Patent Publication Number: US-2022235065-A1

Title: Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof

Description:
RELATED APPLICATIONS 
     This application is a continuation of U.S. application Ser. No. 16/471,151, filed Jun. 19, 2019, which is a U.S. National Phase application, filed under 35 U.S.C. § 371, of International Application No. PCT/US2017/067192, filed Dec. 19, 2017, which claims priority to U.S. Provisional Application Nos. 62/517,840, filed Jun. 9, 2017, and 62/436,139, filed Dec. 19, 2016, the entire contents of each of which are incorporated herein by reference. 
    
    
     BACKGROUND 
     Methylation of protein lysine residues is an important signaling mechanism in eukaryotic cells, and the methylation state of histone lysines encodes signals that are recognized by a multitude of proteins and protein complexes in the context of epigenetic gene regulation. 
     Histone methylation is catalyzed by histone methyltransferases (HMTs), and HMTs have been implicated in various human diseases. HMTs can play a role in either activating or repressing gene expression, and certain HMTs (e.g., euchromatic histone-lysine N-methyltransferase 2 or EHMT2, also called G9a) may methylate many nonhistone proteins, such as tumor suppressor proteins (see, e.g., Liu et al.,  Journal of Medicinal Chemistry  56:8931-8942, 2013 and Krivega et al.,  Blood  126(5):665-672, 2015). 
     Two related HMTs, EHMT1 and EHMT2, are overexpressed or play a role in diseases and disorders such as sickle cell anemia (see, e.g., Renneville et al.,  Blood  126(16): 1930-1939, 2015) and proliferative disorders (e.g., cancers), and other blood disorders. 
     SUMMARY 
     In one aspect, the present disclosure features an amine-substituted heterocyclic compound of any of Formulae (I0)-(IV0) below: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer,
 
wherein
 
     X 1  is N or CR 2 ; 
     X 2  is N or CR 3 ; 
     X 3  is N or CR 4 ; 
     X 4  is N or CR 5 ; 
     X 5  is N or CH; 
     X 6  is N or CR 15 ; 
     X 7  is N or CH; 
     X 8  is NR 13  or CR 11 R 12 ; 
     one of X 13  and X 14  independently is NR 8 R 9 , and the other is R 10 ; 
     B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R 15 ; 
     R 1  is H or C 1 -C 4  alkyl; 
     each of R 2 , R 3 , R 4 , and R 5 , independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkoxyl, C 6 -C 10  aryl, OH, NR a R b , C(O)NR a R b , NR a C(O)R b , C(O)OR a , OC(O)R a , OC(O)NR a R b , NR a C(O)OR b , C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, wherein the C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkoxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, are each optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a  and R b  independently is H or C 1 -C 6  alkyl; 
     R 6  is -Q 1 -T 1 , in which Q 1  is a bond, or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 -C 6  alkoxyl, and T 1  is H, halo, cyano, or R S1 , in which R S1  is C 3 -C 8  cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1  is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, —C(O)R c , —C(O)OR c , —SO 2 R c , —SO 2 N(R c ) 2 , —NR c C(O)R d , —C(O)NR c R d , —NR c C(O)OR d , —OC(O)NR c R d , NR c R d , or C 1 -C 6  alkoxyl, in which each of R c  and R d  independently is H or C 1 -C 6  alkyl; 
     R 7  is -Q 2 -T 2 , in which Q 2  is a bond, C(O)NR e , or NR e C(O), R e  being H or C 1 -C 6  alkyl and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q 3 -T 3 , wherein each Q 3  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 3  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR f , C(O)R f , C(O)OR f , OC(O)R f , S(O) 2 R f , NR f R g , OC(O)NR f R g , NR f C(O)OR g , C(O)NR f R g , and NR f C(O)R g , each of R f  and R g  independently being H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy; or -Q 3 -T 3  is oxo; 
     R 8  is H or C 1 -C 6  alkyl; 
     R 9  is -Q 4 -T 4 , in which Q 4  is a bond or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxyl, and T 4  is H, halo, OR h , R h R i , NR h C(O)R i , C(O)NR h R i , C(O)R h , C(O)OR h NR h C(O)OR i , OC(O)NR h R i , S(O) 2 R h , S(O) 2 NR h R i , or R S2 , in which each of R h  and R i  independently is H or C 1 -C 6  alkyl, and R S2  is C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2  is optionally substituted with one or more -Q 5 -T 5 , wherein each Q 5  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 5  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR j , C(O)R j , C(O)OR j , OC(O)R j , S(O) 2 R j , NR j R k , OC(O)NR j R k , NR j C(O)OR k , C(O)NR j R k , and NR j C(O)R k , each of R j  and R k  independently being H or C 1 -C 6  alkyl; or -Q 5 -T 5  is oxo; 
     R 10  is halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k ; 
     R 11  and R 12  together with the carbon atom to which they are attached form a C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl; 
     R 13  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 12  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; 
     R 14  is H, halo, cyano, P(O)R l R m , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 12  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or —OR 6 , wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl is optionally substituted with one or more of halo or OR 6 , and each of R l  and R m  independently is C 1 -C 6  alkyl; and 
     R 15  is H, halo, cyano, or —OR 6 . 
     Subsets of the compounds of Formulae (I0)-(IV0) include those of Formulae (I)-(III): 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer,
 
wherein
 
     X 1  is N or CR 2 ; 
     X 2  is N or CR 3 ; 
     X 3  is N or CR 4 ; 
     X 4  is N or CR 5 ; 
     X 5  is N or CH; 
     X 6  is N or CR 15 ; 
     X 7  is N or CH; 
     one of X 13  and X 14  independently is NR 8 R 9 , and the other is R 10 ; 
     B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R 15 ; 
     R 1  is H or C 1 -C 4  alkyl; 
     each of R 2 , R 3 , R 4 , and R 5 , independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkoxyl, C 6 -C 10  aryl, OH, NR a R b , C(O)NR a R b , NR a C(O)R b , C(O)OR a , OC(O)R a , OC(O)NR a R b , NR a C(O)OR b , C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, wherein the C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkoxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, are each optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a  and R b  independently is H or C 1 -C 6  alkyl; 
     R 6  is -Q 1 -T 1 , in which Q 1  is a bond, or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 -C 6  alkoxyl, and T 1  is H, halo, cyano, or R S1 , in which R S1  is C 3 -C 8  cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1  is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, —C(O)R c , —C(O)OR c , —SO 2 R c , —SO 2 N(R c ) 2 , —NR c C(O)R d , —C(O)NR c R d , —NR c C(O)OR d , —OC(O)NR c R d , NR c R d , or C 1 -C 6  alkoxyl, in which each of R c  and R d  independently is H or C 1 -C 6  alkyl; 
     R 7  is -Q 2 -T 2 , in which Q 2  is a bond, C(O)NR e , or NR e C(O), R e  being H or C 1 -C 6  alkyl and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q 3 -T 3 , wherein each Q 3  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 3  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR f , C(O)R f , C(O)OR f , OC(O)R f , S(O) 2 R f , NR f R g , OC(O)NR f R g , NR f C(O)OR g , C(O)NR f R g , and NR f C(O)R g , each of R f  and R g  independently being H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy; or -Q 3 -T 3  is oxo; 
     R 8  is H or C 1 -C 6  alkyl; 
     R 9  is -Q 4 -T 4 , in which Q 4  is a bond or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxyl, and T 4  is H, halo, OR h , R h R i , NR h C(O)R i , C(O)NR h R i , C(O)R h , C(O)OR h NR h C(O)OR i , OC(O)NR h R i , S(O) 2 R h , S(O) 2 NR h R i , or R S2 , in which each of R h  and R i  independently is H or C 1 -C 6  alkyl, and R S2  is C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2  is optionally substituted with one or more -Q 5 -T 5 , wherein each Q 5  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 5  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR j , C(O)R j , C(O)OR j , OC(O)R j , S(O) 2 R j , NR j R k , OC(O)NR j R k , NR j C(O)OR k , C(O)NR j R k , and NR j C(O)R k , each of R j  and R k  independently being H or C 1 -C 6  alkyl; or -Q 5 -T 5  is oxo; 
     R 10  is halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k ; 
     R 11  and R 12  together with the carbon atom to which they are attached form a C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl; and 
     R 15  is H, halo, cyano, or —OR 6 . 
     Subsets of the compounds of Formula (I0) include those of Formulae (I0a)-(I0l): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers. 
     Subsets of the compounds of Formula (I0) include those of Formulae (I0a′)-(I0i′): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers. 
     Subsets of the compounds of Formula (I) include those of Formulae (Ia)-(Il): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (I) include those of Formulae (Ia′)-(Ii′): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (II0) include those of Formulae (II0a) and (II0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (III0) include those of Formulae (III0a) and (III0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (IV0) include those of Formulae (IV0a) and (IV0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (II) include those, wherein (i) each of X 5 , X 6  and X 7  is CH; (ii) at least one of X 5 , X 6  and X 7  is N; or (iii) at most one of X 5 , X 6  and X 7  is N, and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     Subsets of the compounds of Formula (III) include those, wherein (i) each of X 5  and X 6  is CH; (ii) each of X 5  and X 6  is N; or (iii) one of X 5  and X 6  is CH and the other is CH, and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, one or more of the compounds disclosed herein are selective inhibitors of EHMT2. In some embodiments, one or more of the compounds disclosed herein inhibit EHMT2 with an enzyme inhibition IC 50  value of about 1 μM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, or about 50 nM or less. 
     In some embodiments, one or more of the compounds disclosed herein inhibit a kinase with an enzyme inhibition IC 50  value of about 100 nM or greater, 1 μM or greater, 10 μM or greater, 100 μM or greater, or 1000 μM or greater. 
     In some embodiments, one or more of the compounds disclosed herein inhibit a kinase with an enzyme inhibition IC 50  value of about 1 mM or greater. 
     In some embodiments, one or more of the compounds disclosed herein inhibit a kinase with an enzyme inhibition IC 50  value of 1 μM or greater, 2 μM or greater, 5 μM or greater, or 10 μM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src. 
     Also provided herein are pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more compounds of any of the Formulae disclosed herein, such as Formulae (I0)-(IV0) and Formulae (I)-(III) described herein. 
     Another aspect of this disclosure is a method of preventing or treating an EHMT-mediated disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of any of the Formulae disclosed herein, such as Formulae (I0)-(IV0) and Formulae (I)-(III), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. The EHMT-mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EHMT1 or EHMT2 or both. In one embodiment, the EHMT-mediated disorder is a blood disease or disorder. In certain embodiments, the EHMT-mediated disorder is selected from proliferative disorders (e.g., cancers such as leukemia, hepatocellular carcinoma, prostate carcinoma, and lung cancer), addiction (e.g., cocaine addiction), and mental retardation. 
     Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EHMT-mediated disorders. For example, the disclosure also provides methods of identifying an inhibitor of EHMT1 or EHMT2 or both. 
     For example, the EHMT-mediated disease or disorder comprises a disorder that is associated with gene silencing by EHMT1 or EHMT2, e.g., blood diseases or disorders associated with gene silencing by EHMT2. 
     For example, the method comprises the step of administering to a subject having a disease or disorder associated with gene silencing by EHMT1 or EHMT2 a therapeutically effective amount of one or more compounds of the Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT1 or EHMT2, thereby treating the disease or disorder. 
     For example, the blood disease or disorder is selected from the group consisting of sickle cell anemia and beta-thalassemia. 
     For example, the blood disease or disorder is hematological cancer. 
     For example, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL). 
     For example, the method further comprises the steps of performing an assay to detect the degree of histone methylation by EHMT1 or EHMT2 in a sample comprising blood cells from a subject in need thereof. 
     In one embodiment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups. 
     In one embodiment, the labeled methyl groups are isotopically labeled methyl groups. 
     In one embodiment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises contacting the histone substrate with an antibody that binds specifically to dimethylated H3-K9. 
     Still another aspect of the disclosure is a method of inhibiting conversion of H3-K9 to dimethylated H3-K9. The method comprises the step of contacting a mutant EHMT, the wild-type EHMT, or both, with a histone substrate comprising H3-K9 and an effective amount of a compound of the present disclosure, wherein the compound inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated H3-K9. 
     Further, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes. 
     In some aspects, the present disclosure provides a compound disclosed herein for use in preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2. 
     In some aspects, the present disclosure provides a compound disclosed herein for use in preventing or treating a cancer via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2. 
     In some aspects, the present disclosure provides use of a compound disclosed herein in manufacture of a medicament for preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2. 
     In some aspects, the present disclosure provides use of a compound disclosed herein in manufacture of a medicament for preventing or treating a cancer via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2. 
     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 disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. 
     Other features and advantages of the disclosure will be apparent from the following detailed description and claims. 
    
