, 0.778 mmol, 1.20 equiv) and methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (100.00 mg, 0.649 mmol, 1.00 equiv) in MeOH was added NaBH(OAc) 3  (549.91 mg, 2.595 mmol, 4.00 equiv) in portions at room temperature. The resulting solution was stirred for 4 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (8:1) to afford methyl-3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-methyl] bicyclo[1.1.1]pentane-1-carboxylate (220 mg, 71.02%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=478. 
     Step 2: Preparation of 3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) (methyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (i61-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of methyl 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate (200.00 mg, 0.419 mmol, 1.00 equiv) and LiOH.H 2 O (35.15 mg, 0.838 mmol, 2.00 equiv) in THF (6 mL) was added H 2 O (2.00 mL) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The mixture was acidified to pH &lt;7 with conc. HCl. The resulting mixture was concentrated under vacuum. The 3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (215 mg crude) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=464. 
     Step 3: Preparation of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)-amino)methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide (Compound D55) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylic acid (50.00 mg, 0.108 mmol, 1.00 equiv) and 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (65.44 mg, 0.162 mmol, 1.50 equiv) in DMF were added DIEA (55.76 mg, 0.431 mmol, 4.00 equiv) and HATU (61.52 mg, 0.162 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (NB-Prep-HPLC-01); Column, XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (16% PhaseB up to 17% in 20 min hold 17% In 8 minutes); Detector, uv. This resulted in 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)ami-no) methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyc-lo[1.1.1]pentane-1-carboxamide; formic acid (4.1 mg, 4.24%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.55 (s, 1H), 7.78 (s, 1H), 7.65 (d, J=5.9 Hz, 1H), 7.52 (dd, J=8.6, 7.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.99 (d, J=7.1 Hz, 1H), 6.84 (s, 2H), 5.07 (dd, J=12.4, 5.4 Hz, 1H), 4.22 (s, 2H), 3.95 (s, 6H), 3.77 (t, J=5.2 Hz, 2H), 3.73 (s, 3H), 3.71-3.65 (m, 4H), 3.59 (t, J=5.4 Hz, 2H), 3.52 (t, J=5.2 Hz, 2H), 3.44-3.38 (m, 2H), 3.28-3.24 (m, 1H), 2.91-2.81 (m, 1H), 2.80-2.77 (m, 1H), 2.75-2.69 (m, 1H), 2.68 (s, 3H), 2.20 (s, 6H), 2.17-2.05 (m, 2H). LCMS (ESI) m/z: [M+H]+=850.45. 
     Example 62—Preparation of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide (Compound D56) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of methyl 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate (i62-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one (264.18 mg, 0.778 mmol, 1.20 equiv) and methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (100.00 mg, 0.649 mmol, 1.00 equiv) in MeOH was added NaBH(OAc) 3  (549.91 mg, 2.595 mmol, 4.00 equiv) in portions at room temperature. The resulting solution was stirred for 4 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 C 2 /MeOH (8:1) to afford methyl-3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-methyl] bicyclo[1.1.1]pentane-1-carboxylate (220 mg, 71.02%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=478. 
     Step 2: Preparation of 3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) (methyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (i62-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of methyl 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate (200.00 mg, 0.419 mmol, 1.00 equiv) and LiOH.H 2 O (35.15 mg, 0.838 mmol, 2.00 equiv) in THF (6 mL) was added H 2 O (2.00 mL) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The mixture was acidified to pH &lt;7 with conc. HCl. The resulting mixture was concentrated under vacuum. The 3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (215 mg crude) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=464. 
     Step 3: Preparation of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl) amino)methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1] pentane-1-carboxamide (Compound D56) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylic acid (50.00 mg, 0.108 mmol, 1.00 equiv) and 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (65.44 mg, 0.162 mmol, 1.50 equiv) in DMF was added DIEA (55.76 mg, 0.431 mmol, 4.00 equiv) and HATU (61.52 mg, 0.162 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The crude product was purified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (16% Phase B up to 17% in 20 min hold 17% in 8 minutes); Detector, UV). This resulted in 3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)-methyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl))bicyclo[1.1.1]pentane-1-carboxamide (12.3 mg, 13.42%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=804.45. 
     Example 63—Preparation of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl) amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide; formic acid (Compound D57 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of methyl-3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (163-2) 
     
       
         
         
             
             
         
       
     
     To a solution of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (195.2 mg, 1.099 mmol, 1.10 equiv) in MeOH (5.00 mL) was added Et 3 N (111.0 mg, 1.099 mmol, 1.10 equiv), and then 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (324.0 mg, 0.999 mmol, 1.00 equiv) was added. After 10 minutes stirring, NaBH 3 CN (125.6 mg, 1.998 mmol, 2.00 equiv) was added in portions at ambient atmosphere. The resulting mixture was concentrated after stirring for 1 hour at room temperature. The mixture was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =450. 
     Step 2: Preparation of methyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (63-3) 
     
       
         
         
             
             
         
       
     
     To a solution of crude methyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] amino)bicyclo[1.1.1]pentane-1-carboxylate obtained last step in MeOH (5.00 mL, 12.349 mmol) was added formaldehyde in water (226.0 μL). After 10 min stirring, NaBH 3 CN (125.8 mg, 2.002 mmol, 2.00 equiv) was added in portions at ambient atmosphere. The resulting mixture was concentrated after stirring for 1 hour at room temperature. The mixture was purified by Prep-TLC (EtOAc) to afford methyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-ylphenyl]methyl](methyl)(amino)bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 24.8%) as a light yellow solid. LCMS (ESI) m/z: [M+H] + =464. 
     Step 3: Preparation of 3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) (methyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (i63-4) 
     
       
         
         
             
             
         
       
     
     A mixture of methyl 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (120.0 mg, 0.259 mmol, 1.00 equiv) in conc. HCl (2.00 mL) was stirred for 1 hour at 90° C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=450. 
     Step 4: Preparation of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl]bicyclo[1.1.1]pentane-1-carboxamide formic acid (Compound D57 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid hydrochloride (50 mg, 0.103 mmol, 1.00 equiv) and 4-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; trifluoroacetic acid (53.5 mg, 0.113 mmol, 1.10 equiv) in DMF (2.00 mL) was added DIEA (39.9 mg, 0.309 mmol, 3.00 equiv). The mixture was stirred at room temperature for 5 minutes, and then HATU (78.2 mg, 0.206 mmol, 2.00 equiv) was added. After stirring at room temperature for 2 hours, the mixture was purified by Prep-HPLC (conditions: X-select CSH F-Phenyl OBD Column 19*150 mm 5 μm, mobile phase, Water (0.05% TFA) and ACN (10% Phase B up to 26% in 15 minutes)). This resulted in of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide formic acid (i5.2 mg, 17.2%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.57 (s, 1H), 8.71 (d, J=5.9 Hz, 1H), 8.18 (brs, 0.4H, FA), 7.86 (s, 1H), 7.72 (s, 1H), 7.58 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd, J=7.8, 5.2 Hz, 2H), 6.90 (s, 2H), 5.06 (dd, J=12.0, 5.4 Hz, 1H), 4.51 (s, 2H), 3.99 (s, 6H), 3.73 (s, 3H), 3.41-3.35 (m, 2H), 3.31-3.23 (m, 2H), 2.89-2.64 (m, 6H), 2.42 (s, 6H), 2.17-2.08 (m, 1H), 1.78-1.67 (m, 2H), 1.66-1.56 (m, 2H), 1.54-1.43 (m, 2H). LCMS (ESI) m/z: [M+H] + =790.40. 
     Example 64—Preparation of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino)-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy] ethyl]bicyclo[1.1.1]pentane-1-carboxamide (Compound D58) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (50.0 mg, 0.111 mmol, 1.00 equiv) in DMF (2.00 mL) was added EDCI (42.7 mg, 0.222 mmol, 2.00 equiv) and 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (49.5 mg, 0.122 mmol, 1.10 equiv). The mixture was stirred at room temperature for 30 minutes, and then DIEA (71.9 mg, 0.556 mmol, 5.00 equiv) and 4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (9.9 mg, 0.024 mmol, 1.10 equiv) were added. After stirring at room temperature for 2 hours, without any additional work-up, the mixture was purified by Prep-HPLC (conditions: column, Phenomenex Gemini C6-Phenyl, 21.2*250 mm, 5 μm; mobile phase, Water (0.05% FA) and ACN (11% Phase B up to 21% in 28 minutes). This resulted in 3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide (10.5 mg, 10.6%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J=5.7 Hz, 1H), 7.55 (dd, J=8.6.7.1 Hz, 1H), 7.07 (dd, J=19.4, 7.8 Hz, 2H), 6.74 (s, 2H), 5.07 (dd, J=12.3, 5.4 Hz, 1H), 3.88 (s, 6H), 3.77 (t, J=5.2 Hz, 2H), 3.73-3.63 (m, 9H), 3.59 (t, J=5.5 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H), 3.41 (t, J=5.5 Hz, 2H), 2.90-2.68 (m, 3H), 2.27 (s, 3H), 2.20-2.06 (m, 7H). LCMS (ESI) m/z: [M+H] + =836.40. 
     Example 65—Preparation of N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]ami no]ethoxy)ethoxy]propanamide formic acid (Compound D59 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl (3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl))benzyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (i65-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-[3-aminobicyclo[1.1.1]pentan-1-yl]carbamate (134.49 mg, 0.678 mmol, 1.10 equiv) and tert-butyl N-[3-aminobicyclo[1.1.1]pentan-1-yl]carbamate (134.49 mg, 0.678 mmol, 1.00 equiv) in MeOH (3 ml) was added NaBH 3 CN (77.50 mg, 1.233 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The crude resulting mixture was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =507. 
     Step 2: Preparation of tert-butyl N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate (i65-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of the product from step 1 was added NaBH 3 CN (49.62 mg, 0.790 mmol, 2.00 equiv) and formaldehyde (59.27 mg, 1.974 mmol, 5.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (8:1) to afford tert-butyl N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate (146 mg, 71.03%) as a light yellow oil. LCMS (ESI) m/z: [M+H] + =521. 
     Step 3: Preparation of 4-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)(methyl)amino)methyl)-3,5-dimethoxy phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i65-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl] methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate (146.00 mg, 0.300 mmol, 1.00 equiv) in DCM was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (210 mg crude), which was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =421. 
     Step 4: Preparation of N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide formic acid (Compound D59 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[4-[([3-aminobicyclo[1.1.1]pentan-1-yl](methyl)amino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (80.00 mg, 0.190 mmol, 1.00 equiv) and EDCI (72.94 mg, 0.380 mmol, 2.00 equiv) In DMF (1 mL) was added HOBT (51.41 mg, 0.380 mmol, 2.00 equiv) and DIEA (98.35 mg, 0.761 mmol, 4.00 equiv) in portions at room temperature. To the above mixture was added 3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoic acid (82.45 mg, 0.190 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional overnight at room temperature. Desired product could be detected by LCMS. The crude product (78.2 mg) was purified by prep-HPLC (conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm: Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 15 B to 22 B in 17 minutes; 254/220 nm; R T :15.32 minutes) to afford N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide formic acid (23.7 mg, 14.13%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.70 (d, J=5.8 Hz, 1H), 8.20 (brs, 0.3H, FA), 7.78 (s, 1H), 7.63 (d, J=5.7 Hz, 1H), 7.55 (dd, J=8.6.7.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.85 (s, 2H), 5.08 (dd, J=12.3, 5.4 Hz, 1H), 4.20 (s, 2H), 3.95 (s, 6H), 3.78-3.63 (m, 11H), 3.52 (t, J=5.3 Hz, 2H), 2.99-2.68 (m, 6H), 2.52-2.34 (m, 8H), 2.18-2.08 (m, 1H). LCMS (ESI) m/z: [M+H] + =836.65. 
     Example 66—Preparation of N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hex anamide formic acid (Compound D60 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[4-[([3-aminobicyclo[1.1.1]pentan-1-yl](methyl)amino)methyl]-3,5-dimethoxy phenyl]-2-methyl-2,7-naphthyridin-1-one (80.00 mg, 0.190 mmol, 1.00 equiv) and EDCI (72.94 mg, 0.380 mmol, 2.00 equiv) in DMF (1 mL) was added HOBt (51.41 mg, 0.380 mmol, 2.00 equiv) at room temperature. To the above mixture was added DIEA (98.35 mg, 0.761 mmol, 4.00 equiv). The resulting mixture was stirred for overnight at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5 B to 35 B in 13 minutes; 254/220 nm; R t :12.05 minutes) to afford N-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl) amino)bicycle [1.1.1]pentan-1-yl]-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamide formic acid (i4.9 mg, 9.38%) as a white solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.44 (brs, 0.3H, FA), 7.84-7.74 (m, 2H), 7.64 (d, J=5.8 Hz, 1H), 7.46 (d, J=7.9 Hz, 2H), 6.78 (s, 2H), 5.10 (dd, J=12.0, 5.4 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H), 3.91 (s, 8H), 3.72 (s, 3H), 2.91-2.67 (m, 3H), 2.39 (s, 3H), 2.29-2.20 (m, 8H), 2.18-2.08 (m, 1H), 1.91 (p, J=6.5 Hz, 2H), 1.73 (p, J=7.2 Hz, 2H), 1.60 (q, J=8.1 Hz, 2H). LCMS (ESI) m/z: [M+H] + =791.40. 
     Example 67—Preparation of 5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D61) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyldin-1(2H)-one (i67-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH 3 CN (290 mg, 4.62 mmol, 3.00 equiv) and 3-(prop-2-yn-1-yloxy)azetidine hydrochloride (269 mg, 1.84 mmol, 1.20 equiv). The resulting mixture was stirred for 2 hours at room temperature. Solvent was removed and the residue was purified by Flash column chromatography with EtOAc/PE (0-100%) to afford 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (451 mg, 70%) as a solid. LCMS (ESI) m/z: [M+H] + =420.4. 
     Step 2: Preparation of 5-(2-azidoethoxy)-2-(2,6-dioxopipedin-3-yl)isoindoline-1,3-dione (i67-6) 
     
       
         
         
             
             
         
       
     
     2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol, 1.0 equiv) was dissolved in DMF (15 mL). Potassium carbonate was then added (753 mg, 545 mmol, 3 equiv) followed by potassium Iodide (451 mg, 2.72 mmol, 1.5 equiv) and 1-azido-2-bromoethane (286 mg, 1.91 mmol, 1.05 equiv). The mixture was then heated to 80° C. and stirred for 2 hours. The solvent was then removed and Flash column chromatography with EtOAc/PE (0-100%), to afford 5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-ylisoindoline-1,3-dione (385 mg, 62%) as a solid. LCMS (ESI) m/z: [M+H] + =344.4. 
     Step 3: Preparation of 5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyldin-4-yl)benzyl)azetidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D61) 
     
       
         
         
             
             
         
       
     
     5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20 mg, 0.0595 mmol, 1.0 equiv) and 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (25 mg, 0.0595 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). HÜnig&#39;s base (0.020 mL, 0.119 mmol, 2 equiv) was then added followed by CuI (5.69 mg, 0.0297 mmol, 0.5 equiv). The mixture was stirred for 1 hour at room temperature. The solution was submitted directly for HPLC purification to give 5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidine-3-yl)oxy)methy)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i4.8 mg, 33%) as a solid.  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 9.42 (s, 1H), 8.70 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.52 (d, J=5.8 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.69 (s, 2H), 5.09 (dd, J=12.8, 5.4 Hz, 1H), 4.79 (t, J=4.9 Hz, 2H), 4.60 (t, J=5.0 Hz, 2H), 4.39 (s, 2H), 4.00 (t, J=6.1 Hz, 1H), 3.83-3.76 (m, 1H), 3.76 (s, 6H), 3.57 (d, J=4.2 Hz, 5H), 2.93-2.84 (m, 1H), 2.83 (s, 3H), 2.68-2.63 (m, 2H), 2.59 (s, 1H), 2.54 (s, 1H), 2.08-1.95 (m, 2H). LCMS (ESI) m/z: [M+H]+=761.4. 
     Example 68—Preparation of 5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D62) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 4-(3,5-dimethoxy-4-((methyl(prop-2-yn-1-yl)amino)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i68-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH 3 CN (290 mg, 4.62 mmol, 3.00 equiv) and N-methylprop-2-yn-1-amine (127 mg, 1.84 mmol, 1.20 equiv). The resulting mixture was stirred for 2 hours at room temperature. Solvent was removed and the residue was purified by Flash column chromatography with EtOAc/PE (0-100%), to afford 4-(3,5-dimethoxy-4-((methyl(prop-2-yn-1-yl)amino)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (390 mg, 67%) as a solid. LCMS (ESI) m/z: [M+H] + =378.7. 
     Step 2: Preparation of 5-azido-2-(2,6-dioxopiperidin-3-isoindoline-1,3-dione (i68-5) 
     
       
         
         
             
             
         
       
     
     2-(2,6dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol, 1.0 equiv) was dissolved in DMSO (5 mL). Hünig&#39;s base was then added (0.944 mL, 5.43 mmol, 3 equiv) followed by sodium azide (176 mg, 2.71 mmol, 1.5 equiv) and 1-azido-2-bromoethane (288 mg, 1.91 mmol, 1.05 equiv). The mixture was then heated to 50° C. and stirred for 2 hours. The solution was then loaded directly onto silica gel and purified over silica gel with EtOAc/PE (0-100%) to afford 5-azido-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (480 mg, 89%) as a solid. LCMS (ESI) m/z: [M+H]+=300.1. 
     Step 3: 5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound D62) 
     
       
         
         
             
             
         
       
     
     5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i9.8 mg, 0.0662 mmol, 1.0 equiv) and 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (25 mg, 0.0662 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). Hünig&#39;s base (0.023 mL, 0.132 mmol, 2 equiv) was then added followed by CuI (6.3 mg, 0.0279 mmol, 0.5 equiv). The mixture was stirred for 1 hour at room temperature. The solution was submitted directly for HPLC purification to 5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.3 mg, 28%) as a solid.  1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.43 (s, 1H), 9.03 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.52-8.45 (m, 2H), 8.13 (d, J=14.2 Hz, 1H), 7.85 (s, 1H), 7.54 (d, J=5.7 Hz, 1H), 6.73 (s, 2H), 5.20 (dd, J=12.9, 5.3 Hz, 1H), 3.78 (s, 6H), 3.58 (s, 3H), 2.96-2.83 (m, 1H), 2.65-2.58 (m, 1H), 2.58-2.50 (m, 1H), 2.22 (s, 5H), 2.13-2.03 (m, 1H). LCMS (ESI) m/z: [M+H]+=675.4. 
     Example 69—Preparation of 5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolidine-1,3-dione (Compound D63) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyldin-1(2H)-one (i69-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH 3 CN (290 mg, 4.62 mmol, 3.00 equiv) and 3-(prop-2-yn-1-yloxy)piperidine hydrochloride (321 mg, 1.84 mmol, 1.20 equiv). The resulting mixture was stirred for 2 hours at room temperature. Solvent was removed and the residue was purified by Flash column chromatography with EtOAc/PE (0-100%) to afford 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (323 mg, 47%) as a solid. LCMS (ESI) m/z: [M+H] + =448.5. 
     Step 2: Preparation of 5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i69-6) 
     
       
         
         
             
             
         
       
     
     2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol, 1.0 equiv) was dissolved in THF (18 mL). Triphenylphosphine was then added (571 mg, 2.18 mmol, 1.2 equiv) followed by 4-azidobutan-1-ol (248 mg, 2.91 mmol, 1.05 equiv). The solution was cooled to 0° C. and 1-diisopropyl azodicarboxylate (358 mL, 1.82 mmol, 1.0 equiv) was added. The mixture was then warmed to room temperature and stirred for 2 hours. Water was added and the reaction extracted 3 times with ethyl acetate. The organics were dried over MgSO 4 , filtered, and evaporated. The resulting oil was columned over silica gel with EtOAc/PE (0-100%), to afford 5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (391 mg, 58%) as a solid. LCMS (ESI) m/z: [M+H] + =372.4. 
     Step 3: 5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound D63) 
     
       
         
         
             
             
         
       
     
     5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.5 mg, 0.0558 mmol, 1.0 equiv) and 4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (25 mg, 0.0558 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). Hünig&#39;s base (0.0192 mL, 0.111 mmol, 2 equiv) was then added followed by CuI (5.31 mg, 0.0279 mmol, 0.5 equiv). The mixture was stirred for 1 hour at room temperature. The solution was submitted directly for HPLC purification to give 5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (6.2 mg, 12%) as a solid.  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.77-7.58 (m, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.73 (s, 2H), 6.58-6.39 (m, 1H), 5.09 (dd, J=12.9, 5.4 Hz, 1H), 4.59-4.47 (m, 2H), 4.42 (t, J=7.0 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 3.80 (s, 6H), 3.70 (s, 2H), 3.58 (s, 2H), 3.00 (s, 1H), 2.87 (ddd, J=17.4, 14.1, 5.4 Hz, 1H), 2.74 (s, 1H), 2.68-2.63 (m, OH), 2.62-2.50 (m, 2H), 2.33-2.27 (m, 1H), 2.05 (s, 3H), 2.03-1.93 (m, 1H), 1.97-1.78 (m, OH), 1.71 (q, J=6.7 Hz, 3H), 1.40 (s, 1H). LCMS (ESI) m/z: [M+H] + =817.2. 
     Example 70—Preparation of 5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-ox a-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D64 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid (21.46 mg, 0.065 mmol, 1.00 equiv) and 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (30.00 mg, 0.065 mmol, 1.00 equiv) In DMF (1 ml) was added HATU (49.11 mg, 0.129 mmol, 2.00 equiv) and DIEA (33.38 mg, 0.258 mmol, 4.00 equiv) at room temperature. The mixture was stirred at room temperature for 16 hours. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 8 B to 33 B in 10 minutes; 254/220 nm; R T : 8.05 minutes) to afford 5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid as a white gum (6.8 mg, 12.77%).  1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (brs, 0.3H, FA), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.76 (d, J=2.5 Hz, 1H), 7.67-7.62 (m, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.40 (dd, J=8.3, 2.2 Hz, 1H), 6.81 (d, J=4.5 Hz, 2H), 5.16-5.00 (m, 3H), 4.18-3.98 (m, 2H), 3.92 (d, J=1.6 Hz, 6H), 3.85-3.75 (m, 2H), 3.72 (s, 3H), 3.67-3.59 (m, 2H), 3.56-3.45 (m, 2H), 3.11-2.91 (m, 3H), 2.90-2.64 (m, 4H), 2.18-2.09 (m, 1H), 2.08-1.91 (m, 2H), 1.85-1.69 (m, 2H). LCMS (ESI) m/z: [M+H]+=779.55. 
     Example 71—Preparation of N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy] acetamide (Compound D65 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (171-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (100.00 mg, 0.308 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (86.14 mg, 0.482 mmol, 1.50 equiv) in MeOH (1 mL) was added NaBH(OAc) 3  (261.38 mg, 1.233 mmol, 4.00 equiv) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford product left-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl] methyl]piperazine-1-carboxylate (115 mg, 75.4%) as a yellow gum. LCMS (ESI) m/z: [M+H] + =495. 
     Step 2: Preparation of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (i71-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (115.00 mg) and TFA (1.00 mL) in DCM (1.00 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (305 mg, crude), which was used directly without further purification. LCMS (ESI) m/z: [M+H] + =395. 
     Step 3: Preparation of N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide (Compound D65) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (22.05 mg, 0.056 mmol, 1.20 equiv) and 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (20.00 mg, 0.047 mmol, 1.00 equiv) in DMF (1 mL) was added HATU (35.42 mg, 0.093 mmol, 2.00 equiv) and DIEA (12.04 mg, 0.093 mmol, 2.00 equiv) at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 12 minutes; 254/220 nm; R t : 9.45 minutes). Pure fractions were evaporated to dryness to afford N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]meth-yl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide (12.4 mg, 33.04%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.68 (dd, J=5.8, 1.8 Hz, 1H), 8.43 (brs, 0.5H, FA), 7.81 (ddd, J=8.4, 7.3, 3.5 Hz, 1H), 7.75 (d, J=3.7 Hz, 1H), 7.65-7.61 (m, 1H), 7.54 (dd, J=6.9, 1.6 Hz, 1H), 7.45 (dd, J=8.3, 2.5 Hz, 1H), 6.76 (d, J=2.5 Hz, 2H), 5.19-5.11 (m, 1H), 4.80-4.68 (m, 2H), 3.93-3.81 (m, 9H), 3.78-3.68 (m, 5H), 3.51-3.35 (m, 2H), 3.29-3.16 (m, 1H), 2.93-2.67 (m, 7H), 2.21-2.06 (m, 2H), 1.72-1.60 (m, 1H), 1.21-1.12 (m, 1H), 1.09-0.99 (m, 1H). LCMS (ESI) m/z: [M+H] + =806.70. 
     Example 72—Preparation of N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-6-yl]oxy]acetamide formic acid (Compound D66 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one (22.05 mg, 0.056 mmol, 1.20 equiv) and 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (20.00 mg, 0.047 mmol, 1.00 equiv) in DMF (1 mL) was added HATU (35.42 mg, 0.093 mmol, 2.00 equiv) and DIEA (12.04 mg, 0.093 mmol, 2.00 equiv) at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 12 minutes; 254/220 nm; R T : 10.22 minutes). Pure fractions were evaporated to dryness to afford N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamide (7.4 mg, 19.18%) as a white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.46 (brs, 1.0H, FA), 7.82 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.40 (dd, J=8.3, 2.3 Hz, 1H), 6.78 (s, 2H), 5.11 (dd, J=12.4, 5.4 Hz, 1H), 4.68 (s, 2H), 3.95 (s, 2H), 3.89 (s, 6H), 3.81 (s, 2H), 3.70 (s, 3H), 3.63 (s, 1H), 3.42-3.34 (m, 2H), 3.29-3.20 (m, 1H), 2.94-2.67 (m, 7H), 2.18-2.09 (m, 1H), 2.09-2.00 (m, 1H), 1.62 (q, J=7.5 Hz, 1H), 1.11 (q, J=5.5 Hz, 1H), 1.01 (td, J=8.1, 4.5 Hz, 1H). LCMS (ESI) m/z: [M+H] + =806.40. 
     Example 73—Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl] methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl) azetidine-3-sulfonamide formic acid (Compound D67 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl [(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl) sulfamoyl]azetidine-1-carboxylate (i73-2) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 5-[(6-aminohexyl)amino]-2-(2,6-dioxopiperdin-3-yl)isoindole-1,3-dione (60.00 mg, 0.161 mmol, 1.00 equiv) and tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (102.99 mg, 0.403 mmol, 2.50 equiv) in DCM (2.00 mL) was added TEA (48.91 mg, 0.483 mmol, 3.00 equiv). After stirring for 1.5 hours at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 /EA=1:2) to afford tert-butyl-3-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl)sulfamoyl]azetidine-1-carboxylate (61.8 mg, 60.29%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=592. 
     Step 2: Preparation of N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)azetidine-3-sulfonamide (i73-3) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of tert-butyl 3-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl)sulfamoyl]azetidine-1-carboxylate (61.8 mg, 0.104 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (0.40 mL, 5.385 mmol, 51.56 equiv). After stirring for 1 hour at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H] + =492. 
     Step 3: Preparation of 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamide formic acid (Compound D67 Formic Acid) 
     
       
         
         
             
             
         
       
     
     A mixture of N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamide (51.38 mg, 0.104 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (33.89 mg, 0.104 mmol, 1.00 equiv) in DMF (2 mL) was stirred at room temperature. The reaction mixture was then adjusted to pH 8-9 with TEA. To the above mixture was added NaBH 3 CN (19.70 mg, 0.313 mmol, 3.00 equiv) in portions, and the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure, the residue was purified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (15% Phase B up to 30% In 14 minutes); Detector. UV). This gave 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]hexyl)azetidine-3-sulfonamide formic acid (i3 mg, 14.12%) as a yellow solid.  1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.14 (s, 0.2H, FA), 7.87 (s, 1H), 7.56 (d, J=5.7 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.27 (br s, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.82 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (s, 2H), 6.56 (d, J=8.2 Hz, 2H), 5.10 (dd, J=13.0, 5.4 Hz, 1H), 4.01 (br s, 2H), 3.84 (s, 7H), 3.60 (s, 6H), 3.47-3.35 (m, 2H), 3.05-2.83 (m, 3H), 2.77-2.65 (m, 1H), 2.49-2.41 (m, 2H), 2.03-1.96 (m, 1H), 1.39 (t, J=7.0 Hz, 4H), 1.24 (s, 4H). LCMS (ESI) m/z: [M+H] + =800.25. 
     Example 74—Preparation of N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](meth-yl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide formic acid (Compound D68 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)methyl]bicyclo[1.1.1]pentan-1- yl]carbamate (i74-2) 
     
       
         
         
             
             
         
       
     
     To a stirred mixture of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (200.00 mg, 0.617 mmol, 1.00 equiv) and tert-butyl N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]carbamate (144.00 mg, 0.678 mmol, 1.10 equiv) in MeOH (1 mL) was added NaBH 3 CN (77.50 mg, 1.233 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. To the above mixture was added formaldehyde (0.50 mL). The resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions was concentrated under vacuum to afford tert-butyl N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)methyl]bicyclo[1.1.1]pentan-1-yl] carbamate (284.8 mg) as a yellow gum. LCMS (ESI) m/z: [M+H] + =535. 
     Step 2: Preparation of 4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimeth oxyphenyl)-2-methyl-2,7-naphthyridin-1-one (i74-3) 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](me-thyl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]carbamate (284.80 mg) and TFA (1.00 mL) in DCM (1 mL) was stirred for overnight at room temperature. The reaction mixture was concentrated under vacuum to afford 4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (639.4 mg, crude) as a yellow gum. LCMS (ESI) m/z: [M+H] + =435. 
     Step 3: Preparation of N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1)pentan-1-yl]-3-(2-(2-[[(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide formic acid (Compound D8 formic acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl)methyl)(methyl)amino]methyl]-3,5-dimet-hoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (20.05 mg, 0.046 mmol, 1 equiv) and 3-[2-(2-[[2-(2,6-diox-opiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoic acid (20.00 mg, 0.046 mmol, 1.00 equiv) in DMF (1 mL) was added EDCI (17.69 mg, 0.092 mmol, 2.00 equiv), HOBT (12.47 mg, 0.092 mmol, 2.00 equiv), and DIEA (23.86 mg, 0.185 mmol, 4.00 equiv). The resulting mixture was stirred overnight at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: Column: Gemini-NX C18 AXAI Packed, 21.2*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 8 B to 25 B in 12 minutes; 254/220 nm; R T : 11.04 minutes) to afford N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl-l)amino)methyl]bicycle[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amin-o]ethoxy)ethoxy]propanamide (3.4 mg, 8.67%) as a yellow solid.  1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.45 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 8.29 (s, 1H), 8.23 (brs, 1.0H, FA), 7.87 (s, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.14 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.72 (s, 2H), 6.61 (t, J=5.8 Hz, 1H), 5.06 (dd, J=12.7, 5.4 Hz, 1H), 3.81 (s, 6H), 3.58-3.54 (m, 5H), 3.54-3.49 (m, 6H), 3.48-3.42 (m, 4H), 2.96-2.81 (m, 1H), 2.64-2.58 (m, 1H), 2.55 (s, 3H), 2.26 (t, J=6.4 Hz, 2H), 2.12 (s, 3H), 2.08-1.98 (m, 1H), 1.92 (s, 6H). LCMS (ESI) m/z: [M+H] + =850.50. 
     Example 75—Preparation of N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](meth-yl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]-8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]ox-y]pentanamide (Compound D69) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-(4-[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one (23.22 mg, 0.053 mmol, 1.00 equiv) and 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoic acid (20.00 mg, 0.053 mmol, 1.00 equiv) in DMF (1 mL) was added EDCI (20.48 mg, 0.107 mmol, 2.00 equiv) and HOBT (14.44 mg, 0.107 mmol, 2.00 equiv) at room temperature. To the above mixture was added DIEA (27.62 mg, 0.214 mmol, 4.00 equiv). The resulting mixture was stirred for overnight at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 13 minutes; 254/220 nm; R T : 12.5 minutes) to afford N-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl-l]bicyclo[1.1.1] pentan-1-yl]-5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanamide (6.9 mg, 17.75%) as a white solid.  1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.46 (d, J=0.8 Hz, 1H), 8.74 (d, J=5.7 Hz, 1H), 8.36 (s, 1H), 7.88 (s, 1H), 7.82 (dd, J=8.5, 7.2 Hz, 1H), 7.60-7.42 (m, 3H), 6.79 (s, 2H), 5.08 (dd, J=12.8, 5.4 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.86 (s, 6H), 3.61 (s, 3H), 3.40 (s, 2H), 2.98-2.80 (m, 2H), 2.62 (s, 2H), 2.46-2.30 (m, 4H), 2.15-2.00 (m, 9H), 1.78-1.64 (m, 4H). LCMS (ESI) m/z: [M+H] + =791.40. 
     Example 76—Preparation of 5-(4-[2-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]meth yl](methyl)amino)propoxy]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D70 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-[3-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propyl]-N-methylcarbamate (176-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (250.00 mg, 0.730 mmol, 1.00 equiv) and tert-butyl N-methyl-N-[3-(2-oxoethoxy)propyl]carbamate (168.90 mg, 0.730 mmol, 1 equiv) in MeOH (3.00 mL) was added NaBH 3 CN (91.78 mg, 1.480 mol, 2 equiv). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether/EtOAc 1:3) to afford tert-butyl N-[3-(2-[4-[2-(2,8-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propy]-N-methylcarbamate (400 mg, crude) as a dark grey solid. LCMS (ESI) m/z: [M+H]+=558. 
     Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione (i76-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-[3-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propyl]-N-methylcarbamate (200.00 mg, 0.359 mmol, 1.00 equiv) in DCM (4.00 mL, 62.920 mmol) was added TFA (1.00 mg, 0.009 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione (280 mg, crude) as a dark grey solid. LCMS (ESI) m/z: [M+H]+=458. 
     Step 3: Preparation of 5-(4-(2-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl) (methyl)amino)propoxy]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D70 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione (100.00 mg, 0.219 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (70.89 mg, 0.219 mmol, 1 equiv) in DMF (1.50 mL) was added NaBH(OAc) 3  (92.65 mg, 0.437 mmol, 2 equiv). The mixture was stirred at mom temperature for 2 hours. The crude product (100 mg) was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 5 B to 13 B In 15 minutes; 254 nm; R T : 12.23 minutes) to afford 5-(4-[2-[3-([2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)(amino)propoxyethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; formic acid (10 mg, 5.38%) as a yellow solid.  1 H NMR (300 MHz, Methanol-d4) δ 9.51 (d, J=18.3 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.53 (brs, 4.1H, FA), 7.76 (s, 1H), 7.64 (d, J=7.4 Hz, 2H), 7.25 (s, 1H), 7.17 (d, J=8.6 Hz, 1H), 6.90 (s, 2H), 5.11-5.04 (m, 2H), 4.69-4.53 (m, 2H), 4.47 (s, 2H), 4.00 (s, 6H), 3.74-3.62 (m, 7H), 3.40 (d, J=5.5 Hz, 4H), 2.91 (s, 3H), 2.87-2.73 (m, 3H), 2.69 (s, 6H), 2.23-2.08 (m, 3H). LCMS (ESI) m/z: [M+H] + =768.45. 
     Example 77—Preparation of 4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](meth yl)amino)acetamido]-N-(3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]bicycle[1.1.1] pentan-1-yl)butanamide (Compound D71) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-(2,6-dimethoxy-4-(2-methyl)-1-oxo-1,2-dihydro-2,7-naphthydrin-4-yl) benzyl)-N-methylglycinate (i77-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (250.00 mg, 0.771 mmol, 1.00 equiv) and ter-butyl 2-(methylamino)acetate (111.92 mg, 0.771 mmol, 1.00 equiv) In MeOH (10.00 mL) was added NaBH 3 CN (96.88 mg, 1.542 mmol, 2.00 equiv) in portions at 50° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (3×30 mL). The resulting solid was dried under vacuum. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm). This resulted in tert-butyl N-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-methylglycinate (101 mg, 28.92%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=454. 
     Step 2: Preparation of N-(2,6-dimethoxy-4-(2-methyl 1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-methylglycine (i77-3) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl) amino) acetate (101.00 mg, 0.223 mmol, 1.00 equiv) and TFA (7.21 mL, 63.270 mmol, 436.14 equiv) in DCM (29.00 mL) was stirred for 15 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue (108 mg, crude) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=398. 
     Step 3: Preparation of tert-butyl 4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-)benzyl)(methyl)amino)acetamido)butanoate (i77-4) 
     