    
     DETAILED DESCRIPTION 
     The present disclosure provides novel amine-substituted heterocyclic compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds. 
     In one aspect, the compounds disclosed herein may be used to treat a blood disorder, e.g., sickle-cell anemia (i.e., sickle-cell disease). Non-limiting examples of sickle-cell anemia forms that may be treated using the contemplated compounds include hemoglobin SS disease, hemoglobin SC disease, hemoglobin Sβ 0  thalassemia disease, hemoglobin Sβ +  thalassemia disease, hemoglobin SD disease, and hemoglobin SE disease. 
     Without wishing to be bound by any theory, it is believed that sickle-cell anemia describes a group of inherited red blood cell disorders in which at least some of the red blood cells of a subject having sickle-cell anemia contain hemoglobin S (“HbS”). Hemoglobin S is a mutated, abnormal form of adult hemoglobin. Without wishing to be bound by any theory, it is believed that the contemplated compounds may treat sickle cell anemia by inducing fetal hemoglobin (“HbF”) expression. See, e.g., Renneville et al.,  Blood  126(16): 1930-1939, 2015, the content of which is incorporated herein by reference in its entirety. 
     In some embodiments, one or more complications of sickle-cell anemia may be treated or prevented using the contemplated compounds disclosed herein. Non-limiting examples of complications that may be treated or prevented using the contemplated compounds include anemia (e.g., severe anemia), hand-foot syndrome, splenic sequestration, delayed developmental growth, eye disorders (e.g., vision loss caused by, e.g., blockages in blood vessels supplying the eyes), skin ulcers (e.g., leg ulcers), heart disease, chest syndrome (e.g., acute chest syndrome), priapism, and pain. 
     The present disclosure provides compounds of any of Formulae (I0)-(IV0) below: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer,
 