       
         
         
             
             
         
       
     
     A solution of ([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetic acid (i08 mg (crude), 0.272 mmol, 1.00 equiv), DIEA (105.36 mg, 0.815 mmol, 3.00 equiv), and HATU (206.53 mg, 0.543 mmol, 2.00 equiv) in DMF (2.00 mL) was stirred for 30 minutes at room temperature under nitrogen atmosphere. To the above mixture was added tert-butyl 4-aminobutanoate (43.27 mg, 0.272 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 12 hours at room temperature. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm). This resulted in tert-butyl 4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)acetamido) butanoate (75 mg, 62.33%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=539. 
     Step 4: Preparation of 4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthydrin-4-yl)benzyl)(methyl)amino)acetamido)butanoic acid (177-5) 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl 4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](meth yl)amino) acetamido]butanoate (75.00 mg, 0.139 mmol, 1.00 equiv) and TFA (1 mL) in DCM (4.00 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue (73 mg, crude) was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+=483. 
     Step 5: Preparation of 4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl) (methyl)amino)acetamido)-N-(3-((2-(2,6-dioxopiperdin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)bicycle[1.1.1]pentan-1-yl)butanamide (Compound D71) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino) acetamido]butanoic acid (73.00 mg (crude), 0.151 mmol, 1.00 equiv), DIEA (58.66 mg, 0.454 mmol, 3.00 equiv), and EDCI (58.00 mg, 0.303 mmol, 2.00 equiv) in DMF (2.00 mL) was added HOBT (40.88 mg, 0.303 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. The reaction mixture was irradiated with microwave radiation for 1 hour at room temperature. To the above mixture was added 4-([3-aminobicyclo[1.1.1]pentan-1-yl]amino)-2-(2,6-dioxopiperidin-3-yl) isoindole-1,3-dione (53.61 mg, 0.151 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 2 days at room temperature. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm). The crude product (70 mg) was purified by Prep-HPLC (conditions: Atlantis HILIC OBD Column 19*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 40 mL/minute; Gradient: 24% B to 24% B in 12 minutes; 254/220 nm; R t : 11.43 minutes) to afford 4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino) acetamido]-N-(3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]bicyclo[1.1.1]pentan-1-yl)butane mide (10 mg, 8.07%) as a light yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.75 (d, J=5.9 Hz, 1H), 7.58 (dd, J=9.5.5.0 Hz, 1H), 7.27 (dd, J=8.6, 3.5 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.89 (s, 2H), 5.08 (dd, J=12.4, 5.4 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.01-3.97 (m, 7H), 3.93-3.87 (m, 1H), 3.73 (s, 3H), 3.29-3.23 (m, 2H), 2.97 (s, 3H), 2.90-2.83 (m, 1H), 2.80-2.68 (m, 2H), 2.43 (s, 6H), 2.22 (t, J=7.3 Hz, 2H), 2.16-2.10 (m, 1H), 1.80 (p, J=7.2 Hz, 2H). LCMS (ESI) m/z: [M+H] + =819.35. 
     Example 78—Preparation of N-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-6-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-8-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methyl pentanamide formic acid (Compound D72 Formic acid) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione (i78-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (1.67 g, 6.516 mmol, 1.20 equiv) In NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 6 hours at 90° C. under nitrogen atmosphere. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase. ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2 g, 72%) as a green oil. LCMS (ESI) m/z: [M+H]+=513. 
     Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione (i78-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (430.00 mg, 0.839 mmol, 1.00 equiv) In DCM (3.50 mL) was added TFA (1.00 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro [5.5]undecan-9-yl]isoindole-1,3-dione (670 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H]+=413 
     Step 3: Preparation of methyl 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate (i78-4) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione (200.00 mg, 0.485 mmol, 1.00 equiv) and methyl 5-oxopentanoate (75.73 mg, 0.582 mmol, 1.2 equiv) in MeOH (2.00 mL) was added NaBH 3 CN (60.95 mg, 0.970 mmol, 2 equiv). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether/EtOAc 1:3) to afford methyl 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate (80 mg, 31.33%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =527. 
     Step 4: Preparation of 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoic acid (i78-5) 
     
       
         
         
             
             
         
       
     
     Methyl 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate (70.00 mg, 0.133 mmol, 1.00 equiv) was stirred at room temperature with HCl (aq.) for 2 hours. The resulting mixture was concentrated under reduced pressure. This resulted in 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoic acid (70 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H] + =513. 
     Step 5: Preparation of N-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamide formic acid (Compound D72 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5] undecan-4-yl]pentanoic acid (55.00 mg, 0.107 mmol, 1.00 equiv) and 4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one (36.42 mg, 0.107 mmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA (69.34 mg, 0.537 mmol, 5.00 equiv) and HATU (61.20 mg, 0.161 mmol, 1.50 equiv). The mixture was stirred at room temperature for 1 hours. The crude product (55 mg) was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 9 B to 28 B In 13 minutes; 254 nm; R T : 14.08 minutes) to afford N-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamide formic acid (8.2 mg, 8.68%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.50 (d, J=3.4 Hz, 1H), 8.65 (dd, J=12.4.5.8 Hz, 1H), 8.39 (brs, 0.6H, FA), 7.74 (d, J=4.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.28 (dd, J=12.7, 2.3 Hz, 1H), 7.22-7.14 (m, 1H), 6.80 (d, J=20.6 Hz, 2H), 5.04 (dt, J=12.8, 5.8 Hz, 1H), 4.75 (d, J=16.1 Hz, 2H), 3.90 (d, J=16.5 Hz, 6H), 3.87-3.82 (m, 2H), 3.74-3.63 (m, 5H), 3.32-3.26 (m, 2H), 2.92-2.82 (m, 2H), 2.78 (d, J=6.8 Hz, 4H), 2.73-2.53 (m, 7H), 2.47 (t, J=6.7 Hz, 1H), 2.17-2.01 (m, 3H), 1.82-1.62 (m, 6H). LCMS (ESI) m/z: [M+H] + =834.40. 
     Example 79—Preparation of 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] (methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diaza spiro[5.5]undecan-4-yl]butyl)acetamide formic acid (Compound D73 formic acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate (i79-2) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione (200.00 mg, 0.485 mmol, 1.00 equiv) and tert-butyl N-(4-oxobutyl)carbamate (907.94 mg, 4.849 mmol, 10.00 equiv) in DMF (1.50 mL) was added NaBH 3 CN (60.95 mg, 0.970 mmol, 2.00 equiv). The mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (Petroleum ether/EtOAc 1:3) to afford tert-butyl N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]buty)carbamate (200 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H]+=584. 
     Step 2: Preparation of 5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i79-3) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of tert-butyl N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate (200.00 mg, 0.343 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00 mL). The mixture was stirred at room temperature for 2 hours. The residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH 10:1) to afford 5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (60 mg, 36.21%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=484. 
     Step 3: Preparation of 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperdin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamide formic acid (Compound D73 formic acid) 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (60.00 mg, 0.124 mmol, 1.00 equiv) and ([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetic acid (49.31 mg, 0.124 mmol, 1.00 equiv) in DMF (1.00 mg) was added DIEA (80.18 mg, 0.620 mmol, 5.00 equiv) and HATU (70.77 mg, 0.186 mmol, 1.50 equiv). The mixture was stirred at room temperature for 1 hour. The crude product (60 mg) was purified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 8 B to 17 B in 12 minutes; 254 nm; R T : 11.87 minutes) to afford 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamide formic acid (12.6 mg, 10.72%) as a yellow solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.53 (brs, 0.9H, FA), 7.74 (s, 1H), 7.62 (dd, J=7.3, 6.3 Hz, 2H), 7.27 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.6, 2.4 Hz, 1H), 6.82 (s, 2H), 5.05 (dd, J=12.7, 5.5 Hz, 1H), 4.15 (s, 2H), 3.94 (s, 6H), 3.75 (1, J=4.8 Hz, 2H), 3.69 (s, 3H), 3.64 (d, J=13.0 Hz, 2H), 3.54 (s, 2H), 3.31-3.25 (m, 4H), 2.94-2.81 (m, 1H), 2.80-2.68 (m, 2H), 2.63 (s, 3H), 2.48 (s, 2H), 2.37 (t, J=6.6 Hz, 2H), 2.32 (s, 2H), 2.17-2.00 (m, 3H), 1.68-1.51 (m, 6H). LCMS (ESI) m/z: [M+H] + =863.50. 
     Example 80—Preparation of 5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D74 Formic Acid) 
     
       
         
         
             
             
         
       
     
     Step 1: Preparation of tert-butyl N-(2-(2-[3-([[2-(2,6-dioxopiperdin-3-yl)-1,3-dioxoisoindol-5-yl)oxy]methyl) azetidin-1-yl]-2-oxoethoxy]ethylcarbamate (i80-2) 
     
       
         
         
             
             
         
       
     
     To a solution of [2-[(tert-butoxycarbonyl)amino]ethoxy]acetic acid (30.65 mg, 0.140 mmol, 1.20 equiv) and HATU (88.60 mg, 0.233 mmol, 2.00 equiv) in DMF (1.00 mL) was added 5-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (40.00 mg, 0.117 mmol, 1.00 equiv) and DIEA (45.17 mg, 0.350 mmol, 3.00 equiv), and the resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated. The residue was applied onto a silica gel column with CH 2 Cl 2 /MeOH (20:1). This resulted in (50 mg, 78.81%) of tert-butyl N-(2-[2-[3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]methyl)azetidin-1-yl]-2-oxoethoxy]ethyl)carbamate as a yellow solid. LCMS (ESI) m/z: [M+H]+=545.30. 
     Step 2: Preparation of 5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (i80-3) 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl N-(2-[2-[3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]methyl) azetidin-1-yl]-2-oxoethoxy]ethyl)carbamate (50.00 mg, 0.092 mmol, 1.00 equiv) in TFA (2.00 mL) and DCM (2.00 mL), and the resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated and used directly without further purification. This resulted in (60 mg, crude) of 5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid. LCMS (ESI) m/z: [M+H]+=445.50. 
     Step 3. Preparation of 5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (Compound D74 Formic Acid) 
     
       
         
         
             
             
         
       
     
     To a solution of 5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (20 mg, 0.045 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (17.51 mg, 0.054 mmol, 1.20 equiv) in DMF (2.00 mL) was added NaBH 3 CN (5.68 mg, 0.090 mmol, 2.00 equiv). The resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated. The crude product was purified by preparative HPLC Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R t : 7.12 minutes). This resulted in (10 mg, 27.82%) of 5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl] amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as an off-white solid.  1 H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.57 (brs, 3.2H, FA), 7.82 (d, J=8.3 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J=5.7 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.35 (dd, J=8.1, 2.3 Hz, 1H), 6.84 (s, 2H), 5.12 (dd, J=12.6, 5.4 Hz, 1H), 4.40 (t, J=8.8 Hz, 1H), 4.35 (d, J=3.8 Hz, 4H), 4.27-4.13 (m, 4H), 4.02-3.93 (m, 7H), 3.83 (t, J=4.9 Hz, 2H), 3.71 (s, 3H), 3.27-3.21 (m, 3H), 2.94-2.83 (m, 1H), 2.82-2.67 (m, 2H), 2.20-2.10 (m, 1H). LCMS (ESI) m/z: [M+H]+=753.40. 
     Example 81—Preparation of Compounds 1D75-13177 
     In analogy to the procedures described in the examples above, compounds D75-D177 were prepared using the appropriate starting materials. 
     
       
         
           
               
               
             
               
                   
               
               
                 Compound 
                   
               
               
                 No. 
                 Analytical Data 
               
               
                   
               
             
            
               
                 D75  
                 LCMS: (ESI) m/z: [M + H] +  = 835.70 
               
               
                 D76  
                 LCMS: (ESI) m/z: [M + H] +  = 788.20 
               
               
                 D77  
                 LCMS: (ESI) m/z: [M + H] +  = 774.10 
               
               
                 D78  
                 LCMS: 789.2;  1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H), 
               
               
                   
                 8.73 (d, J = 5.7 Hz, 1H), 8.21 (s, 0.7H, FA), 8.05 (d, J = 7.5 Hz, 1H), 7.87 (s, 
               
               
                   
                 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59-7.54 (m, 1H), 7.31-7.24 (m, 2H), 6.73 
               
               
                   
                 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t, J = 6.8 Hz, 1H), 4.14-3.99 
               
               
                   
                 (m, 1H), 3.81 (s, 6H), 3.66 (s, 2H), 3.61 (s, 3H), 3.44-3.35 (m, 3H), 2.98 
               
               
                   
                 (s, 2H), 2.92-2.83 (m, 1H), 2.73-2.55 (m, 4H), 2.44-2.32 (m, 1H), 2.25 
               
               
                   
                 (dd, J = 18.0, 6.8 Hz, 3H), 2.15-2.00 (m, 3H), 1.95 (td, J = 11.2, 8.4 Hz, 
               
               
                   
                 2H). 
               
               
                 D79  
                 LCMS: (ESI) m/z: [M + H] +  = 789.20;  1 H NMR (400 MHz, DMSO-d6) δ 11.11 
               
               
                   
                 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.21 (s, 0.7H, FA), 8.05 (d, J = 
               
               
                   
                 7.5 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59-7.54 (m, 1H), 
               
               
                   
                 7.31-7.24 (m, 2H), 6.73 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t, J = 
               
               
                   
                 6.8 Hz, 1H), 4.14-3.99 (m, 1H), 3.81 (s, 6H), 3.66 (s, 2H), 3.61 (s, 3H), 
               
               
                   
                 3.44-3.35 (m, 3H), 2.98 (s, 2H), 2.92-2.83 (m, 1H), 2.73-2.55 (m, 4H), 
               
               
                   
                 2.44-2.32 (m, 1H), 2.25 (dd, J = 18.0, 6.8 Hz, 3H), 2.15-2.00 (m, 3H), 
               
               
                   
                 1.95 (td, J = 11.2, 8.4 Hz, 2H). 
               
               
                 D80  
                 LCMS: (ESI) m/z: [M + H] +  = 803.15;  1 H NMR (400 MHz, DMSO-d6) δ 11.12 
               
               
                   
                 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.21 (s, 0.6H, FA), 7.97- 
               
               
                   
                 7.77 (m, 2H), 7.56 (d, J = 5.7 Hz, 1H), 7.37-7.20 (m, 2H), 6.74 (s, 2H), 
               
               
                   
                 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.10-4.97 (m, 1H), 3.82 (d, J = 2.0 Hz, 
               
               
                   
                 6H), 3.70 (s, 2H), 3.61 (s, 3H), 3.36 (s, 5H), 3.09-2.95 (m, 2H), 2.88 (d, J = 
               
               
                   
                 13.9 Hz, 1H), 2.58 (d, J = 10.3 Hz, 8H), 2.16-1.99 (m, 1H), 1.87 (d, J =  
               
               
                   
                 9.8 Hz, 2H), 1.63 (s, 1H), 1.55 (s, 2H), 1.47 (s, 1H). 
               
               
                 D81  
                 LCMS: (ESI) m/z: [M + H] +  = 715.20 
               
               
                 D82  
                 LCMS: (ESI) m/z: [M + H] +  = 821.25;  1 H NMR (300 MHz, Methanol-d4) δ 9.54 
               
               
                   
                 (d, J = 0.9 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.54 (s, 0.4H, FA), 7.86-7.75 
               
               
                   
                 (m, 2H), 7.63 (dd, J = 5.8, 0.9 Hz, 1H), 7.50 (dd, J = 7.8, 5.7 Hz, 2H), 6.87 
               
               
                   
                 (s, 2H), 5.14 (dd, J = 12.3, 5.4 Hz, 1H), 4.44-4.32 (m, 4H), 4.24 (p, J = 8.3 
               
               
                   
                 Hz, 1H), 3.97 (s, 6H), 3.93-3.83 (m, 4H), 3.72 (s, 3H), 3.22-3.02 (m, 2H), 
               
               
                   
                 2.99-2.65 (m, 4H), 2.46 (t, J = 5.9 Hz, 2H), 2.27 (s, 2H), 2.22-2.09 (m, 
               
               
                   
                 2H), 1.91 (s, 2H), 1.76 (s, 4H). 
               
               
                 D83  
                 LCMS: (ESI) m/z: [M + H] +  = 781.55;  1 H NMR (300 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.82-7.66 (m, 2H), 7.50- 
               
               
                   
                 7.36 (m, 2H), 6.85 (d, J = 1.2 Hz, 2H), 5.12 (dd, J = 12.5, 5.4 Hz, 1H), 4.50 
               
               
                   
                 (s, 1H), 4.42 (s, 1H), 4.35-4.11 (m, 4H), 4.02 (dd, J = 11.0, 6.7 Hz, 1H), 
               
               
                   
                 3.94 (d, J = 2.7 Hz, 6H), 3.91-3.76 (m, 5H), 3.71 (d, J = 1.5 Hz, 3H), 3.22 
               
               
                   
                 (t, J = 6.5 Hz, 2H), 3.08-2.59 (m, 4H), 2.46 (t, J = 5.8 Hz, 2H), 2.21-2.07 
               
               
                   
                 (m, 1H), 1.84 (p, J = 7.2, 6.7 Hz, 2H). 
               
               
                 D84  
                 LCMS: (ESI) m/z: [M + H] +  = 793.55 
               
               
                 D85  
                 LCMS: (ESI) m/z: [M + H] +  = 807.25 
               
               
                 D86  
                 LCMS: (ESI) m/z: [M + H] +  = 779.20 
               
               
                 D87  
                 LCMS: (ESI) m/z: [M + H] +  = 793.45 
               
               
                 D88  
                 LCMS: (ESI) m/z: [M + H] +  = 807.90;  1 H NMR (400 MHz, Methanol-d4) δ 9.55 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.56 (s, 0.5H, FA), 7.86-7.73 
               
               
                   
                 (m, 2H), 7.63 (d, J = 5.8 Hz, 1H), 7.48 (dd, J = 7.9, 6.2 Hz, 2H), 6.85 (s, 
               
               
                   
                 2H), 5.24-5.02 (m, 1H), 4.38 (t, J = 4.3 Hz, 2H), 4.33 (s, 2H), 3.95 (s, 6H), 
               
               
                   
                 3.93-3.81 (m, 4H), 3.72 (s, 4H), 3.71-3.40 (m, 4H), 3.25-3.01 (m, 3H), 
               
               
                   
                 2.98-2.82 (m, 2H), 2.82-2.61 (m, 3H), 2.21-2.07 (m, 1H), 1.91 (s, 2H), 
               
               
                   
                 1.63 (d, J = 17.7 Hz, 4H). 
               
               
                 D89  
                 LCMS: (ESI) m/z: [M + H] +  = 821.30 
               
               
                 D90  
                 LCMS: (ESI) m/z: [M + H] +  = 793.45 
               
               
                 D91  
                 LCMS: (ESI) m/z: [M + H] +  = 807.50 
               
               
                 D92  
                 LCMS: (ESI) m/z: [M + H] +  = 793.60;  1 H NMR (300 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (s, 1H), 8.68 (dd, J = 5.8, 2.4 Hz, 1H), 8.52 (s, 0.5H, FA), 7.90-7.73 (m, 
               
               
                   
                 2H), 7.62 (s, 1H), 7.47 (dd, J = 9.3, 3.5 Hz, 2H), 6.89-6.74 (m, 2H), 5.24- 
               
               
                   
                 5.04 (m, 1H), 4.31 (d, J = 33.1 Hz, 5H), 3.90 (dd, J = 6.6, 4.5 Hz, 12H), 3.78- 
               
               
                   
                 3.58 (m, 7H), 3.00-2.48 (m, 6H), 2.26-1.78 (m, 3H). 
               
               
                 D93  
                 LCMS: (ESI) m/z: [M + H] +  = 793.50 
               
               
                 D94  
                 LCMS: (ESI) m/z: [M + H] +  = 865.55 
               
               
                 D95  
                 LCMS: (ESI) m/z: [M + H] +  = 793.65 
               
               
                 D96  
                 LCMS: (ESI) m/z: [M + H] +  = 835.45 
               
               
                 D97  
                 LCMS: (ESI) m/z: [M + H] +  = 865.50;  1 H NMR (300 MHz, Methanol-d4) δ 9.54 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.55 (s, 0.6H, FA), 7.90-7.71 
               
               
                   
                 (m, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.48 (dd, J = 7.9, 3.5 Hz, 2H), 6.87 (s, 
               
               
                   
                 2H), 5.12 (dd, 12.3, 5.4 Hz, 1H), 4.50-4.23 (m, 4H), 3.97 (s, 6H), 3.95- 
               
               
                   
                 3.79 (m, 5H), 3.72 (s, 5H), 3.66 (dd, J = 5.8, 1.9 Hz, 1H), 3.59-3.32 (m, 
               
               
                   
                 3H), 3.30-2.98 (m, 2H), 2.98-2.59 (m, 6H), 2.25-1.70 (m, 7H), 1.49 (s, 
               
               
                   
                 2H). 
               
               
                 D98  
                 LCMS: (ESI) m/z: [M + H] +  = 779.40;  1 H NMR (400 MHz, Methanol-d4) δ 9.51 
               
               
                   
                 (d, J = 1.5 Hz, 1H), 8.67 (d, J = 5.7 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.63- 
               
               
                   
                 7.49 (m, 2H), 7.27 (dd, J = 5.8, 2.3 Hz, 1H), 7.16 (ddd, J = 11.0, 8.4, 2.3 Hz, 
               
               
                   
                 1H), 6.65 (d, J = 2.1 Hz, 2H), 5.04 (td, J = 12.4, 5.5 Hz, 1H), 4.80 (d, J =  
               
               
                   
                 10.2 Hz, 1H), 4.33 (d, J = 10.5 Hz, 2H), 4.25 (d, J = 16.3 Hz, 2H), 4.03 (d, J = 
               
               
                   
                 11.4 Hz, 1H), 3.95-3.74 (m, 12H), 3.74 (d, J = 1.3 Hz, 4H), 3.39-3.30 
               
               
                   
                 (m, 1H), 2.80 (dt, J = 13.9, 4.7 Hz, 1H), 2.76-2.54 (m, 3H), 2.46-2.22 (m, 
               
               
                   
                 3H), 2.03 (td, J = 7.3, 6.8, 3.3 Hz, 1H). 
               
               
                 D99  
                 LCMS: (ESI) m/z: [M + H] +  = 793.45 
               
               
                 D100 
                 LCMS: (ESI) m/z: [M + H] +  = 793.35 
               
               
                 D101 
                 LCMS: (ESI) m/z: [M + H] +  = 793.45;  1 H NMR (300 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.56 (s, 0.7H, FA), 7.86-7.73 
               
               
                   
                 (m, 2H), 7.64-7.56 (m, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 
               
               
                   
                 Hz, 1H), 6.84 (s, 2H), 5.12 (dd, J = 12.4, 5.4 Hz, 1H), 4.36-4.20 (m, 4H), 
               
               
                   
                 4.20-4.05 (m, 3H), 3.96 (d, J = 8.5 Hz, 8H), 3.90-3.75 (m, 4H), 3.71 (s, 
               
               
                   
                 3H), 2.97-2.55 (m, 5H), 2.43 (t, J = 5.9 Hz, 2H), 2.25-2.08 (m, 3H). 
               
               
                 D102 
                 LCMS: (ESI) m/z: [M + H] +  = 761.2 
               
               
                 D103 
                 LCMS: (ESI) m/z: [M + H] +  = 747.3 
               
               
                 D104 
                 LCMS: (ESI) m/z: [M + H] +  = 747.3 
               
               
                 D105 
                 LCMS: (ESI) m/z: [M + H] +  = 719.3 
               
               
                 D106 
                 LCMS: (ESI) m/z: [M + H] +  = 733.4 
               
               
                 D107 
                 LCMS: (ESI) m/z: [M + H] +  = 733.3 
               
               
                 D108 
                 LCMS: (ESI) m/z: [M + H] +  = 807.45 
               
               
                 D109 
                 LCMS: (ESI) m/z: [M + H] +  = 865.35 
               
               
                 D110 
                 LCMS: (ESI) m/z: [M + H] +  = 835.75 
               
               
                 D111 
                 LCMS: (ESI) m/z: [M + H] +  = 793.50 
               
               
                 D112 
                 LCMS: (ESI) m/z: [M + H] +  = 793.50 
               
               
                 D113 
                 LCMS: (ESI) m/z: [M + H] +  = 779.35 
               
               
                 D114 
                 LCMS: (ESI) m/z: [M + H] +  = 851.25 
               
               
                 D115 
                 LCMS: (ESI) m/z: [M + H] +  = 793.45 
               
               
                 D116 
                 LCMS: (ESI) m/z: [M + H] +  = 821.30 
               
               
                 D117 
                 LCMS: (ESI) m/z: [M + H] +  = 781.60;  1 H NMR (300 MHz, Methanol-d4) δ 9.51 
               
               
                   
                 (s, 1H), 8.68 (d, J = 5.8 Hz, 1H), 8.56 (s, 0.7H, FA), 7.76 (d, J = 8.6 Hz, 2H), 
               
               
                   
                 7.60 (d, J = 5.8 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.3, 2.3 Hz, 
               
               
                   
                 1H), 6.84 (s, 2H), 5.10 (dd, J = 12.5, 5.4 Hz, 1H), 4.37 (s, 2H), 4.33-4.24 
               
               
                   
                 (m, 2H), 4.22-4.08 (m, 2H), 3.95 (s, 6H), 3.85 (dq, J = 7.2, 5.7 Hz, 6H), 
               
               
                   
                 3.70 (s, 3H), 3.20 (t, J = 6.5 Hz, 2H), 3.02-2.62 (m, 4H), 2.47 (t, J = 5.8 
               
               
                   
                 Hz, 2H), 2.23-2.05 (m, 1H), 1.84 (q, J = 6.9 Hz, 2H). 
               
               
                 D118 
                 LCMS: (ESI) m/z: [M + H] +  = 807.60;  1 H NMR (300 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.55 (s, 0.7H, FA), 7.89-7.75 
               
               
                   
                 (m, 2H), 7.61 (dd, J = 5.8, 0.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.37-7.30 
               
               
                   
                 (m, 1H), 6.85 (s, 2H), 5.10 (dd, J = 12.4, 5.4 Hz, 1H), 4.41 (s, 2H), 4.35- 
               
               
                   
                 4.25 (m, 2H), 3.95 (s, 6H), 3.91-3.77 (m, 8H), 3.72 (s, 3H), 3.54 (q, J = 5.6 
               
               
                   
                 Hz, 4H), 2.96-2.63 (m, 5H), 2.12 (dtd, J = 12.8, 4.8, 2.1 Hz, 1H), 1.83 (dt, 
               
               
                   
                 J = 16.1, 5.8 Hz, 4H). 
               
               
                 D119 
                 LCMS: (ESI) m/z: [M + H] +  = 807.45 
               
               
                 D120 
                 LCMS: (ESI) m/z: [M + H] +  = 821.45 
               
               
                 D121 
                 LCMS: (ESI) m/z: [M + H] +  = 807.40;  1 H NMR (400 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (d, J = 1.0 Hz, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.54 (s, 0.5H, FA), 7.88-7.73 
               
               
                   
                 (m, 2H), 7.66-7.59 (m, 1H), 7.41 (dd, J = 4.4, 2.3 Hz, 1H), 7.32 (ddd, J =  
               
               
                   
                 8.1, 6.0, 2.1 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 5.10 (dd, J = 6.9, 5.4 Hz, 1H), 
               
               
                   
                 4.38 (s, 1H), 4.30 (d, J = 4.9 Hz, 3H), 3.95 (d, J = 8.8 Hz, 6H), 3.87 (t, J =  
               
               
                   
                 4.6 Hz, 4H), 3.71 (d, J = 1.2 Hz, 3H), 3.71-3.56 (m, 2H), 3.55-3.37 (m, 
               
               
                   
                 3H), 3.33-3.26 (m, 3H), 2.97-2.52 (m, 5H), 2.21-1.92 (m, 5H). 
               
               
                 D122 
                 LCMS: (ESI) m/z: [M + H] +  = 793.35;  1 H NMR (400 MHz, Methanol-d4) δ 9.53 
               
               
                   
                 (d, J = 2.5 Hz, 1H), 8.68 (dd, J = 5.7, 1.6 Hz, 1H), 8.54 (s, 0.6H, FA), 7.85- 
               
               
                   
                 7.70 (m, 2H), 7.60 (dd, J = 6.0, 3.1 Hz, 1H), 7.42 (dd, J = 3.5, 2.2 Hz, 1H), 
               
               
                   
                 7.37-7.29 (m, 1H), 6.84 (d, J = 9.2 Hz, 2H), 5.11 (dd, J = 12.5, 5.4 Hz, 
               
               
                   
                 1H), 4.40 (s, 1H), 4.31 (dt, J = 6.1, 3.1 Hz, 3H), 4.08-4.00 (m, 2H), 3.99- 
               
               
                   
                 3.91 (m, 8H), 3.90-3.82 (m, 4H), 3.81 (s, 1H), 3.71 (d, J = 1.2 Hz, 3H), 
               
               
                   
                 3.68-3.58 (m, 2H), 3.47 (t, J = 7.1 Hz, 1H), 2.96-2.81 (m, 1H), 2.74 (dtt, 
               
               
                   
                 J = 12.1, 6.1 3.4 Hz, 2H), 2.62 (dt, J = 11.5, 5.9 Hz, 2H), 2.25 (t, J = 7.0 Hz, 
               
               
                   
                 1H), 2.22-2.05 (m, 2H). 
               
               
                 D123 
                 LCMS: (ESI) m/z: [M + H] +  = 807.30 
               
               
                 D124 
                 LCMS: (ESI) m/z: [M + H] +  = 865.90 
               
               
                 D125 
                 LCMS: (ESI) m/z: [M + H] +  = 793.20 
               
               
                 D126 
                 LCMS: (ESI) m/z: [M + H] +  = 793.20 
               
               
                 D127 
                 LCMS: (ESI) m/z: [M + H] +  = 793.55 
               
               
                 D128 
                 LCMS: (ESI) m/z: [M + H] +  = 779.40 
               
               
                 D129 
                 LCMS: (ESI) m/z: [M + H] +  = 835.70 
               
               
                 D130 
                 LCMS: (ESI) m/z: [M + H] +  = 851.40 
               
               
                 D131 
                 LCMS: (ESI) m/z: [M + H] +  = 865.35 
               
               
                 D132 
                 LCMS: (ESI) m/z: [M + H] +  = 775.3 
               
               
                 D133 
                 LCMS: (ESI) m/z: [M + H] +  = 777.5 
               
               
                 D134 
                 LCMS: (ESI) m/z: [M + H] +  = 761.4 
               
               
                 D135 
                 LCMS: (ESI) m/z: [M + H] +  = 763.4 
               
               
                 D136 
                 LCMS: (ESI) m/z: [M + H] +  = 775.2 
               
               
                 D137 
                 LCMS: (ESI) m/z: [M + H] +  = 789.3 
               
               
                 D138 
                 LCMS: (ESI) m/z: [M + H] +  = 803.5 
               
               
                 D139 
                 LCMS: (ESI) m/z: [M + H] +  = 805.4 
               
               
                 D140 
                 LCMS: (ESI) m/z: [M + H] +  = 775.2 
               
               
                 D141 
                 LCMS: (ESI) m/z: [M + H] +  = 789.3 
               
               
                 D142 
                 LCMS: (ESI) m/z: [M + H] +  = 803.5 
               
               
                 D143 
                 LCMS: (ESI) m/z: [M + H] +  = 817.5 
               
               
                 D144 
                 LCMS: (ESI) m/z: [M + H] +  = 819.3 
               
               
                 D145 
                 LCMS: (ESI) m/z: [M + H] +  = 689.3 
               
               
                 D146 
                 LCMS: (ESI) m/z: [M + H] +  = 717.3 
               
               
                 D147 
                 LCMS: (ESI) m/z: [M + H] +  = 731.4 
               
               
                 D148 
                 LCMS: (ESI) m/z: [M + H] +  = 745.2 
               
               
                 D149 
                 LCMS: (ESI) m/z: [M + H] +  = 745.3 
               
               
                 D150 
                 LCMS: (ESI) m/z: [M + H] +  = 789.5 
               
               
                 D151 
                 LCMS: (ESI) m/z: [M + H] +  = 805.9 
               
               
                 D152 
                 LCMS: (ESI) m/z: [M + H] +  = 831.4 
               
               
                 D153 
                 LCMS: (ESI) m/z: [M + H] +  = 833.3 
               
               
                 D154 
                 LCMS: (ESI) m/z: [M + H] +  = 789.3 
               
               
                 D155 
                 LCMS: (ESI) m/z: [M + H] +  = 803.2 
               
               
                 D156 
                 LCMS: (ESI) m/z: [M + H] +  = 817.6 
               
               
                 D157 
                 LCMS: (ESI) m/z: [M + H] +  = 831.6 
               
               
                 D158 
                 LCMS: (ESI) m/z: [M + H] +  = 833.5 
               
               
                 D159 
                 LCMS: (ESI) m/z: [M + H] +  = 851.25 
               
               
                 D160 
                 LCMS: (ESI) m/z: [M + H] +  = 821.45 
               
               
                 D161 
                 LCMS: (ESI) m/z: [M + H] +  = 821.35 
               
               
                 D162 
                 LCMS: (ESI) m/z: [M + H] +  = 807.35 
               
               
                 D163 
                 LCMS: (ESI) m/z: [M + H] +  = 835.50 
               
               
                 D164 
                 LCMS: (ESI) m/z: [M + H] +  = 821.60 
               
               
                 D165 
                 LCMS: (ESI) m/z: [M + H] +  = 849.60;  1 H NMR (300 MHz, Methanol-d4) δ  
               
               
                   
                 9.60-9.41 (m, 1H), 8.69 (dd, J = 5.6, 3.0 Hz, 1H), 8.53 (s, 0.6H, FA), 7.79- 
               
               
                   
                 7.50 (m, 3H), 7.44-7.15 (m, 2H), 6.81-6.47 (m, 2H), 5.11 (dt, J = 11.6, 
               
               
                   
                 4.5 Hz, 1H), 4.57-4.07 (m, 5H), 4.05-3.76 (m, 13H), 3.74-3.66 (m, 3H), 
               
               
                   
                 3.64-3.44 (m, 1H), 3.05-2.65 (m, 5H), 2.64-2.02 (m, 6H). 
               