wherein
 
     X 1  is N or CR 2 ; 
     X 2  is N or CR 3 ; 
     X 3  is N or CR 4 ; 
     X 4  is N or CR 5 ; 
     X 5  is N or CH; 
     X 6  is N or CR 15 ; 
     X 7  is N or CH; 
     X 8  is NR 13  or CR 11 R 12 ; 
     one of X 13  and X 14  independently is NR 8 R 9 , and the other is R 10 ; 
     B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R 15 ; 
     R 1  is H or C 1 -C 4  alkyl; 
     each of R 2 , R 3 , R 4 , and R 5 , independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkoxyl, C 6 -C 10  aryl, OH, NR a R b , C(O)NR a R b , NR a C(O)R b , C(O)OR a , OC(O)R a , OC(O)NR a R b , NR a C(O)OR b , C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, wherein the C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6  alkoxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, are each optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a  and R b  independently is H or C 1 -C 6  alkyl; 
     R 6  is -Q 1 -T 1 , in which Q 1  is a bond, or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 -C 6  alkoxyl, and T 1  is H, halo, cyano, or R S1 , in which R S1  is C 3 -C 8  cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1  is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, —C(O)R c , —C(O)OR c , —SO 2 R c , —SO 2 N(R c ) 2 , —NR c C(O)R d —C(O)NR c R d , —NR c C(O)OR d , —OC(O)NR c R d , NR c R d , or C 1 -C 6  alkoxyl, in which each of R c  and R d  independently is H or C 1 -C 6  alkyl; 
     R 7  is -Q 2 -T 2 , in which Q 2  is a bond, C(O)NR e , or NR e C(O), R e  being H or C 1 -C 6  alkyl and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q 3 -T 3 , wherein each Q 3  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 3  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR f , C(O)R f , C(O)OR f , OC(O)R f , S(O) 2 R f , NR f R g , OC(O)NR f R g , NR f C(O)OR g , C(O)NR f R g , and NR f C(O)R g , each of R f  and R g  independently being H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy; or -Q 3 -T 3  is oxo; 
     R 8  is H or C 1 -C 6  alkyl; 
     R 9  is -Q 4 -T 4 , in which Q 4  is a bond or C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxyl, and T 4  is H, halo, OR h , NR h R i , NR h C(O)R i , C(O)NR h R i , C(O)R h , C(O)OR h , NR h C(O)OR i , OC(O)NR h R i , S(O) 2 R h , S(O) 2 NR h R i , or R S2 , in which each of R h  and R i  independently is H or C 1 -C 6  alkyl, and R S2  is C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2  is optionally substituted with one or more -Q 5 -T 5 , wherein each Q 5  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 5  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR j , C(O)R j , C(O)OR i , OC(O)R j , S(O) 2 R j , NR j R k , OC(O)NR j R k , NR j C(O)OR k , C(O)NR j R k , and NR j C(O)R k , each of R j  and R k  independently being H or C 1 -C 6  alkyl; or -Q 5 -T 5  is oxo; 
     R 10  is halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k ; R 11  and R 12  together with the carbon atom to which they are attached form a C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3 -C 12  cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl; 
     R 13  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 12  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; and 
     R 14  is H, halo, cyano, P(O)R l R m , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 12  cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or —OR 6 , wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl is optionally substituted with one or more of halo or OR 6 , and each of R l  and R m  independently is C 1 -C 6  alkyl; and 
     R 15  is H, halo, cyano, or —OR 6 . 
     The present disclosure also provides compounds of any of Formulae (I)-(III) below: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     The compounds of the Formulae disclosed herein, such as Formulae (I0)-(IV0) and Formulae (I)-(III) may include one or more of the following features when applicable. 
     In some embodiments, the compound is of Formula (III0), in which X 8  is NR 13    
     In some embodiments, R 13  is H, C 1 -C 6  alkyl, C 3 -C 12  cycloalkyl (e.g., C 3 -C 8  cycloalkyl), or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.) 
     In some embodiments, R 13  is C 2 -C 6  alkenyl or C 2 -C 6  alkynyl. 
     In some embodiments, the compound is of Formula (III0), in which X 8  is CR 11 R 12    
     In some embodiments, the compound is of Formula (I0), (II0), or (IV0), in which R 14  is H, halo, or C 1 -C 6  alkyl. 
     In some embodiments, the compound is of Formula (I0), (II0), or (IV0), in which R 14  is C 2 -C 6  alkenyl or C 2 -C 6  alkynyl. 
     In some embodiments, the compound is of Formula (I0), (II0), or (IV0), in which R 14  is —OR 6 . 
     In some embodiments, R 14  is H. 
     In some embodiments, R 14  is halo (e.g., F, Cl, Br, or I). In some embodiments, R 14  is F. 
     In some embodiments, R 14  is Cl. In some embodiments, R 14  is Br. In some embodiments, R 14  is I. 
     In some embodiments, R 14  is cyano. 
     In some embodiments, R 14  is P(O)R l R m , wherein each of R l  and R m  independently is C 1 -C 6  alkyl (e.g., each of R l  and R m  is CH3). 
     In some embodiments, R 14  is C 1 -C 6  alkyl optionally substituted with one or more of halo or OR 6 . In some embodiments, R 14  is C 1 -C 6  alkyl (e.g., CH 3 ). In some embodiments, R 14  is C 1 -C 6  alkyl substituted with one or more halo (e.g., CF 3 ). In some embodiments, R 14  is C 1 -C 6  alkyl substituted with one or more OR 6 . In some embodiments, R 14  is C 1 -C 6  alkyl substituted with one or more OCH 3 . 
     In some embodiments, R 14  is C 3 -C 12  cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). 
     In some embodiments, R 14  is 4- to 7-membered heterocycloalkyl (e.g., oxetanyl, or tetrahydrofuranyl). 
     In some embodiments, R 14  is 5- to 6-membered heteroaryl (e.g., isoxazolyl). 
     In some embodiments, R 14  is —OR 6  (e.g., OCH 3 ). 
     In some embodiments, R 15  is H. 
     In some embodiments, R 15  is halo (e.g., F, Cl, Br, or I). In some embodiments, R 15  is F. 
     In some embodiments, R 15  is Cl. In some embodiments, R 15  is Br. In some embodiments, R 15  is I. 
     In some embodiments, R 15  is cyano. 
     In some embodiments, R 15  is —OR 6  (e.g., OCH 3 ). 
     In some embodiments, the compound is of Formula (I0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, at least one of X 1 , X 2 , X 3  and X 4  is N. 
     In some embodiments, X 1  and X 3  are N. In some embodiments, X 2  is CR 3  and X 4  is CR 5 . 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, ring B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl. 
     In some embodiments, ring B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl substituted with one or more R 15 . 
     In some embodiments, ring B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl substituted with one R 15 . 
     In some embodiments, ring B is C 6 -C 10  aryl or 5- to 10-membered heteroaryl substituted with two or more R 15 . 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compounds of Formula (I0) include those of any of Formulae (I0a)-(I0l): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers. 
     In some embodiments, the compounds of Formula (I0) include those of any of Formulae (I0a′)-(I0i′): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers. 
     In some embodiments, R 1  is C 1 -C 4  alkyl. In some embodiments, R 1  is methyl. In some embodiments, R 1  is H. 
     In some embodiments, R 3  is C 1 -C 6  alkyl. In some embodiments, R 3  is methyl. In some embodiments, R 3  is H. 
     In some embodiments, R 5  is C 1 -C 6  alkyl. In some embodiments, R 5  is methyl. 
     In some embodiments, R 8  is C 1 -C 6  alkyl. In some embodiments, R 8  is methyl. In some embodiments, R 8  is H. 
     In some embodiments, R 9  is -Q 4 -T 4 , in which Q 4  is C 1 -C 6  alkylene, and T 4  is H. In some time, R 9  is methyl. 
     In some embodiments, R 7  is -Q 2 -T 2 , in which Q 2  is a bond or C(O)NR e , and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q3-T 3 . 
     In some embodiments, R 7  is -Q 2 -T 2 , in which Q 2  is a bond, and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, R 7  is -Q 2 -T 2 , in which Q 2  is a bond, and T 2  is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is selected from 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, each of which is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is selected from 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, each of which is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, each Q 3  independently is a C 1 -C 3  alkylene linker, and each T 3  independently is selected from the group consisting of OR f , C(O)R f , C(O)OR f , OC(O)R f , S(O) 2 R f , NR f R g , OC(O)NR f R g , NR f C(O)OR g , C(O)NR f R g , and NR f C(O)R g , each of R f  and R g  independently being H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy. 
     In some embodiments, each Q 3  independently is a C 1 -C 3  alkylene linker, and each T 3  independently is NR f R g , each of R f  and R g  independently being H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy. 
     In some embodiments, each Q 3  independently is a C 1 -C 3  alkylene linker, and each T 3  independently is NR f R g , each of R f  and R g  independently being H or C 1 -C 6  alkyl. 
     In some embodiments, each Q 3  independently is a C 1 -C 3  alkylene linker, and each T 3  independently is NR f R g , each of R f  and R g  independently being H or methyl. 
     In some embodiments, each Q 3  independently is a C 1 -C 3  alkylene linker, and each T 3  independently is NHCH 3 . 
     In some embodiments, each Q 3  independently is methylene, and each T 3  independently is NHCH 3 . 
     In some embodiments, R 7  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 14  is H, halo, or —OR 6 . 
     In some embodiments, R 14  is halo or —OR 6 . 
     In some embodiments, R 14  is H. 
     In some embodiments, R 14  is halo. In some embodiments, R 14  is F. In some embodiments, R 14  is Cl. In some embodiments, R 14  is Br. In some embodiments, R 14  is I. 
     In some embodiments, R 14  is —OR 6 . In some embodiments, R 6  is -Q 1 -T 1 , in which Q 1  is a C 1 -C 6  alkylene linker, and T 1  is H. In some embodiments, R 6  is -Q 1 -T 1 , in which Q 1  is methylene, and T 1  is H. In some embodiments, R 14  is —OCH 3 . 
     In some embodiments, R 15  is H or halo. 
     In some embodiments, R 15  is H. 
     In some embodiments, R 15  is halo. In some embodiments, R 15  is F. In some embodiments, R 15  is Cl. In some embodiments, R 15  is Br. In some embodiments, R 15  is I. 
     In some embodiments, R 14  is halo or —OR 6 , and R 15  is H or halo. 
     In some embodiments, R 14  is halo, and R 15  is H. In some embodiments, R 14  is F, and R 15  is H. In some embodiments, R 14  is Cl, and R 15  is H. In some embodiments, R 14  is Br, and R 15  is H. In some embodiments, R 14  is I, and R 15  is H. 
     In some embodiments, R 14  is —OR 6 , and R 15  is H. In some embodiments, R 14  is —OCH 3 , and R 15  is H. 
     In some embodiments, R 14  is halo, and R 15  is halo. In some embodiments, R 14  is F, and R 15  is F. In some embodiments, R 14  is Cl, and R 15  is F. In some embodiments, R 14  is Br, and R 15  is F. In some embodiments, R 14  is I, and R 15  is F. In some embodiments, R 14  is F, and R 15  is Cl. 
     In some embodiments, R 14  is Cl, and R 15  is Cl. In some embodiments, R 14  is Br, and R 15  is Cl. In some embodiments, R 14  is I, and R 15  is Cl. In some embodiments, R 14  is F, and R 15  is Br. In some embodiments, R 14  is Cl, and R 15  is Br. In some embodiments, R 14  is Br, and R 15  is Br. In some embodiments, R 14  is I, and R 15  is Br. In some embodiments, R 14  is F, and R 15  is I. In some embodiments, R 14  is Cl, and R 15  is I. In some embodiments, R 14  is Br, and R 15  is I. In some embodiments, R 14  is I, and R 15  is I. 
     In some embodiments, R 14  is —OR 6 , and R 15  is halo. In some embodiments, R 14  is —OCH 3 , and R 15  is halo. In some embodiments, R 14  is —OCH 3 , and R 15  is F. In some embodiments, R 14  is —OCH 3 , and R 15  is Cl. In some embodiments, R 14  is —OCH 3 , and R 15  is Br. In some embodiments, R 14  is —OCH 3 , and R 15  is I. 
     In some embodiments, the compound is of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl). 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl) optionally substituted with one or more R 15 . 
     In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl) optionally substituted with one R 15 . 
     In some embodiments, 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compounds of Formula (I) include those of any of Formulae (Ia)-(Il): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, the compounds of Formula (I) include those of any of Formulae 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, the compound is of Formula (II0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, the compounds of Formula (II0) include those of any of Formulae (II0a) and (II0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, the compound is of Formula (II) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, the compound is of Formula (II) include those of any of Formulae (IIa) and (IIb): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, the compound is of Formula (III0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, the compounds of Formula (III0) include those of any of Formulae (III0a) and (III0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, the compound is of Formula (III) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, the compound is of Formula (IV0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. 
     In some embodiments, the compounds of Formula (IV0) include those of Formulae (IV0a) and (IV0b): 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers. 
     In some embodiments, at most one of R 3  and R 5  is not H. 
     In some embodiments, at least one of R 3  and R 5  is not H. 
     In some embodiments, R 3  is H or halo. 
     In some embodiments, at most one of R 4  and R 5  is not H. 
     In some embodiments, at least one of R 4  and R 5  is not H. 
     In some embodiments, R 4  is H, C 1 -C 6  alkyl, or halo. 
     In some embodiments, at most one of R 2  and R 5  is not H. 
     In some embodiments, at least one of R 2  and R 5  is not H. 
     In some embodiments, R 2  is H, C 1 -C 6  alkyl, or halo. 
     In some embodiments, R 5  is C 1 -C 6  alkyl optionally substituted with one or more of halo, hydroxyl, or C 1 -C 6  alkoxyl. In some embodiments, R 5  is unsubstituted C 1 -C 6  alkyl (e.g., methyl or ethyl). 
     In some embodiments, each of X 5 , X 6  and X 7  is CH. 
     In some embodiments, at least one of X 5 , X 6  and X 7  is N. 
     In some embodiments, at most one of X 5 , X 6  and X 7  is N. 
     In some embodiments, R 10  is optionally substituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.). In some embodiments, R 10  is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k . 
     In some embodiments, R 10  is connected to the bicyclic group of Formula (II) via a carbon-carbon bond. In some embodiments, R 10  is connected to the bicyclic group of Formula (II) via a carbon-nitrogen bond. 
     In some embodiments, R 10  is halo. 
     In some embodiments, R 10  is optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, e.g., optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k . 
     In some embodiments, R 10  is C 3 -C 8  cycloalkyl optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di-alkylamino, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C(O)NR j R k , or NR j C(O)R k . 
     In some embodiments, R 10  is C 3 -C 8  cycloalkyl optionally substituted with C(O)NR j R k  or NR j C(O)R k . 
     In some embodiments, R 11  and R 12  together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.), wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6  alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl. 
     In some embodiments, R 11  and R 12  together with the carbon atom to which they are attached form an unsubstituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.). 
     In some embodiments, R 11  and R 12  together with the carbon atom to which they are attached form a C 4 -C 8  cycloalkyl which is optionally substituted with one or more of halo, C 1 -C 6  alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl. 
     In some embodiments, R 11  and R 12  together with the carbon atom to which they are attached form an unsubstituted C 4 -C 8  cycloalkyl. 
     In some embodiments, each of X 5  and X 6  is CH. 
     In some embodiments, each of X 5  and X 6  is N. 
     In some embodiments, one of X 5  and X 6  is CH and the other is CH. 
     In some embodiments, R 6  is -Q 1 -T 1 , in which Q 1  is a bond or C 1 -C 6  alkylene linker optionally substituted with one or more of halo, and T 1  is H, halo, cyano, or R S1 , in which R S1  is C 3 -C 8  cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1  is optionally substituted with one or more of halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, NR c R d , or C 1 -C 6  alkoxyl. 
     In some embodiments, R 6  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxyl. 
     In some embodiments, R 6  is unsubstituted C 1 -C 6  alkyl (e.g., methyl). 
     In some embodiments, R 7  is -Q 2 -T 2 , in which Q 2  is a bond or C(O)NR e , and T 2  is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q3-T 3 . 
     In some embodiments, Q 2  is a bond. 
     In some embodiments, Q 2  is CONH or NHCO. 
     In some embodiments, T 2  is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic heterocycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like), which is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is 8- to 12-membered bicyclic heterocycloalkyl that comprises a 5- or 6-membered aryl or heteroaryl ring fused with a non-aromatic ring. In some embodiments, the 5- or 6-membered aryl or heteroaryl ring is connected to Q 2 . 
     In some embodiments, T 2  is 5- to 10-membered heteroaryl. 
     In some embodiments, T 2  is selected from 
     
       
         
         
             
             
         
       
     
     and tautomers thereof, each of which is optionally substituted with one or more -Q 3 -T 3 , wherein X 8  is NH, O, or S, each of X 9 , X 10 , X 11 , and X 12  is independently CH or N, and at least one of X 9 , X 10 , X 11 , and X 12  is N, and ring A is a C 5 -C 8  cycloalkyl, phenyl, 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S. 
     In some embodiments, T 2  is selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, each of which is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, T 2  is selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and tautomers thereof, each of which is optionally substituted with one or more -Q 3 -T 3 . 
     In some embodiments, each Q 3  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy. 
     In some embodiments, each T 3  independently is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 4- to 7-membered heterocycloalkyl, OR f , C(O)R f , C(O)OR f , NR f R g , C(O)NR f R g , and NR f C(O)R g , in which the C 3 -C 8  cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy. 
     In some embodiments, -Q 3 -T 3  is oxo. 
     In some embodiments, each T 3  independently is NR f R g , C(O)NR f R g , or NR f C(O)R g . In some embodiments, each of R f  and R g  is H. In some embodiments, each of R f  and R g  independently is H, C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl. In some embodiments, one of R f  and R g  is H and the other is C 1 -C 6  alkyl optionally substituted with C 3 -C 8  cycloalkyl. In some embodiments, one of R f  and R g  is H and the other is C 3 -C 8  cycloalkyl. In some embodiments, one of R f  and R g  is C 1 -C 6  alkyl and the other is C 3 -C 8  cycloalkyl. 
     In some embodiments, at least one of R 8  and R 9  is H. 
     In some embodiments, each of R 8  and R 9  is H. 
     In some embodiments, R 8  is H. 
     In some embodiments, R 9  is -Q 4 -T 4 , in which Q 4  is a bond or C 1 -C 6  alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxyl, and T 4  is H, halo, OR h  NR h R i , NR h C(O)R i , C(O)NR h R i , C(O)R h , C(O)OR h , or R S2 , in which R S2  is C 3 -C 8  cycloalkyl or 4- to 7-membered heterocycloalkyl, and R S2  is optionally substituted with one or more -Q 5 -T 5 . 
     In some embodiments, each Q 5  independently is a bond or C 1 -C 3  alkylene linker. 
     In some embodiments, each T 5  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, OR j , C(O)R j , C(O)OR j , NR j R k , C(O)NR j R k , and NR j C(O)R k . 
     In some embodiments, R 9  is C 1 -C 3  alkyl. 
     For a compound of any one of formulae (I0)-(IV0), (I)-(III), (I0a)-(I0l), (I0a′)-(I0i′), (Ia)-(Il), (Ia′)-(Ii′), (II0a)-(II0b), (III0a)-(III0b), and (IV0a)-(IV0b), X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , and R m  can each be, where applicable, selected from any of the groups described herein, and any group described herein for any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , and R m  can be combined, where applicable, with any group described herein for one or more of the remainder of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , and R m . 
     In some embodiments, the compound is selected from those in Table 1, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers. 
     In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) inhibit a kinase with an enzyme inhibition IC 50  value of about 100 nM or greater, 1 μM or greater, 10 μM or greater, 100 μM or greater, or 1000 μM or greater. 
     In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) inhibit a kinase with an enzyme inhibition IC 50  value of about 1 mM or greater. 
     In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) inhibit a kinase with an enzyme inhibition IC 50  value of 1 μM or greater, 2 μM or greater, 5 μM or greater, or 10 μM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src. 
     The present disclosure provides a pharmaceutical composition comprising a compound of any one of the Formulae described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     The present disclosure provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any of Formulae (I0)-(IV0) and Formulae (I)-(III). 
     The present disclosure provides a method of preventing or treating cancer (e.g., via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any of Formulae (I0)-(IV0) and Formulae (I)-(III). 
     In some embodiments, the blood disorder is sickle cell anemia or β-thalassemia. 
     In some embodiments, the blood disorder is a hematological cancer. 
     In some embodiments, the cancer is lymphoma, leukemia, melanoma, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate carcinoma, lung cancer, brain cancer, or hematological cancer. 
     In some embodiments, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL). 
     In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) are selective inhibitors of EHMT2. 
     Representative compounds of the present disclosure include compounds listed in Table 1 or tautomers and salts thereof. 
     
       
         
           
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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     As used herein, “alkyl”, “C 1 , C 2 , C 3 , C 4 , C 5  or C 6  alkyl” or “C 1 -C 6  alkyl” is intended to include C 1 , C 2 , C 3 , C 4 , C 5  or C 6  straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5  or C 6  branched saturated aliphatic hydrocarbon groups. In some embodiments, C 1 -C 6  alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5  and C 6  alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl. 
     In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C 1 -C 6  for straight chain, C 3 -C 6  for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. 
     As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C 3 -C 12 , C 3 -C 10 , or C 3 -C 8 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. The term “heterocycloalkyl” refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl, 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-yl, 3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole). 
     The term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 
     As used herein, “alkyl linker” or “alkylene linker” is intended to include C 1 , C 2 , C 3 , C 4 , C 5  or C 6  straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C 3 , C 4 , C 5  or C 6  branched saturated aliphatic hydrocarbon groups. In some embodiments, C 1 -C 6  alkylene linker is intended to include C 1 , C 2 , C 3 , C 4 , C 5  and C 6  alkylene linker groups. Examples of alkylene linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (—CH 2 —), ethyl (—CH 2 CH 2 —), n-propyl (—CH 2 CH 2 CH 2 —), i-propyl (—CHCH 3 CH 2 —), n-butyl (—CH 2 CH 2 CH 2 CH 2 —), s-butyl (—CHCH 3 CH 2 CH 2 —), i-butyl (—C(CH 3 ) 2 CH 2 —), n-pentyl (—CH 2 CH 2 CH 2 CH 2 CH 2 —), s-pentyl (—CHCH 3 CH 2 CH 2 CH 2 —) or n-hexyl (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —). 
     “Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. In some embodiments, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. 
     In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6  for straight chain, C 3 -C 6  for branched chain). The term “C 2 -C 6 ” includes alkenyl groups containing two to six carbon atoms. The term “C 3 -C 6 ” includes alkenyl groups containing three to six carbon atoms. 
     The term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 
     “Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. In some embodiments, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6  for straight chain, C 3 -C 6  for branched chain). The term “C 2 -C 6 ” includes alkynyl groups containing two to six carbon atoms. The term “C 3 -C 6 ” includes alkynyl groups containing three to six carbon atoms. As used herein, “C 2 -C 6  alkenylene linker” or “C 2 -C 6  alkynylene linker” is intended to include C 2 , C 3 , C 4 , C 5  or C 6  chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. In some embodiments, C 2 -C 6  alkenylene linker is intended to include C 2 , C 3 , C 4 , C 5  and C 6  alkenylene linker groups. 
     The term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 
     Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. In some embodiments, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. 
     “Aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. Examples include phenyl, naphthalenyl, etc. 
     “Heteroaryl” groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.” As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p , where p=1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. 
     Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. 
     Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. 
     The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). 
     As used herein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. In some embodiments, a C 3 -C 14  carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included. 
     As used herein, “heterocycle” or “heterocyclic group” includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycle includes heterocycloalkyl and heteroaryl. 
     Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran. 
     Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxole-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. 
     The term “substituted,” as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom&#39;s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., ═O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 
     The term “optionally substituted,” as used herein, means not being substituted (e.g., none of the one or more hydrogen atoms on the designated variable is replaced with any other group) or being substituted (e.g., any one or more hydrogen atoms on the designated variable is replaced with a selection from the indicated groups, provided that the designated atom&#39;s normal valency is not exceeded, and that the substitution results in a stable compound). 
     When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. 
     When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, in some embodiments, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. 
     The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O − . 
     As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. The term “perhalogenated” generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. 
     The term “carbonyl” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. 
     The term “carboxyl” refers to —COOH or its C 1 -C 6  alkyl ester. 
     “Acyl” includes moieties that contain the acyl radical (R—C(O)—) or a carbonyl group. “Substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 
     “Aroyl” includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. 
     “Alkoxyalkyl,” “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms. 
     The term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy. 
     The term “ether” or “alkoxy” includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. In some embodiments, the term includes “alkoxyalkyl,” which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group. 
     The term “ester” includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. 
     The term “thioalkyl” includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. 
     The term “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. 
     The term “thioether” includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group; and alkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. 
     As used herein, “amine” or “amino” refers to —NH 2 . “Alkylamino” includes groups of compounds wherein the nitrogen of —NH 2  is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includes groups wherein the nitrogen of —NH 2  is bound to two alkyl groups. 
     Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. “Arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. “Aminoaryl” and “aminoaryloxy” refer to aryl and aryloxy substituted with amino. “Alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. “Acylamino” includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. 
     The term “amide” or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes “alkaminocarboxy” groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes “arylaminocarboxy” groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”, “alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted. 
     Compounds of the present disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N→O or N + —O − ). Furthermore, in other instances, the nitrogens in the compounds of the present disclosure can be converted to N-hydroxy or N-alkoxy compounds. In some embodiments, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R is substituted or unsubstituted C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives. 
     In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. In addition, a crystal polymorphism may be present for the compounds represented by the formula. 
     It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure. 
     “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” 
     A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” 
     “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. 
     Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al.,  Angew. Chem. Inter. Edit.  1966, 5, 385; errata 511; Cahn et al.,  Angew. Chem.  1966, 78, 413; Cahn and Ingold,  J. Chem. Soc.  1951 (London), 612; Cahn et al.,  Experientia  1956, 12, 81; Cahn,  J. Chem. Educ.  1964, 41, 116). 
     “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. 
     It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. 
     Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. 
     “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. 
     Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. 
     Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. 
     Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. Examples of lactam-lactim tautomerism are as shown below. 
     