               
                 D166 
                 LCMS: (ESI) m/z: [M + H] +  = 835.65 
               
               
                 D167 
                 LCMS: (ESI) m/z: [M + H] +  = 851.25 
               
               
                 D168 
                 LCMS: (ESI) m/z: [M + H] +  = 851.25 
               
               
                 D169 
                 LCMS: (ESI) m/z: [M + H] +  = 821.35 
               
               
                 D170 
                 LCMS: (ESI) m/z: [M + H] +  = 821.35 
               
               
                 D171 
                 LCMS: (ESI) m/z: [M + H] +  = 807.35 
               
               
                 D172 
                 LCMS: (ESI) m/z: [M + H] +  = 835.35 
               
               
                 D173 
                 LCMS: (ESI) m/z: [M + H] +  = 835.60 
               
               
                 D174 
                 LCMS: (ESI) m/z: [M + H] +  = 821.65 
               
               
                 D175 
                 LCMS: (ESI) m/z: [M + H] +  = 849.80 
               
               
                 D176 
                 LCMS: (ESI) m/z: [M + H] +  = 835.70 
               
               
                 D177 
                 LCMS: (ESI) m/z: [M + H] +  = 835.65 
               
               
                   
               
            
           
         
       
     
     Example 82—Preparation of Compounds D178-D37 
     In analogy to the procedures described in the examples above, compounds D178-D371 were prepared using the appropriate starting materials. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Compound 
                   
                   
               
               
                 No. 
                 LCMS 
                   1 H NMR 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 D178 
                 723.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 1.55 (2H, d), 1.77 (2H, d), 2.03 
               
               
                   
                   
                 (3H, d), 2.16 (3H, s), 2.44 (3H, d), 2.73 (2H, s), 2.88-3.08 (3H, 
               
               
                   
                   
                 m), 3.61 (5H, s), 3.80 (6H, s), 4.30 (2H, s), 5.12 (1H, m), 6.72 (2H, 
               
               
                   
                   
                 s), 7.38 (1H, m), 7.48 (1H, d), 7.57 (1H, d), 7.80-7.90 (2H, m), 
               
               
                   
                   
                 8.23 (1H, s), 8.72 (1H, d), 9.45 (1H, s), 11.12 (1H, s). 
               
               
                 D179 
                 813.3 
                   1 H NMR(400 MHz, D .79 (brs, 0.8H, FA(COOH), 11.08 (s, 1H), 
               
               
                   
                   
                 9.44 (s, 1H), 8.71 (d, J = 5.7 Hz, 1H), 8.14 (s, 0.8H, FA), 7.86 (s, 
               
               
                   
                   
                 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 5.8 Hz, 1H), 7.33 (d, J = 
               
               
                   
                   
                 2.3 Hz, 1H), 7.24 (dd, J = 8.8, 2.3 Hz, 1H), 7.11 (s, 1H), 6.73 (s, 
               
               
                   
                   
                 2H), 5.07 (dd, J = 13.0, 5.4 Hz, 1H), 4.08-4.02 (m, 1H), 3.82 (s, 
               
               
                   
                   
                 7H), 3.69-3.62 (m, 2H), 3.60 (s, 3H), 3.50-3.39 (m, 8H), 3.12- 
               
               
                   
                   
                 3.05 (m, 2H), 2.95-2.83 (m, 1H), 2.63-2.55 (m, 3H), 2.55 (s, 
               
               
                   
                   
                 2H), 2.47-2.39 (m, 3H), 2.07-1.98 (m, 1H). 
               
               
                 D180 
                 788.2 
               
               
                 D181 
                 774.7 
               
               
                 D182 
                 789.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.21 (s, 0.7H, FA), 8.05 (d, J = 7.5 Hz, 1H), 
               
               
                   
                   
                 7.87 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59-7.54 (m, 1H), 7.31- 
               
               
                   
                   
                 7.24 (m, 2H), 6.73 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t, 
               
               
                   
                   
                 J = 6.8 Hz, 1H), 4.14-3.99 (m, 1H), 3.81 (s, 6H), 3.66 (s, 2H), 3.61 
               
               
                   
                   
                 (s, 3H), 3.44-3.35 (m, 3H), 2.98 (s, 2H), 2.92-2.83 (m, 1H), 2.73- 
               
               
                   
                   
                 2.55 (m, 4H), 2.44-2.32 (m, 1H), 2.25 (dd, J = 18.0, 6.8 Hz, 3H), 
               
               
                   
                   
                 2.15-2.00 (m, 3H), 1.95 (td, J = 11.2, 8.4 Hz, 2H). 
               
               
                 D183 
                 789.5 
               
               
                 D184 
                 803.15 
               
               
                 D185 
                 715.2 
               
               
                 D186 
                 804.65 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.45 (d, J = 4.3 Hz, 
               
               
                   
                   
                 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.16 (s, 0.6H, FA), 7.90 (d, J = 6.4 
               
               
                   
                   
                 Hz, 1H), 7.64 (dd, J = 8.3, 2.2 Hz, 1H), 7.58 (d, J = 5.7 Hz, 1H), 
               
               
                   
                   
                 6.90-6.72 (m, 3H), 6.65 (dd, J = 8.5, 2.3 Hz, 1H), 5.06 (dd, J = 
               
               
                   
                   
                 12.9, 5.4 Hz, 1H), 4.57 (d, J = 23.1 Hz, 2H), 3.83 (d, J = 18.2 Hz, 
               
               
                   
                   
                 6H), 3.74 (s, 4H), 3.60 (d, J = 3.3 Hz, 3H), 2.88 (ddd, J = 17.7, 
               
               
                   
                   
                 14.0, 5.4 Hz, 1H), 2.72 (s, 1H), 2.65 (s, 2H), 2.62-2.53 (m, 4H), 
               
               
                   
                   
                 2.44-2.26 (m, 6H), 2.08-1.94 (m, 1H), 1.77 (d, J = 6.5 Hz, 4H), 
               
               
                   
                   
                 1.53 (s, 4H). 
               
               
                 D187 
                 790.5 
               
               
                 D188 
                 804.6 
               
               
                 D189 
                 802.65 
               
               
                 D190 
                 788.6 
               
               
                 D191 
                 802.55 
               
               
                 D192 
                 788.8 
               
               
                 D193 
                 774.55 
               
               
                 D194 
                 774.75 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.22 (s, 1H, FA), 8.12 (d, J = 7.4 Hz, 1H), 7.88 
               
               
                   
                   
                 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 5.7 Hz, 1H), 6.74 (d, 
               
               
                   
                   
                 J = 6.3 Hz, 3H), 6.67-6.56 (m, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 
               
               
                   
                   
                 4.08 (d, J = 10.2 Hz, 3H), 3.97 (s, 2H), 3.82 (s, 6H), 3.67 (s, 2H), 
               
               
                   
                   
                 3.61 (s, 3H), 3.51 (s, 2H), 3.01 (d, J = 7.1 Hz, 2H), 2.95-2.80 (m, 
               
               
                   
                   
                 1H), 2.65-2.53 (m, 5H), 2.29 (d, J = 7.6 Hz, 2H), 2.12 (t, J = 10.3 
               
               
                   
                   
                 Hz, 2H), 2.07-1.93 (m, 1H). 
               
               
                 D195 
                 760.5 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.45 (s, 1H), 8.74 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, 
               
               
                   
                   
                 J = 5.6 Hz, 1H), 6.82 (d, J = 2.4 Hz, 3H), 6.68 (dd, J = 8.4, 2.1 Hz, 
               
               
                   
                   
                 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.32 (s, 2H), 4.20 (s, 6H), 4.06 
               
               
                   
                   
                 (s, 3H), 3.88 (s, 8H), 3.61 (s, 4H), 2.98-2.74 (m, 2H), 2.59 (d, J = 
               
               
                   
                   
                 16.5 Hz, 2H), 2.44 (d, J = 7.2 Hz, 2H), 2.11-1.95 (m, 1H). 
               
               
                 D196 
                 757.5 
               
               
                 D197 
                 743.35 
               
               
                 D198 
                 743.25 
               
               
                 D199 
                 731.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.52 (s, 1H), 8.77 
               
               
                   
                   
                 (d, J = 6.0 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85 (dd, 
               
               
                   
                   
                 J = 5.5, 1.6 Hz, 2H), 7.75 (d, J = 6.0 Hz, 1H), 6.87 (s, 2H), 5.16 (dd, 
               
               
                   
                   
                 J = 12.8, 5.4 Hz, 1H), 4.43 (d, J = 13.9 Hz, 1H), 4.29 (s, 2H), 4.14- 
               
               
                   
                   
                 4.03 (m, 1H), 3.91 (s, 6H), 3.64 (s, 4H), 3.40 (t, J = 8.2 Hz, 2H), 
               
               
                   
                   
                 3.18 (m, 2H), 3.23-3.13 (m, 2H), 3.02-2.72 (m, 4H), 2.68-2.56 
               
               
                   
                   
                 (m, 2H), 2.12-1.99 (m, 1H). 
               
               
                 D200 
                 743.15 
               
               
                 D201 
                 804.7 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.45 (t, J = 1.4 Hz, 
               
               
                   
                   
                 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.23 (s, 0.8H, FA), 7.90 (d, J = 6.0 
               
               
                   
                   
                 Hz, 1H), 7.76-7.56 (m, 2H), 7.40-7.16 (m, 2H), 6.77 (d, J = 10.7 
               
               
                   
                   
                 Hz, 2H), 5.17-4.99 (m, 1H), 4.56 (d, J = 19.2 Hz, 2H), 3.83 (d, J = 
               
               
                   
                   
                 13.5 Hz, 6H), 3.60 (d, J = 2.3 Hz, 3H), 3.43 (s, 6H), 3.01 (d, J = 5.0 
               
               
                   
                   
                 Hz, 4H), 2.98-2.78 (m, 1H), 2.72 (d, J = 5.9 Hz, 1H), 2.65 (s, 2H), 
               
               
                   
                   
                 2.63-2.55 (m, 1H), 2.47 (s, 2H), 2.27 (dd, J = 4.3, 2.4 Hz, 1H), 
               
               
                   
                   
                 2.10-1.91 (m, 1H), 1.73 (d, J = 6.4 Hz, 4H), 1.62-1.47 (m, 2H), 
               
               
                   
                   
                 1.44-1.26 (m, 2H). 
               
               
                 D202 
                 818.4 
               
               
                 D203 
                 790.6 
               
               
                 D204 
                 790.8 
               
               
                 D205 
                 776.35 
               
               
                 D206 
                 776.6 
               
               
                 D207 
                 805.65 
               
               
                 D208 
                 819.55 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.72 
               
               
                   
                   
                 (dd, J = 5.7, 2.2 Hz, 1H), 8.20 (s, 0.6H, FA), 7.90 (d, J = 3.6 Hz, 
               
               
                   
                   
                 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 (dt, J = 5.7, 1.2 Hz, 1H), 7.37- 
               
               
                   
                   
                 7.22 (m, 2H), 6.77 (d, J = 9.7 Hz, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 
               
               
                   
                   
                 1H), 5.04-4.92 (m, 1H), 4.56 (d, J = 17.5 Hz, 2H), 3.82 (d, J = 
               
               
                   
                   
                 13.3 Hz, 6H), 3.60 (s, 3H), 2.90 (ddd, J = 17.3, 13.9, 5.4 Hz, 1H), 
               
               
                   
                   
                 2.71 (s, 1H), 2.61 (d, J = 20.0 Hz, 5H), 2.47-2.22 (m, 9H), 2.06 (d, 
               
               
                   
                   
                 J = 5.9 Hz, 1H), 1.80 (dd, J = 12.2, 6.3 Hz, 2H), 1.70-1.43 (m, 
               
               
                   
                   
                 8H). 
               
               
                 D209 
                 774.6 
               
               
                 D210 
                 760.7 
               
               
                 D211 
                 743.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.44 (s, 1H), 8.72 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.94-7.79 (m, 4H), 7.56 (d, J = 
               
               
                   
                   
                 5.7 Hz, 1H), 6.75 (s, 2H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 3.82 (d, 
               
               
                   
                   
                 J = 9.2 Hz, 8H), 3.60 (s, 4H), 3.46-3.40 (m, 6H), 2.90 (ddd, J = 16.9, 
               
               
                   
                   
                 13.8, 5.4 Hz, 1H), 2.70 (s, 2H), 2.66-2.53 (m, 5H), 2.07 (ddd, J = 
               
               
                   
                   
                 13.3, 5.6, 3.2 Hz, 1H), 1.94 (t, J = 7.0 Hz, 2H), 1.74 (p, J = 7.1 Hz, 
               
               
                   
                   
                 2H). 
               
               
                 D212 
                 757.35 
               
               
                 D213 
                 771.2 
               
               
                 D214 
                 717.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.19 (s, 1H FA), 7.87 (d, J = 9.1 Hz, 4H), 7.58 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 6.74 (s, 2H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 
               
               
                   
                   
                 3.81 (s, 6H), 3.60 (s, 6H), 3.47 (s, 5H), 2.94-2.85 (m, 1H), 2.68- 
               
               
                   
                   
                 2.58 (m, 2H), 2.44 (t, J = 7.2 Hz, 6H), 2.12-2.01 (m, 1H), 1.73 (p, 
               
               
                   
                   
                 J = 7.1 Hz, 2H). 
               
               
                 D215 
                 729.35 
               
               
                 D216 
                 703.15 
               
               
                 D217 
                 771.15 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.47 (s, 1H), 8.75 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 7.97-7.79 (m, 4H), 7.58 (d, J = 5.6 Hz, 1H), 
               
               
                   
                   
                 6.87 (s, 2H), 5.16 (dd, J = 12.9, 5.3 Hz, 1H), 4.27 (d, J = 4.0 Hz, 
               
               
                   
                   
                 2H), 4.02 (s, 1H), 3.90 (s, 7H), 3.75 (s, 1H), 3.62 (s, 4H), 3.11 (s, 
               
               
                   
                   
                 2H), 3.08 (s, 2H), 2.96-2.84 (m, 1H), 2.69 (dd, J = 7.2, 3.6 Hz, 
               
               
                   
                   
                 2H), 2.66-2.54 (m, 2H), 2.47-2.39 (m, 2H), 2.13-2.00 (m, 3H), 
               
               
                   
                   
                 1.92 (t, J = 12.4 Hz, 2H). 
               
               
                 D218 
                 757.35 
               
               
                 D219 
                 771.35 
                   1 H NMR (300 MHz, DMSO-d5) δ 11.15 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.20 (s, 1H FA), 7.97-7.77 (m, 4H), 7.57 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 6.74 (s, 2H), 5.24-5.08 (m, 1H), 3.82 (s, 6H), 3.71 
               
               
                   
                   
                 (s, 3H), 3.61 (s, 4H), 3.11 (s, 4H), 2.98-2.80 (m, 2H), 2.76-2.62 
               
               
                   
                   
                 (m, 6H), 2.15-2.01 (m, 1H), 1.61 (d, J = 27.8 Hz, 5H) 
               
               
                 D220 
                 785.15 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (d, J = 2.0 Hz, 
               
               
                   
                   
                 1H), 8.73 (dd, J = 5.6, 2.2 Hz, 1H), 7.94-7.87 (m, 2H), 7.84 (q, J = 
               
               
                   
                   
                 2.9 Hz, 2H), 7.58 (dd, J = 5.7, 2.6 Hz, 1H), 6.74 (s, 2H), 5.16 (dd, 
               
               
                   
                   
                 J = 12.8, 5.4 Hz, 1H), 3.82 (s, 6H), 3.60 (d, J = 1.4 Hz, 5H), 3.52 (t, 
               
               
                   
                   
                 J = 7.0 Hz, 1H), 3.17 (s, 2H), 2.89 (ddd, J = 16.6, 13.6, 5.4 Hz, 1H), 
               
               
                   
                   
                 2.70 (t, J = 7.0 Hz, 2H), 2.66-2.56 (m, 7H), 2.41 (s, 2H), 2.12- 
               
               
                   
                   
                 2.00 (m, 1H), 1.76 (t, J = 7.1 Hz, 1H), 1.67 (t, J = 7.2 Hz, 1H), 1.49 
               
               
                   
                   
                 (s, 4H). 
               
               
                 D221 
                 817.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.20 (s, 1H, FA), 7.92-7.80 (m, 2H), 7.60 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.38-7.21 (m, 2H), 6.74 (s, 2H), 5.12 (dd, J = 12.9, 
               
               
                   
                   
                 5.4 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 3.81 (s, 6H), 3.61 (s, 3H), 3.58 
               
               
                   
                   
                 (s, 2H), 3.44 (s, 4H), 2.96-2.82 (m, 3H), 2.66-2.54 (m, 5H), 2.21- 
               
               
                   
                   
                 1.98 (m, 3H), 1.93-1.81 (m, 2H), 1.66-1.43 (m, 8H). 
               
               
                 D222 
                 776.4 
               
               
                 D223 
                 776.35 
               
               
                 D224 
                 790.4 
               
               
                 D225 
                 776.35 
               
               
                 D226 
                 762.8 
               
               
                 D227 
                 748.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.44 (s, 1H), 8.72 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.17 (s, 0.6H, FA), 7.88 (s, 1H), 7.59 (dd, J = 
               
               
                   
                   
                 9.7, 7.0 Hz, 2H), 6.76 (d, J = 7.3 Hz, 3H), 6.61 (d, J = 8.4 Hz, 1H), 
               
               
                   
                   
                 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t, J = 5.4 Hz, 1H), 4.15-3.95 
               
               
                   
                   
                 (m, 2H), 3.84 (s, 6H), 3.67 (d, J = 15.2 Hz, 3H), 3.60 (s, 3H), 3.11- 
               
               
                   
                   
                 2.71 (m, 2H), 2.66-2.55 (m, 5H), 2.27 (s, 3H), 2.12-1.88 (m, 
               
               
                   
                   
                 4H), 1.75 (d, J = 10.1 Hz, 1H), 1.64-1.36 (m, 4H). 
               
               
                 D228 
                 791.55 
               
               
                 D229 
                 751.2 
               
               
                 D230 
                 791.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (t, J = 1.2 Hz, 
               
               
                   
                   
                 1H), 8.73 (dd, J = 5.7, 1.0 Hz, 1H), 8.19 (s, 0.3H, FA), 7.99-7.73 
               
               
                   
                   
                 (m, 2H), 7.66-7.50 (m, 1H), 7.39-7.22 (m, 2H), 6.77 (d, J = 9.5 
               
               
                   
                   
                 Hz, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 (t, J = 6.8 Hz, 1H), 
               
               
                   
                   
                 4.56 (d, J = 19.1 Hz, 2H), 3.82 (d, J = 13.1 Hz, 6H), 3.60 (d, J = 1.5 
               
               
                   
                   
                 Hz, 3H), 3.26 (s, 2H), 3.17 (s, 2H), 2.89 (s, 1H), 2.78-2.61 (m, 
               
               
                   
                   
                 6H), 2.61-2.52 (m, 2H), 2.48-2.33 (m, 2H), 2.28 (dd, J = 3.8, 1.9 
               
               
                   
                   
                 Hz, 1H), 2.19 (dd, J = 11.7, 8.0 Hz, 2H), 2.04 (d, J = 11.6 Hz, 1H), 
               
               
                   
                   
                 1.53 (d, J = 7.9 Hz, 2H), 1.42-1.19 (m, 2H). 
               
               
                 D231 
                 774.2 
               
               
                 D232 
                 774.4 
               
               
                 D233 
                 735.2 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (d, J = 0.8 Hz, 
               
               
                   
                   
                 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.18 (s, 0.5H, FA), 7.93-7.79 (m, 
               
               
                   
                   
                 2H), 7.56 (dd, J = 5.7, 0.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 6.74 (s, 
               
               
                   
                   
                 2H), 5.27 (s, 1H), 5.14 (dd, J = 12.9, 5.3 Hz, 1H), 4.63 (t, J = 8.1 
               
               
                   
                   
                 Hz, 1H), 4.34 (dd, J = 10.5, 6.5 Hz, 1H), 4.13 (d, J = 8.3 Hz, 1H), 
               
               
                   
                   
                 3.82 (s, 7H), 3.73 (s, 2H), 3.60 (s, 3H), 3.50 (d, J = 9.7 Hz, 2H), 
               
               
                   
                   
                 3.07 (s, 2H), 2.98-2.80 (m, 1H), 2.71-2.53 (m, 3H), 2.38 (d, J = 
               
               
                   
                   
                 7.5 Hz, 2H), 2.17-1.97 (m, 1H). 
               
               
                 D234 
                 775.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (dd, J = 5.7, 1.2 Hz, 1H), 8.20 (s, 1H, FA), 7.96-7.76 (m, 2H), 
               
               
                   
                   
                 7.69-7.54 (m, 1H), 7.42-7.19 (m, 2H), 6.75 (d, J = 1.7 Hz, 2H), 
               
               
                   
                   
                 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 4.90 (t, J = 6.7 Hz, 1H), 4.14 (d, J = 
               
               
                   
                   
                 27.9 Hz, 2H), 3.92 (s, 1H), 3.83 (d, J = 2.2 Hz, 7H), 3.75 (s, 2H), 
               
               
                   
                   
                 3.61 (s, 3H), 3.49 (t, J = 6.8 Hz, 3H), 3.08 (s, 2H), 2.99-2.70 (m, 
               
               
                   
                   
                 4H), 2.68-2.55 (m, 3H), 2.40-2.19 (m, 4H), 2.15-1.94 (m, 1H). 
               
               
                 D235 
                 729.3 
               
               
                 D236 
                 715.15 
               
               
                 D237 
                 689.2 
               
               
                 D238 
                 743.4 
               
               
                 D239 
                 729.35 
               
               
                 D240 
                 757.35 
               
               
                 D241 
                 729.15 
               
               
                 D242 
                 729.2 
               
               
                 D243 
                 757.35 
               
               
                 D244 
                 791.23 
               
               
                 D245 
                 762.4 
               
               
                 D246 
                 791.4 
               
               
                 D247 
                 790.4 
               
               
                 D248 
                 762.3 
               
               
                 D249 
                 723.3 
               
               
                 D250 
                 762.4 
               
               
                 D251 
                 763.6 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 8.21 (s, 1.4H, FA), 7.88 (s, 1H), 7.82 (d, J = 8.2 
               
               
                   
                   
                 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.24 (dd, 
               
               
                   
                   
                 J = 8.3, 2.3 Hz, 1H), 6.75 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 
               
               
                   
                   
                 4.90-4.80 (m, 1H), 3.82 (s, 6H), 3.61 (d, J = 3.2 Hz, 5H), 3.36 (s, 
               
               
                   
                   
                 2H), 3.27 (s, 2H), 2.89 (ddd, J = 16.7, 13.7, 5.3 Hz, 1H), 2.75- 
               
               
                   
                   
                 2.56 (m, 4H), 2.45 (q, J = 7.1, 6.7 Hz, 4H), 2.26-2.13 (m, 5H), 
               
               
                   
                   
                 2.11-1.98 (m, 1H), 1.50 (t, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 
               
               
                   
                   
                 2H). 
               
               
                 D252 
                 762.4 
               
               
                 D253 
                 777.35 
               
               
                 D254 
                 748.4 
               
               
                 D255 
                 790.25 
               
               
                 D256 
                 818.2 
               
               
                 D257 
                 777.7 
               
               
                 D258 
                 790.4 
               
               
                 D259 
                 777.2 
               
               
                 D260 
                 805.35 
               
               
                 D261 
                 819.2 
               
               
                 D262 
                 819.25 
               
               
                 D263 
                 805.35 
               
               
                 D264 
                 803.2 
               
               
                 D265 
                 803.15 
               
               
                 D266 
                 789.3 
               
               
                 D267 
                 789.3 
               
               
                 D268 
                 715.3 
               
               
                 D269 
                 757.35 
               
               
                 D270 
                 719.35 
               
               
                 D271 
                 719.28 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.42 (s, 1H), 8.68 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.61 (d, J = 8.3 Hz, 
               
               
                   
                   
                 1H), 7.55 (d, J = 5.7 Hz, 1H), 6.80 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 
               
               
                   
                   
                 6.62 (dd, J = 8.4, 2.1 Hz, 1H), 5.53 (s, 2H), 5.02 (dd, J = 12.8, 5.4 
               
               
                   
                   
                 Hz, 1H), 4.57 (td, J = 6.3, 3.2 Hz, 1H), 4.53 (s, 2H), 4.24-4.15 (m, 
               
               
                   
                   
                 2H), 3.86 (s, 6H), 3.79 (dd, J = 9.7, 3.9 Hz, 2H), 3.56 (s, 3H), 3.15 
               
               
                   
                   
                 (d, J = 5.3 Hz, 1H), 2.85 (ddd, J = 16.8, 13.8, 5.3 Hz, 1H), 2.60- 
               
               
                   
                   
                 2.50 (m, 2H), 2.05 (s, 1H), 2.03-1.94 (m, 1H). 
               
               
                 D272 
                 747.28 
               
               
                 D273 
                 720.03 
               
               
                 D274 
                 735.52 
               
               
                 D275 
                 765.06 
               
               
                 D276 
                 776.47 
               
               
                 D277 
                 776.33 
               
               
                 D278 
                 804.19 
               
               
                 D279 
                 761.28 
                   1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 9.43 (s, 1H), 8.71 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.3 Hz, 
               
               
                   
                   
                 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 
               
               
                   
                   
                 8.4, 2.3 Hz, 1H), 6.76 (s, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.41 
               
               
                   
                   
                 (t, J = 6.6 Hz, 2H), 3.83 (s, 5H), 3.59 (s, 2H), 3.15 (d, J = 5.1 Hz, 
               
               
                   
                   
                 1H), 3.11 (d, J = 6.4 Hz, 1H), 2.87 (ddd, J = 17.2, 13.9, 5.3 Hz, 1H), 
               
               
                   
                   
                 2.70-2.51 (m, 2H), 2.03 (d, J = 15.9 Hz, 5H). 
               
               
                 D280 
                 802.16 
               
               
                 D281 
                 830.16 
               
               
                 D282 
                 735.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.97 (s, 1H), 7.86 
               
               
                   
                   
                 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.32 (dd, 
               
               
                   
                   
                 J = 8.3, 2.2 Hz, 1H), 6.71 (s, 2H), 5.26 (s, 2H), 4.40 (s, 1H), 3.78 
               
               
                   
                   
                 (s, 5H), 3.55 (s, 3H), 2.88 (ddd, J = 18.2, 13.8, 5.4 Hz, 1H), 2.71- 
               
               
                   
                   
                 2.53 (m, 2H), 2.38-2.24 (m, 2H), 2.09 (d, J = 28.1 Hz, 4H). 
               
               
                 D283 
                 749.31 
               
               
                 D284 
                 779.27 
               
               
                 D285 
                 790.33 
               
               
                 D286 
                 790.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.08 (s, 1H), 7.85 
               
               
                   
                   
                 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.72 (s, 2H), 5.03 (dd, J = 12.9, 
               
               
                   
                   
                 5.4 Hz, 1H), 4.55 (s, 2H), 4.20 (dd, J = 9.2, 6.3 Hz, 2H), 3.80 (s, 
               
               
                   
                   
                 6H), 3.58 (s, 2H), 2.97-2.72 (m, 0H), 2.18 (s, 1H), 2.05 (s, 1H), 
               
               
                   
                   
                 2.02-1.94 (m, 1H). 
               
               
                 D287 
                 818.26 
               
               
                 D288 
                 765.27 
               
               
                 D289 
                 747.35 
               
               
                 D290 
                 791.24 
               
               
                 D291 
                 802.37 
               
               
                 D292 
                 779.2 
               
               
                 D293 
                 809.16 
               
               
                 D294 
                 820.29 
               
               
                 D295 
                 820.08 
               
               
                 D296 
                 847.22 
               
               
                 D297 
                 719.28 
               
               
                 D298 
                 733.49 
               
               
                 D299 
                 763.31 
               
               
                 D300 
                 774.44 
               
               
                 D301 
                 774.02 
               
               
                 D302 
                 802.58 
               
               
                 D303 
                 708.22 
               
               
                 D304 
                 803.4 
                   1 H NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.70 (d, J = 6.0 
               
               
                   
                   
                 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 (d, 
               
               
                   
                   
                 J = 6.1 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.26 (dd, J = 8.3, 2.3 Hz, 
               
               
                   
                   
                 1H), 6.89 (s, 2H), 5.13 (dd, J = 12.6, 5.4 Hz, 1H), 4.98 (t, J = 6.5 
               
               
                   
                   
                 Hz, 1H), 4.43 (s, 2H), 3.98 (d, J = 4.3 Hz, 6H), 3.74 (s, 3H), 3.70- 
               
               
                   
                   
                 3.50 (m, 4H), 3.33-2.94 (m, 6H), 2.93-2.66 (m, 4H), 2.56 (s, 
               
               
                   
                   
                 1H), 2.27 (s, 1H), 2.17-1.95 (m, 10H), 1.67 (q, J = 12.6 Hz, 1H). 
               
               
                 D305 
                 789.7 
                   1 H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J = 5.8 
               
               
                   
                   
                 Hz, 1H), 8.50 (s, 2H, FA), 7.83 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 
               
               
                   
                   
                 7.62 (d, J = 5.7 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.3, 
               
               
                   
                   
                 2.2 Hz, 1H), 6.82 (s, 2H), 5.13 (dd, J = 12.5, 5.4 Hz, 1H), 5.01- 
               
               
                   
                   
                 4.97 (m, 1H), 4.17 (s, 2H), 3.95 (s, 6H), 3.77-3.65 (m, 5H), 3.56- 
               
               
                   
                   
                 3.40 (m, 5H), 3.28 (s, 1H), 3.07-2.92 (m, 3H), 2.91-2.84 (m, 
               
               
                   
                   
                 1H), 2.81-2.65 (m, 4H), 2.50-2.40 (m, 1H), 2.18-2.07 (m, 6H), 
               
               
                   
                   
                 2.05-1.96 (m, 2H). 
               
               
                 D306 
                 715.3 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (s, 1H), 8.72 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 8.18 (s, 1H FA), 7.89 (d, J = 17.4 Hz, 4H), 7.56 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 6.74 (s, 2H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 
               
               
                   
                   
                 3.82 (s, 6H), 3.74 (s, 2H), 3.63 (d, J = 19.3 Hz, 6H), 3.27 (s, 3H), 
               
               
                   
                   
                 2.90 (ddd, J = 16.8, 13.7, 5.3 Hz, 1H), 2.78 (s, 2H), 2.66-2.57 (m, 
               
               
                   
                   
                 3H), 2.55 (s, 1H), 2.11-2.02 (m, 1H), 1.96 (t, J = 6.9 Hz, 2H). 
               
               
                 D307 
                 729.3 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (s, 1H), 8.72 
               
               
                   
                   
                 (d, J = 5.7 Hz, 1H), 7.99-7.80 (m, 4H), 7.56 (d, J = 5.7 Hz, 1H), 
               
               
                   
                   
                 6.73 (s, 2H), 5.16 (dd, J = 12.7, 5.4 Hz, 1H), 3.82 (s, 6H), 3.71 (s, 
               
               
                   
                   
                 2H), 3.60 (s, 3H), 3.53 (s, 2H), 3.10 (s, 4H), 2.90 (ddd, J = 16.7, 
               
               
                   
                   
                 13.6, 5.4 Hz, 1H), 2.65-2.54 (m, 1H), 2.44 (s, 5H), 2.12-2.01 (m, 
               
               
                   
                   
                 1H), 1.67 (t, J = 5.5 Hz, 4H). 
               
               
                 D308 
                 743.35 
               
               
                 D309 
                 701.3 
               
               
                 D310 
                 743.55 
               
               
                 D311 
                 743.3 
               
               
                 D312 
                 757.3 
               
               
                 D313 
                 771.45 
               
               
                 D314 
                 743.3 
               
               
                 D315 
                 743.3 
               
               
                 D316 
                 717.3 
               
               
                 D317 
                 729.3 
               
               
                 D318 
                 757.3 
               
               
                 D319 
                 761.35 
               
               
                 D320 
                 761.28 
               
               
                 D321 
                 763.24 
               
               
                 D322 
                 747.42 
               
               
                 D323 
                 746.83 
               
               
                 D324 
                 746.55 
               
               
                 D325 
                 747.33 
               
               
                 D326 
                 747.45 
               
               
                 D327 
                 706.67 
               
               
                 D328 
                 779.84 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.48 (d, J = 2.7 Hz, 
               
               
                   
                   
                 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.19 (s, 2H), 7.65 (d, J = 8.5 Hz, 1H), 
               
               
                   
                   
                 7.30 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 8.6, 2.3 Hz, 1H), 6.85 (d, J = 
               
               
                   
                   
                 5.6 Hz, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.83 (d, J = 2.7 Hz, 
               
               
                   
                   
                 7H), 3.59 (s, 3H), 3.48 (d, J = 5.0 Hz, 2H), 3.39 (t, J = 5.0 Hz, 4H), 
               
               
                   
                   
                 2.81 (dd, J = 25.4, 11.4 Hz, 3H), 2.63-2.51 (m, 2H), 2.32-2.22 
               
               
                   
                   
                 (m, 2H), 2.06-1.90 (m, 1H), 1.56 (s, 1H), 1.34 (d, J = 7.5 Hz, 2H), 
               
               
                   
                   
                 1.09 (s, 1H) 
               
               
                 D329 
                 725.87 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.24-8.12 (m, 
               
               
                   
                   
                 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.88-7.72 (m, 1H), 7.65 (d, J = 8.5 
               
               
                   
                   
                 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.6, 2.3 Hz, 1H), 
               
               
                   
                   
                 6.79 (s, 2H), 3.83 (s, 6H), 3.57 (s, 2H), 3.51 (s, 3H), 3.40 (t, J = 5.1 
               
               
                   
                   
                 Hz, 4H), 2.91-2.78 (m, 3H), 2.66-2.50 (m, 2H), 2.36-2.24 (m, 
               
               
                   
                   
                 2H), 2.14 (t, J = 11.6 Hz, 2H), 2.08 (s, 3H), 1.99 (ddd, J = 11.5, 6.0, 
               
               
                   
                   
                 3.7 Hz, 1H), 1.61 (d, J = 12.4 Hz, 2H), 1.35 (q, J = 7.0 Hz, 2H), 
               
               
                   
                   
                 1.26 (s, 2H), 1.13 (q, J = 11.2, 10.7 Hz, 2H). 
               