       
         
         
             
             
         
       
     
     It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. 
     The term “crystal polymorphs”, “polymorphs” or “crystal forms” means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions. 
     The compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also include those salts containing quaternary nitrogen atoms. 
     Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. 
     “Solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. 
     Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. 
     As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. 
     As defined herein, the term “derivative” refers to compounds that have a common core structure, and are substituted with various groups as described herein. In some embodiments, all of the compounds represented by Formula (II) are substituted bi-heterocyclic compounds, and have Formula (II) as a common core. 
     The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. 
     Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie,  Chem. Rev.  96, 3147-3176, 1996. 
     The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14. 
     As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. 
     The present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. 
     Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. 
     The synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. 
     Compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J.,  March&#39;s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,  5 th  edition, John Wiley &amp; Sons: New York, 2001; Greene, T. W., Wuts, P. G. M.,  Protective Groups in Organic Synthesis,  3 rd  edition, John Wiley &amp; Sons: New York, 1999; R. Larock,  Comprehensive Organic Transformations , VCH Publishers (1989); L. Fieser and M. Fieser,  Fieser and Fieser&#39;s Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed.,  Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. 
     Compounds of the present disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this disclosure having any of the Formulae described herein may be prepared according to the procedures illustrated in Schemes 1-4 below, from commercially available starting materials or starting materials which can be prepared using literature procedures. Certain variables (such as R 6  and R 7 ) in Schemes 1-4 are as defined in any Formula described herein, unless otherwise specified. 
     One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. 
     One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M.,  Protective Groups in Organic Synthesis,  3 rd  edition, John Wiley &amp; Sons: New York, 1999. 
     Preferred protecting groups include, but are not limited to: 
     For a hydroxyl moiety: TBS, benzyl, THP, Ac 
     For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester 
     For amines: Cbz, BOC, DMB 
     For diols: Ac (×2) TBS (×2), or when taken together acetonides 
     For thiols: Ac 
     For benzimidazoles: SEM, benzyl, PMB, DMB 
     For aldehydes: di-alkyl acetals such as dimethoxy acetal or diethyl acetyl. 
     In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is understood to mean all possible stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that the reactions can be optimized to give one isomer preferentially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC may be used to separate the isomers. 
     The following abbreviations are used throughout the specification and are defined below: 
     ACN acetonitrile 
     Ac acetyl 
     AcOH acetic acid 
     AlCl 3  aluminum chloride 
     BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) 
     t-BuOK potassium t-butoxide 
     tBuONa or t-BuONa sodium t-butoxide 
     br broad 
     BOC tert-butoxy carbonyl 
     Cbz benzyloxy carbonyl 
     CDCl 3 CHCl 3  chloroform 
     CH 2 Cl 2  dichloromethane 
     CH 3 CN acetonitrile 
     CsCO 3  cesium carbonate 
     CH 3 NO 3  nitromethane 
     d doublet 
     dd doublet of doublets 
     dq doublet of quartets 
     DCE 1,2 dichloroethane 
     DCM dichloromethane 
     Δ heat 
     δ chemical shift 
     DIEA N,N-diisopropylethylamine (Hunig&#39;s base) 
     DMB 2,4 dimethoxy benzyl 
     DMF N,N-Dimethylformamide 
     DMSO Dimethyl sulfoxide 
     DMSO-d6 deuterated dimethyl sulfoxide 
     EA or EtOAc Ethyl acetate 
     ES electrospray 
     Et 3 N triethylamine 
     equiv equivalents 
     g grams 
     h hours 
     H 2 O water 
     HCl hydrogen chloride or hydrochloric acid 
     HPLC High performance liquid chromatography 
     Hz Hertz 
     IPA isopropyl alcohol 
     i-PrOH isopropyl alcohol 
     J NMR coupling constant 
     K 2 CO 3  potassium carbonate 
     HI potassium iodide 
     KCN potassium cyanide 
     LCMS or LC-MS Liquid chromatography mass spectrum 
     M molar 
     m multiplet 
     mg milligram 
     MHz megahertz 
     mL milliliter 
     mm millimeter 
     mmol millimole 
     mol mole 
     [M+1] molecular ion plus one mass unit 
     m/z mass/charge ratio 
     m-CPBA meta-chloroperbenzoic acid 
     MeCN Acetonitrile 
     MeOH methanol 
     Mel Methyl iodide 
     min minutes 
     μm micron 
     MsCl Mesyl chloride 
     MW microwave irradiation 
     N normal 
     Na 2 SO 4  sodium sulfate 
     NH 3  ammonia 
     NaBH(AcO) 3  sodium triacetoxyborohydride 
     NaI sodium iodide 
     Na 2 SO 4  sodium sulfate 
     NH 4 Cl ammonium chloride 
     NH 4 HCO 3  ammonium bicarbonate 
     nm nanometer 
     NMP N-methylpyrrolidinone 
     NMR Nuclear Magnetic Resonance 
     Pd(OAc) 2  palladium (II) acetate 
     Pd/C Palladium on carbon 
     Pd 2 (dba) 3  Tris(dibenzylideneacetone)dipalladium(0) 
     PMB para methoxybenzyl 
     ppm parts per million 
     POCl 3  phosphoryl chloride 
     prep-HPLC preparative High Performance Liquid Chromatography 
     PTSA para-toluenesulfonic acid 
     p-TsOH para-toluenesulfonic acid 
     RT retention time 
     rt room temperature 
     s singlet 
     t triplet 
     t-BuXPhos 2-Di-tert-butylphosphino-2′, 4′, 6′-triisopropylbiphenyl 
     TEA Triethylamine 
     TFA trifluoroacetic acid 
     TfO triflate 
     THP tetrahydropyran 
     TsOH tosic acid 
     UV ultraviolet 
     
       
         
         
             
             
         
       
     
     Scheme 1 shows the synthesis of N2-(4-methoxy-3-(1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine C1 following a general route. An aryl iodide such as N2-(3-iodo-4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine A1 or a like reagent is heated in an organic solvent (e.g., DMSO) with a copper salt (e.g., CuI) and a nitrogen-containing heterocycle (e.g., disubstituted pyrazole B1). The resulting substituted aryl or heteroaryl analog C1 can be used in further elaboration such as alkylation and salt formation. 
     
       
         
         
             
             
         
       
     
     Scheme 2 shows the synthesis of N2-(4-methoxy-3-(1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine C2 following an alternate general route. An aryl iodide such as N2-(3-iodo-4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine A2 or a like reagent is combined in an organic solvent (e.g., DMSO) with a copper salt (e.g., CuI), a mild base (e.g., K 3 PO 4 ), a diamine ligand (e.g., (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine B2-b) and a nitrogen-containing heterocycle (e.g., disubstituted pyrazole B2-a). The resulting substituted aryl or heteroaryl analog C2 can be used in further elaboration such as alkylation and salt formation. 
     