               
                 D330 
                 614.68 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.15 (s, 1H), 8.02 
               
               
                   
                   
                 (d, J = 2.7 Hz, 1H), 7.79 (dd, J = 2.8, 1.3 Hz, 1H), 7.63 (d, J = 8.5 
               
               
                   
                   
                 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.3 Hz, 1H), 
               
               
                   
                   
                 6.80 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.84 (s, 6H), 3.55 (s, 
               
               
                   
                   
                 2H), 3.37 (t, J = 5.1 Hz, 4H), 2.66-2.53 (m, 2H), 2.08 (s, 3H). 
               
               
                 D331 
                 654.74 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.12 (s, 1H), 8.04 
               
               
                   
                   
                 (d, J = 2.6 Hz, 1H), 7.80 (dd, J = 2.7, 1.3 Hz, 1H), 7.61 (d, J = 8.3 
               
               
                   
                   
                 Hz, 1H), 6.82 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 5.02 (dd, J = 12.9, 
               
               
                   
                   
                 5.4 Hz, 1H), 3.85 (s, 6H), 3.72 (s, 5H), 3.52 (s, 3H), 2.93-2.74 (m, 
               
               
                   
                   
                 1H), 2.08 (s, 3H), 1.98 (dd, J = 9.2, 4.2 Hz, 1H), 1.76 (s, 5H). 
               
               
                 D332 
                 669.75 
               
               
                 D333 
                 724.79 
               
               
                 D334 
                 594.73 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.13 (s, 1H), 8.05 
               
               
                   
                   
                 (d, J = 2.7 Hz, 1H), 7.80 (dd, J = 2.8, 1.3 Hz, 1H), 6.82 (s, 2H), 5.73 
               
               
                   
                   
                 (s, 1H), 3.85 (s, 6H), 3.71 (s, 2H), 3.52 (s, 3H), 3.08-2.85 (m, 4H), 
               
               
                   
                   
                 2.79-2.53 (m, 3H), 2.38-2.28 (m, 3H), 2.08 (s, 3H), 1.86-1.74 
               
               
                   
                   
                 (m, 1H), 1.65 (d, J = 12.7 Hz, 2H), 1.33 (s, 3H), 1.27-1.12 (m, 
               
               
                   
                   
                 3H). 
               
               
                 D335 
                 609.66 
               
               
                 D336 
                 654.74 
               
               
                 D337 
                 640.72 
               
               
                 D338 
                 640.72 
               
               
                 D339 
                 626.69 
               
               
                 D340 
                 679.75 
                   1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.03 (s, 1H), 8.14 
               
               
                   
                   
                 (d, J = 1.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.34 (t, 
               
               
                   
                   
                 J = 2.8 Hz, 1H), 6.82 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 6.62 (dd, J = 
               
               
                   
                   
                 8.4, 2.2 Hz, 1H), 6.54 (t, J = 2.4 Hz, 1H), 5.73 (s, 1H), 5.02 (dd, J = 
               
               
                   
                   
                 12.9, 5.4 Hz, 1H), 3.83 (s, 6H), 3.71 (s, 4H), 3.58 (s, 3H), 3.53 (s, 
               
               
                   
                   
                 2H), 2.86 (ddd, J = 17.3, 13.9, 5.4 Hz, 1H), 2.64-2.50 (m, 1H), 
               
               
                   
                   
                 1.98 (dd, J = 9.2, 4.0 Hz, 1H), 1.72 (d, J = 5.8 Hz, 4H). 
               
               
                 D341 
                 690.72 
                   1 H NMR (400 MHz, DMSO-d6) δ 8.13 (dd, J = 9.6, 2.7 Hz, 2H), 
               
               
                   
                   
                 6.83 (d, J = 0.9 Hz, 2H), 11.03 (s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 
               
               
                   
                   
                 7.60 (d, J = 8.3 Hz, 1H), 6.78-6.71 (m, 1H), 6.62 (dd, J = 8.4, 2.1 
               
               
                   
                   
                 Hz, 1H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 3.84 (d, J = 0.8 Hz, 6H), 
               
               
                   
                   
                 3.69 (s, 4H), 3.57 (s, 3H), 3.50 (d, J = 4.1 Hz, 2H), 2.86 (ddd, J = 
               
               
                   
                   
                 17.3, 13.9, 5.4 Hz, 1H), 2.38 (s, 5H), 1.69 (s, 4H). 
               
               
                 D342 
                 712.15 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.04 (d, J = 3.3 Hz, 
               
               
                   
                   
                 1H), 8.66 (d, J = 3.4 Hz, 1H), 8.20 (s, 1H, FA), 7.64 (d, J = 8.5 Hz, 
               
               
                   
                   
                 1H), 7.29 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 5.06 (dd, 
               
               
                   
                   
                 J = 13.0, 5.3 Hz, 1H), 4.02 (d, J = 12.8 Hz, 2H), 3.84 (s, 6H), 3.57- 
               
               
                   
                   
                 3.47 (m, 5H), 2.91 (dt, J = 22.4, 13.1 Hz, 3H), 2.71-2.55 (m, 2H), 
               
               
                   
                   
                 2.42-2.23 (m, 10H), 2.09-1.93 (m, 1H), 1.82-1.68 (m, 2H), 
               
               
                   
                   
                 1.64-1.50 (m, 1H), 1.39-1.30 (m, 2H), 1.22-1.09 (m, 2H). 
               
               
                 D343 
                 628.5 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.47 (s, 1H, TFA), 
               
               
                   
                   
                 7.77 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.38-7.23 (m, 
               
               
                   
                   
                 2H), 6.69 (s, 2H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 4.33 (s, 2H), 4.18 
               
               
                   
                   
                 (d, J = 12.1 Hz, 2H), 3.89 (s, 6H), 3.55 (s, 4H), 3.53-3.45 (m, 5H), 
               
               
                   
                   
                 2.99-2.81 (m, 1H), 2.60 (d, J = 18.3 Hz, 2H), 2.35 (s, 3H), 2.05 (s, 
               
               
                   
                   
                 4H). 
               
               
                 D344 
                 600.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.21 (d, J = 2.8 Hz, 
               
               
                   
                   
                 1H), 8.14 (s, 1H FA), 7.97-7.88 (m, 1H), 7.67 (d, J = 8.5 Hz, 1H), 
               
               
                   
                   
                 7.32 (d, J = 2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.85 (s, 2H), 6.50 (d, 
               
               
                   
                   
                 J = 9.4 Hz, 1H), 5.10-5.00 (m, 1H), 3.87 (s, 6H), 3.67 (s, 2H), 
               
               
                   
                   
                 3.53 (s, 3H), 3.44 (d, 5H), 2.97-2.78 (m, 1H), 2.67-2.60 (m, 5H), 
               
               
                   
                   
                 2.58-2.52 (m, 1H), 2.09-1.92 (m, 1H). 
               
               
                 D345 
                 737.3 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.31 (s, 1H FA), 7.65 (d, J = 8.3 
               
               
                   
                   
                 Hz, 1H), 7.48 (s, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.72-6.63 (m, 3H), 
               
               
                   
                   
                 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.48 (s, 2H), 4.25 (s, 2H), 4.06- 
               
               
                   
                   
                 3.90 (m, 8H), 3.82 (s, 4H), 3.58 (d, J = 20.8 Hz, 4H), 2.97-2.66 
               
               
                   
                   
                 (m, 5H), 2.63 (s, 3H), 2.27-2.03 (m, 8H), 1.95 (s, 4H). 
               
               
                 D346 
                 737.7 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.16 (s, 1H, FA), 
               
               
                   
                   
                 7.64 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 6.77 (d, J = 2.1 
               
               
                   
                   
                 Hz, 1H), 6.69-6.53 (m, 3H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.92- 
               
               
                   
                   
                 3.85 (m, 2H), 3.82 (s, 6H), 3.74 (s, 4H), 3.71-3.61 (m, 2H), 3.54 
               
               
                   
                   
                 (s, 4H), 2.98-2.78 (m, 2H), 2.71-2.54 (m, 2H), 2.54-2.50 (m, 
               
               
                   
                   
                 2H), 2.48-2.42 (m, 3H), 2.37-2.20 (m, 4H), 2.11-1.93 (m, 4H), 
               
               
                   
                   
                 1.82-1.65 (m, 4H), 1.20 (d, J = 26.6 Hz, 1H). 
               
               
                 D347 
                 709.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.23 (s, 1H), 8.17 
               
               
                   
                   
                 (s, 1H, FA), 7.94 (d, J = 9.6 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 6.86 
               
               
                   
                   
                 (d, J = 4.5 Hz, 2H), 6.77 (d, J = 2.1 Hz, 1H), 6.64 (dd, J = 8.4, 2.2 
               
               
                   
                   
                 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H), 
               
               
                   
                   
                 3.88 (t, J = 2.1 Hz, 7H), 3.79 (s, 2H), 3.73 (s, 5H), 3.54 (s, 6H), 
               
               
                   
                   
                 3.19 (d, J = 29.3 Hz, 1H), 2.99-2.81 (m, 1H), 2.58 (d, J = 16.2 Hz, 
               
               
                   
                   
                 2H), 2.44 (s, 2H), 2.28 (s, 3H), 2.01 (d, J = 12.4 Hz, 1H), 1.73 (s, 
               
               
                   
                   
                 4H). 
               
               
                 D348 
                 749.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 2.6 Hz, 1H), 7.88 (t, 
               
               
                   
                   
                 J = 1.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 2H), 
               
               
                   
                   
                 6.77 (d, J = 2.2 Hz, 1H), 6.66 (m, J = 8.3, 2.0 Hz, 1H), 6.09-5.91 
               
               
                   
                   
                 (m, 1H),, 5.19 (m, J = 10.3, 1.5 Hz, 1H), 5.14-4.98 (m, 2H), 4.62 
               
               
                   
                   
                 (d, J = 5.4 Hz, 2H), 4.34 (d, J = 16.5 Hz, 2H), 4.18 (s, 2H), 3.99 (d, 
               
               
                   
                   
                 J = 10.2 Hz, 2H), 3.92 (s, 6H), 3.87 (s, 2H), 3.81 (s, 2H), 3.41 (d, 
               
               
                   
                   
                 J = 6.6 Hz, 4H), 3.17 (d, J = 8.1 Hz, 1H), 2.94 (s, 3H), 2.89-2.78 (m, 
               
               
                   
                   
                 1H), 2.65-2.54 (m, 1H), 2.40-2.23 (m, 1H), 2.11 (s, 4H), 2.06- 
               
               
                   
                   
                 1.83 (m, 3H). 
               
               
                 D349 
                 723.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.78 (s, 2H, TFA), 
               
               
                   
                   
                 7.69 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 6.75 (dd, J = 21.5, 3.2 Hz, 
               
               
                   
                   
                 3H), 6.66 (dd, J = 8.3, 2.4 Hz, 1H), 6.38 (s, 1H), 5.06 (dd, J = 12.9, 
               
               
                   
                   
                 5.4 Hz, 1H), 4.39 (s, 1H), 4.34 (d, J = 5.5 Hz, 1H), 4.22 (s, 2H), 
               
               
                   
                   
                 4.01 (d, J = 8.8 Hz, 2H), 3.89 (s, 8H), 3.82 (s, 2H), 3.46 (s, 5H), 
               
               
                   
                   
                 3.25-3.08 (m, 2H), 3.03-2.82 (m, 3H), 2.64-2.59 (m, 2H), 2.21- 
               
               
                   
                   
                 2.09 (m, 5H), 2.09-1.77 (m, 4H). 
               
               
                 D350 
                 795.4 
                   1 H NMR (300 MHz, MeOD) δ 8.04 (d, 1H), 7.82 (d, 1H), 7.67 (d, 
               
               
                   
                   
                 1H), 6.95-6.84 (m, 3H), 6.71 (dd, 1H), 5.08 (dd, 1H), 4.58-4.45 
               
               
                   
                   
                 (m, 2H), 4.34 (t, 2H), 4.24 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (s, 6H), 
               
               
                   
                   
                 3.94-3.86 (m, 4H), 3.69 (s, 3H), 3.55-3.49 (m, 5H), 3.20-3.03 
               
               
                   
                   
                 (m, 2H), 2.91-2.77 (m, 2H), 2.72 (s, 4H), 2.35-2.00 (m, 5H). 
               
               
                 D351 
                 748.7 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.94 (br s, 2H, TFA 
               
               
                   
                   
                 salt), 8.07 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 3.7 Hz, 3H), 
               
               
                   
                   
                 6.66 (dd, J = 8.4, 2.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.40 
               
               
                   
                   
                 (s, 1H), 4.35 (d, J = 5.6 Hz, 1H), 4.27-4.16 (m, 2H), 4.03 (q, J = 
               
               
                   
                   
                 8.7, 7.5 Hz, 2H), 3.88 (s, 8H), 3.82 (s, 2H), 3.55 (s, 3H), 3.39 (s, 
               
               
                   
                   
                 5H), 3.18 (s, 1H), 3.04-2.82 (m, 3H), 2.64-2.54 (m, 2H), 2.36 (s, 
               
               
                   
                   
                 3H), 2.15 (d, J = 14.0 Hz, 2H), 2.02 (dd, J = 9.7, 4.6 Hz, 1H), 1.97- 
               
               
                   
                   
                 1.84 (m, 2H). 
               
               
                 D352 
                 734.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.69 
               
               
                   
                   
                 (s, 1H), 8.14 (s, 0.4H, FA), 7.67 (d, J = 8.3 Hz, 1H), 7.02 (s, 2H), 
               
               
                   
                   
                 6.77 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 12.6, 5.4 Hz, 
               
               
                   
                   
                 1H), 4.30 (s, 2H), 4.14 (s, 3H), 3.95 (s, 7H), 3.91-3.78 (m, 6H), 
               
               
                   
                   
                 3.63 (s, 4H), 2.96-2.80 (m, 2H), 2.97-2.79 (m, 5H), 2.05-1.79 
               
               
                   
                   
                 (m, 5H). 
               
               
                 D353 
                 723.5 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.16 (s, 1H FA), 
               
               
                   
                   
                 7.72 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 2.7, 
               
               
                   
                   
                 1.2 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.78 (d, J = 2.1 Hz, 1H), 
               
               
                   
                   
                 6.65 (dd, J = 8.5, 2.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.78 
               
               
                   
                   
                 (s, 3H), 3.74 (d, J = 2.8 Hz, 7H), 3.60 (s, 2H), 3.49 (s, 6H), 2.90 (s, 
               
               
                   
                   
                 3H), 2.73-2.58 (m, 5H), 2.39-2.19 (m, 3H), 2.05 (s, 3H), 2.02 (d, 
               
               
                   
                   
                 J = 7.1 Hz, 1H), 1.74 (s, 4H). 
               
               
                 D354 
                 737.45 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 2H FA), 7.64 (d, J = 8.3 
               
               
                   
                   
                 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 6.83 (d, J = 2.0 Hz, 
               
               
                   
                   
                 1H), 6.67 (dd, J = 8.3, 2.0 Hz, 1H), 5.07 (dd, J = 12.4, 5.5 Hz, 1H), 
               
               
                   
                   
                 4.43 (s, 2H), 4.26 (s, 2H), 4.03 (s, 2H), 3.91 (s, 3H), 3.83 (s, 4H), 
               
               
                   
                   
                 3.79 (s, 3H), 3.60 (s, 3H), 3.29 (s, 1H), 3.03 (s, 2H), 2.95-2.64 (m, 
               
               
                   
                   
                 7H), 2.16 (s, 3H), 2.15-2.07 (m, 1H), 2.07-1.87 (m, 7H). 
               
               
                 D355 
                 809.5 
                   1 H NMR (300 MHz, MeOD) δ 8.07 (d, 1H), 7.74-7.63 (m, 2H), 
               
               
                   
                   
                 6.88 (d, 3H), 6.71 (dd, 1H), 5.08 (dd, 1H), 4.58-4.45 (m, 2H), 4.41- 
               
               
                   
                   
                 4.28 (m, 4H), 4.19-4.07 (m, 2H), 4.01 (s, 6H), 3.98-3.82 (m, 
               
               
                   
                   
                 4H), 3.70 (s, 3H), 3.58-3.41 (m, 5H), 3.18-3.02(m, 2H), 2.98 (s, 
               
               
                   
                   
                 3H), 2.93-2.79 (m, 2H), 2.76 (s, 3H), 2.77-2.66 (m, 1H), 2.40- 
               
               
                   
                   
                 2.01 (m, 5H). 
               
               
                 D356 
                 745.5 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.93 (br s, 2H, TFA 
               
               
                   
                   
                 salt), 8.36 (d, J = 8.0 Hz, 1H), 7.78-7.53 (m, 4H), 7.41 (d, J = 8.5 
               
               
                   
                   
                 Hz, 1H), 6.85 (s, 2H), 6.70 (s, 2H), 5.07 (dd, J = 13.2, 4.9 Hz, 1H), 
               
               
                   
                   
                 4.50-3.96 (m, 8H), 3.90 (s, 6H), 3.78-3.55 (m, 8H), 3.53-3.49 
               
               
                   
                   
                 (m, 1H), 3.28-3.12 (m, 2H), 3.09-2.82 (m, 3H), 2.75-2.56 (m, 
               
               
                   
                   
                 1H), 2.43-2.24 (m, 2H), 2.19-1.83 (m, 5H) 
               
               
                 D357 
                 641.748028 
               
               
                 D358 
                 641.748028 
               
               
                 D359 
                 737.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.32-9.43 (m, 
               
               
                   
                   
                 2H), 7.69 (d, J = 8.3 Hz, 1H), 7.22-7.05 (m, 2H), 6.92 (s, 1H), 
               
               
                   
                   
                 6.83-6.74 (m, 1H), 6.66 (dd, J = 8.2, 2.1 Hz, 1H), 5.17-4.99 (m, 
               
               
                   
                   
                 1H), 4.57-4.33 (m, 2H), 4.34-4.15 (m, 2H), 4.15-3.94 (m, 2H), 
               
               
                   
                   
                 3.90 (s, 2H), 3.82 (s, 6H), 3.73 (m, 3H), 3.52 (s, 4H), 3.25-3.10 
               
               
                   
                   
                 (m, 2H), 3.08-2.79 (m, 4H), 2.62 (m, 2H), 2.59-2.54 (m, 1H), 
               
               
                   
                   
                 2.54-2.41 (m, 1H), 2.23-2.06 (m, 3H), 2.02 (s, 4H), 2.00-1.83 
               
               
                   
                   
                 (m, 2H). 
               
               
                 D360 
                 745.6 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.83 (br s, 2H, TFA 
               
               
                   
                   
                 salt), 8.36 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.66-7.48 
               
               
                   
                   
                 (m, 4H), 6.85 (s, 2H), 6.55-6.44 (m, 2H), 5.04 (dd, J = 13.2, 4.8 Hz, 
               
               
                   
                   
                 1H), 4.40 (t, J = 13.8 Hz, 2H), 4.32-4.13 (m, 4H), 4.05 (s, 2H), 
               
               
                   
                   
                 3.90 (s, 6H), 3.81-3.65 (m, 5H), 3.60 (s, 4H), 3.55-3.50 (m, 2H), 
               
               
                   
                   
                 3.20 (s, 1H), 3.10-2.80 (m, 3H), 2.62 (s, 1H), 2.41-2.24 (m, 1H), 
               
               
                   
                   
                 2.19-2.05 (m, 2H), 2.02-1.82 (m, 3H). 
               
               
                 D361 
                 735.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.14 (s, FA, 1H), 
               
               
                   
                   
                 7.91 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 7.03 (s, 2H), 
               
               
                   
                   
                 6.73-6.67 (m, 2H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.34 (s, J = 
               
               
                   
                   
                 16.7 Hz, 3H), 4.30 (d, J = 16.7 Hz, 1H) 4.19 (d, J = 16.7 Hz, 1H), 
               
               
                   
                   
                 4.14 (m, 2H), 3.92 (s, 6H), 3.90-3.80 (m, 2H), 3.63 (s, 4H), 3.06 (s, 
               
               
                   
                   
                 2H), 2.96-2.82 (m, 3H), 2.74-2.56 (m, 3H), 2.45-2.32 (m, 2H), 
               
               
                   
                   
                 2.01-1.92 (m, 2H), 1.87 (s, 5H). 
               
               
                 D362 
                 725.3 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.17 (s, 1H, FA), 
               
               
                   
                   
                 7.55-7.46 (m, 2H), 7.04 (s, 2H), 6.54 (s, 2H), 5.04 (dd, J = 13.3, 
               
               
                   
                   
                 5.1 Hz, 1H), 4.36-4.12 (m, 2H), 3.85 (d, J = 12.7 Hz, 2H), 3.77 (s, 
               
               
                   
                   
                 6H), 3.53 (s, 2H), 3.46 (s, 3H), 2.97-2.74 (m, 3H), 2.61 (s, 1H), 
               
               
                   
                   
                 2.47-2.28 (m, 11H), 2.06 (d, J = 2.7 Hz, 6H), 1.97 (s, 1H), 1.73 (d, 
               
               
                   
                   
                 J = 12.6 Hz, 2H), 1.50 (s, 1H), 1.36 (d, J = 7.5 Hz, 2H), 1.26-1.13 
               
               
                   
                   
                 (m, 2H). 
               
               
                 D363 
                 735.6 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.33 (s, 1H), 8.22 
               
               
                   
                   
                 (s, FA, 1H), 7.89 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.92 
               
               
                   
                   
                 (s, 2H), 6.53-6.43 (t, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, 
               
               
                   
                   
                 J = 16.9 Hz, 1H), 4.17 (d, J = 16.9 Hz, 1H), 3.85 (s, 6H), 3.67 (s, 
               
               
                   
                   
                 2H), 3.61 (s, J = 6.9 Hz, 6H), 3.47 (s, J = 6.9 Hz, 4H), 2.98 (m, J = 
               
               
                   
                   
                 6.9 Hz, 4H), 2.60 (s, 1H), 2.46-2.34 (m, 3H), 2.28 (s, 3H), 1.99- 
               
               
                   
                   
                 1.89 (m, 1H), 1.72 (t, J = 5.2 Hz, 4H). 
               
               
                 D364 
                 781.2 
                   1 H NMR (300 MHz, MeOD) δ 8.05 (d, J = 2.5 Hz, 1H), 7.83 (s, 1H), 
               
               
                   
                   
                 7.41 (d, J = 8.2 Hz, 1H), 6.95-6.84 (m, 3H), 6.79 (d, J = 8.2 Hz, 
               
               
                   
                   
                 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.51-1.45 (m, 2H), 4.44- 
               
               
                   
                   
                 4.30 (m, 4H), 4.25 (s, 2H), 4.14 (s, 2H), 4.01 (s, 6H), 3.79-3.73 
               
               
                   
                   
                 (m, 4H), 3.69 (s, 3H), 3.55-3.48 (m, 4H), 3.18-3.04 (m, 2H), 3.00- 
               
               
                   
                   
                 2.78 (m, 2H), 2.72 (s, 3H), 2.60-2.41 (m, 1H), 2.28-2.12 (m, 
               
               
                   
                   
                 5H), 1.38-1.28 (m, 2H). 
               
               
                 D365 
                 735.45 
                   1 H NMR (400 MHz, MeOD) δ 8.48 (s, FA, 1H), 7.93 (d, J = 1.6 Hz, 
               
               
                   
                   
                 1H), 7.77 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 
               
               
                   
                   
                 7.25 (s, 2H), 6.85 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.3, 2.2 Hz, 1H), 
               
               
                   
                   
                 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.48 (s, 2H), 4.45-4.33 (m, 2H), 
               
               
                   
                   
                 4.23 (s, 735.452H), 4.02 (s, 6H), 3.97 (s, 2H), 3.72 (s, 3H), 3.67 (s, 
               
               
                   
                   
                 4H), 3.43-3.35 (m, 1H), 3.22-3.01 (m, 1H), 2.96-2.85 (m, 1H), 
               
               
                   
                   
                 2.84-2.75 (m, 1H), 2.74 (s, 2H), 2.64-2.42 (m, 5H), 2.23-2.13 
               
               
                   
                   
                 (m, 1H), 1.91 (s, 4H). 
               
               
                 D366 
                 790.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.56 (d, J = 5.4 Hz, 
               
               
                   
                   
                 1H), 9.29 (s, 2H, TFA), 8.39 (d, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.64 
               
               
                   
                   
                 (dd, J = 8.4, 3.2 Hz, 1H), 7.17-7.04 (m, 3H), 7.02-6.95 (m, 1H), 
               
               
                   
                   
                 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (p, J = 6.7 Hz, 1H), 4.43- 
               
               
                   
                   
                 4.14 (m, 4H), 3.90 (s, 6H), 3.65 (s, 3H), 3.47-3.15 (m, 4H), 3.09- 
               
               
                   
                   
                 2.78 (m, 7H), 2.60 (d, J = 16.2 Hz, 2H), 2.46-2.34 (m, 2H), 2.17- 
               
               
                   
                   
                 2.08 (m, 1H), 1.98-1.87 (m, 6H), 1.86-1.82 (m, 3H), 1.49 (q, J = 
               
               
                   
                   
                 12.7 Hz, 2H). 
               
               
                 D367 
                 790.5 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.56 (d, J = 5.4 Hz, 
               
               
                   
                   
                 1H), 9.29 (s, 2H, TFA), 8.39 (d, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.64 
               
               
                   
                   
                 (dd, J = 8.4, 3.2 Hz, 1H), 7.17-7.04 (m, 3H), 7.02-6.95 (m, 1H), 
               
               
                   
                   
                 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (p, J = 6.7 Hz, 1H), 4.43- 
               
               
                   
                   
                 4.14 (m, 4H), 3.90 (s, 6H), 3.65 (s, 3H), 3.47-3.15 (m, 4H), 3.09- 
               
               
                   
                   
                 2.78 (m, 7H), 2.60 (d, J = 16.2 Hz, 2H), 2.46-2.34 (m, 2H), 2.17- 
               
               
                   
                   
                 2.08 (m, 1H), 1.98-1.87 (m, 6H), 1.86-1.82 (m, 3H), 1.49 (q, J = 
               
               
                   
                   
                 12.7 Hz, 2H). 
               
               
                 D368 
                 790.65 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.75 (s, 1H), 9.55 
               
               
                   
                   
                 (s, 1H), 9.32 (br s, 1H, TFA salt), 8.20 (s, 1H), 7.52 (dd, J = 8.4, 2.7 
               
               
                   
                   
                 Hz, 1H), 7.19-7.09 (m, 2H), 6.97 (s, 2H), 5.11 (dd, J = 13.3, 5.1 
               
               
                   
                   
                 Hz, 1H), 4.93-4.85 (m, 1H), 4.38 (d, J = 16.9 Hz, 2H), 4.26 (d, J = 
               
               
                   
                   
                 16.9 Hz, 2H), 3.92 (s, 6H), 3.68 (s, 3H), 3.54-3.38 (m, 4H), 3.25- 
               
               
                   
                   
                 3.21 (m, 1H), 3.06-2.82 (m, 6H), 2.67-2.56 (m, 2H), 2.44-2.38 
               
               
                   
                   
                 (m, 2H), 2.18-1.73 (m, 10H), 1.54-1.46 (m, 2H). 
               
               
                 D369 
                 749.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.05-9.61 (m, 
               
               
                   
                   
                 2H, TFA salt), 8.15 (s, 1H), 7.56-7.46 (m, 2H), 6.90 (d, J = 4.6 
               
               
                   
                   
                 Hz, 2H), 6.54-6.45 (m, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.40- 
               
               
                   
                   
                 4.28 (m, 2H), 4.27-4.15 (m, 4H), 4.12-3.98 (m, 2H), 3.90 (s, 
               
               
                   
                   
                 6H), 3.78 (s, 2H), 3.70 (s, 2H), 3.60 (d, J = 2.0 Hz, 3H), 3.52 (s, 
               
               
                   
                   
                 3H), 3.41 (s, 3H), 3.17 (s, 1H), 2.99-2.90 (m, 3H), 2.68-2.52 (m, 
               
               
                   
                   
                 2H), 2.47-2.28 (m, 1H), 2.13 (d, J = 13.9 Hz, 2H), 2.00-1.88 (m, 
               
               
                   
                   
                 3H). 
               
               
                 D370 
                 749.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.99-9.58 (m, 2H, 
               
               
                   
                   
                 TFA salt), 8.63 (s, 1H), 7.92 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.41 
               
               
                   
                   
                 (s, 2H), 6.54-6.45 (m, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.42- 
               
               
                   
                   
                 4.27 (m, 2H), 4.25-4.14 (m, 4H), 4.08 (s, 3H), 4.05-3.95 (m, 
               
               
                   
                   
                 2H), 3.94 (s, 6H), 3.77 (s, 2H), 3.69 (s, 2H), 3.54 (s, 3H), 3.38 (s, 
               
               
                   
                   
                 3H), 3.17 (d, J = 6.7 Hz, 1H), 2.96 (s, 3H), 2.65-2.51 (m, 2H), 2.43- 
               
               
                   
                   
                 2.36 (m, 1H), 2.12 (d, J = 14.3 Hz, 2H), 2.00-1.88 (m, 3H). 
               
               
                 D371 
                 805.45 
                 1H NMR (400 MHz, Methanol-d4) δ 7.86 (d, J = 9.7 Hz, 1H), 7.72 
               
               
                   
                   
                 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.06-6.97 (m, 2H), 6.90-6.79 
               
               
                   
                   
                 (m, 3H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.39 (m, 4H), 4.01- 
               
               
                   
                   
                 3.86 (m, 6H), 3.74 (s, 3H), 3.69-3.52 (m, 3H), 3.41-3.36 (m, 
               
               
                   
                   
                 1H), 3.28-3.16 (m, 2H), 3.13-2.98 (m, 4H), 2.96-2.86 (m, 2H), 
               
               
                   
                   
                 2.85-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.60-2.43 (m, 2H), 2.27 
               
               
                   
                   
                 (s, 1H), 2.22-2.15 (m, 1H), 2.14-1.92 (m, 8H), 1.73-1.59 (m, 
               
               
                   
                   
                 2H). 
               
               
                   
               
            
           
         
       
     
     Example 83—Preparation of Compounds DD1-DD10 
     In analogy to the procedures described in the examples above, compounds DD1-DD10 were prepared using the appropriate starting materials. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Compound 
                   
                   
               
               
                 No. 
                 LCMS 
                   1 H NMR 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 DD1 
                 942.5 
                   1 H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.98 (s, 1H), 8.72 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.19 (s, 1.0H, FA), 7.87 (s, 
               
               
                   
                   
                 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.47-7.35 (m, 5H), 6.72 (s, 2H), 4.57 
               
               
                   
                   
                 (d, J = 9.5 Hz, 1H), 4.47-4.33 (m, 3H), 4.30-4.21 (m, 1H), 3.97 (s, 
               
               
                   
                   
                 2H), 3.80 (s, 6H), 3.68-3.50 (m, 18H), 2.58 (t, J = 6.1 Hz, 2H), 2.44 
               
               
                   
                   
                 (s, 3H), 2.18 (s, 3H), 2.11-2.00 (m, 1H), 1.97-1.85 (m, 1H), 0.95 
               
               
                   
                   
                 (s, 9H). 
               
               
                 DD2 
                 754.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.43 (s, 1H), 8.71 (d, 
               
               
                   
                   
                 J = 5.8 Hz, 1H), 8.22 (s, 1.5H, FA), 8.11 (s, 1H), 7.88-7.81 (m, 2H), 
               
               
                   
                   
                 7.54 (d, J = 5.6 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 6.72 
               
               
                   
                   
                 (s, 2H), 5.16-5.07 (m, 1H), 4.68 (s, 2H), 3.80 (s, 6H), 3.62-3.58 
               
               
                   
                   
                 (m, 5H), 3.31-3.10 (m, 7H), 2.93-2.83 (m, 1H), 2.46 (s, 2H), 2.21 
               
               
                   
                   
                 (s, 3H), 2.17 (s, 3H), 2.16-1.94 (m, 2H). 
               
               
                 DD3 
                 740.45 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.70 (d, J = 5.8 Hz, 
               
               
                   
                   
                 1H), 8.55 (s, 1H, FA), 7.74 (s, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.38 (t, 
               
               
                   
                   
                 J = 8.1 Hz, 1H), 6.77 (s, 2H), 6.63 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 8.4 
               
               
                   
                   
                 Hz, 1H), 5.21 (dd, J = 10.9, 5.7 Hz, 1H), 4.52-4.25 (m, 2H), 4.12- 
               
               
                   
                   
                 4.00 (m, 1H), 3.90 (s, 8H), 3.85-3.75 (m, 6H), 3.71 (s, 3H), 3.53- 
               
               
                   
                   
                 3.42 (m, 2H), 2.93-2.70 (m, 7H), 2.64 (s, 3H), 2.26-2.17 (m, 1H). 
               
               
                 DD4 
                 709.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.48 (s, 1H), 8.75 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 2H), 7.92 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.29 (t, J = 7.7 
               
               
                   
                   
                 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.87 (s, 2H), 6.74 (d, J = 8.0 Hz, 
               
               
                   
                   
                 1H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.37-4.26 (m, 2H), 4.22-4.13 
               
               
                   
                   
                 (m, 2H), 3.89 (s, 7H), 3.62 (s, 3H), 3.21-3.03 (m, 4H), 2.98-2.84 
               
               
                   
                   
                 (m, 1H), 2.77-2.63 (m, 3H), 2.30-2.23 (m, 1H), 2.10-1.98 (m, 
               
               
                   
                   
                 1H), 1.84-1.66 (m, 2H), 1.66-1.53 (m, 2H), 1.44-1.29 (m, 8H). 
               
               
                 DD5 
                 736.45 
                   1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.69 (d, J = 5.7 Hz, 
               
               
                   
                   
                 1H), 8.56 (s, 1H, FA), 7.76 (s, 1H), 7.61 (dd, J = 5.8, 0.9 Hz, 1H), 
               
               
                   
                   
                 7.47 (t, J = 8.1 Hz, 1H), 6.87 (s, 2H), 6.67 (d, J = 7.8 Hz, 1H), 6.46 
               
               
                   
                   
                 (d, J = 8.4 Hz, 1H), 5.19 (dd, J = 11.0, 5.7 Hz, 1H), 4.29 (s, 2H), 3.96 
               
               
                   
                   
                 (s, 6H), 3.68 (s, 3H), 3.37-3.36 (m, 1H), 3.14-3.02 (m, 3H), 2.91- 
               
               
                   
                   
                 2.70 (m, 6H), 2.63 (s, 3H), 2.24-2.17 (m, 1H), 1.87-1.76 (m, 
               
               
                   
                   
                 2H), 1.74-1.64 (m, 2H), 1.54-1.36 (m, 8H). 
               
               
                 DD6 
                 722.54 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H), 8.72 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.91 (d, J = 44.8 Hz, 2H), 7.55 (d, J = 5.7 Hz, 1H), 
               
               
                   
                   
                 6.84 (s, 2H), 5.22-5.02 (m, 0H), 4.98 (s, 1H), 4.71 (s, 1H), 4.35 (s, 
               
               
                   
                   
                 2H), 3.94-3.78 (m, 6H), 3.59 (s, 3H), 3.13-2.80 (m, 2H), 2.73 (s, 
               
               
                   
                   
                 2H), 2.67-2.53 (m, 1H), 2.05 (s, 2H). 
               
               
                 DD7 
                 800.3 
                 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.40 (s, 1H), 8.68 (d, 
               
               
                   
                   
                 J = 5.6 Hz, 1H), 8.14-8.04 (m, 3H), 7.92 (d, J = 8.3 Hz, 1H), 7.83 
               
               
                   
                   
                 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 5.6 Hz, 1H), 7.00 (d, 
               
               
                   
                   
                 J = 8.7 Hz, 2H), 6.74 (s, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 4.06 (q, 
               
               
                   
                   
                 J = 5.2 Hz, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.82 (s, 6H), 3.64 (s, 2H), 
               
               
                   
                   
                 3.56 (s, 3H), 3.29-3.12 (m, 5H), 3.00 (s, 3H), 2.95-2.82 (m, 1H), 
               
               
                   
                   
                 2.64-2.50 (m, 2H), 2.22 (s, 3H), 2.06 (d, J = 11.5 Hz, 1H), 1.71 (d, 
               
               
                   
                   
                 J = 15.0 Hz, 0H), 1.71 (s, 2H), 1.59 (q, J = 7.3 Hz, 2H). 
               
               
                 DD8 
                 814.3 
                 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.40 (s, 1H), 8.68 (d, 
               
               
                   
                   
                 J = 5.6 Hz, 1H), 8.23 (s, 1H), 8.10-8.01 (m, 2H), 7.90 (d, J = 8.3 
               
               
                   
                   
                 Hz, 1H), 7.83 (s, 1H), 7.76-7.64 (m, 3H), 7.52 (d, J = 6.2 Hz, 1H), 
               
               
                   
                   
                 7.00 (d, J = 8.8 Hz, 2H), 6.72 (s, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 
               
               
                   
                   
                 4.00 (t, J = 6.3 Hz, 2H), 3.81 (s, 6H), 3.58 (d, J = 14.7 Hz, 5H), 3.18 
               
               
                   
                   
                 (d, J = 6.3 Hz, 1H), 3.15 (s, 5H), 2.94 (s, 2H), 2.92-2.82 (m, 1H), 
               
               
                   
                   
                 2.62 (s, 1H), 2.59-2.50 (m, 1H), 2.16 (s, 3H), 2.07 (d, J = 11.7 Hz, 
               
               
                   
                   
                 1H), 1.73 (t, J = 7.0 Hz, 2H), 1.49 (d, J = 5.5 Hz, 2H), 1.42 (d, J = 
               
               
                   
                   
                 7.9 Hz, 3H). 
               
               
                 DD9 
                 571.61 
                   1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.09-8.02 (m, 1H), 
               
               
                   
                   
                 7.82-7.77 (m, 1H), 7.73 (s, 1H), 7.63 (s, 0H), 6.87 (d, J = 8.0 Hz, 
               
               
                   
                   
                 1H), 6.82 (s, 2H), 5.09 (dt, J = 11.9, 5.8 Hz, 1H), 3.92 (d, J = 3.9 Hz, 
               
               
                   
                   
                 5H), 3.86 (d, J = 3.7 Hz, 6H), 3.51 (d, J = 2.0 Hz, 4H), 3.15 (s, 1H), 
               
               
                   
                   
                 2.08 (d, J = 2.6 Hz, 4H). 
               
               
                 DD10 
                 803.2 
                 1H NMR (300 MHz, DMSO) δ 11.13 (s, 1H), 8.20 (s, FA, 1H), 8.09 
               
               
                   
                   
                 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 
               
               
                   
                   
                 7.69-7.59 (m, 1H), 7.58-7.49 (m, 1H), 7.43 (d, J = 7.5 Hz, 1H), 
               
               
                   
                   
                 7.34-7.23 (m, 2H), 6.73 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 
               
               
                   
                   
                 5.05-4.94 (m, 1H), 3.81 (s, 6H), 3.73-3.67 (m, 1H), 3.03-2.89 (m, 
               
               
                   
                   
                 2H), 2.88-2.81 (m, 1H), 2.66-2.53 (m, 2H), 2.49-2.39 (m, 6H), 
               
               
                   
                   
                 2.36-2.21 (m, 6H), 2.14-1.99 (m, 3H), 1.89-1.75 (m, 2H), 1.72- 
               
               
                   
                   
                 1.45 (m, 7H), 1.26-1.06 (m, 2H). 
               
               
                   
               
            
           
         
       
     
     Example 84—Preparation of Compounds D372-D476 
     In analogy to the procedures described in the examples above, compounds D372-D476 were prepared using the appropriate starting materials. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Compound 
                   
                   
               
               
                 No. 
                 LCMS 
                   1 H NMR 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 D372 
                 638.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (s, 1H), 8.73 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.88 (d, J = 14.1 Hz, 2H), 7.57 (d, J = 5.6 Hz, 1H), 
               
               
                   
                   
                 7.36-7.28 (m, 2H), 6.79 (s, 2H), 5.18-5.01 (m, 2H), 4.25-3.92 (m, 
               
               
                   
                   
                 3H), 3.84 (s, 7H), 3.61 (s, 4H), 2.96-2.81 (m, 1H), 2.70-2.53 (m, 
               
               
                   
                   
                 3H), 2.10-2.01 (m, 1H). 
               
               
                 D373 
                 691.30 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.45 (d, J = 0.8 Hz, 
               
               
                   
                   
                 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.18 (s, FA, 1H), 7.89 (s, 1H), 7.67- 
               
               
                   
                   
                 7.57 (m, 2H), 6.81-6.72 (m, 3H), 6.66 (dd, J = 8.4, 2.1 Hz, 1H), 
               
               
                   
                   
                 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.82 (s, 6H), 3.74 (s, 4H), 3.58 (d, 
               
               
                   
                   
                 J = 20.8 Hz, 6H), 2.95-2.82 (m, 1H), 2.63-2.52 (m, 2H), 2.46-2.41 
               
               
                   
                   
                 (m, 3H), 2.04-1.97 (m, 1H), 1.77-1.70 (m, 4H). 
               
               
                 D374 
                 677.30 
                   1 H NMR (400 MHz, MeOD) δ 9.59 (s, 1H), 8.71 (d, J = 6.1 Hz, 1H), 
               
               
                   
                   
                 7.94 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.67-7.60 (m, 1H), 6.91 (s, 
               
               
                   
                   
                 2H), 6.59 (d, J = 7.8 Hz, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (s, 
               
               
                   
                   
                 2H), 4.40 (d, J = 7.0 Hz, 2H), 4.00 (s, 6H), 3.92 (s, 2H), 3.80 (s, 2H), 
               
               
                   
                   
                 3.75 (s, 3H), 3.62-3.55 (m, 3H), 3.31-3.21 (m, 1H), 2.98-2.85 (m, 
               
               
                   
                   
                 1H), 2.85-2.74 (m, 1H), 2.55-2.39 (m, 1H), 2.33-2.24 (m, 2H), 
               
               
                   
                   
                 2.21-2.06 (m, 3H). 
               
               
                 D375 
                 624.25 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.57 (s, 1H), 8.70 (d, J = 6.0 Hz, 
               
               
                   
                   
                 1H), 7.90 (s, 1H), 7.77 (dd, J = 14.9, 7.1 Hz, 2H), 7.09 (d, J = 10.5 
               
               
                   
                   
                 Hz, 2H), 6.89 (s, 2H), 5.41-5.20 (m, 1H), 5.15 (dd, J = 13.3, 5.2 
               
               
                   
                   
                 Hz, 1H), 4.86-4.60 (m, 4H), 4.49 (d, J = 4.5 Hz, 2H), 4.44-4.27 
               
               
                   
                   
                 (m, 2H), 3.97 (d, J = 14.5 Hz, 6H), 3.73 (s, 3H), 3.01-2.74 (m, 2H), 
               
               
                   
                   
                 2.60-2.41 (m, 1H), 2.25-2.13 (m, 1H). 
               
               
                 D376 
                 652.30 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.81 (s, TFA, 1H), 
               
               
                   
                   
                 9.48 (d, J = 0.8 Hz, 1H), 8.75 (d, J = 5.7 Hz, 1H), 7.96-7.89 (m, 
               
               
                   
                   
                 2H), 7.57 (d, J = 5.7 Hz, 1H), 7.44-7.34 (m, 2H), 6.88 (s, 2H), 5.15 
               
               
                   
                   
                 (dd, J = 12.8, 5.4 Hz, 2H), 4.74-4.57 (m, 2H), 4.55-4.42 (m, 2H), 
               
               
                   
                   
                 4.09 (s, 1H), 3.92 (s, 6H), 3.63 (s, 3H), 2.97-2.84 (m, 1H), 2.66- 
               
               
                   
                   
                 2.52 (m, 2H), 2.10-2.03 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H). 
               
               
                 D377 
                 677.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.16 (s, 1H), 7.73 (s, 
               
               
                   
                   
                 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, 
               
               
                   
                   
                 J = 2.3 Hz, 1H), 6.74 (d, J = 20.0 Hz, 3H), 5.10 (dd, J = 13.3, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.38-4.15 (m, 2H), 3.93 (s, 3H), 3.79 (s, 6H), 3.73 (d, J = 12.3 
               
               
                   
                   
                 Hz, 3H), 3.57-3.52 (m, 5H), 2.97-2.84 (m, 1H), 2.75-2.64 (m, 
               
               
                   
                   
                 2H), 2.64-2.55 (m, 1H), 2.48-2.38 (m, 4H), 2.38-2.20 (m, 6H), 
               
               
                   
                   
                 2.03-1.94 (m, 1H), 1.74 (d, J = 12.4 Hz, 2H), 1.52-1.42 (m, 1H), 
               
               
                   
                   
                 1.41-1.32 (m, 2H), 1.31-1.17 (m, 2H). 
               
               
                 D378 
                 624.30 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.69 (d, J = 5.9 Hz, 
               
               
                   
                   
                 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.33-7.16 
               
               
                   
                   
                 (m, 2H), 6.89 (s, 2H), 5.40-5.07 (m, 2H), 4.84-4.61 (m, 4H), 4.59- 
               
               
                   
                   
                 4.44 (m, 2H), 4.44-4.28 (m, 2H), 4.07-3.85 (m, 6H), 3.73 (s, 
               
               
                   
                   
                 3H), 3.01-2.86 (m, 1H), 2.86-2.75 (m, 1H), 2.61-2.43 (m, 1H), 
               
               
                   
                   
                 2.25-2.14 (m, 1H). 
               
               
                 D379 
                 810.35 
                   1 H NMR (400 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.70 (d, J = 5.8 Hz, 
               
               
                   
                   
                 1H), 8.56 (s, 1H, FA), 7.78 (s, 1H), 7.69-7.56 (m, 2H), 6.88 (s, 2H), 
               
               
                   
                   
                 6.65-6.53 (m, 2H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.53-4.24 (m, 
               
               
                   
                   
                 4H), 4.06 (d, 2H), 3.98 (s, 6H), 3.76 (d, J = 8.0 Hz, 2H), 3.72 (s, 3H), 
               
               
                   
                   
                 3.56-3.48 (m, 2H), 3.16-3.01 (m, 2H), 2.99-2.85 (m, 1H), 2.84- 
               
               
                   
                   
                 2.64 (m, 3H), 2.60-2.40 (m, 3H), 2.36 (s, 2H), 2.21-2.11 (m, 
               
               
                   
                   
                 3H), 2.05 (d, J = 13.9 Hz, 2H), 1.92 (s, 1H), 1.59-1.38 (m, 2H). 
               
               
                 D380 
                 661.35 
                 1H), 9.49 (s, 1H), 8.75 (d, J = 5.9 Hz, 1H), 7.99 (s, 1H), 7.56 (d, J = 
               
               
                   
                   
                 5.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.12 (t, J = 2.0 Hz, 1H), 7.04 
               
               
                   
                   
                 (d, J = 2.0 Hz, 2H), 6.74-6.67 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.32 (d, J = 16.6 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.86 (s, 
               
               
                   
                   
                 3H), 3.67 (s, 6H), 3.61 (s, 3H), 3.39 (s, 2H), 2.98-2.84 (m, 1H), 2.63- 
               
               
                   
                   
                 2.59 (m, 1H), 2.42-2.33 (m, 1H), 2.02-1.95 (m, 1H), 1.90-1.72 
               
               
                   
                   
                 (m, 4H). 
               
               
                 D381 
                 767.40 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.86-10.81 (m, HCl, 1H), 9.52 
               
               
                   
                   
                 (s, 1H), 8.80-8.73 (m, 1H), 8.52 (s, 3H), 8.07 (s, 1H), 7.93 (d, J = 
               
               
                   
                   
                 8.2 Hz, 1H), 7.72 (s, 1H), 7.44-7.34 (m, 2H), 6.88 (d, J = 6.1 Hz, 
               
               
                   
                   
                 2H), 5.93-5.84 (m, 1H), 5.75-5.67 (m, 1H), 5.53-5.21 (m, 2H), 
               
               
                   
                   
                 4.81-4.73 (m, 1H), 4.67-4.53 (m, 1H), 4.52-4.44 (m, 2H), 4.33- 
               
               
                   
                   
                 4.29 (m, 1H), 4.17-4.12 (m, 1H), 3.92 (s, 3H), 3.87 (s, 4H), 3.64 (s, 
               
               
                   
                   
                 3H), 3.13-3.05 (m, 1H), 2.93-2.84 (m, 1H), 2.70-2.56 (m, 1H), 
               
               
                   
                   
                 2.18-2.11 (m, 2H), 0.98-0.90 (m, 6H). 
               
               
                 D382 
                 663.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.47 (s, 1H), 8.92 (s, 
               
               
                   
                   
                 1H, FA), 8.76 (d, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.59 (d, J = 5.7 Hz, 
               
               
                   
                   
                 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.87 (s, 2H), 6.75-6.52 (m, 2H), 5.19 
               
               
                   
                   
                 (dd, J = 9.1, 6.3 Hz, 1H), 4.49 (d, J = 16.8 Hz, 1H), 4.38-4.15 (m, 
               
               
                   
                   
                 3H), 3.91 (s, 7H), 3.76 (s, 2H), 3.62 (s, 6H), 3.21-3.04 (m, 2H), 
               
               
                   
                   
                 3.04-2.79 (m, 2H), 2.21-1.90 (m, 4H). 
               
               
                 D383 
                 667.30 
                   1 H NMR (400 MHz, DMSO-d6 with a drop of D 2 O) δ 9.46 (s, 1H), 
               
               
                   
                   
                 8.75 (d, J = 5.7 Hz, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.60 
               
               
                   
                   
                 (d, J = 5.6 Hz, 1H), 6.86 (s, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.67 (dd, 
               
               
                   
                   
                 J = 8.4, 2.1 Hz, 1H), 5.21 (dd, J = 9.6, 5.6 Hz, 1H), 4.29 (s, 2H), 3.91 
               
               
                   
                   
                 (d, J = 8.4 Hz, 8H), 3.81 (s, 2H), 3.61 (s, 3H), 3.38 (d, J = 12.6 Hz, 
               
               
                   
                   
                 2H), 3.13 (t, J = 12.0 Hz, 2H), 3.05-2.95 (m, 1H), 2.82 (dd, J = 
               
               
                   
                   
                 17.9, 5.5 Hz, 1H), 2.15 (d, J = 14.1 Hz, 2H), 2.01 (t, J = 12.8 Hz, 
               
               
                   
                   
                 2H). 
               
               
                 D384 
                 753.40 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H, HCl salt), 9.49 (s, 
               
               
                   
                   
                 1H), 8.79-8.72 (m, 1H), 8.51 (br s, 3H), 7.99 (s, 1H), 7.71 (d, J = 
               
               
                   
                   
                 8.4 Hz, 1H), 7.67-7.59 (m, 1H), 7.39-7.01 (m, 3H), 6.87 (d, J = 
               
               
                   
                   
                 5.1 Hz, 2H), 5.86-5.78 (m, 1H), 5.76-5.68 (m, 1H), 5.35-5.02 
               
               
                   
                   
                 (m, 2H), 4.80-4.67 (m, 1H), 4.60-4.54 (m, 1H), 4.52-4.41 (m, 
               
               
                   
                   
                 3H), 4.34-4.22 (m, 2H), 4.16-4.10 (m, 1H), 3.94-3.82 (m, 7H), 
               
               
                   
                   
                 3.63 (s, 3H), 3.20-3.06 (m, 1H), 2.91-2.82 (m, 1H), 2.46-2.36 
               
               
                   
                   
                 (m, 1H), 2.21-2.06 (m, 2H), 0.97-0.90 (m, 6H). 
               
               
                 D385 
                 636.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 8.13 (s, 0.1 H, FA salt), 7.90-7.81 (m, 2H), 7.51 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.37-7.27 (m, 2H), 6.94 (s, 2H), 5.18-4.99 (m, 
               
               
                   
                   
                 2H), 3.84 (s, 6H), 3.60 (s, 4H), 3.28-3.25 (m, 2H), 2.99-2.72 (m, 
               
               
                   
                   
                 3H), 2.61-2.53 (m, 2H), 2.11-1.99 (m, 1H), 1.21 (t, J = 7.5 Hz, 3H). 
               
               
                 D386 
                 650.30 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 
               
               
                   
                   
                 (dd, J = 5.7, 2.3 Hz, 1H), 8.13 (s, 0.1H, FA salt), 7.89-7.80 (m, 2H), 
               
               
                   
                   
                 7.49 (dd, J = 6.0, 2.1 Hz, 1H), 7.37-7.28 (m, 2H), 6.92 (s, 2H), 5.12 
               
               
                   
                   
                 (dd, J = 12.9, 5.3 Hz, 1H), 4.63 (s, 1H), 3.90-3.68 (m, 6H), 3.60 (s, 
               
               
                   
                   
                 4H), 3.44-3.37 (m, 1H), 2.99-2.72 (m, 3H), 2.62-2.52 (m, 2H), 
               
               
                   
                   
                 2.11-1.95 (m, 1H), 1.29-1.12 (m, 6H). 
               
               
                 D387 
                 647.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.45 (s, 1H), 8.73 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.48-7.36 (m, 2H), 7.01-6.89 (m, 
               
               
                   
                   
                 3H), 6.73-6.65 (m, 2H), 5.11-5.04 (m, 1H), 4.31-4.18 (m, 2H), 
               
               
                   
                   
                 3.82 (s, 3H), 3.60 (s, 7H), 3.52 (s, 2H), 2.94-2.87 (m, 1H), 2.67- 
               
               
                   
                   
                 2.61 (m, 1H), 2.46-2.34 (m, 4H), 2.04-1.92 (m, 2H), 1.83-1.73 
               
               
                   
                   
                 (m, 4H). 
               
               
                 D388 
                 705.45 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.48 (s, 1H), 9.07 (br 
               
               
                   
                   
                 s, 1H), 8.76 (d, J = 5.7 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 8.2 Hz, 
               
               
                   
                   
                 1H), 7.61 (d, J = 5.8 Hz, 1H), 6.88 (s, 2H), 6.78 (d, J = 2.1 Hz, 1H), 
               
               
                   
                   
                 6.67 (dd, J = 8.3, 2.2 Hz, 1H), 5.14 (dd, 1H), 4.38-4.24 (m, 2H), 
               
               
                   
                   
                 3.97-3.88 (m, 8H), 3.83 (s, 2H), 3.63 (s, 3H), 3.46-3.35 (m, 3H), 
               
               
                   
                   
                 3.18-3.06 (m, 3H), 2.76-2.66 (m, 1H), 2.22-2.13 (m, 2H), 2.11- 
               
               
                   
                   
                 1.80 (m, 5H). 
               
               
                 D389 
                 663.30 
                   1 H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.74 (d, J = 5.7 Hz, 
               
               
                   
                   
                 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.36 (d, J = 
               
               
                   
                   
                 8.7 Hz, 1H), 6.80 (s, 2H), 6.70-6.64 (m, 2H), 4.64 (dd, J = 10.8, 6.8 
               
               
                   
                   
                 Hz, 1H), 4.38-4.25 (m, 1H), 4.21-4.07 (m, 1H), 3.96-3.80 (m, 
               
               
                   
                   
                 8H), 3.66-3.59 (m, 7H), 3.23-3.11 (m, 3H), 2.94-2.74 (m, 3H), 
               
               
                   
                   
                 2.09-1.80 (m, 8H). 
               
               
                 D390 
                 663.50 
                   1 H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.99 (s, 1H, TFA), 
               
               
                   
                   
                 8.76 (d, J = 5.7 Hz, 1H), 7.91 (s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.54 
               
               
                   
                   
                 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.88 (s, 2H), 6.73-6.64 
               
               
                   
                   
                 (m, 2H), 4.41-4.27 (m, 5H), 3.92 (s, 6H), 3.76 (s, 3H), 3.64 (s, 4H), 
               
               
                   
                   
                 3.45-3.34 (m, 2H), 3.34-3.06 (m, 4H), 2.44-2.29 (m, 2H), 2.19- 
               
               
                   
                   
                 1.85 (m, 6H). 
               
               
                 D391 
                 667.45 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.54 (s, 1H), 9.10 (s, 
               
               
                   
                   
                 1H), 8.97 (d, J = 8.2 Hz, 1H), 8.82 (d, J = 5.7 Hz, 1H), 8.37 (d, J = 
               
               
                   
                   
                 5.9 Hz, 1H), 7.96 (s, 1H), 7.65 (d, J = 5.7 Hz, 1H), 6.94 (s, 2H), 6.60 
               
               
                   
                   
                 (d, J = 6.0 Hz, 1H), 4.85-4.71 (m, 1H), 4.42-4.32 (m, 2H), 4.12-3.89 
               
               
                   
                   
                 (m, 11H), 3.69 (s, 3H), 3.27-3.15 (m, 3H), 2.98-2.78 (m, 1H), 2.71- 
               
               
                   
                   
                 2.60 (m, 1H), 2.32-1.99 (m, 6H). 
               
               
                 D392 
                 665.25 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.63 (s, 1H), 8.72 (d, J = 6.4 Hz, 
               
               
                   
                   
                 1H), 8.08 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 
               
               
                   
                   
                 7.23 (dt, J = 7.9, 1.2 Hz, 1H), 7.02 (t, J = 2.0 Hz, 1H), 6.91 (s, 2H), 
               
               
                   
                   
                 6.71 (ddd, J = 8.0, 2.5, 1.1 Hz, 1H), 4.86-4.85 (m, 1H), 4.46 (s, 
               
               
                   
                   
                 2H), 4.00 (s, 6H), 3.85 (s, 2H), 3.75 (d, J = 9.0 Hz, 5H), 3.58 (d, J = 
               
               
                   
                   
                 12.9 Hz, 2H), 3.25 (t, J = 11.8 Hz, 2H), 2.95-2.65 (m, 2H), 2.34- 
               
               
                   
                   
                 2.05 (m, 6H). 
               
               
                 D393 
                 571.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.45 (d, J = 0.8 Hz, 
               
               
                   
                   
                 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.19 (.1.0 FA, s, 1H), 7.89 (s, 1H), 7.63- 
               
               
                   
                   
                 7.50 (m, 2H), 7.36 (s, 1H), 6.74 (s, 2H), 5.27 (dd, J = 11.5, 5.1 Hz, 
               
               
                   
                   
                 1H), 3.83 (s, 6H), 3.60 (d, J = 4.2 Hz, 5H), 2.92 (d, J = 11.3 Hz, 2H), 
               
               
                   
                   
                 2.84-2.68 (m, 1H), 2.68-2.53 (m, 1H), 2.49-2.35 (m, 2H), 2.24- 
               
               
                   
                   
                 2.09 (m, 3H), 1.80 (d, J = 12.8 Hz, 2H), 1.58-1.38 (m, 2H). 
               
               
                 D394 
                 613.25 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.60 (s, 1H), 8.71 (d, 1H), 7.97 
               
               
                   
                   
                 (s, 1H), 7.85 (d, 1H), 6.91 (s, 2H), 6.70 (s, 1H), 6.12 (dd, 1H), 4.48 
               
               
                   
                   
                 (s, 2H), 4.00 (s, 6H), 3.75 (s, 4H), 3.71 (s, 1H), 3.58-3.42 (m, 1H), 
               
               
                   
                   
                 3.27 (s, 1H), 3.06-2.95 (m, 1H), 2.90-2.76 (m, 2H), 2.60 (d, 3H), 
               
               
                   
                   
                 2.40-2.27 (m, 2H), 2.12 (dd, 4H). 
               
               
                 D395 
                 667.45 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.45 (s, 1H), 9.00 (d, 
               
               
                   
                   
                 J = 8.4 Hz, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.54 (d, J = 1.2 Hz, 1H), 
               
               
                   
                   
                 8.17 (s, 1H, FA), 7.88 (s, 1H), 7.63-7.55 (m, 1H), 6.89 (d, J = 1.2 
               
               
                   
                   
                 Hz, 1H), 6.74 (s, 2H), 4.76 (ddd, J = 12.9, 8.4, 5.3 Hz, 1H), 3.82 (d, 
               
               
                   
                   
                 J = 4.1 Hz, 10H), 3.61 (s, 3H), 3.58 (s, 2H), 2.84-2.74 (m, 1H), 2.55 
               
               
                   
                   
                 (s, 2H), 2.48-2.40 (m, 3H), 2.25-2.13 (m, 1H), 2.05-1.93 (m, 
               
               
                   
                   
                 1H), 1.75 (s, 4H). 
               
               
                 D396 
                 640.31 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.19 (s, FA, 1H), 
               
               
                   
                   
                 7.41-7.26 (m, 2H), 6.72-6.66 (m, 2H), 6.53 (s, 2H), 5.09 (dd, J = 
               
               
                   
                   
                 13.2, 5.0 Hz, 1H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 
               
               
                   
                   
                 1H), 3.79 (s, 6H), 3.77 (d, J = 7.1 Hz, 2H), 3.74-3.66 (m, 4H), 3.54 
               
               
                   
                   
                 (s, 3H), 2.97-2.84 (m, 1H), 2.77 (s, 2H), 2.64-2.59 (m, 2H), 2.40- 
               
               
                   
                   
                 2.28 (m, 5H), 2.04 (s, 3H), 2.01-1.95 (m, 3H). 
               
               
                 D397 
                 751.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.19 (br s, TFA salt, 
               
               
                   
                   
                 2H), 7.45-7.38 (m, 1H), 7.28 (s, 1H), 6.74-6.66 (m, 4H), 5.07 (dd, 
               
               
                   
                   
                 J = 13.3, 5.1 Hz, 1H), 4.37-4.16 (m, 4H), 3.87 (s, 6H), 3.74 (d, J = 
               
               
                   
                   
                 8.5 Hz, 2H), 3.67 (d, J = 6.9 Hz, 2H), 3.65 (s, 5H), 3.53-3.50 (m, 
               
               
                   
                   
                 2H), 3.21 (s, 1H), 3.07-2.85 (m, 6H), 2.65-2.55 (m, 1H), 2.43- 
               
               
                   
                   
                 2.31 (m, 4H), 2.20-2.07 (m, 3H), 2.05 (s, 3H), 2.02-1.87 (m, 5H), 
               
               
                   
                   
                 1.58-1.39 (m, 2H). 
               
               
                 D398 
                 761.2 
                 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H, FA), 8.15 (d, J = 2.5 Hz, 
               
               
                   
                   
                 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 
               
               
                   
                   
                 8.7, 2.3 Hz, 1H), 7.14-6.71 (m, 3H), 5.06 (dd, J = 12.8, 5.3 Hz, 
               
               
                   
                   
                 1H), 4.03 (d, J = 13.0 Hz, 2H), 3.85 (s, 6H), 3.59 (s, 3H), 3.54 (s, 
               
               
                   
                   
                 2H), 3.00-2.80 (m, 3H), 2.65-2.52 (m, 2H), 2.48-2.24 (m, 10H), 
               
               
                   
                   
                 2.06-1.96 (m, 1H), 1.73 (d, J = 12.6 Hz, 2H), 1.60-1.54 (m, 1H), 
               
               
                   
                   
                 1.37 (t, J = 7.3 Hz, 2H), 1.16 (q, J = 11.6 Hz, 2H). 
               
               
                 D399 
                 747.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.40 (d, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.19 (s, 1H, FA), 8.15 (d, J = 2.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 
               
               
                   
                   
                 1H), 7.24 (dd, J = 8.6, 2.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.12- 
               
               
                   
                   
                 6.72 (m, 3H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.33 (d, J = 16.7 Hz, 
               
               
                   
                   
                 1H), 4.19 (d, J = 16.7 Hz, 1H), 3.85 (s, 6H), 3.72 (d, J = 12.1 Hz, 
               
               
                   
                   
                 2H), 3.59 (s, 3H), 3.53 (s, 2H), 3.01-2.82 (m, 1H), 2.78-2.51 (m, 
               
               
                   
                   
                 4H), 2.46-2.20 (m, 10H), 1.98 (d, J = 13.3 Hz, 1H), 1.73 (d, J = 
               
               
                   
                   
                 12.4 Hz, 2H), 1.47-1.36 (m, 3H), 1.24 (q, J = 11.2 Hz, 2H). 
               
               
                 D400 
                 751.5 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.63 (s, 1H), 7.91 (s, 
               
               
                   
                   
                 1H), 7.47-7.39 (m, 3H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.20 (d, J = 
               
               
                   
                   
                 2.3 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.40-4.14 (m, 4H), 
               
               
                   
                   
                 4.08 (s, 3H), 3.92 (s, 6H), 3.78-3.74 (m, 8H), 3.54 (s, 3H), 3.14 (s, 
               
               
                   
                   
                 4H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.75 (t, J = 11.8 Hz, 2H), 
               
               
                   
                   
                 2.65-2.56 (m, 1H), 2.43-2.34 (m, 1H), 2.04-1.95 (m, 1H), 1.78 
               
               
                   
                   
                 (d, J = 12.4 Hz, 2H), 1.64-1.46 (m, 3H), 1.38-1.23 (m, 2H). 
               
               
                 D401 
                 690.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.37 (s, 1H), 8.24 (s, 
               
               
                   
                   
                 1H), 8.15 (s, 1H, FA), 7.41-7.32 (m, 1H), 7.20-6.73 (m, 3H), 6.68 
               
               
                   
                   
                 (dd, J = 5.1, 2.5 Hz, 2H), 5.09 (dd, J = 13.3, 5.0 Hz, 1H), 4.45-4.10 
               
               
                   
                   
                 (m, 2H), 4.00 (t, J = 7.5 Hz, 2H), 3.87 (s, 6H), 3.81-3.66 (m, 6H), 
               
               
                   
                   
                 2.94-2.83 (m, 1H), 2.75 (s, 2H), 2.64-2.52 (m, 2H), 2.42-2.25 
               
               
                   
                   
                 (m, 2H), 1.98 (t, J = 7.0 Hz, 3H), 1.75 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 
               
               
                   
                   
                 7.3 Hz, 3H). 
               
               
                 D402 
                 749.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.95-9.63 (m, 2H, 
               
               
                   
                   
                 TFA salt), 8.63 (s, 1H), 7.92 (s, 1H), 7.45-7.38 (m, 3H), 6.73-6.66 
               
               
                   
                   
                 (m, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.43-4.28 (m, 3H), 4.24- 
               
               
                   
                   
                 4.15 (m, 3H), 4.08 (s, 3H), 4.03-3.98 (m, 2H), 3.94 (s, 6H), 3.76- 
               
               
                   
                   
                 3.62 (m, 4H), 3.54 (s, 3H), 3.22-3.12 (m, 2H), 2.97-2.88 (m, 4H), 
               
               
                   
                   
                 2.70-2.56 (m, 2H), 2.44-2.30 (m, 2H), 2.12 (d, J = 14.1 Hz, 2H), 
               
               
                   
                   
                 2.02-1.89 (m, 3H). 
               
               
                 D403 
                 662.15 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.41 (s, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.16 (s, 1H, FA), 7.37 (d, J = 8.8 Hz, 1H), 6.86-7.08 (m, 3H), 
               
               
                   
                   
                 6.72-6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 
               
               
                   
                   
                 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.87 (s, 6H), 3.79-3.67 (m, 
               
               
                   
                   
                 6H), 3.60 (s, 3H), 2.97-2.84 (m, 2H), 2.76 (s, 2H), 2.63-2.55 (m, 
               
               
                   
                   
                 3H), 2.31-2.42 (m, 2H), 2.02-1.94 (m, 3H). 
               