       
         
         
             
             
         
       
     
     Scheme 3 shows the synthesis of N2-(4-substituted-phenyl)-N4,6-dimethylpyrimidine-2,4-diamine C3 following a general route. An aryl halide such as N2-(3-iodo-4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine A3 or a like reagent is combined in a mixture of an organic solvent (e.g., dioxane) and water with a palladium (II) compound (e.g., Pd(dppf)Cl 2 ), a mild base (e.g., K 2 CO 3 ), and an aryl or heteroaryl boronate (e.g., B3) to yield a substituted aryl or heteroaryl analog C3. 
     
       
         
         
             
             
         
       
     
     Scheme 4 depicts the synthesis of 2-(2-methoxy-5-nitrophenyl)-2H-pyrazolo compound C4 following a general route (X can be CH 2  or NH or O). An aryl hydrazide such as (2-methoxy-5-nitrophenyl)hydrazine A4 or a like reagent is combined in an organic solvent (e.g., methanol) with an enamineodiketone (e.g., B4) in the presence of an acid (e.g., acetic acid) to yield a substituted aryl or heteroaryl intermediate C4 via a cyclocondensation reaction. 
     A person of ordinary skill in the art will recognize that in the above schemes the order of many of the steps are interchangeable. 
     Compounds of the present disclosure inhibit the histone methyltransferase activity of G9a, also known as KMT1C (lysine methyltransferase 1C) or EHMT2 (euchromatic histone methyltransferase 2), or a mutant thereof and, accordingly, in one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders in which EHMT2 plays a role. The present disclosure provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof. 
     Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. 
     In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need thereof. In some embodiments, the method comprises the step of administering to a subject having a cancer expressing a mutant EHMT2 a therapeutically effective amount of a compound described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT2, thereby treating the cancer. 
     In some embodiments, the EHMT2-mediated cancer is selected from the group consisting of leukemia, prostate carcinoma, hepatocellular carcinoma, and lung cancer. 
     In some embodiments, the compounds disclosed herein can be used for treating cancer. In some embodiments, the cancer is a hematological cancer. 
     In some embodiments, the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer. Preferably, a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lymphoma, myeloma, and/or sarcoma. Exemplary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancer includes ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Alternatively, cancers to be treated by the compounds of the disclosure are non NHL cancers. 
     In some embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Preferably, the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), medulloblastoma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epithelioid sarcoma, renal medullary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma. 
     In some embodiments, the cancer is lymphoma, leukemia or melanoma. In some embodiments, the cancer is lymphoma selected from the group consisting of follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and Burkitt&#39;s lymphoma, and Non-Hodgkin&#39;s Lymphoma. Preferably, the lymphoma is non-Hodgkin&#39;s lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma. Alternatively, the leukemia is chronic myelogenous leukemia (CMIL), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia. 
     In some embodiments, the EHMT2-mediated disorder is a hematological disorder. 
     The compound(s) of the present disclosure inhibit the histone methyltransferase activity of EHMT2 or a mutant thereof and, accordingly, the present disclosure also provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. In one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present disclosure. 
     As used herein, a “subject” is interchangeable with a “subject in need thereof”, both of which refer to a subject having a disorder in which EHMT2-mediated protein methylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a precancerous condition. A subject in need thereof can have refractory or resistant cancer (i.e., cancer that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission on most recent therapy. In some embodiments, the subject in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In a preferred embodiment, the subject has cancer or a cancerous condition. In some embodiments, the cancer is leukemia, prostate carcinoma, hepatocellular carcinoma, and lung cancer. 
     As used herein, “candidate compound” refers to a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher or clinician. A candidate compound is a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof. The biological or medical response can be the treatment of cancer. The biological or medical response can be treatment or prevention of a cell proliferative disorder. The biological response or effect can also include a change in cell proliferation or growth that occurs in vitro or in an animal model, as well as other biological changes that are observable in vitro. In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. 
     In some embodiments, an in vitro biological assay that can be used includes the steps of (1) mixing a histone substrate (e.g., an isolated histone sample or an isolated histone peptide representative of human histone H3 residues 1-15) with recombinant EHMT2 enzymes; (2) adding a compound of the disclosure to this mixture; (3) adding non-radioactive and  3 H-labeled S-Adenosyl methionine (SAM) to start the reaction; (4) adding excessive amount of non-radioactive SAM to stop the reaction; (4) washing off the free non-incorporated  3 H-SAM; and (5) detecting the quantity of  3 H-labeled histone substrate by any methods known in the art (e.g., by a PerkinElmer TopCount platereader). 
     In some embodiments, an in vitro study that can be used includes the steps of (1) treating cancer cells (e.g., breast cancer cells) with a compound of this disclosure; (2) incubating the cells for a set period of time; (3) fixing the cells; (4) treating the cells with primary antibodies that bind to dimethylated histone substrates; (5) treating the cells with a secondary antibody (e.g. an antibody conjugated to an infrared dye); (6) detecting the quantity of bound antibody by any methods known in the art (e.g., by a Licor Odyssey Infrared Scanner). 
     As used herein, “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. 
     A compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. 
     One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al.,  Current Protocols in Molecular Biology , John Wiley and Sons, Inc. (2005); Sambrook et al.,  Molecular Cloning, A Laboratory Manual  (3 rd  edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al.,  Current Protocols in Immunology , John Wiley &amp; Sons, N.Y.; Enna et al.,  Current Protocols in Pharmacology , John Wiley &amp; Sons, N.Y.; Fingl et al.,  The Pharmacological Basis of Therapeutics  (1975),  Remington&#39;s Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa., 18 th  edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. 
     As used herein, “combination therapy” or “co-therapy” includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. 
     The present disclosure also provides pharmaceutical compositions comprising a compound of any of the Formulae described herein in combination with at least one pharmaceutically acceptable excipient or carrier. 
     A “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. 
     As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
     “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. 
     A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. 
     A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. In some embodiments, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. 
     The term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject&#39;s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder. 
     For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50  (the dose therapeutically effective in 50% of the population) and LD 50  (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD 50 /ED 50 . Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. 
     Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. 
     The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. 
     Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 
     Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. 
     For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. 
     Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. 
     Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. 
     The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. 
     It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. 
     In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient&#39;s weight in kg, body surface area in m 2 , and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. In some embodiments, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. 
     The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. 
     The compounds of the present disclosure are capable of further forming salts. All of these forms are also contemplated within the scope of the claimed disclosure. 
     As used herein, “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. In some embodiments, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. 
     Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. 
     It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. 
     The compounds of the present disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. In some embodiments, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester. 
     The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration. 
     The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. 
     Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in  Remington: the Science and Practice of Pharmacy,  19 th  edition, Mack Publishing Co., Easton, Pa. (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. 
     All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. 
     In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. 
     Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. In some embodiments, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. 
     Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. 
     Various In vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. 
     All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. 
     Example 1: Synthesis of Compound 1 
     Synthesis of 2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 3-iodo-4-methoxyaniline 
     Into a 250-mL round-bottom flask was placed 2-iodo-1-methoxy-4-nitrobenzene (6 g, 21.50 mmol, 1.00 equiv), Fe (3.61 g, 3.00 equiv), NH 4 Cl (3.42 g, 63.94 mmol, 3.00 equiv), ethanol (50 mL), and water (10 mL). The resulting solution was stirred for 1 h at 85° C. The solids were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 5.35 g (100%) of the title compound as a brown solid. 
     LC-MS: (ES, m/z): RT=0.847 min, LCMS 53: m/z=250 [M+1]. 
     Step 2: Synthesis of 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 250-mL round-bottom flask was placed 3-iodo-4-methoxyaniline (5.25 g, 21.08 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (3.31 g, 21.00 mmol, 1.00 equiv), trifluoroacetic acid (4.81 g, 42.55 mmol, 2.00 equiv), and iso-propanol (80 mL). The resulting solution was stirred for 3 h at 85° C. The solids were collected by filtration. This resulted in 7.2 g (92%) of the title compound as a solid. 
     LC-MS: (ES, m/z): RT=1.041 min, LCMS 15: m/z=371 [M+1].  1 H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.14 (d, J=2.6 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 6.02 (s, 1H), 3.81 (s, 3H), 2.90 (d, J=4.6 Hz, 3H), 2.24 (s, 3H). 
     Step 3: Synthesis of tert-butyl 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 
     Into a 25-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (2.8 g, 7.56 mmol, 1.00 equiv), CuI (580 mg, 3.04 mmol, 0.40 equiv), K 3 PO 4  (4.88 g, 22.98 mmol, 3.00 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (300 mg, 2.10 mmol, 0.20 equiv), tert-butyl 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g, 8.96 mmol, 1.10 equiv), and DMSO (10 mL). The resulting solution was stirred for 36 h at 140° C. in an oil bath. The crude product was purified by C18 column: ACN:H 2 O (0.05% TFA)=1/5. This resulted in 1.4 g (40%) of the title compound as a yellow solid. 
     LC-MS: (ES, m/z): RT=1.552 min, LCMS 33: m/z=466 [M+1]. 
     Step 4: Synthesis of 2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask was placed tert-butyl 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.5 g, 1.07 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), and dichloromethane (5 mL). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and ACN (23.0% ACN up to 34.0% in 10 min); detector, UV 254/220 nm. This resulted in 55.9 mg (7%) of the title compound as a light yellow solid. 
     Example 2: Synthesis of Compound 2 
     Synthesis of 2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 100-mL round-bottom flask was placed 2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (500 mg, 1.37 mmol, 1.00 equiv), methanol (6 mL), and formaldehyde (82 mg, 2.56 mmol, 1.00 equiv) and stirred for 30 min at 25° C. Then NaBH 3 CN (345 mg, 5.49 mmol, 4.00 equiv), HOAc (0.02 mL) was added. The resulting solution was stirred for 2 h at 25° C. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, Water (10 mmol/L NH 4 HCO 3 ) and ACN (23.0% ACN up to 34.0% in 10 min); detector, UV 254/220 nm. This resulted in 16.3 mg (2%) of the title compound as a white solid. 
     Example 3: Synthesis of Compound 4 
     Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 5-(pyrrolidin-1-ylmethyl)-1H-pyrazole 
     Into a 250-mL round-bottom flask was placed 1H-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol, 1.00 equiv), methanol (20 mL), NaBH 3 CN (656 mg, 10.44 mmol, 2.01 equiv), and pyrrolidine (370 mg, 5.20 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 25° C. The residue was applied onto a silica gel column with H 2 O:CH 3 CN (89/11). This resulted in 350 mg (44%) the title compound as a yellow oil. 
     LC-MS: (ES, m/z): RT=0.15 min, LCMS 32, m/z=152.1 [M+1]. 
     Step 2: Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid 
     Into a 30-mL round-bottom flask was placed 5-(pyrrolidin-1-ylmethyl)-1H-pyrazole (190 mg, 1.26 mmol, 1.00 equiv), DMSO (4 mL), 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (230 mg, 0.62 mmol, 0.49 equiv), 1-N,2-N-dimethylcyclohexane-1,2-diamine (73 mg, 0.51 mmol, 0.41 equiv), CuI (47 mg, 0.25 mmol, 0.20 equiv), and K 3 PO 4  (400 mg, 1.88 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 120° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 18.2 mg (3%) of the title compound as a white solid. 
     LC-MS: (ES, m/z): RT=1.06 min, LCMS 28, m/z=394.2 [M+1].  1 H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J=2.5 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.74-7.65 (m, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 5.99 (d, J=1.1 Hz, 1H), 4.48 (s, 2H), 3.93 (d, J=5.7 Hz, 3H), 3.65 (s, 2H), 3.30 (d, J=7.4 Hz, 2H), 3.02 (s, 3H), 2.34-2.29 (m, 3H), 2.21-2.11 (m, 2H), 2.10-1.99 (m, 2H). 
     Step 3: Synthesis of 5-(pyrrolidin-1-ylmethyl)-1H-pyrazole 
     Into a 250-mL round-bottom flask was placed 1H-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol, 1.00 equiv), methanol (20 mL), NaBH 3 CN (656 mg, 10.44 mmol, 2.01 equiv), and pyrrolidine (370 mg, 5.20 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 25° C. The residue was applied onto a silica gel column with H 2 O:CH 3 CN (89/11). This resulted in 350 mg (44%) of 5-(pyrrolidin-1-ylmethyl)-1H-pyrazole as a yellow oil. 
     LC-MS: (ES, m/z): RT=0.15 min, LCMS 32, m/z=152.1[M+1]. 
     Step 4: Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid 
     Into a 30-mL round-bottom flask was placed 5-(pyrrolidin-1-ylmethyl)-1H-pyrazole (190 mg, 1.26 mmol, 1.00 equiv), DMSO (4 mL), 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (230 mg, 0.62 mmol, 0.49 equiv), 1-N,2-N-dimethylcyclohexane-1,2-diamine (73 mg, 0.51 mmol, 0.41 equiv), CuI (47 mg, 0.25 mmol, 0.20 equiv), and K 3 PO 4  (400 mg, 1.88 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 120° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 18.2 mg (3%) of the title compound as a white solid. 
     Example 4: Synthesis of Compound 5 
     Synthesis of 2-N-[4-methoxy-3-[4-(pyrrolidin-1-ylmethyl)-1H-pyrazol-1-yl]phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 4-(pyrrolidin-1-ylmethyl)-1H-pyrazole 
     Into a 250-mL round-bottom flask was placed 1H-pyrazole-3-carbaldehyde (1 g, 10.41 mmol, 1.00 equiv), Ti(OiPr) 4  (10 g), ethanol (20 mL), pyrrolidine (740 mg, 10.40 mmol, 1.00 equiv), and NaBH 3  (792 mg). The resulting solution was stirred for 2 h at 25° C. The residue was applied onto a silica gel column with H 2 O:CH 3 CN (83/17). This resulted in 570 mg (36%) of the title compound as a white solid. 
     LC-MS: (ES, m/z): RT=0.395 min, LCMS 31, m/z=152.2 [M+1]. 
     Step 2: Synthesis of 2-N-[4-methoxy-3-[4-(pyrrolidin-1-ylmethyl)-1H-pyrazol-1-yl]phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid 
     Into a 30-mL round-bottom flask was placed 4-(pyrrolidin-1-ylmethyl)-1H-pyrazole (80 mg, 0.53 mmol, 1.00 equiv), DMSO (5 mL), K 3 PO 4  (171 mg, 0.81 mmol, 1.52 equiv), CuI (21 mg, 0.11 mmol, 0.21 equiv), and 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 0.51 equiv). The resulting solution was stirred for 16 h at 140° C. 
     The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 26.6 mg (10%) of the title compound as a light yellow solid. 
     Example 5: Synthesis of Compound 8 
     Synthesis of 2-N-(4-methoxy-3-[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine 
     Into a 250-mL round-bottom flask was placed [1,2,4]triazolo[1,5-a]pyrazin-2-amine (5 g, 37.00 mmol, 1.00 equiv), NaNO 2  (2 g, 28.99 mmol, 0.78 equiv), CuBr (1.8 g), AcOH (40 mL), and water (15 mL), HBr (25 mL). The resulting solution was stirred for 10 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.5 g (20%) of the title compound as a white solid. 
     LC-MS: (ES, m/z): RT=1.189 min, LCMS 07: m/z=199 [M+1]. 
     Step 1: Synthesis of (2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)boronic acid 
     Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (2 g, 5.40 mmol, 1.00 equiv), B 2 pin 2  (5 g), KOAc (3 g, 30.57 mmol, 5.66 equiv), Pd(dppf)Cl 2  (600 mg, 0.82 mmol, 0.15 equiv), and dioxane (200 mL). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.2 g (77%) of the title compound as a yellow solid. 
     LC-MS: (ES, m/z): RT=0.981 min, LCMS 07: m/z=289 [M+1]. 
     Step 2: Synthesis of 2-N-(4-methoxy-3-[[1,2,4]triazolo[1,5-a]pyrazin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 125-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)boronic acid (500 mg, 1.74 mmol, 1.00 equiv), 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine (350 mg, 1.76 mmol, 1.01 equiv), Pd(PPh 3 ) 4  (100 mg, 0.09 mmol, 0.05 equiv), K 2 CO 3  (800 mg, 2.46 mmol, 1.41 equiv), dioxane (8 mL), and water (1.5 mL). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 600 mg (95%) of the title compound as a white solid. 
     LC-MS: (ES, m/z): RT=1.003 min, LCMS 07: m/z=363 [M+1]. 
     Step 3: Synthesis of 2-N-(4-methoxy-3-[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazine-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 125-mL round-bottom flask was placed 2-N-(4-methoxy-3-[[1,2,4]triazolo[1,5-a]pyrazin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.83 mmol, 1.00 equiv), PtO 2  (20 mg), methanol (10 mL), and hydrogen. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 280 mg (92%) of the title compound as a yellow solid. 
     LC-MS: (ES, m/z): RT=2.985 min, LCMS 07: m/z=367 [M+1]. 
     Step 4: Synthesis of 2-N-(4-methoxy-3-[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     Into a 25-mL round-bottom flask was placed 2-N-(4-methoxy-3-[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), and hydrogen chloride (2 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (mL) was purified by Flash-Prep-HPLC; mobile phase, water (0.05% HCl) and ACN (5% ACN up to 15% in 7 min), detector, 254/220 nm. This resulted in 40.1 mg (97%) of the title compound as a white solid. 
     Example 6: Synthesis of Compound 10 
     Synthesis of 2-N-(4-methoxy-3-[5-methyl-octahydro-1H-pyrazolidino[4,3-c]pyridin-2-yl]cyclohexyl)-4-N,6-dimethyl-1,3-diazinane-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-(4-methoxy-3-[5-methyl-octahydro-1H-pyrazolidino[4,3-c]pyridin-2-yl]cyclohexyl)-4-N,6-dimethyl-1,3-diazinane-2,4-diamine 