               
                 D404 
                 688.15 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.34 (d, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.22 (s, 1H), 8.18 (s, 1H, FA), 7.37 (d, J = 8.8 Hz, 1H), 7.16- 
               
               
                   
                   
                 6.73 (m, 3H), 6.68 (dq, J = 4.0, 2.3 Hz, 2H), 6.03 (ddd, J = 17.2, 
               
               
                   
                   
                 10.5, 5.3 Hz, 1H), 5.33-5.00 (m, 3H), 4.68 (d, J = 5.5 Hz, 2H), 4.31 
               
               
                   
                   
                 (d, J = 16.7 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.90-3.79 (m, 7H), 
               
               
                   
                   
                 3.77-3.71 (m, 2H), 3.72-3.63 (m, 3H), 3.00-2.82 (m, 1H), 2.76 
               
               
                   
                   
                 (s, 2H), 2.59 (d, J = 17.1 Hz, 3H), 2.43-2.28 (m, 1H), 1.98 (t, J = 
               
               
                   
                   
                 6.9 Hz, 3H). 
               
               
                 D405 
                 777.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.61 (s, 1H), 8.19- 
               
               
                   
                   
                 8.14 (m, 1H, FA), 7.89-7.82 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.36- 
               
               
                   
                   
                 7.29 (m, 2H), 6.72-6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 
               
               
                   
                   
                 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 4.08 (s, 3H), 
               
               
                   
                   
                 3.87 (s, 6H), 3.79 (s, 2H), 3.58 (s, 4H), 3.53 (s, 3H), 3.08-3.01 (m, 
               
               
                   
                   
                 2H), 2.98-2.84 (m, 1H), 2.68-2.55 (m, 2H), 2.43-2.30 (m, 6H), 
               
               
                   
                   
                 2.11 (d, J = 7.0 Hz, 2H), 2.02-1.93 (m, 1H), 1.77-1.67 (m, 6H), 
               
               
                   
                   
                 1.59 (s, 1H), 1.21-1.17 (m, 2H). 
               
               
                 D406 
                 676.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.41 (d, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.19 (s, 1H, FA), 8.15 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 
               
               
                   
                   
                 1H), 7.15-6.74 (m, 4H), 6.64 (dd, J = 8.3, 2.1 Hz, 1H), 5.06 (dd, J = 
               
               
                   
                   
                 12.8, 5.4 Hz, 1H), 3.99-3.85 (m, 4H), 3.87 (s, 6H), 3.70 (s, 2H), 
               
               
                   
                   
                 3.59 (s, 3H), 2.97-2.80 (m, 1H), 2.77 (s, 2H), 2.63-2.53 (m, 4H), 
               
               
                   
                   
                 2.02 (t, J = 7.0 Hz, 3H). 
               
               
                 D407 
                 773.89 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.42 (s, 1H, TFA), 
               
               
                   
                   
                 9.25 (s, 1H, TFA), 8.50 (d, J = 2.7 Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H), 
               
               
                   
                   
                 7.44-7.38 (m, 1H), 7.11-6.79 (m, 3H), 6.70 (dd, J = 5.8, 2.4 Hz, 
               
               
                   
                   
                 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.38-4.14 (m, 4H), 3.95 (s, 
               
               
                   
                   
                 6H), 3.66 (d, J = 7.8 Hz, 2H), 3.61 (s, 3H), 3.54-3.39 (m, 4H), 3.21- 
               
               
                   
                   
                 3.14 (m, 1H), 3.02-2.82 (m, 7H), 2.64-2.56 (m, 1H), 2.43-2.35 
               
               
                   
                   
                 (m, 1H), 2.15-2.07 (m, 3H), 2.02-1.88 (m, 5H), 1.48 (q, J = 12.8 
               
               
                   
                   
                 Hz, 2H), 1.26 (q, J = 7.2, 6.7 Hz, 1H). 
               
               
                 D408 
                 662.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.41 (d, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.21 (s, 1H, FA), 8.17-8.10 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 
               
               
                   
                   
                 7.18-6.73 (m, 3H), 6.54-6.42 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.16 (d, J = 16.9 Hz, 1H), 3.87 (s, 
               
               
                   
                   
                 6H), 3.79 (q, J = 7.9 Hz, 4H), 3.70 (s, 2H), 3.59 (s, 3H), 2.99-2.81 
               
               
                   
                   
                 (m, 1H), 2.80-2.74 (m, 2H), 2.63-2.52 (m, 2H), 2.41-2.29 (m, 
               
               
                   
                   
                 2H), 2.05-1.89 (m, 3H). 
               
               
                 D409 
                 676.25 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.55 (s, 1H, FA), 7.68 (s, 1H), 
               
               
                   
                   
                 7.42 (d, J = 8.2 Hz, 1H), 7.03-6.77 (m, 3H), 6.71 (s, 2H), 5.14 (dd, 
               
               
                   
                   
                 J = 13.3, 5.1 Hz, 1H), 4.48-4.33 (m, 4H), 4.03-3.89 (m, 10H), 
               
               
                   
                   
                 3.71 (s, 3H), 3.64-3.54 (m, 2H), 3.47-3.37 (m, 2H), 3.00-2.85 
               
               
                   
                   
                 (m, 1H), 2.85-2.74 (m, 1H), 2.58-2.41 (m, 6H), 2.23-2.13 (m, 
               
               
                   
                   
                 1H). 
               
               
                 D410 
                 787.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.17 (s, 1H, FA), 
               
               
                   
                   
                 7.61 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 55.2 Hz, 1H), 6.74- 
               
               
                   
                   
                 6.65 (m, 2H), 6.61 (s, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, 
               
               
                   
                   
                 J = 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.81 (s, 6H), 3.69 (s, 
               
               
                   
                   
                 2H), 3.63-3.58 (m, 6H), 3.01-2.88 (m, 4H), 2.65-2.59 (m, 1H), 
               
               
                   
                   
                 2.41 (s, 4H), 2.37-2.26 (m, 6H), 2.11 (d, J = 6.9 Hz, 2H), 2.02- 
               
               
                   
                   
                 1.95 (m, 1H), 1.79-1.64 (m, 6H), 1.54 (s, 1H), 1.21-1.08 (m, 2H). 
               
               
                 D411 
                 680.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.06 (s, 1H, TFA 
               
               
                   
                   
                 salt), 8.15 (s, 1H), 7.56-7.48 (m, 2H), 6.91 (s, 2H), 6.55-6.46 (m, 
               
               
                   
                   
                 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.25 (m, 3H), 4.19 (d, J = 
               
               
                   
                   
                 16.9 Hz, 1H), 3.92 (s, 6H), 3.81 (s, 2H), 3.70 (s, 2H), 3.63 (s, 3H), 
               
               
                   
                   
                 3.52 (s, 3H), 3.13 (q, J = 11.1 Hz, 2H), 2.91 (ddd, J = 17.1, 13.6, 5.3 
               
               
                   
                   
                 Hz, 1H), 2.64-2.55 (m, 3H), 2.44-2.28 (m, 1H), 2.14 (d, J = 13.9 
               
               
                   
                   
                 Hz, 2H), 2.05-1.92 (m, 3H). 19F NMR (377 MHz, DMSO-d6) 
               
               
                   
                   
                 δ −73.65. 
               
               
                 D412 
                 680.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.90 (s, 1H, TFA 
               
               
                   
                   
                 salt), 8.63 (s, 1H), 7.93 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.43 (s, 
               
               
                   
                   
                 2H), 6.55-6.46 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.15 
               
               
                   
                   
                 (m, 4H), 4.09 (s, 3H), 3.95 (s, 6H), 3.80 (s, 2H), 3.69 (s, 2H), 3.55 (s, 
               
               
                   
                   
                 3H), 3.14-3.07 (m, 2H), 2.97-2.84 (m, 1H), 2.71-2.57 (m, 3H), 
               
               
                   
                   
                 2.39-2.31 (m, 1H), 2.17-2.09 (m, 2H), 2.04-1.93 (m, 3H). 19F 
               
               
                   
                   
                 NMR (377 MHz, DMSO-d6) δ −73.66. 
               
               
                 D413 
                 694.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.19-8.14 (m, 1H, 
               
               
                   
                   
                 FA), 8.12 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 6.81-6.74 
               
               
                   
                   
                 (m, 3H), 6.69-6.62 (m, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.82 (s, 
               
               
                   
                   
                 6H), 3.74 (s, 4H), 3.61-3.54 (m, 5H), 3.51 (s, 3H), 2.95-2.82 (m, 
               
               
                   
                   
                 1H), 2.63-2.52 (m, 2H), 2.46-2.39 (m, 4H), 2.06-1.97 (m, 1H), 
               
               
                   
                   
                 1.78-1.69 (m, 4H). 
               
               
                 D414 
                 680.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.16 (s, 1H, FA), 
               
               
                   
                   
                 8.12 (s, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.76 (s, 2H), 6.72- 
               
               
                   
                   
                 6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.36-4.12 (m, 2H), 
               
               
                   
                   
                 3.82 (s, 6H), 3.61-3.55 (m, 9H), 3.51 (s, 3H), 2.94-2.85 (m, 1H), 
               
               
                   
                   
                 2.66-2.54 (m, 2H), 2.46-2.40 (m, 4H), 2.02-1.95 (m, 1H), 1.76- 
               
               
                   
                   
                 1.69 (m, 4H). 
               
               
                 D415 
                 694.3 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.60 (s, 1H), 8.17 (s, 
               
               
                   
                   
                 1H, FA), 7.80 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.27 (s, 2H), 6.78 (d, 
               
               
                   
                   
                 J = 2.1 Hz, 1H), 6.68-6.61 (m, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H), 
               
               
                   
                   
                 4.08 (s, 3H), 3.84 (s, 6H), 3.73 (s, 4H), 3.56 (s, 2H), 3.53 (s, 3H), 
               
               
                   
                   
                 2.91-2.81 (m, 1H), 2.62-2.52 (m, 2H), 2.46-2.41 (m, 4H), 2.04- 
               
               
                   
                   
                 1.96 (m, 1H), 1.77-1.70 (m, 4H). 
               
               
                 D416 
                 680.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.59 (s, 1H), 8.18 (s, 
               
               
                   
                   
                 1H, FA), 7.80 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.27 (s, 2H), 6.72- 
               
               
                   
                   
                 6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.35-4.13 (m, 2H), 
               
               
                   
                   
                 4.08 (s, 3H), 3.85 (s, 6H), 3.59-3.50 (m, 9H), 2.96-2.84 (m, 1H), 
               
               
                   
                   
                 2.64-2.53 (m, 2H), 2.48-2.36 (m, 4H), 2.02-1.94 (m, 1H), 1.76- 
               
               
                   
                   
                 1.69 (m, 4H). 
               
               
                 D417 
                 694.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.65 (s, 1H), 8.20 (s, 
               
               
                   
                   
                 1H FA), 7.83 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (s, 2H), 6.72- 
               
               
                   
                   
                 6.64 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (q, J = 7.3 Hz, 
               
               
                   
                   
                 2H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.7 Hz, 1H), 3.85 (s, 
               
               
                   
                   
                 6H), 3.57 (d, J = 4.1 Hz, 6H), 3.53 (s, 3H), 2.98-2.84 (m, 1H), 2.70- 
               
               
                   
                   
                 2.52 (m, 2H), 2.49-2.42 (m, 3H), 2.37 (dd, J = 13.2, 4.6 Hz, 1H), 
               
               
                   
                   
                 2.03-1.94 (m, 1H), 1.74 (t, J = 5.5 Hz, 4H), 1.50 (t, J = 7.3 Hz, 3H). 
               
               
                 D418 
                 693.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.85 (d, J = 2.7 Hz, 1H), 11.09 (s, 
               
               
                   
                   
                 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.17-7.10 (m, 2H), 6.78 (d, J = 2.1 
               
               
                   
                   
                 Hz, 1H), 6.70 (s, 2H), 6.65 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (dd, J = 
               
               
                   
                   
                 12.9, 5.4 Hz, 1H), 3.82 (d, J = 22.7 Hz, 12H), 3.55 (s, 3H), 2.95- 
               
               
                   
                   
                 2.83 (m, 2H), 2.82-2.66 (m, 2H), 2.64-2.53 (m, 4H), 2.01 (dd, J = 
               
               
                   
                   
                 9.4, 4.3 Hz, 1H), 1.87 (s, 6H). 
               
               
                 D419 
                 665.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.98 (s, 1H), 8.15 
               
               
                   
                   
                 (s, 1H, FA), 7.48 (s, 1H), 7.38-7.36 (m, 2H), 6.85 (s, 2H), 6.71- 
               
               
                   
                   
                 6.68 (m, 2H), 6.58-6.55 (m, 1H), 5.11-5.05 (m, 1H), 4.34-4.15 
               
               
                   
                   
                 (m, 2H), 3.85 (s, 6H), 3.60 (s, 3H), 3.58 (s, 6H), 2.97-2.89 (m, 1H), 
               
               
                   
                   
                 2.74-2.72 (m, 3H), 2.40-2.34 (m, 2H), 2.00-1.97 (m, 1H), 1.73 
               
               
                   
                   
                 (s, 4H), 1.35-1.24 (m, 1H). 
               
               
                 D420 
                 666.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 10.97 (s, 1H), 8.15 
               
               
                   
                   
                 (s, 1H), 7.77 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.88 (s, 2H), 6.73- 
               
               
                   
                   
                 6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.6 Hz, 
               
               
                   
                   
                 1H), 4.18 (d, J = 16.5 Hz, 1H), 3.89 (s, 6H), 3.69 (s, 2H), 3.60 (s, 
               
               
                   
                   
                 4H), 3.55 (s, 3H), 2.96-2.84 (m, 1H), 2.64-2.55 (m, 4H), 2.42- 
               
               
                   
                   
                 2.22 (m, 2H), 1.98 (d, J = 12.9 Hz, 1H), 1.79 (s, 4H). 
               
               
                 D421 
                 680.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.45 (s, 1H), 8.18 (s, 
               
               
                   
                   
                 1H, FA), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.83 (s, 2H), 6.72- 
               
               
                   
                   
                 6.64 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.31 (d, J = 16.6 Hz, 
               
               
                   
                   
                 1H), 4.18 (d, J = 16.6 Hz, 1H), 4.12 (s, 3H), 3.87 (s, 6H), 3.57 (s, 
               
               
                   
                   
                 3H), 3.56-3.53 (m, 6H), 2.95-2.86 (m, 1H), 2.63-2.56 (m, 1H), 
               
               
                   
                   
                 2.49-2.34 (m, 5H), 2.04-1.94 (m, 1H), 1.79-1.62 (m, 4H). 
               
               
                 D422 
                 679.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.99 (s, 1H), 9.05- 
               
               
                   
                   
                 8.75 (m, 1H, TFA), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.94 (s, 
               
               
                   
                   
                 2H), 6.71 (d, J = 5.7 Hz, 2H), 6.30 (s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.36-4.15 (m, 4H), 3.95 (s, 6H), 3.76 (s, 2H), 3.65-3.63 (m, 
               
               
                   
                   
                 2H), 3.62-3.60 (m, 3H), 3.38-3.33 (m, 2H), 3.18-3.05 (m, 2H), 
               
               
                   
                   
                 3.00-2.84 (m, 1H), 2.67-2.59 (m, 1H), 2.44-2.39 (m, 1H), 2.36 
               
               
                   
                   
                 (s, 3H), 2.13 (d, J = 13.3 Hz, 2H), 2.01 (d, J = 11.3 Hz, 3H). 
               
               
                 D423 
                 614.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 8.5 Hz, 1H), 7.31 (d, 
               
               
                   
                   
                 J = 1.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.56 (s, 2H), 5.00 (dd, J = 
               
               
                   
                   
                 13.3, 5.1 Hz, 1H), 4.39-4.15 (m, 2H), 3.77 (d, J = 18.2 Hz, 8H), 
               
               
                   
                   
                 3.53 (s, 3H), 3.32 (t, J = 4.8 Hz, 4H), 2.94-2.81 (m, 1H), 2.79- 
               
               
                   
                   
                 2.67 (m, 4H), 2.65-2.55 (m, 1H), 2.43-2.28 (m, 4H), 2.03 (s, 3H), 
               
               
                   
                   
                 2.01-1.92 (m, 1H). 
               
               
                 D424 
                 671.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.24 (s, 1H, FA), 7.77 
               
               
                   
                   
                 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.25 (s, 2H), 7.21 (d, J = 6.0 Hz, 
               
               
                   
                   
                 1H), 7.15 (d, 1H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.34-4.20 (m, 
               
               
                   
                   
                 2H), 4.07 (s, 3H), 4.00 (d, J = 12.7 Hz, 1H), 3.86 (s, 6H), 3.83-3.77 
               
               
                   
                   
                 (m, 1H), 3.28-3.14 (m, 4H), 3.06-2.96 (m, 2H), 2.91-2.79 (m, 
               
               
                   
                   
                 1H), 2.66-2.55 (m, 1H), 2.43-2.20 (m, 1H), 2.00 (s, 1H), 1.26 (d, 
               
               
                   
                   
                 J = 6.1 Hz, 6H). 
               
               
                 D425 
                 676.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.41 (d, J = 2.6 Hz, 
               
               
                   
                   
                 1H), 8.19 (d, J = 6.8 Hz, 1H), 8.16 (d, J = 2.6 Hz, 1H, FA), 7.36 (d, 
               
               
                   
                   
                 J = 8.0 Hz, 1H), 6.90 (d, J = 33.7 Hz, 3H), 6.72-6.64 (m, 2H), 5.13- 
               
               
                   
                   
                 5.04 (m, 1H), 4.31 (d, J = 16.5 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 
               
               
                   
                   
                 3.87 (s, 6H), 3.60 (s, 3H), 3.54 (d, J = 15.6 Hz, 7H), 2.97-2.84 (m, 
               
               
                   
                   
                 1H), 2.63-2.54 (m, 1H), 2.45-2.31 (m, 4H), 1.98 (d, J = 12.6 Hz, 
               
               
                   
                   
                 1H), 1.71 (s, 4H). 
               
               
                 D426 
                 679.5 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.98 (s, 1H), 8.24 
               
               
                   
                   
                 FA (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20-7.06 (m, 2H), 6.76-6.54 
               
               
                   
                   
                 (m, 4H), 5.09 (dd, J = 13.3, 5.0 Hz, 1H), 4.40-4.10 (m, 2H), 3.80 (s, 
               
               
                   
                   
                 6H), 3.60-3.54 (m, 9H), 3.00-2.83 (m, 2H), 2.62 (s, 1H), 2.40 (s, 
               
               
                   
                   
                 3H), 1.99 (s, 2H), 1.85 (s, 3H), 1.78-1.64 (m, 4H). 
               
               
                 D427 
                 614.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.42 (d, J = 8.4 Hz, 
               
               
                   
                   
                 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, 
               
               
                   
                   
                 J = 2.3 Hz, 1H), 6.59-6.52 (m, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 
               
               
                   
                   
                 4.39-4.16 (m, 2H), 3.81 (s, 6H), 3.62 (s, 2H), 3.54 (s, 3H), 3.22- 
               
               
                   
                   
                 3.11 (m, 4H), 2.98-2.84 (m, 1H), 2.72-2.56 (m, 5H), 2.46-2.36 
               
               
                   
                   
                 (m, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 2.02-1.94 (m, 1H). 
               
               
                 D428 
                 666.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.15 (d, 
               
               
                   
                   
                 J = 0.9 Hz, 1H, FA), 7.89 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.12 (s, 
               
               
                   
                   
                 1H), 6.93 (s, 2H), 6.69 (d, J = 7.7 Hz, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.43-4.14 (m, 2H), 3.86 (s, 6H), 3.64-3.57 (m, 6H), 3.44 (s, 
               
               
                   
                   
                 5H), 2.99-2.84 (m, 2H), 2.68-2.60 (m, 1H), 2.45-2.32 (m, 2H), 
               
               
                   
                   
                 2.05-1.91 (m, 1H), 1.81-1.68 (m, 4H). 
               
               
                 D429 
                 627.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.50 (d, J = 1.2 Hz, 
               
               
                   
                   
                 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.18 (s, 2H), 
               
               
                   
                   
                 6.68 (d, J = 7.7 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.42-4.14 
               
               
                   
                   
                 (m, 2H), 3.88 (s, 6H), 3.77 (s, 2H), 3.60 (s, 4H), 3.56 (s, 4H), 2.97- 
               
               
                   
                   
                 2.84 (m, 1H), 2.69 (s, 3H), 2.64-2.55 (m, 2H), 2.39 (td, J = 13.1, 
               
               
                   
                   
                 4.4 Hz, 1H), 2.02-1.93 (m, 1H), 1.82 (s, 4H). 
               
               
                 D430 
                 654.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.66 (d, J = 8.2 Hz, 
               
               
                   
                   
                 1H), 7.53 (s, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.73-6.54 (m, 3H), 5.06 
               
               
                   
                   
                 (dd, J = 12.8, 5.3 Hz, 1H), 4.14-3.94 (m, 5H), 3.85 (s, 6H), 3.49- 
               
               
                   
                   
                 3.46 (m, 5H), 3.14-2.97 (m, 2H), 2.96-2.70 (m, 2H), 2.68-2.58 
               
               
                   
                   
                 (m, 1H), 2.36-2.17 (m, 2H), 2.14-1.95 (m, 7H). 
               
               
                 D431 
                 665.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.94 (s, 1H, TFA), 
               
               
                   
                   
                 7.50 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 4.0 Hz, 
               
               
                   
                   
                 1H), 6.92 (s, 2H), 6.87 (dd, J = 10.2, 5.1 Hz, 2H), 6.75-6.66 (m, 
               
               
                   
                   
                 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.12 (m, 4H), 3.95 (s, 
               
               
                   
                   
                 6H), 3.76 (s, 2H), 3.70 (s, 2H), 3.43-3.31 (m, 5H), 3.17-3.11 (m, 
               
               
                   
                   
                 2H), 3.00-2.82 (m, 1H), 2.63 (s, 1H), 2.44-2.30 (m, 1H), 2.19- 
               
               
                   
                   
                 2.08 (m, 2H), 2.06-1.96 (m, 3H). 
               
               
                 D432 
                 664.3 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.30 (d, J = 2.6 Hz, 1H), 8.20- 
               
               
                   
                   
                 8.13 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.10-6.61 (m, 3H), 6.26 (dd, 
               
               
                   
                   
                 J = 7.6, 2.0 Hz, 1H), 5.67 (d, J = 1.8 Hz, 1H), 5.25 (dd, J = 12.5, 5.3 
               
               
                   
                   
                 Hz, 1H), 4.43 (s, 2H), 4.17-3.96 (m, 10H), 3.72 (s, 3H), 3.67 (s, 
               
               
                   
                   
                 2H), 3.51-3.45 (m, 2H), 2.99-2.76 (m, 2H), 2.73-2.49 (m, 1H), 
               
               
                   
                   
                 2.52-2.46 (m, 2H), 2.36-2.23 (m, 1H). 
               
               
                 D433 
                 666.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 14.27 (s, 1H), 10.98 (s, 1H), 8.24 
               
               
                   
                   
                 (s, 1H, FA), 8.15 (s, 1H), 7.61 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.90 
               
               
                   
                   
                 (s, 2H), 6.74-6.64 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.25 
               
               
                   
                   
                 (dd, 2H), 3.90 (s, 6H), 3.74 (s, 2H), 3.61 (d, J = 6.9 Hz, 7H), 2.98- 
               
               
                   
                   
                 2.84 (m, 1H), 2.79-2.54 (m, 5H), 2.42-2.32 (m, 1H), 2.03-1.93 
               
               
                   
                   
                 (m, 1H), 1.81 (s, 4H). 
               
               
                 D434 
                 666.25 
                   1 H NMR (300 MHz, MeOD) δ 8.85-8.49 (m, 1H), 7.85 (d, J = 1.9 
               
               
                   
                   
                 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.17-7.09 (m, 2H), 6.89 (d, J = 
               
               
                   
                   
                 2.2 Hz, 1H), 6.81 (dd, J = 8.2, 2.3 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 
               
               
                   
                   
                 Hz, 1H), 4.49-4.31 (m, 4H), 4.04 (s, 6H), 3.85 (s, 2H), 3.78 (s, 3H), 
               
               
                   
                   
                 3.73 (s, 2H), 3.56 (d, J = 12.7 Hz, 2H), 3.24 (t, J = 11.9, 11.9 Hz, 
               
               
                   
                   
                 2H), 3.02-2.86 (m, 1H), 2.85-2.72 (m, 1H), 2.59-2.41 (m, 1H), 
               
               
                   
                   
                 2.34-2.22 (m, 2H), 2.21-2.04 (m, 3H). 
               
               
                 D435 
                 665.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.23 (s, 1H, FA), 
               
               
                   
                   
                 7.61 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 7.7 Hz, 
               
               
                   
                   
                 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.77 (s, 2H), 
               
               
                   
                   
                 6.70-6.67 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.34-4.14 (m, 
               
               
                   
                   
                 2H), 3.85 (s, 6H), 3.56 (s, 3H), 3.51-3.50 (m, 6H), 2.98-2.83 (m, 
               
               
                   
                   
                 1H), 2.68-2.57 (m, 1H), 2.48-2.22 (m, 5H), 2.06-1.91 (m, 1H), 
               
               
                   
                   
                 1.72-1.70 (m, 4H). 
               
               
                 D436 
                 614.3 
                   1 H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 8.5 Hz, 1H), 7.60 (s, 
               
               
                   
                   
                 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H), 6.65 (s, 
               
               
                   
                   
                 2H), 6.52 (s, 1H), 5.09 (dd, J = 12.3, 5.4 Hz, 1H), 3.91 (d, 8H), 3.58 
               
               
                   
                   
                 (d, J = 18.3 Hz, 7H), 2.99-2.89 (m, 4H), 2.87-2.66 (m, 3H), 2.21 
               
               
                   
                   
                 (s, 3H), 2.18-2.07 (m, 1H). 
               
               
                 D437 
                 693.4 
                   1 H NMR (300 MHz, Methanol-d4) 7.41 (d, J = 8.2 Hz, 1H), 6.99- 
               
               
                   
                   
                 6.78 (m, 2H), 6.70 (s, 2H), 5.86 (s, 1H), 5.29-5.05 (m, 1H), 4.52- 
               
               
                   
                   
                 4.29 (m, 2H), 4.22-3.98 (m, 5H), 3.91 (s, 6H), 3.74 (s, 4H), 3.21- 
               
               
                   
                   
                 2.72 (m, 6H), 2.66-2.40 (m, 1H), 2.35 (s, 3H), 2.27-2.15 (m, 4H), 
               
               
                   
                   
                 2.15-1.94 (m, 4H). 
               
               
                 D438 
                 595.3 
                   1 H NMR (400 MHz, DMSO-d6 with a drop of D 2 O) δ 8.15 (s, 1H, 
               
               
                   
                   
                 FA), 8.05 (d, J = 2.7 Hz, 1H), 7.82 (dd, J = 2.7, 1.3 Hz, 1H), 7.70- 
               
               
                   
                   
                 7.59 (m, 3H), 6.82 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (dd, 
               
               
                   
                   
                 2H), 3.86 (s, 6H), 3.66 (s, 2H), 3.65-3.56 (m, 2H), 3.53 (s, 3H), 
               
               
                   
                   
                 3.34 (s, 1H), 3.28 (d, J = 7.7 Hz, 2H), 2.97-2.84 (m, 1H), 2.66- 
               
               
                   
                   
                 2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.10 (s, 3H), 2.07-1.95 (m, 1H). 
               
               
                 D439 
                 631.3 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.79 
               
               
                   
                   
                 (d, J = 1.2 Hz, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (d, J = 7.9 
               
               
                   
                   
                 Hz, 1H), 7.09-6.61 (m, 3H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.61- 
               
               
                   
                   
                 4.42 (m, 2H), 4.23 (s, 2H), 4.16 (t, J = 8.8 Hz, 2H), 4.00 (s, 6H), 3.97- 
               
               
                   
                   
                 3.85 (m, 2H), 3.77-3.63 (m, 4H), 3.03-2.75 (m, 2H), 2.61-2.40 
               
               
                   
                   
                 (m, 1H), 2.29-2.13 (m, 1H). 
               
               
                 D440 
                 595.3 
                   1 H NMR (400 MHz, Methanol-d4) δ 7.99-7.90 (m, 1H), 7.84-7.74 
               
               
                   
                   
                 (m, 2H), 7.72-7.49 (m, 2H), 6.91 (d, J = 2.6 Hz, 2H), 5.20-5.11 
               
               
                   
                   
                 (m, 1H), 4.55-4.37 (m, 6H), 4.34-4.22 (m, 2H), 4.00 (s, 6H), 3.95- 
               
               
                   
                   
                 3.84 (m, 1H), 3.66 (d, J = 6.7 Hz, 3H), 2.98-2.85 (m, 1H), 2.81 (s, 
               
               
                   
                   
                 1H), 2.54-2.40 (m, 1H), 2.20 (d, J = 5.0 Hz, 4H). 
               
               
                 D441 
                 631.5 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.32-8.07 (m, 2H), 7.77 (d, J = 
               
               
                   
                   
                 7.8 Hz, 1H), 7.70-7.53 (m, 2H), 7.07-6.67 (m, 3H), 5.15 (dd, J = 
               
               
                   
                   
                 13.3, 5.1 Hz, 1H), 4.62-4.39 (m, 6H), 4.35-4.23 (m, 2H), 4.17- 
               
               
                   
                   
                 3.83 (m, 7H), 3.68 (s, 3H), 2.98-2.84 (m, 1H), 2.78 (d, J = 17.4 Hz, 
               
               
                   
                   
                 1H), 2.48 (qd, J = 13.1, 4.7 Hz, 1H), 2.22-2.14 (m, 1H). 
               
               
                 D442 
                 609.5 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.56 (s, FA, 1H), 7.96 (d, 1H), 
               
               
                   
                   
                 7.85-7.79 (m, 2H), 7.71-7.63 (m, 1H), 7.58 (d, 1H), 6.90 (s, 2H), 
               
               
                   
                   
                 5.23-5.11 (m, 1H), 4.52 (d, 2H), 4.41 (s, 2H), 4.00 (s, 6H), 3.69 (s, 
               
               
                   
                   
                 3H), 3.63-3.50 (m, 2H), 3.48-3.36 (m, 3H), 3.00-2.73 (m, 2H), 
               
               
                   
                   
                 2.61-2.39 (m, 2H), 2.31-2.11 (m, 5H). 
               
               
                 D443 
                 623.35 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.06 (d, J = 2.7 Hz, 
               
               
                   
                   
                 1H), 7.89-7.75 (m, 1H), 7.69-7.54 (m, 3H), 6.82 (s, 2H), 5.11 (dd, 
               
               
                   
                   
                 J = 13.2, 5.1 Hz, 1H), 4.61-4.25 (m, 2H), 3.86 (s, 6H), 3.58 (s, 2H), 
               
               
                   
                   
                 3.54 (s, 3H), 3.02-2.84 (m, 1H), 2.84-2.70 (m, 2H), 2.67-2.53 
               
               
                   
                   
                 (m, 2H), 2.48-2.35 (m, 1H), 2.33-2.21 (m, 2H), 2.10 (s, 3H), 2.06- 
               
               
                   
                   
                 1.95 (m, 1H), 1.92-1.79 (m, 2H), 1.69-1.53 (m, 2H). 
               
               
                 D444 
                 659.3 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.40 (.1.0 FA, d, J = 
               
               
                   
                   
                 2.6 Hz, 1H), 8.26-8.05 (m, 2H), 7.75-7.51 (m, 3H), 7.20-6.69 
               
               
                   
                   
                 (m, 3H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.61-4.21 (m, 2H), 3.87 (s, 
               
               
                   
                   
                 6H), 3.60 (s, 3H), 3.56 (s, 2H), 3.00-2.83 (m, 1H), 2.82-2.69 (m, 
               
               
                   
                   
                 2H), 2.68-2.53 (m, 2H), 2.48-2.32 (m, 1H), 2.32-2.18 (m, 2H), 
               
               
                   
                   
                 2.08-1.93 (m, 1H), 1.84 (d, 2H), 1.70-1.49 (m, 2H). 
               
               
                 D445 
                 707.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.58 (s, 1H), 11.08 (s, 1H), 8.28- 
               
               
                   
                   
                 8.13 (m, 1H, FA), 7.64 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 
               
               
                   
                   
                 6.77 (d, J = 2.1 Hz, 1H), 6.64 (dd, J = 8.4, 2.2 Hz, 1H), 6.51 (s, 2H), 
               
               
                   
                   
                 5.06 (dd, J = 12.7, 5.2 Hz, 1H), 3.74 (d, J = 8.4 Hz, 10H), 3.58 (d, 
               
               
                   
                   
                 J = 3.6 Hz, 5H), 2.94-2.83 (m, 1H), 2.65-2.55 (m, 3H), 2.47-2.38 
               
               
                   
                   
                 (m, 3H), 2.17 (s, 3H), 2.07-1.97 (m, 1H), 1.79-1.67 (m, 4H), 1.51 
               
               
                   
                   
                 (s, 3H). 
               
               
                 D446 
                 707.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.85 (s, 1H), 7.65 
               
               
                   
                   
                 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.70-6.62 (m, 1H), 
               
               
                   
                   
                 6.59 (s, 2H), 5.83 (s, 1H), 5.06 (dd, J = 12.7, 5.3 Hz, 1H), 4.00 (s, 
               
               
                   
                   
                 3H), 3.89-3.72 (m, 10H), 3.68 (s, 2H), 3.00-2.78 (m, 1H), 2.70- 
               
               
                   
                   
                 2.53 (m, 6H), 2.27 (s, 3H), 2.14 (s, 3H), 2.09-1.96 (m, 1H), 1.81 (s, 
               
               
                   
                   
                 4H). 
               
               
                 D447 
                 666.4 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.52 (br s, 0.2H, FA), 7.84 (d, 
               
               
                   
                   
                 J = 1.2 Hz, 1H), 7.64 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 
               
               
                   
                   
                 7.10 (s, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 8.2, 2.2 Hz, 1H), 
               
               
                   
                   
                 5.20 (dd, 1H), 4.47 (d, J = 5.4 Hz, 2H), 4.41 (s, 2H), 4.07 (s, 6H), 
               
               
                   
                   
                 3.86-3.71 (m, 8H), 3.38-3.28 (m, 3H) 3.18-2.80 (m, 2H), 2.62- 
               
               
                   
                   
                 2.54 (m, 1H), 2.36-2.10 (m, 5H). 
               
               
                 D448 
                 599.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.19 (s, 1H, FA), 
               
               
                   
                   
                 8.06 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.54 (s, 1H), 7.51 
               
               
                   
                   
                 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 6.81 (s, 2H), 5.10 
               
               
                   
                   
                 (dd, J = 13.3, 5.2 Hz, 1H), 4.46-4.23 (m, 2H), 3.84 (s, 6H), 3.72 (d, 
               
               
                   
                   
                 J = 4.9 Hz, 2H), 3.53 (s, 3H), 3.46 (s, 2H), 3.07 (s, 2H), 2.96-2.85 
               
               
                   
                   
                 (m, 1H), 2.64-2.56 (m, 4H), 2.39 (dd, J = 13.3, 4.7 Hz, 1H), 2.10 (s, 
               
               
                   
                   
                 3H), 2.03-1.96 (m, 1H), 1.79 (q, J = 7.5 Hz, 2H). 
               
               
                 D449 
                 585.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.19 (s, 1H, FA), 
               
               
                   
                   
                 8.06 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.54 (s, 1H), 7.51 
               
               
                   
                   
                 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 6.81 (s, 2H), 5.10 
               
               
                   
                   
                 (dd, J = 13.3, 5.2 Hz, 1H), 4.46-4.23 (m, 2H), 3.84 (s, 6H), 3.72 (d, 
               
               
                   
                   
                 J = 4.9 Hz, 2H), 3.53 (s, 3H), 3.46 (s, 2H), 3.07 (s, 2H), 2.96-2.85 
               
               
                   
                   
                 (m, 1H), 2.64-2.56 (m, 4H), 2.39 (dd, J = 13.3, 4.7 Hz, 1H), 2.10 (s, 
               
               
                   
                   
                 3H), 2.03-1.96 (m, 1H), 1.79 (q, J = 7.5 Hz, 2H). 
               
               
                 D450 
                 609.30 
                   1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H, FA), 8.04 (d, J = 2.7 
               
               
                   
                   
                 Hz, 1H), 7.86-7.80 (m, 1H), 7.70-7.57 (m, 3H), 6.82 (s, 2H), 5.09 
               
               
                   
                   
                 (dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.31 (m, 2H), 3.86 (s, 6H), 3.66 (s, 
               
               
                   
                   
                 2H), 3.54 (s, 3H), 3.43 (d, J = 6.8 Hz, 2H), 3.27 (d, J = 6.8 Hz, 2H), 
               
               
                   
                   
                 2.99-2.81 (m, 1H), 2.74-2.58 (m, 1H), 2.46-2.32 (m, 1H), 2.10 
               
               
                   
                   
                 (s, 3H), 2.07-1.97 (m, 1H), 1.51 (s, 3H). 
               
               
                 D451 
                 538.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.48 (d, J = 2.4 Hz, 
               
               
                   
                   
                 1H), 8.22 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.18- 
               
               
                   
                   
                 6.74 (m, 3H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.43 (dd, 2H), 3.79 
               
               
                   
                   
                 (s, 6H), 3.62 (s, 3H), 3.04-2.91 (m, 1H), 2.67-2.59 (m, 1H), 2.47- 
               
               
                   
                   
                 2.34 (m, 1H), 2.07-1.97 (m, 1H). 
               
               
                 D452 
                 600.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.39 (s, 1H), 8.16 (d, 
               
               
                   
                   
                 J = 2.7 Hz, 1H, FA), 7.88 (dd, J = 2.7, 1.3 Hz, 1H), 7.49 (d, J = 8.4 
               
               
                   
                   
                 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 6.96 
               
               
                   
                   
                 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 16.9 Hz, 1H), 
               
               
                   
                   
                 4.31 (d, J = 4.2 Hz, 2H), 4.23 (d, J = 16.9 Hz, 1H), 3.96 (s, 6H), 3.88 
               
               
                   
                   
                 (d, J = 13.1 Hz, 2H), 3.55 (s, 3H), 3.47 (d, J = 12.0 Hz, 2H), 3.33- 
               
               
                   
                   
                 3.20 (m, 2H), 3.12 (t, J = 12.4 Hz, 2H), 2.98-2.84 (m, 1H), 2.60 (d, 
               
               
                   
                   
                 J = 17.7 Hz, 1H), 2.43-2.32 (m, 1H), 2.11 (s, 3H), 2.04-1.94 (m, 
               
               
                   
                   
                 1H). 
               
               
                 D453 
                 609.50 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.25 (s, 1H, FA salt), 
               
               
                   
                   
                 8.05 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.63-7.56 (m, 
               
               
                   
                   
                 3H), 6.82 (s, 2H), 5.10 (dd, J = 13.3, 5.2 Hz, 1H), 4.37 (dd, 2H), 3.86 
               
               
                   
                   
                 (s, 6H), 3.62-3.58 (m, 2H), 3.53 (s, 3H), 3.15-3.13 (m, 1H), 2.96- 
               
               
                   
                   
                 2.89 (m, 2H), 2.86-2.83 (m, 2H), 2.62-2.58 (m, 1H), 2.41-2.35 
               
               
                   
                   
                 (m, 1H), 2.09 (s, 3H), 2.03-1.98 (m, 1H), 1.11 (d, J = 5.9 Hz, 3H). 
               
               
                 D454 
                 706.4 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.28 (s, 1H), 7.82 (s, 
               
               
                   
                   
                 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.85 (s, 2H), 6.62 (d, J = 
               
               
                   
                   
                 8.2 Hz, 2H), 5.73-5.62 (m, 1H), 5.59-5.48 (m, 1H), 5.00 (dd, J = 
               
               
                   
                   
                 13.2, 5.1 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 4.28-4.07 (m, 2H), 3.79 
               
               
                   
                   
                 (s, 6H), 3.61-3.49 (m, 8H), 2.91-2.77 (m, 1H), 2.54 (d, J = 3.7 Hz, 
               
               
                   
                   
                 3H), 2.37-2.23 (m, 1H), 1.96-1.86 (m, 1H), 1.68 (t, J = 6.6 Hz, 4H), 
               
               
                   
                   
                 1.60 (d, J = 6.3 Hz, 3H). 
               
               
                 D455 
                 593.25 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.6 Hz, 1H), 8.11- 
               
               
                   
                   
                 8.05 (m, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.99-6.78 (m, 3H), 6.76 (s, 
               
               
                   
                   
                 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45-4.31 (m, 5H), 3.99 (q, J = 
               
               
                   
                   
                 5.5, 4.1 Hz, 2H), 3.82 (s, 6H), 3.67 (s, 3H), 2.97-2.83 (m, 1H), 2.83- 
               
               
                   
                   
                 2.72 (m, 1H), 2.56-2.40 (m, 1H), 2.21-2.11 (m, 1H). 
               
               
                 D456 
                 666.5 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 0.67H, FA), 7.93 (d, J = 
               
               
                   
                   
                 2.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.22-7.15 (m, 
               
               
                   
                   
                 3H), 6.86 (d, J = 2.2 Hz, 1H), 6.81-6.74 (m, 1H), 5.16-5.07 (m, 
               
               
                   
                   
                 1H), 4.45-4.30 (m, 4H), 3.97 (s, 6H), 3.75 (s, 4H), 3.63 (s, 3H), 3.39- 
               
               
                   
                   
                 3.36 (m, 2H), 3.28-3.21 (m, 2H), 2.96-2.83 (m, 1H), 2.82-2.72 
               
               
                   
                   
                 (m, 1H), 2.56-2.40 (m, 1H), 2.19-2.02 (m, 5H). 
               
               
                 D457 
                 597.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.67-9.52 (m, 1H, 
               
               
                   
                   
                 TFA salt), 8.17-8.10 (m, 1H), 7.88-7.78 (m, 2H), 7.71-7.64 (m, 
               
               
                   
                   
                 1H), 7.62-7.56 (m, 1H), 6.98-6.91 (m, 2H), 6.71-6.62 (m, 5.7 
               
               
                   
                   
                 Hz, 2H), 5.17-5.06 (m, 1H), 4.49-4.41 (m, 1H), 4.41-4.27 (m, 
               
               
                   
                   
                 3H), 4.27-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.95 (s, 6H), 3.54 (s, 
               
               
                   
                   
                 3H), 2.97-2.85 (m, 1H), 2.61 (d, J = 17.1 Hz, 1H), 2.43-2.35 (m, 
               
               
                   
                   
                 2H), 2.10 (s, 3H), 2.04-1.97 (m, 2H). 
               
               
                 D458 
                 613.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.89 (s, 1H), 7.79 (d, 
               
               
                   
                   
                 J = 8.0 Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 6.92 (s, 2H), 5.09 (dd, J = 
               
               
                   
                   
                 13.3, 5.1 Hz, 1H), 4.86-4.57 (m, 4H), 4.57-4.45 (m, 3H), 4.40 (d, 
               
               
                   
                   
                 J = 18.1 Hz, 1H), 3.94 (s, 6H), 3.54 (s, 3H), 2.97-2.83 (m, 1H), 
               
               
                   
                   
                 2.71-2.59 (m, 1H), 2.47-2.33 (m, 1H), 2.16-2.01 (s, 4H). 
               
               
                 D459 
                 526.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.87 (d, J = 2.7 Hz, 
               
               
                   
                   
                 1H), 7.69 (dd, J = 2.7, 1.3 Hz, 1H), 7.46 (t, J = 8.7 Hz, 3H), 7.35 (dd, 
               
               
                   
                   
                 J = 8.4, 2.4 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 
               
               
                   
                   
                 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46-4.19 (m, 2H), 3.50 (s, 
               
               
                   
                   
                 3H), 3.35 (s, 8H), 2.98-2.85 (m, 1H), 2.60 (d, J = 17.0 Hz, 1H), 
               
               
                   
                   
                 2.43-2.32 (m, 1H), 2.07 (s, 3H), 2.04-1.95 (m, 1H). 
               
               
                 D460 
                 540.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 2.7 Hz, 1H), 7.75 (d, 
               
               
                   
                   
                 J = 2.6 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H), 7.43 (dd, J = 11.4, 7.8 Hz, 
               
               
                   
                   
                 3H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (s, 1H), 5.09 (dd, J = 13.3, 
               
               
                   
                   
                 5.1 Hz, 1H), 4.44-4.17 (m, 2H), 3.66 (s, 3H), 3.52 (s, 3H), 3.24 (s, 
               
               
                   
                   
                 3H), 2.97-2.84 (m, 1H), 2.77-2.64 (m, 1H), 2.67 (s, 4H), 2.45- 
               
               
                   
                   
                 2.33 (m, 1H), 2.09 (s, 3H), 2.04-1.95 (m, 1H). 
               
               
                 D461 
                 641.25 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.00 (s, 1H, TFA), 
               
               
                   
                   
                 8.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.32 (s, 2H), 6.77 (dt, J = 4.0, 
               
               
                   
                   
                 2.0 Hz, 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.46-4.21 (m, 4H), 
               
               
                   
                   
                 4.02 (s, 6H), 3.81 (s, 2H), 3.71 (s, 2H), 3.62 (s, 3H), 3.43 (d, J = 12.6 
               
               
                   
                   
                 Hz, 2H), 3.18 (t, J = 11.4 Hz, 2H), 3.07-2.89 (m, 1H), 2.67 (d, J = 
               
               
                   
                   
                 17.2 Hz, 1H), 2.56-2.31 (m, 4H), 2.19 (d, J = 14.0 Hz, 2H), 2.12- 
               
               
                   
                   
                 1.98 (m, 3H), 0.08 (s, 1H). 
               
               
                 D462 
                 696.5 
                   1 H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ 8.75 (s, 1H), 
               
               
                   
                   
                 8.26 (s, 1H, FA), 7.89 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.24 (s, 2H), 
               
               
                   
                   
                 6.74-6.67 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.15 (m, 
               
               
                   
                   
                 5H), 3.88 (s, 6H), 3.80 (s, 2H), 3.61 (s, 4H), 3.55 (s, 3H), 2.95-2.82 
               
               
                   
                   
                 (m, 1H), 2.81-2.57 (m, 5H), 2.45-2.31 (m, 1H), 2.06-1.95 (m, 
               
               
                   
                   
                 1H), 1.85 (t, J = 5.5 Hz, 4H). 
               
               
                 D463 
                 654.35 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.90 (s, 1H), 8.28 (d, J = 1.1 Hz, 
               
               
                   
                   
                 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (d, 
               
               
                   
                   
                 J = 7.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.39-7.31 (m, 2H), 7.15 
               
               
                   
                   
                 (s, 1H), 5.95-5.80 (m, 1H), 5.71-5.54 (m, 1H), 5.13 (dd, J = 13.3, 
               
               
                   
                   
                 5.1 Hz, 1H), 4.52 (d, J = 6.4 Hz, 2H), 4.48-4.34 (m, 2H), 4.01 (t, 
               
               
                   
                   
                 J = 5.3 Hz, 2H), 3.59-3.52 (m, 2H), 3.42-3.38 (m, 2H), 3.36-3.32 
               
               
                   
                   
                 (m, 1H), 3.28-3.20 (m, 1H), 2.95-2.83 (m, 1H), 2.82-2.73 (m, 
               
               
                   
                   
                 1H), 2.56-2.42 (m, 1H), 2.23-2.13 (m, 1H), 1.73 (dd, J = 6.5, 1.6 
               
               
                   
                   
                 Hz, 3H). 
               
               
                 D464 
                 704.1 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.22 (s, 1H), 8.08- 
               
               
                   
                   
                 7.95 (m, 3H), 7.92 (s, 1H), 7.79 (s, 1H), 7.67 (s, 2H), 7.05 (s, 1H), 
               
               
                   
                   
                 5.82-5.66 (m, 1H), 5.66-5.51 (m, 1H), 5.18 (dd, J = 13.2, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.68-4.46 (m, 3H), 4.41 (d, J = 6.0 Hz, 2H), 3.51 (s, 2H), 3.02- 
               
               
                   
                   
                 2.84 (m, 8H), 2.62 (d, J = 17.0 Hz, 1H), 2.49-2.34 (m, 1H), 2.05 
               
               
                   
                   
                 (dd, J = 12.7, 6.4 Hz, 1H), 1.65 (dd, J = 6.3, 1.4 Hz, 3H). 
               
               
                 D465 
                 680.4 
                   1 H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.86 (s, 1H), 7.68- 
               
               
                   
                   
                 7.60 (m, 2H), 7.52 (dd, J = 7.9, 1.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 
               
               
                   
                   
                 6.79-6.73 (m, 2H), 6.67 (dd, J = 8.2, 2.3 Hz, 1H), 5.82-5.68 (m, 
               
               
                   
                   
                 1H), 5.61-5.47 (m, 1H), 5.02 (dd, J = 13.3, 5.2 Hz, 1H), 4.39 (d, J = 
               
               
                   
                   
                 6.3 Hz, 2H), 4.34-4.20 (m, 2H), 3.71 (s, 2H), 3.59 (s, 4H), 2.87- 
               
               
                   
                   
                 2.74 (m, 1H), 2.72-2.65 (m, 1H), 2.62-2.51 (m, 4H), 2.45-2.31 
               
               
                   
                   
                 (m, 1H), 2.10-2.03 (m, 1H), 1.87-1.81 (m, 4H), 1.63 (dd, J = 6.5, 
               
               
                   
                   
                 1.5 Hz, 3H). 
               
               
                 D466 
                 640.4 
                   1 H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.32 (s, 1H), 8.02- 
               
               
                   
                   
                 7.76 (m, 4H), 7.61-7.49 (m, 1H), 7.43-7.27 (m, 2H), 7.16 (s, 1H), 
               
               
                   
                   
                 5.90-5.76 (m, 1H), 5.74-5.60 (m, 1H), 5.18 (dd, J = 13.2, 5.1 Hz, 
               
               
                   
                   
                 1H), 4.88-4.57 (m, 1H), 4.54-4.38 (m, 3H), 4.36-4.24 (m, 1H), 
               
               
                   
                   
                 4.10-3.56 (m, 3H), 3.32-3.14 (m, 3H), 3.07-2.90 (m, 2H), 2.75- 
               
               
                   
                   
                 2.62 (m, 3H), 2.52-2.38 (m, 1H), 2.14-2.04 (m, 1H), 1.78-1.70 
               
               
                   
                   
                 (m, 3H). 
               
               
                 D467 
                 719.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.18 (d, J = 6.1 Hz, 1H), 10.96 (s, 
               
               
                   
                   
                 1H), 8.94 (s, 1H, TFA), 7.40 (d, J = 8.9 Hz, 1H), 7.11 (s, 1H), 6.89 
               
               
                   
                   
                 (s, 2H), 6.70 (h, J = 2.3 Hz, 2H), 6.35 (s, 1H), 5.67-5.55 (m, 1H), 
               
               
                   
                   
                 5.45-5.29 (m, 1H), 5.15 (d, J = 5.5 Hz, 2H), 5.07 (dd, J = 13.2, 5.1 
               
               
                   
                   
                 Hz, 1H), 4.32 (d, J = 16.7 Hz, 1H), 4.25 (d, J = 4.6 Hz, 2H), 4.19 (d, 
               
               
                   
                   
                 J = 16.6 Hz, 1H), 3.93 (s, 6H), 3.75 (s, 2H), 3.64 (s, 2H), 3.41-3.33 
               
               
                   
                   
                 (m, 2H), 3.11 (q, J = 11.1 Hz, 2H), 2.90 (ddd, J = 17.5, 13.4, 5.4 Hz, 
               
               
                   
                   
                 1H), 2.70-2.52 (m, 1H), 2.39 (dd, J = 13.2, 8.5 Hz, 1H), 2.34 (s, 
               
               
                   
                   
                 3H), 2.12 (d, J = 13.9 Hz, 2H), 2.04-1.94 (m, 3H), 1.62 (dd, J = 6.6, 
               
               
                   
                   
                 1.6 Hz, 3H). 
               
               
                 D468 
                 679.5 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.19 (d, J = 6.2 Hz, 1H), 10.98 (s, 
               
               
                   
                   
                 1H), 9.42 (s, 1H, TFA), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 
               
               
                   
                   
                 2.4 Hz, 1H), 7.29-7.20 (m, 1H), 7.12 (d, J = 6.0 Hz, 1H), 6.90 (s, 
               
               
                   
                   
                 2H), 6.36 (s, 1H), 5.66-5.54 (m, 1H), 5.45-5.29 (m, 1H), 5.15 (d, 
               
               
                   
                   
                 J = 5.6 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 16.8 Hz, 
               
               
                   
                   
                 3H), 4.23 (d, J = 16.9 Hz, 1H), 3.94 (s, 6H), 3.89 (d, J = 12.9 Hz, 
               
               
                   
                   
                 2H), 3.74 (d, J = 7.0 Hz, 1H), 3.54-3.46 (m, 2H), 3.29 (d, J = 11.7 
               
               
                   
                   
                 Hz, 2H), 3.14 (t, J = 12.1 Hz, 2H), 2.91 (ddd, J = 17.6, 13.6, 5.4 Hz, 
               
               
                   
                   
                 1H), 2.60 (d, J = 17.0 Hz, 1H), 2.46-2.33 (m, 1H), 2.34 (s, 3H), 
               
               
                   
                   
                 2.03-1.95 (m, 1H), 1.81-1.59 (m, 3H). 
               
               
                 D469 
                 654.25 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.35 (s, 1H), 7.88 (s, 
               
               
                   
                   
                 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.29-7.20 (m, 1H), 7.20-7.06 (m, 
               
               
                   
                   
                 2H), 6.92 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.15 (m, 
               
               
                   
                   
                 2H), 3.86 (s, 6H), 3.66-3.51 (m, 2H), 3.43 (s, 3H), 3.11-2.85 (m, 
               
               
                   
                   
                 5H), 2.70-2.55 (m, 3H), 2.43-2.31 (m, 1H), 2.05-1.93 (m, 1H), 
               
               
                   
                   
                 1.39-1.14 (m, 6H). 
               
               
                 D470 
                 666.735 
               
               
                 D471 
                 666.45 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.62 (s, 1H), 8.72 (d, J = 6.3 Hz, 
               
               
                   
                   
                 1H), 8.15 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J = 6.3 Hz, 1H), 
               
               
                   
                   
                 7.36 (d, J = 2.4 Hz, 1H), 6.90 (s, 2H), 6.79 (dd, J = 7.1, 2.4 Hz, 1H), 
               
               
                   
                   
                 4.96 (d, J = 9.1 Hz, 1H), 4.47 (s, 2H), 4.27 (s, 2H), 4.15 (s, 2H), 3.99 
               
               
                   
                   
                 (s, 6H), 3.76 (s, 3H), 3.63 (d, J = 13.1 Hz, 2H), 3.25 (t, J = 12.2 Hz, 
               
               
                   
                   
                 2H), 2.94-2.70 (m, 2H), 2.27 (dt, J = 28.7, 13.5 Hz, 6H). 
               
               
                 D472 
                 667.20 
                   1 H NMR (300 MHz, Methanol-d4) δ 9.55 (d, J = 0.8 Hz, 1H), 8.70 (d, 
               
               
                   
                   
                 J = 5.8 Hz, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J = 
               
               
                   
                   
                 5.8, 0.9 Hz, 1H), 7.28 (d, J = 4.9 Hz, 1H), 6.85 (s, 2H), 4.82 (dd, J = 
               
               
                   
                   
                 12.6, 5.4 Hz, 1H), 4.20 (s, 2H), 4.06-3.91 (m, 10H), 3.72 (s, 3H), 
               
               
                   
                   
                 3.06 (d, J = 27.6 Hz, 4H), 2.95-2.65 (m, 2H), 2.43-2.27 (m, 1H), 
               
               
                   
                   
                 2.20 (s, 1H), 2.14-1.99 (m, 4H). 
               
               
                 D473 
                 667.20 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.48 (s, 1H), 9.02 (d, 
               
               
                   
                   
                 J = 15.8 Hz, 1H), 8.73 (dd, J = 16.7, 7.0 Hz, 2H), 8.40 (s, 1H), 8.10 
               
               
                   
                   
                 (s, 1H), 7.91 (s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 6.88 (s, 2H), 4.84- 
               
               
                   
                   
                 4.73 (m, 1H), 4.30 (d, J = 4.6 Hz, 2H), 4.02 (s, 2H), 3.91 (s, 8H), 
               
               
                   
                   
                 3.62 (s, 3H), 3.40 (d, J = 12.2 Hz, 2H), 3.21-3.02 (m, 2H), 2.82 (s, 
               
               
                   
                   
                 1H), 2.55 (d, J = 3.7 Hz, 1H), 2.25-2.11 (m, 3H), 2.08-1.91 (m, 
               
               
                   
                   
                 3H). 
               
               
                 D474 
                 677.45 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.45 (s, 1H), 8.74 (d, 
               
               
                   
                   
                 J = 5.7 Hz, 1H), 7.89 (s, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 
               
               
                   
                   
                 8.1 Hz, 1H), 6.76 (s, 2H), 6.70-6.61 (m, 2H), 4.80-4.67 (m, 1H), 
               
               
                   
                   
                 4.33 (s, 2H), 3.83 (s, 6H), 3.67-3.53 (m, 9H), 3.03-2.88 (m, 2H), 
               
               
                   
                   
                 2.78-2.64 (m, 2H), 2.60-2.53 (m, 4H), 1.82-1.69 (m, 4H). 
               
               
                 D475 
                 748.35 
                   1 H NMR (400 MHz, Methanol-d4) δ 7.42 (d, J = 8.2 Hz, 1H), 7.21 (s, 
               
               
                   
                   
                 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.90-6.85 (m, 3H), 6.82-6.78 (m, 
               
               
                   
                   
                 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.64-4.49 (m, 2H), 4.45-4.34 
               
               
                   
                   
                 (m, 4H), 4.25-4.13 (m, 2H), 3.97 (s, 6H), 3.87-3.71 (m, 4H), 3.66 
               
               
                   
                   
                 (s, 3H), 3.62-3.46 (m, 5H), 3.44-3.38 (m, 4H), 3.16-3.05 (m, 
               
               
                   
                   
                 1H), 2.98-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.56-2.42 (m, 1H), 
               
               
                   
                   
                 2.32-2.06 (m, 5H). 
               
               
                 D476 
                 693.2 
                   1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 11.08 (s, 1H), 8.25 
               
               
                   
                   
                 (s, 1H, FA), 7.63 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 6.84-6.75 (m, 
               
               
                   
                   
                 3H), 6.65 (dd, J = 8.5, 2.2 Hz, 1H), 6.29 (s, 1H), 5.05 (dd, J = 12.9, 
               
               
                   
                   
                 5.4 Hz, 1H), 3.84 (s, 6H), 3.73 (s, 4H), 3.58 (s, 3H), 3.52 (s, 2H), 
               
               
                   
                   
                 2.94-2.85 (m, 1H), 2.62-2.55 (m, 2H), 2.44-2.37 (m, 3H), 2.37- 
               
               
                   
                   
                 2.31 (m, 4H), 2.06-1.96 (m, 1H), 1.73 (t, J = 5.2 Hz, 4H). 
               
               
                   
               
            
           
         
       
     
     Example 85—Preparation of Compounds DD11-DD16 
     In analogy to the procedures described in the examples above, compounds DD11-DD16 were prepared using the appropriate starting materials. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Compound 
                   
                   
               
               
                 No. 
                 LCMS 
                   1 H NMR 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 DD11 
                 785.35 
                   1 H NMR (300 MHz, DMSO) δ 11.13 (s, 1H), 8.20 (s, FA, 1H), 8.09 
               
               
                   
                   
                 (d, J = 8.3 Hz, 1H), 7.88-7.80 (m, 2H), 7.74 (s, 1H), 7.56-7.48 (m, 
               
               
                   
                   
                 1H), 7.47-7.39 (m, 1H), 7.39-7.35 (m, 1H), 7.34-7.23 (m, 2H), 
               
               
                   
                   
                 6.73 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 5.06-4.91 (m, 1H), 
               
               
                   
                   
                 3.81 (s, 6H), 3.70 (s, 2H), 3.58-3.50 (m, 1H), 3.00-2.81 (m, 4H), 
               
               
                   
                   
                 2.66-2.53 (m, 1H), 2.49-2.38 (m, 4H), 2.35-2.18 (m, 6H), 2.14- 
               
               
                   
                   
                 1.99 (m, 3H), 1.86-1.75 (m, 2H), 1.72-1.61 (m, 4H), 1.60-1.49 
               
               
                   
                   
                 (m, 3H), 1.27-1.07 (m, 2H). 
               
               
                 DD12 
                 519.45 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.37 (d, J = 8.0 Hz, 
               
               
                   
                   
                 1H), 7.28 (t, J = 8.3 Hz, 1H), 6.72-6.64 (m, 4H), 5.08 (dd, J = 13.3, 
               
               
                   
                   
                 5.1 Hz, 1H), 4.35-4.12 (m, 2H), 3.79 (s, 6H), 3.64 (s, 2H), 3.57 (s, 
               
               
                   
                   
                 4H), 2.98-2.84 (m, 1H), 2.64-2.55 (m, 5H), 2.45-2.33 (m, 1H), 
               
               
                   
                   
                 2.02-1.94 (m, 1H), 1.79-1.72 (m, 4H). 
               
               
                 DD13 
                 676.35 
                   1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.30 (dd, J = 8.2, 1.4 
               
               
                   
                   
                 Hz, 1H), 7.71 (dd, J = 7.4, 1.4 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45 
               
               
                   
                   
                 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 4.3 Hz, 4H), 
               
               
                   
                   
                 6.56 (d, J = 7.6 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.13 
               
               
                   
                   
                 (m, 2H), 3.82 (s, 7H), 3.60 (d, J = 4.4 Hz, 7H), 3.53 (s, 3H), 2.98- 
               
               
                   
                   
                 2.84 (m, 1H), 2.64-2.55 (m, 2H), 2.38 (dd, J = 13.2, 4.6 Hz, 2H), 
               
               
                   
                   
                 2.03-1.94 (m, 1H), 1.75 (t, J = 5.4 Hz, 4H). 
               
               
                 DD14 
                 479.30 
                   1 H NMR (300 MHz, Methanol-d4) δ 8.52 (s, 0.48H, FA), 7.53-7.40 
               
               
                   
                   
                 (m, 2H), 7.40-7.32 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H),, 5.15 (dd, J = 
               
               
                   
                   
                 13.3, 5.1 Hz, 1H), 4.52-4.35 (m, 2H), 4.27 (s, 2H), 3.93 (s, 6H), 
               
               
                   
                   
                 3.62-3.39 (m, 4H), 3.30-3.18 (m, 4H), 3.12-2.73 (m, 2H), 2.62- 
               
               
                   
                   
                 2.41 (m, 1H), 2.26-2.12 (m, 1H). 
               
               
                 DD15 
                 652.30 
                   1 H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.97 (s, 1H), 8.22- 
               
               
                   
                   
                 8.13 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 6.74-6.34 (m, 4H), 5.07 (dd, 
               
               
                   
                   
                 J = 13.6, 5.2 Hz, 1H), 4.34-4.14 (m, 2H), 3.88 (s, 6H), 3.65-3.57 
               
               
                   
                   
                 (m, 6H), 2.94-2.86 (m, 1H), 2.67-2.59 (m, 1H), 2.47-2.26 (m, 
               
               
                   
                   
                 5H), 2.04-1.93 (m, 1H), 1.84-1.59 (m, 4H). 
               
               
                 DD16 
                 518.15 
                   1 H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.47 (d, J = 7.9 Hz, 
               
               
                   
                   
                 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.66-7.53 (m, 1H), 7.45 (m, J = 8.4 
               
               
                   
                   
                 Hz, 1H), 7.37-7.08 (m, 2H), 6.74 (m, J = 7.5, 0.9 Hz, 1H), 5.11 (dd, 
               
               
                   
                   
                 J = 13.2, 5.1 Hz, 1H), 4.44-4.13 (m, 2H), 4.00 (s, 1H), 3.89-3.67 
               
               
                   
                   
                 (m, 2H), 3.52 (s, 3H), 3.00-2.91 (m, 3H), 2.63 (m, 1H), 2.45-2.23 
               
               
                   
                   
                 (m, 1H), 2.11-1.94 (m, 1H), 1.95-1.81 (m, 2H), 1.71-1.61 (m, 
               
               
                   
                   
                 2H). 
               
               
                   
               
            
           
         
       
     
     Example 86—BRD9 Bromodomain TR-FRET Competition Binding Assay 
     This example demonstrates the ability of the compounds of the disclosure to biochemically inhibit BRD9 bromodomain in a competition binding assay. 
     Procedure: His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M2; SEQ ID NO:1 mgsshhhhhhenlyfq/gdykddddkgslevfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMII KHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) was cloned, expressed, purified, and then treated with TEV protease. Cleaved His tag was removed by purification. The binding of a biotinylated small molecule ligand of BRD9 was assessed via the LANCE® TR-FRET platform (PerkinElmer), and the compounds were assayed for inhibitory activity against this interaction. 
     A mixture of biotinylated-ligand and SureLightm Aflophycocyanin-Streptavidin (APC-SA, PerkinElmerAD0201) in 50 mM HEPES (pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01% (w/v) bovine serum albumin was added to a white 384-well PerkinElmer Proxiplate Plus plate. DMSO or 3-fold serially diluted compounds were then added to the Proxiplate followed by addition of Flag-BRD9. After a 10-minute incubation at mom temperature, Eu-W1024 anti-FLAG (PerkinElmer, AD0273) was added. The final reaction mixture that contained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight™ Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG was incubated at room temperature for 90 minutes. 
     Results: The plates were then read on a PerkinElmer Envision plate reader to determine the ratio of emission at 685 nm over 615 nm. Data was normalized to a DMSO control (100%) and a no protein control (0%) and then fit to a four parameter, non-linear curve fit to calculate IC 50  (μM) values as shown in Table 4. As shown by the results in Table 4, a number of compounds of the present disclosure exhibit an IC 50  value of &lt;1 μM for BRD9 binding. Indicating their affinity for targeting BRD9. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Bromodomain 9 (BRD9) TR-FRET Binding 
               
               
                 of Compounds of the Disclosure 
               
            
           
           
               
               
               
            
               
                   
                 Compound No. 
                 Bromodomain TR-FRET BRD9 IC 50  (nM) 
               
               
                   
                   
               
               
                   
                 D1 
                 +++ 
               
               
                   
                 D2 
                 ++++ 
               
               
                   
                 D3 
                 ++++ 
               
               
                   
                 D4 
                 ++++ 
               
               
                   
                 D5 
                 ++++ 
               
               
                   
                 D6 
                 ++++ 
               
               
                   
                 D7 
                 ++++ 
               
               
                   
                 D8 
                 ++++ 
               
               
                   
                 D9 
                 ++++ 
               
               
                   
                 D10 
                 +++ 
               
               
                   
                 D11 
                 +++ 
               
               
                   
                 D12 
                 ++++ 
               
               
                   
                 D13 
                 ++++ 
               
               
                   
                 D14 
                 ++++ 
               
               
                   
                 D15 
                 ++++ 
               
               
                   
                 D16 
                 NT 
               
               
                   
                 D17 
                 NT 
               
               
                   
                 D18 
                 NT 
               
               
                   
                 D19 
                 NT 
               
               
                   
                 D20 
                 NT 
               
               
                   
                 D21 
                 NT 
               
               
                   
                 D22 
                 ++++ 
               
               
                   
                 D23 
                 ++++ 
               
               
                   
                 D24 
                 NT 
               
               
                   
                 D25 
                 ++++ 
               
               
                   
                 D26 
                 +++ 
               
               
                   
                 D27 
                 ++++ 
               
               
                   
                 D28 
                 NT 
               
               
                   
                 D29 
                 NT 
               
               
                   
                 D30 
                 ++++ 
               
               
                   
                 D31 
                 ++++ 
               
               
                   
                 D32 
                 ++++ 
               
               
                   
                 D33 
                 ++++ 
               
               
                   
                 D34 
                 ++++ 
               
               
                   
                 D35 
                 ++++ 
               
               
                   
                 D36 
                 ++++ 
               
               
                   
                 D37 
                 ++++ 
               
               
                   
                 D38 
                 ++++ 
               
               
                   
                 D39 
                 ++++ 
               
               
                   
                 D40 
                 ++++ 
               
               
                   
                 D41 
                 ++++ 
               
               
                   
                 D42 
                 NT 
               
               
                   
                 D43 
                 NT 
               
               
                   
                 D44 
                 NT 
               
               
                   
                 D45 
                 NT 
               
               
                   
                 D46 
                 NT 
               
               
                   
                 D47 
                 NT 
               
               
                   
                 D48 
                 NT 
               
               
                   
                 D49 
                 NT 
               
               
                   
                 D50 
                 NT 
               
               
                   
                 D51 
                 NT 
               
               
                   
                 D52 
                 ++++ 
               
               
                   
                 D53 
                 ++++ 
               
               
                   
                 D54 
                 +++ 
               
               
                   
                 D55 
                 +++ 
               
               
                   
                 D56 
                 ++++ 
               
               
                   
                 D57 
                 +++ 
               
               
                   
                 D58 
                 ++++ 
               
               
                   
                 D59 
                 ++++ 
               
               
                   
                 D60 
                 ++++ 
               
               
                   
                 D61 
                 ++++ 
               
               
                   
                 D62 
                 +++ 
               
               
                   
                 D63 
                 +++ 
               
               
                   
                 D64 
                 +++ 
               
               
                   
                 D65 
                 +++ 
               
               
                   
                 D66 
                 +++ 
               
               
                   
                 D67 
                 ++++ 
               
               
                   
                 D68 
                 ++++ 
               
               
                   
                 D69 
                 ++++ 
               
               
                   
                 D70 
                 +++ 
               
               
                   
                 D71 
                 ++++ 
               
               
                   
                 D72 
                 ++++ 
               
               
                   
                 D73 
                 +++ 
               
               
                   
                 D74 
                 ++++ 
               
               
                   
                 D75 
                 NT 
               
               
                   
                 D76 
                 NT 
               
               
                   
                 D77 
                 NT 
               
               
                   
                 D78 
                 NT 
               
               
                   
                 D79 
                 NT 
               
               
                   
                 D80 
                 NT 
               
               
                   
                 D81 
                 NT 
               
               
                   
                 D82 
                 NT 
               
               
                   
                 D83 
                 NT 
               
               
                   
                 D84 
                 +++ 
               
               
                   
                 D85 
                 +++ 
               
               
                   
                 D86 
                 +++ 
               
               
                   
                 D87 
                 ++++ 
               
               
                   
                 D88 
                 ++++ 
               
               
                   
                 D89 
                 ++++ 
               
               
                   
                 D90 
                 ++++ 
               
               
                   
                 D91 
                 +++ 
               
               
                   
                 D92 
                 ++++ 
               
               
                   
                 D93 
                 ++++ 
               
               
                   
                 D94 
                 +++ 
               
               
                   
                 D95 
                 +++ 
               
               
                   
                 D96 
                 ++++ 
               
               
                   
                 D97 
                 ++++ 
               
               
                   
                 D98 
                 ++ 
               
               
                   
                 D99 
                 +++ 
               
               
                   
                 D100 
                 ++++ 
               
               
                   
                 D101 
                 ++++ 
               
               
                   
                 D102 
                 ++++ 
               
               
                   
                 D103 
                 +++ 
               
               
                   
                 D104 
                 +++ 
               
               
                   
                 D105 
                 +++ 
               
               
                   
                 D106 
                 +++ 
               
               
                   
                 D107 
                 +++ 
               
               
                   
                 D108 
                 ++++ 
               
               
                   
                 D109 
                 ++++ 
               
               
                   
                 D110 
                 +++ 
               
               
                   
                 D111 
                 ++++ 
               
               
                   
                 D112 
                 ++++ 
               
               
                   
                 D113 
                 ++++ 
               
               
                   
                 D114 
                 ++++ 
               
               
                   
                 D115 
                 +++ 
               
               
                   
                 D116 
                 ++++ 
               
               
                   
                 D117 
                 ++++ 
               
               
                   
                 D118 
                 ++++ 
               
               
                   
                 D119 
                 ++++ 
               
               
                   
                 D120 
                 +++ 
               
               
                   
                 D121 
                 +++ 
               
               
                   
                 D122 
                 ++++ 
               
               
                   
                 D123 
                 ++++ 
               
               
                   
                 D124 
                 ++++ 
               
               
                   
                 D125 
                 ++++ 
               
               
                   
                 D126 
                 +++ 
               
               
                   
                 D127 
                 ++++ 
               
               
                   
                 D128 
                 +++ 
               
               
                   
                 D129 
                 ++++ 
               
               
                   
                 D130 
                 ++++ 
               
               
                   
                 D131 
                 ++++ 
               
               
                   
                 D132 
                 ++++ 
               
               
                   
                 D133 
                 ++++ 
               
               
                   
                 D134 
                 +++ 
               
               
                   
                 D135 
                 +++ 
               
               
                   
                 D136 
                 ++++ 
               
               
                   
                 D137 
                 ++++ 
               
               
                   
                 D138 
                 ++++ 
               
               
                   
                 D139 
                 ++++ 
               
               
                   
                 D140 
                 ++++ 
               
               
                   
                 D141 
                 +++ 
               
               
                   
                 D142 
                 +++ 
               
               
                   
                 D143 
                 ++++ 
               
               
                   
                 D144 
                 +++ 
               
               
                   
                 D145 
                 +++ 
               
               
                   
                 D146 
                 ++++ 
               
               
                   
                 D147 
                 +++ 
               
               
                   
                 D148 
                 +++ 
               
               
                   
                 D149 
                 ++++ 
               
               
                   
                 D150 
                 ++++ 
               
               
                   
                 D151 
                 ++++ 
               
               
                   
                 D152 
                 ++++ 
               
               
                   
                 D153 
                 +++ 
               
               
                   
                 D154 
                 ++++ 
               
               
                   
                 D155 
                 ++++ 
               
               
                   
                 D156 
                 ++++ 
               
               
                   
                 D157 
                 +++ 
               
               
                   
                 D158 
                 ++++ 
               
               
                   
                 D159 
                 ++++ 
               
               
                   
                 D160 
                 ++++ 
               
               
                   
                 D161 
                 ++++ 
               
               
                   
                 D162 
                 +++ 
               
               
                   
                 D163 
                 ++++ 
               
               
                   
                 D164 
                 ++++ 
               
               
                   
                 D165 
                 +++ 
               
               
                   
                 D166 
                 ++++ 
               
               
                   
                 D167 
                 ++++ 
               
               
                   
                 D168 
                 ++++ 
               
               
                   
                 D169 
                 ++++ 
               
               
                   
                 D170 
                 +++ 
               
               
                   
                 D171 
                 +++ 
               
               
                   
                 D172 
                 ++++ 
               
               
                   
                 D173 
                 +++ 
               
               
                   
                 D174 
                 +++ 
               
               
                   
                 D175 
                 +++ 
               
               
                   
                 D176 
                 ++++ 
               
               
                   
                 D177 
                 ++++ 
               
               
                   
                   
               
               
                   
                 “+” indicates inhibitory effect of ≥1000 nM; 
               
               
                   
                 “++” indicates inhibitory effect of ≥100 nM; 
               
               
                   
                 “+++” indicates inhibitory effect of ≥10 nM; 
               
               
                   
                 “++++” indicates inhibitory effect of &lt;10 nM; 
               
               
                   
                 “NT” indicates not tested 
               
            
           
         
       
     
     Example 87—SYO1 BRD9 NanoLuc Degradation Assay 
     This example demonstrates the ability of the compounds of the disclosure to degrade a Nanoluciferase-BRD9 fusion protein in a cell-based degradation assay. 
     Procedure: A stable SYO-1 cell line expressing 3×FLAG-NLuc-BRD9 was generated. On day 0 cells were seeded in 30 μL media into each well of 384-well cell culture plates. The seeding density was 8000 cells/well. On day 1, cells were treated with 30 nL DMS0 or 30 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicates with 1 μM as final top dose). Subsequently plates were Incubated for 6 hours in a standard tissue culture incubator and equilibrated at room temperature for 15 minutes. Nanoluciferase activity was measured by adding 15 μL of freshly prepared Nano-Glo Luciferase Assay Reagent (Promega N1130), shaking the plates for 10 minutes and reading the bioluminescence using an EnVision reader. 
     Results: The Inhibition % was calculated using the following formula: % inhibition=100×(Lum HC −Lum sample )/(LUM HC −Lum LC ). DMSO treated cells are employed as High Control (HC) and 1 μM of a known BRD9 degrader standard treated cells are employed as Low Control (LC). The data was fit to a four parameter, non-linear curve fit to calculate IC 50  (μM) values as shown in Table 5A, Table 5B, and Table 5C. As shown by the results in Table 5A, Table 5B, and Table 5C, a number of compounds of the present disclosure exhibit an IC 50  value of &lt;1 μM for the degradation of BRD9, indicating their use as compounds for reducing the levels and/or activity of BRD9 and their potential for treating BRD39-related disorders. 
     
       
         
           
               
             
               
                 TABLE 5A 
               
             
            
               
                   
               
               
                 SYO1 Bromodomain 9-NanoLuc Degradation 
               
               
                 by Compounds of the Disclosure 
               
            
           
           
               
               
               
            
               
                   
                 Compound No. 
                 SYO1 BRD9-NanoLuc degradation IC 50  (nM) 
               
               
                   
                   
               
               
                   
                 D1 
                 ++++ 
               
               
                   
                 D2 
                 +++ 
               
               
                   
                 D3 
                 ++++ 
               
               
                   
                 D4 
                 +++ 
               
               
                   
                 D5 
                 +++ 
               
               
                   
                 D6 
                 ++++ 
               
               
                   
                 D7 
                 +++ 
               
               
                   
                 D8 
                 + 
               
               
                   
                 D9 
                 ++++ 
               
               
                   
                 D10 
                 ++++ 
               
               
                   
                 D11 
                 ++++ 
               
               
                   
                 D12 
                 ++++ 
               
               
                   
                 D13 
                 ++++ 
               
               
                   
                 D14 
                 ++++ 
               
               
                   
                 D15 
                 ++++ 
               
               
                   
                 D16 
                 ++++ 
               
               
                   
                 D17 
                 ++++ 
               
               
                   
                 D18 
                 ++++ 
               
               
                   
                 D19 
                 ++++ 
               
               
                   
                 D20 
                 ++++ 
               
               
                   
                 D21 
                 + 
               
               
                   
                 D22 
                 +++ 
               
               
                   
                 D23 
                 ++++ 
               
               
                   
                 D24 
                 +++ 
               
               
                   
                 D25 
                 ++ 
               
               
                   
                 D26 
                 + 
               
               
                   
                 D27 
                 +++ 
               
               
                   
                 D28 
                 ++ 
               
               
                   
                 D29 
                 +++ 
               
               
                   
                 D30 
                 +++ 
               
               
                   
                 D31 
                 +++ 
               
               
                   
                 D32 
                 +++ 
               
               
                   
                 D33 
                 ++++ 
               
               
                   
                 D34 
                 ++++ 
               
               
                   
                 D35 
                 ++++ 
               
               
                   
                 D36 
                 ++ 
               
               
                   
                 D37 
                 ++++ 
               
               
                   
                 D38 
                 ++++ 
               
               
                   
                 D39 
                 ++++ 
               
               
                   
                 D40 
                 ++++ 
               
               
                   
                 D41 
                 +++ 
               
               
                   
                 D42 
                 ++++ 
               
               
                   
                 D43 
                 ++ 
               
               
                   
                 D44 
                 ++++ 
               
               
                   
                 D45 
                 ++++ 
               
               
                   
                 D46 
                 ++++ 
               
               
                   
                 D47 
                 ++++ 
               
               
                   
                 D48 
                 +++ 
               
               
                   
                 D49 
                 + 
               
               
                   
                 D50 
                 ++++ 
               
               
                   
                 D51 
                 ++++ 
               
               
                   
                 D52 
                 ++++ 
               
               
                   
                 D53 
                 ++++ 
               
               
                   
                 D54 
                 +++ 
               
               
                   
                 D55 
                 ++ 
               
               
                   
                 D56 
                 ++++ 
               
               
                   
                 D57 
                 ++++ 
               
               
                   
                 D58 
                 ++++ 
               
               
                   
                 D59 
                 ++++ 
               
               
                   
                 D60 
                 ++++ 
               
               
                   
                 D61 
                 +++ 
               
               
                   
                 D62 
                 ++ 
               
               
                   
                 D63 
                 +++ 
               
               
                   
                 D64 
                 ++ 
               
               
                   
                 D65 
                 ++ 
               
               
                   
                 D66 
                 ++ 
               
               
                   
                 D67 
                 ++++ 
               
               
                   
                 D68 
                 ++ 
               
               
                   
                 D69 
                 ++++ 
               
               
                   
                 D70 
                 +++ 
               
               
                   
                 D71 
                 ++++ 
               
               
                   
                 D72 
                 ++++ 
               
               
                   
                 D73 
                 ++++ 
               
               
                   
                 D74 
                 ++ 
               
               
                   
                 D75 
                 ++++ 
               
               
                   
                 D76 
                 ++++ 
               
               
                   
                 D77 
                 ++ 
               
               
                   
                 D78 
                 +++ 
               
               
                   
                 D79 
                 ++ 
               
               
                   
                 D80 
                 ++++ 
               
               
                   
                 D81 
                 ++++ 
               
               
                   
                 D82 
                 +++ 
               
               
                   
                 D83 
                 ++ 
               
               
                   
                 D84 
                 + 
               
               
                   
                 D85 
                 ++ 
               
               
                   
                 D86 
                 ++ 
               
               
                   
                 D87 
                 +++ 
               
               
                   
                 D88 
                 +++ 
               
               
                   
                 D89 
                 ++++ 
               
               
                   
                 D90 
                 +++ 
               
               
                   
                 D91 
                 +++ 
               
               
                   
                 D92 
                 ++++ 
               
               
                   
                 D93 
                 +++ 
               
               
                   
                 D94 
                 +++ 
               
               
                   
                 D95 
                 ++ 
               
               
                   
                 D96 
                 +++ 
               
               
                   
                 D97 
                 +++ 
               
               
                   
                 D98 
                 ++ 
               
               
                   
                 D99 
                 +++ 
               
               
                   
                 D100 
                 ++++ 
               
               
                   
                 D101 
                 ++ 
               
               
                   
                 D102 
                 +++ 
               
               
                   
                 D103 
                 +++ 
               
               
                   
                 D104 
                 ++ 
               
               
                   
                 D105 
                 ++ 
               
               
                   
                 D106 
                 ++ 
               
               
                   
                 D107 
                 +++ 
               
               
                   
                 D108 
                 ++++ 
               
               
                   
                 D109 
                 +++ 
               
               
                   
                 D110 
                 +++ 
               
               
                   
                 D111 
                 +++ 
               
               
                   
                 D112 
                 ++ 
               
               
                   
                 D113 
                 ++++ 
               
               
                   
                 D114 
                 +++ 
               
               
                   
                 D115 
                 ++ 
               
               
                   
                 D116 
                 +++ 
               
               
                   
                 D117 
                 ++ 
               
               
                   
                 D118 
                 +++ 
               
               
                   
                 D119 
                 +++ 
               
               
                   
                 D120 
                 +++ 
               
               
                   
                 D121 
                 +++ 
               
               
                   
                 D122 
                 ++++ 
               
               
                   
                 D123 
                 ++++ 
               
               
                   
                 D124 
                 ++++ 
               
               
                   
                 D125 
                 +++ 
               
               
                   
                 D126 
                 ++ 
               
               
                   
                 D127 
                 ++ 
               
               
                   
                 D128 
                 ++++ 
               
               
                   
                 D129 
                 ++++ 
               
               
                   
                 D130 
                 ++++ 
               
               
                   
                 D131 
                 ++++ 
               
               
                   
                 D132 
                 ++++ 
               
               
                   
                 D133 
                 +++ 
               
               
                   
                 D134 
                 +++ 
               
               
                   
                 D135 
                 ++ 
               
               
                   
                 D136 
                 ++ 
               
               
                   
                 D137 
                 +++ 
               
               
                   
                 D138 
                 +++ 
               
               
                   
                 D139 
                 ++ 
               
               
                   
                 D140 
                 +++ 
               
               
                   
                 D141 
                 ++ 
               
               
                   
                 D142 
                 +++ 
               
               
                   
                 D143 
                 ++++ 
               
               
                   
                 D144 
                 +++ 
               
               
                   
                 D145 
                 +++ 
               
               
                   
                 D146 
                 +++ 
               
               
                   
                 D147 
                 +++ 
               
               
                   
                 D148 
                 ++ 
               
               
                   
                 D149 
                 +++ 
               
               
                   
                 D150 
                 +++ 
               
               
                   
                 D151 
                 +++ 
               
               
                   
                 D152 
                 ++++ 
               
               
                   
                 D153 
                 +++ 
               
               
                   
                 D154 
                 +++ 
               
               
                   
                 D155 
                 +++ 
               
               
                   
                 D156 
                 +++ 
               
               
                   
                 D157 
                 ++++ 
               
               
                   
                 D158 
                 +++ 
               
               
                   
                 D159 
                 +++ 
               
               
                   
                 D160 
                 +++ 
               
               
                   
                 D161 
                 +++ 
               
               
                   
                 D162 
                 +++ 
               
               
                   
                 D163 
                 +++ 
               
               
                   
                 D164 
                 +++ 
               
               
                   
                 D165 
                 +++ 
               
               
                   
                 D166 
                 +++ 
               
               
                   
                 D167 
                 ++++ 
               
               
                   
                 D168 
                 ++++ 
               
               
                   
                 D169 
                 +++ 
               
               
                   
                 D170 
                 ++++ 
               
               
                   
                 D171 
                 ++++ 
               
               
                   
                 D172 
                 +++ 
               
               
                   
                 D173 
                 ++++ 
               
               
                   
                 D174 
                 ++ 
               
               
                   
                 D175 
                 +++ 
               
               
                   
                 D176 
                 ++++ 
               
               
                   
                 D177 
                 +++ 
               
               
                   
                   
               
               
                   
                 “+” indicates inhibitory effect of ≥1000 nM; 
               
               
                   
                 “++” indicates inhibitory effect of ≥100 nM; 
               
               
                   
                 “+++” indicates inhibitory effect of ≥10 nM; 
               
               
                   
                 “++++” indicates inhibitory effect of &lt;10 nM; 
               
               
                   
                 “NT” indicates not tested 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B 
               
             
            
               
                   
               
               
                 SYO1 Bromodomain 9-NanoLuc Degradation 
               
               
                 by Compounds of the Disclosure 
               
            
           
           
               
               
               
            
               
                   
                 Compound No. 
                 SYO1 BRD9-NanoLuc degradation IC 50  (nM) 
               
               
                   
                   
               
               
                   
                 D178 
                 ++++ 
               
               
                   
                 D179 
                 +++ 
               
               
                   
                 D180 
                 ++++ 
               
               
                   
                 D181 
                 ++ 
               
               
                   
                 D182 
                 +++ 
               
               
                   
                 D183 
                 ++ 
               
               
                   
                 D184 
                 ++++ 
               
               
                   
                 D185 
                 ++++ 
               
               
                   
                 D186 
                 ++++ 
               
               
                   
                 D187 
                 ++++ 
               
               
                   
                 D188 
                 ++++ 
               
               
                   
                 D189 
                 ++++ 
               
               
                   
                 D190 
                 +++ 
               
               
                   
                 D191 
                 ++++ 
               
               
                   
                 D192 
                 ++ 
               
               
                   
                 D193 
                 ++ 
               
               
                   
                 D194 
                 ++++ 
               
               
                   
                 D195 
                 +++ 
               
               
                   
                 D196 
                 +++ 
               
               
                   
                 D197 
                 ++++ 
               
               
                   
                 D198 
                 ++++ 
               
               
                   
                 D199 
                 ++++ 
               
               
                   
                 D200 
                 +++ 
               
               
                   
                 D201 
                 ++++ 
               
               
                   
                 D202 
                 ++++ 
               
               
                   
                 D203 
                 ++++ 
               
               
                   
                 D204 
                 ++++ 
               
               
                   
                 D205 
                 ++++ 
               
               
                   
                 D206 
                 ++++ 
               
               
                   
                 D207 
                 ++++ 
               
               
                   
                 D208 
                 ++++ 
               
               
                   
                 D209 
                 ++ 
               
               
                   
                 D210 
                 +++ 
               
               
                   
                 D211 
                 ++++ 
               
               
                   
                 D212 
                 +++ 
               
               
                   
                 D213 
                 ++++ 
               
               
                   
                 D214 
                 ++++ 
               
               
                   
                 D215 
                 ++++ 
               
               
                   
                 D216 
                 ++++ 
               
               
                   
                 D217 
                 ++++ 
               
               
                   
                 D218 
                 ++++ 
               
               
                   
                 D219 
                 ++++ 
               
               
                   
                 D220 
                 ++++ 
               
               
                   
                 D221 
                 ++++ 
               
               
                   
                 D222 
                 ++++ 
               
               
                   
                 D223 
                 ++++ 
               
               
                   
                 D224 
                 ++++ 
               
               
                   
                 D225 
                 ++++ 
               
               
                   
                 D226 
                 ++++ 
               
               
                   
                 D227 
                 ++++ 
               
               
                   
                 D228 
                 ++++ 
               
               
                   
                 D229 
                 ++++ 
               
               
                   
                 D230 
                 ++++ 
               
               
                   
                 D231 
                 ++ 
               
               
                   
                 D232 
                 +++ 
               
               
                   
                 D233 
                 ++ 
               
               
                   
                 D234 
                 +++ 
               
               
                   
                 D235 
                 ++++ 
               
               
                   
                 D236 
                 ++++ 
               
               
                   
                 D237 
                 ++++ 
               
               
                   
                 D238 
                 ++++ 
               
               
                   
                 D239 
                 ++++ 
               
               
                   
                 D240 
                 ++++ 
               
               
                   
                 D241 
                 ++++ 
               
               
                   
                 D242 
                 ++++ 
               
               
                   
                 D243 
                 ++++ 
               
               
                   
                 D244 
                 ++++ 
               
               
                   
                 D245 
                 +++ 
               
               
                   
                 D246 
                 ++++ 
               
               
                   
                 D247 
                 ++++ 
               
               
                   
                 D248 
                 +++ 
               
               
                   
                 D249 
                 +++ 
               
               
                   
                 D250 
                 ++++ 
               
               
                   
                 D251 
                 ++++ 
               
               
                   
                 D252 
                 ++++ 
               
               
                   
                 D253 
                 ++++ 
               
               
                   
                 D254 
                 ++++ 
               
               
                   
                 D255 
                 ++++ 
               
               
                   
                 D256 
                 ++++ 
               
               
                   
                 D257 
                 ++++ 
               
               
                   
                 D258 
                 ++++ 
               
               
                   
                 D259 
                 ++++ 
               
               
                   
                 D260 
                 ++++ 
               
               
                   
                 D261 
                 ++++ 
               
               
                   
                 D262 
                 ++++ 
               
               
                   
                 D263 
                 ++++ 
               
               
                   
                 D264 
                 +++ 
               
               
                   
                 D265 
                 ++ 
               
               
                   
                 D266 
                 +++ 
               
               
                   
                 D267 
                 +++ 
               
               
                   
                 D268 
                 ++++ 
               
               
                   
                 D269 
                 ++++ 
               
               
                   
                 D270 
                 +++ 
               
               
                   
                 D271 
                 ++++ 
               
               
                   
                 D272 
                 ++++ 
               
               
                   
                 D273 
                 ++++ 
               
               
                   
                 D274 
                 ++++ 
               
               
                   
                 D275 
                 ++++ 
               
               
                   
                 D276 
                 +++ 
               
               
                   
                 D277 
                 ++++ 
               
               
                   
                 D278 
                 +++ 
               
               
                   
                 D279 
                 ++++ 
               
               
                   
                 D280 
                 ++++ 
               
               
                   
                 D281 
                 +++ 
               
               
                   
                 D282 
                 ++ 
               
               
                   
                 D283 
                 ++ 
               
               
                   
                 D284 
                 +++ 
               
               
                   
                 D285 
                 ++ 
               
               
                   
                 D286 
                 +++ 
               
               
                   
                 D287 
                 ++++ 
               
               
                   
                 D288 
                 ++++ 
               
               
                   
                 D289 
                 ++++ 
               
               
                   
                 D290 
                 ++++ 
               
               
                   
                 D291 
                 ++++ 
               
               
                   
                 D292 
                 ++ 
               
               
                   
                 D293 
                 +++ 
               
               
                   
                 D294 
                 ++ 
               
               
                   
                 D295 
                 ++ 
               
               
                   
                 D296 
                 ++ 
               
               
                   
                 D297 
                 ++++ 
               
               
                   
                 D298 
                 ++++ 
               
               
                   
                 D299 
                 ++++ 
               
               
                   
                 D300 
                 ++++ 
               
               
                   
                 D301 
                 ++++ 
               
               
                   
                 D302 
                 ++++ 
               
               
                   
                 D303 
                 +++ 
               
               
                   
                 D304 
                 ++++ 
               
               
                   
                 D305 
                 ++ 
               
               
                   
                 D306 
                 ++++ 
               
               
                   
                 D307 
                 ++++ 
               
               
                   
                 D308 
                 ++++ 
               
               
                   
                 D309 
                 +++ 
               
               
                   
                 D310 
                 ++++ 
               
               
                   
                 D311 
                 +++ 
               
               
                   
                 D312 
                 ++++ 
               
               
                   
                 D313 
                 ++++ 
               
               
                   
                 D314 
                 +++ 
               
               
                   
                 D315 
                 ++++ 
               
               
                   
                 D316 
                 ++++ 
               
               
                   
                 D317 
                 +++ 
               
               
                   
                 D318 
                 ++++ 
               
               
                   
                 D319 
                 ++++ 
               
               
                   
                 D320 
                 ++++ 
               
               
                   
                 D321 
                 ++++ 
               
               
                   
                 D322 
                 ++++ 
               
               
                   
                 D323 
                 ++++ 
               
               
                   
                 D324 
                 ++++ 
               
               
                   
                 D325 
                 ++++ 
               
               
                   
                 D326 
                 ++++ 
               
               
                   
                 D327 
                 ++++ 
               
               
                   
                 D328 
                 ++++ 
               
               
                   
                 D329 
                 ++++ 
               
               
                   
                 D330 
                 ++++ 
               
               
                   
                 D331 
                 ++++ 
               
               
                   
                 D332 
                 ++++ 
               
               
                   
                 D333 
                 ++++ 
               
               
                   
                 D334 
                 + 
               
               
                   
                 D335 
                 ++++ 
               
               
                   
                 D336 
                 ++++ 
               
               
                   
                 D337 
                 ++++ 
               
               
                   
                 D338 
                 ++++ 
               
               
                   
                 D339 
                 ++++ 
               
               
                   
                 D340 
                 ++++ 
               
               
                   
                 D341 
                 ++++ 
               
               
                   
                 D342 
                 + 
               
               
                   
                 D343 
                 ++++ 
               
               
                   
                 D344 
                 ++++ 
               
               
                   
                 D345 
                 ++++ 
               
               
                   
                 D346 
                 ++++ 
               
               
                   
                 D347 
                 ++++ 
               
               
                   
                 D348 
                 ++++ 
               
               
                   
                 D349 
                 ++++ 
               
               
                   
                 D350 
                 ++ 
               
               
                   
                 D351 
                 + 
               
               
                   
                 D352 
                 + 
               
               
                   
                 D353 
                 ++++ 
               
               
                   
                 D354 
                 ++++ 
               
               
                   
                 D355 
                 + 
               
               
                   
                 D356 
                 ++++ 
               
               
                   
                 D357 
                 ++++ 
               
               
                   
                 D358 
                 ++++ 
               
               
                   
                 D359 
                 ++++ 
               
               
                   
                 D360 
                 ++++ 
               
               
                   
                 D361 
                 ++++ 
               
               
                   
                 D362 
                 ++++ 
               
               
                   
                 D363 
                 ++++ 
               
               
                   
                 D364 
                 ++ 
               
               
                   
                 D365 
                 +++ 
               
               
                   
                 D366 
                 ++++ 
               
               
                   
                 D367 
                 ++++ 
               
               
                   
                 D368 
                 ++++ 
               
               
                   
                 D369 
                 ++++ 
               
               
                   
                 D370 
                 ++++ 
               
               
                   
                 D371 
                 ++++ 
               
               
                   
                 DD1 
                 + 
               
               
                   
                 DD2 
                 ++ 
               
               
                   
                 DD3 
                 + 
               
               
                   
                 DD4 
                 ++++ 
               
               
                   
                 DD5 
                 +++ 
               
               
                   
                 DD6 
                 +++ 
               
               
                   
                 DD7 
                 ++++ 
               
               
                   
                 DD8 
                 ++++ 
               
               
                   
                 DD9 
                 ++++ 
               
               
                   
                 DD10 
                 ++ 
               
               
                   
                   
               
               
                   
                 “+” indicates inhibitory effect of ≥1000 nM; 
               
               
                   
                 “++” indicates inhibitory effect of ≥100 nM; 
               
               
                   
                 “+++” indicates inhibitory effect of ≥10 nM; 
               
               
                   
                 “++++” indicates inhibitory effect of &lt;10 nM; 
               
               
                   
                 “NT” indicates not tested 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5C 
               
             
            
               
                   
               
               
                 SYO1 Bromodomain 9-NanoLuc Degradation 
               
               
                 by Compounds of the Disclosure 
               
            
           
           
               
               
               
            
               
                   
                 Compound No. 
                 SYO1 BRD9-NanoLuc degradation IC 50  (nM) 
               
               
                   
                   
               
               
                   
                 D372 
                 ++++ 
               
               
                   
                 D373 
                 ++++ 
               
               
                   
                 D374 
                 ++++ 
               
               
                   
                 D375 
                 ++++ 
               
               
                   
                 D376 
                 ++++ 
               
               
                   
                 D377 
                 ++++ 
               
               
                   
                 D378 
                 ++++ 
               
               
                   
                 D379 
                 ++++ 
               
               
                   
                 D380 
                 +++ 
               
               
                   
                 D381 
                 ++++ 
               
               
                   
                 D382 
                 ++++ 
               
               
                   
                 D383 
                 + 
               
               
                   
                 D384 
                 ++++ 
               
               
                   
                 D385 
                 ++++ 
               
               
                   
                 D386 
                 ++++ 
               
               
                   
                 D387 
                 ++++ 
               
               
                   
                 D388 
                 ++++ 
               
               
                   
                 D389 
                 + 
               
               
                   
                 D390 
                 + 
               
               
                   
                 D391 
                 ++ 
               
               
                   
                 D392 
                 +++ 
               
               
                   
                 D393 
                 +++ 
               
               
                   
                 D394 
                 + 
               
               
                   
                 D395 
                 ++++ 
               
               
                   
                 D396 
                 ++++ 
               
               
                   
                 D397 
                 ++++ 
               
               
                   
                 D398 
                 ++++ 
               
               
                   
                 D399 
                 ++++ 
               
               
                   
                 D400 
                 ++++ 
               
               
                   
                 D401 
                 ++++ 
               
               
                   
                 D402 
                 ++++ 
               
               
                   
                 D403 
                 ++++ 
               
               
                   
                 D404 
                 ++++ 
               
               
                   
                 D405 
                 ++++ 
               
               
                   
                 D406 
                 ++++ 
               
               
                   
                 D407 
                 ++++ 
               
               
                   
                 D408 
                 ++++ 
               
               
                   
                 D409 
                 ++++ 
               
               
                   
                 D410 
                 ++++ 
               
               
                   
                 D411 
                 ++++ 
               
               
                   
                 D412 
                 ++++ 
               
               
                   
                 D413 
                 ++++ 
               
               
                   
                 D414 
                 ++++ 
               
               
                   
                 D415 
                 ++++ 
               
               
                   
                 D416 
                 ++++ 
               
               
                   
                 D417 
                 ++++ 
               
               
                   
                 D418 
                 ++++ 
               
               
                   
                 D419 
                 ++++ 
               
               
                   
                 D420 
                 ++++ 
               
               
                   
                 D421 
                 ++++ 
               
               
                   
                 D422 
                 ++++ 
               
               
                   
                 D423 
                 ++++ 
               
               
                   
                 D424 
                 ++++ 
               
               
                   
                 D425 
                 ++++ 
               
               
                   
                 D426 
                 ++++ 
               
               
                   
                 D427 
                 ++++ 
               
               
                   
                 D428 
                 ++++ 
               
               
                   
                 D429 
                 + 
               
               
                   
                 D430 
                 ++++ 
               
               
                   
                 D431 
                 ++++ 
               
               
                   
                 D432 
                 +++ 
               
               
                   
                 D433 
                 ++++ 
               
               
                   
                 D434 
                 ++++ 
               
               
                   
                 D435 
                 + 
               
               
                   
                 D436 
                 ++++ 
               
               
                   
                 D437 
                 + 
               
               
                   
                 D438 
                 ++++ 
               
               
                   
                 D439 
                 ++++ 
               
               
                   
                 D440 
                 ++++ 
               
               
                   
                 D441 
                 ++++ 
               
               
                   
                 D442 
                 ++++ 
               
               
                   
                 D443 
                 ++++ 
               
               
                   
                 D444 
                 ++++ 
               
               
                   
                 D445 
                 + 
               
               
                   
                 D446 
                 + 
               
               
                   
                 D447 
                 ++ 
               
               
                   
                 D448 
                 ++++ 
               
               
                   
                 D449 
                 +++ 
               
               
                   
                 D450 
                 ++++ 
               
               
                   
                 D451 
                 +++ 
               
               
                   
                 D452 
                 ++++ 
               
               
                   
                 D453 
                 ++++ 
               
               
                   
                 D454 
                 ++++ 
               
               
                   
                 D455 
                 ++++ 
               
               
                   
                 D456 
                 ++++ 
               
               
                   
                 D457 
                 ++++ 
               
               
                   
                 D458 
                 ++++ 
               
               
                   
                 D459 
                 ++++ 
               
               
                   
                 D460 
                 ++++ 
               
               
                   
                 D461 
                 +++ 
               
               
                   
                 D462 
                 ++++ 
               
               
                   
                 D463 
                 ++++ 
               
               
                   
                 D464 
                 + 
               
               
                   
                 D465 
                 ++++ 
               
               
                   
                 D466 
                 ++++ 
               
               
                   
                 D467 
                 + 
               
               
                   
                 D468 
                 + 
               
               
                   
                 D469 
                 NT 
               
               
                   
                 D470 
                 NT 
               
               
                   
                 D471 
                 ++++ 
               
               
                   
                 D472 
                 + 
               
               
                   
                 D473 
                 + 
               
               
                   
                 D474 
                 + 
               
               
                   
                 D475 
                 +++ 
               
               
                   
                 D476 
                 ++++ 
               
               
                   
                 DD11 
                 + 
               
               
                   
                 DD12 
                 + 
               
               
                   
                 DD13 
                 +++ 
               
               
                   
                 DD14 
                 + 
               
               
                   
                 DD15 
                 +++ 
               
               
                   
                 DD16 
                 +++ 
               
               
                   
                   
               
               
                   
                 “+” indicates inhibitory effect of ≥1000 nM; 
               
               
                   
                 “++” indicates inhibitory effect of ≥100 nM; 
               
               
                   
                 “+++” indicates inhibitory effect of ≥10 nM; 
               
               
                   
                 “++++” indicates inhibitory effect of &lt;10 nM; 
               
               
                   
                 “NT” indicates not tested 
               
            
           
         
       
     
     Other Embodiments 
     All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. 
     Where a term in the present application is found to be defined differently in a document Incorporated herein by reference, the definition provided herein is to serve as the definition for the term. 
     While the Invention has been described in connection with specific embodiments thereof, it will be understood that Invention is capable of further modifications and this application is Intended to cover any variations, uses, or adaptations of the Invention following, in general, the principles of the Invention and Including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. 
     Other embodiments are in the claims.