     Into a 25-mL round-bottom flask was placed 2-N-(4-methoxy-3-[2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), HCHO (16 mg, 2.00 equiv), methanol (2 mL), NaBH 3 CN (69 mg, 1.10 mmol, 4.00 equiv), and acetic acid (0.002 mL). The resulting solution was stirred for 30 min at 25° C. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-prep-HPLC; mobile phase, H 2 O/ACN=38%, detector, UV 254 nm. This resulted in 10 mg (7%) of the title compound as a white solid. 
     Example 7: Synthesis of Compound 12 
     Synthesis of: 2-N-[4-methoxy-3-(1H-pyrazol-4-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-[4-methoxy-3-(1H-pyrazol-4-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 100-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (500 mg, 1.35 mmol, 1.00 equiv), 1,4-dioxane (15 mL), water (5 mL), Cs 2 CO 3  (1321.6 mg, 4.06 mmol, 3.00 equiv), Pd(pph 3 ) 4  (156.2 mg, 0.14 mmol, 0.10 equiv), and 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (393 mg, 2.03 mmol, 1.50 equiv). The resulting solution was stirred for 6 h at 80° C. The resulting solution was diluted with 50 mL of water, and the resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers was washed with 3×50 mL of brine and concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and ACN (10.0% ACN up to 60.0% in 5 min); detector, UV 254/220 nm. This resulted in 36.9 mg (8.8%) of the title compound as a white solid. 
     Example 8: Synthesis of Compound 14 
     Synthesis of 2-N-[3-(4-cyclopropyl-1H-pyrazol-1-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-[3-(4-cyclopropyl-1H-pyrazol-1-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), 4-cyclopropyl-1H-pyrazole hydrochloride (140 mg, 0.97 mmol, 1.20 equiv), (1R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol, 0.6 equiv), potassium carbonate (335 mg, 2.42 mmol, 3.00 equiv), DMSO (8 mL), and CuI (123 mg, 0.65 mmol, 0.80 equiv). The resulting solution was stirred for 4 h at 140° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and ACN (20.0% ACN up to 45.0% in 7 min), detector, UV 254 nm. This resulted in 38.9 mg (14%) of the title compound as a white solid. 
     Example 9: Synthesis of Compound 15 
     Synthesis of 2-N-[4-methoxy-3-(1H-pyrazol-1-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-[4-methoxy-3-(1H-pyrazol-1-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 100-mL round-bottom flask was placed DMSO (20 mL), 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), 1H-pyrazole (165 mg, 2.42 mmol, 2.99 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (92 mg, 0.65 mmol, 0.80 equiv), CuI (62 mg, 0.33 mmol, 0.40 equiv), and K 3 PO 4  (516 mg, 2.43 mmol, 3.00 equiv). The flask was purged and maintained with N2. The resulting solution was stirred for 12 h at 120° C., then concentrated under vacuum. The crude product (102 mg) was purified by prep-HPLC; mobile phase, Water (0.05% TFA) and ACN (3.0% ACN up to 18.0% in 8 min), detector, UV 254/220 nm. This resulted in 53.3 mg (15%) of the title compound as a gray solid. 
     Example 10: Synthesis of Compound 22 
     Synthesis of 2-N-(4-methoxy-3-[2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl 2-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate 
     Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (1 g, 2.70 mmol, 1.00 equiv), CuI (15 mg, 0.08 mmol, 0.10 equiv), DMSO (10 mL), K 3 PO 4  (2.51 g, 8.12 mmol, 3.00 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (110 mg, 0.54 mmol, 0.20 equiv), and tert-butyl 2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate (1.2 g, 5.37 mmol, 2.00 equiv). The resulting solution was stirred for 4 days at 140° C. in an oil bath. The solids were filtered out. The residue was applied onto a silica gel column with H 2 O (0.05% TFA):ACN (2:1). This resulted in 200 mg (15%) of the title compound as a white solid. 
     LC-MS: (ES, m/z): RT=1.142 min; LCMS 33: m/z=466 [M+1].  1 H-NMR: δ8.55 (d, J=2.7 Hz, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 6.06 (d, J=1.2 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.56 (t, J=6.3 Hz, 2H), 3.13-2.97 (m, 5H), 2.48-2.26 (m, 3H), 1.52 (s, 9H). 
     Step 2: Synthesis of 2-N-(4-methoxy-3-[2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     Into a 50-mL round-bottom flask was placed tert-butyl 2-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate (200 mg, 0.43 mmol, 1.00 equiv), trifluoroacetic acid (147 mg, 1.30 mmol, 3.00 equiv), and dichloromethane (10 mL). The resulting solution was stirred for 14 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H 2 O (0.05% TFA):ACN (1:1). This resulted in 9.3 mg (5%) of the title compound as a light yellow solid. 
     Example 11: Synthesis of Compound 23 
     Synthesis of 2-N-[3-[4-(aminomethyl)-1H-pyrazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl N-[[1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazol-4-yl]methyl]carbamate 
     Into a 30-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), DMSO (4 mL), CuI (21 mg, 0.11 mmol, 0.41 equiv), K 3 PO 4  (172 mg, 0.81 mmol, 3.00 equiv), tert-butyl N-(1H-pyrazol-4-ylmethyl)carbamate (212 mg, 1.07 mmol, 3.98 equiv), and 1-N,2-N-dimethylcyclohexane-1,2-diamine (31 mg, 0.22 mmol, 0.81 equiv). The resulting solution was stirred for 12 h at 120° C. The crude product was purified by flash-prep-HPLC; mobile phase, H 2 O/CH 3 CN=1/1; Detector, UV 254 nm. This resulted in 80 mg (67%) of the title compound as white solid. 
     LC-MS: (ES, m/z): RT=1.096 min, LCMS 28, m/z=440.2 [M+1]. 
     Step 2: Synthesis of 2-N-[3-[4-(aminomethyl)-1H-pyrazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask was placed tert-butyl N-[[1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazol-4-yl]methyl]carbamate (80 mg, 0.18 mmol, 1.00 equiv), dichloromethane (3 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h at 25° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 52.4 mg of the title compound as a white solid. 
     Example 12: Synthesis of Compound 26 
     Synthesis of 2-N-[4-methoxy-3-(4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl 2-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)hydrazine-1-carboxylate 
     Into a 100-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (2 g, 5.40 mmol, 1.00 equiv), DMSO (20 mL), 3rd-brettphos (388 mg), (tert-butoxy)carbohydrazide (566 mg, 4.28 mmol, 0.79 equiv), cesium carbonate (4.2 g, 12.85 mmol, 2.38 equiv). The resulting solution was stirred for 12 h at 80° C. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5×100 mL of water and 1×100 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g (74%) of the title compound as a brown solid. 
     LC-MS: (ES, m/z): RT=0.699 min, LCMS 30, m/z=375.1[M+1]. 
     Step 2: Synthesis of (2E)-2-[(dimethylamino)methylidene]cyclohexan-1-one 
     Into a 30-mL round-bottom flask was placed cyclohexanone (1 g, 10.19 mmol, 1.00 equiv). DMFDMA (1.3 g, 56.46 mmol, 5.54 equiv). The resulting solution was stirred for 12 h at 80° C. The crude product was purified by Flash-Prep-HPLC; mobile phase, dichloromethane/CH 3 OH=60/40; Detector, UV 254 nm. This resulted in 150 mg (10%) of the title compound as a yellow oil. 
     LC-MS: (ES, m/z): RT=4.90 min, GCMS04, m/z=153 [M]. 
     Step 3: Synthesis of 2-N-(3-hydrazinyl-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 100-mL round-bottom flask was placed N-2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)(tert-butoxy)carbohydrazide (600 mg, 1.60 mmol, 1.00 equiv), dichloromethane (5 mL), and trifluoroacetic acid (3 mL). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (68%) of the title compound as a black solid. 
     LC-MS: (ES, m/z): RT=0.500 min, LCMS 45, m/z=275.2[M+1]. 
     Step 4: Synthesis of 2-N-[4-methoxy-3-(4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask was placed 2-N-(3-hydrazinyl-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (180 mg, 0.66 mmol, 1.00 equiv), (2E)-2-[(dimethylamino)methylidene]cyclohexan-1-one (100 mg, 0.65 mmol, 0.99 equiv), and hydrogen chloride (0.1 mL). The resulting solution was stirred for 1 h at 70° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 22.5 mg (7%) of the title compound as a light yellow solid. 
     Example 13: Synthesis of Compound 27 
     Synthesis of 5-fluoro-2-N-(4-methoxy-3-[2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Synthesis of 2,4-dichloro-5-fluoro-6-methylpyrimidine 
     Into a 250-mL 3-necked round-bottom flask was placed bromo(methyl) magnesium (6 mL, 1.50 equiv), oxolane (10 mL), 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol, 1.00 equiv), ethylene glycol dimethyl ether (10 mL), TEA (2 mL), and diiodane (3 g, 11.82 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 15° C. The resulting solution was allowed to react, with stirring, for an additional 1 min while the temperature was maintained at −5° C. in an ice/salt bath. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 700 mg (32%) of the title compound as a yellow oil. 
     LC-MS: (ES, m/z): RT=0.84 min, LCMS 15: m/z=181 [M+1]. 
     Synthesis of 2-chloro-5-fluoro-N,6-dimethylpyrimidin-4-amine 
     Into a 50-mL round-bottom flask was placed 2,4-dichloro-5-fluoro-6-methylpyrimidine (700 mg, 3.87 mmol, 1.00 equiv), CH 3 NH 2 .THF (5 mL), TEA (1.2 g, 11.86 mmol, 3.00 equiv), tetrahydrofuran (10 mL). The resulting solution was stirred for 2 h at 20° C. The resulting mixture was concentrated under vacuum. The crude product (700 mg) was purified by flash-prep-HPLC; mobile phase, CH 3 CN/H 2 O=30%/70% increasing to CH 3 CN/H 2 O=40%/60% within 10 min; detector, UV 254 nm. This resulted in 400 mg (59%) of the title compound as an off-white solid. 
     LC-MS: (ES, m/z): RT=1.01 min, LCMS 15: m/z=176.03 [M+1].  1 H NMR (400 MHz, Methanol-d4) δ 2.97 (s, 3H), 2.27 (d, J=3.0 Hz, 3H). 
     Synthesis of tert-butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate (for use in Step 2) 
     Into a 20-mL round-bottom flask was placed tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.02 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), DMF-DMA (598 mg, 1.10 equiv). The resulting solution was stirred for 6 h at 80° C. in an oil bath. The crude product (1 g) was purified by flash-prep-HPLC; mobile phase, CH 3 CN/H 2 O (NH 4 HCO 3 )=30%/70% increasing to CH 3 CN/H 2 O(NH 4 HCO 3 )=40%/60% within 10 min, detector, UV 254 nm. This resulted in 800 mg (63%) of the title compound as a yellow oil. 
     LC-MS: (ES, m/z): RT=0.95 min, LCMS 34: m/z=255 [M+1]. 
     Step 1: Synthesis of (2-methoxy-5-nitrophenyl)hydrazine 
     Into a 250-mL 3-necked round-bottom flask was placed 2-methoxy-5-nitroaniline (2 g, 11.89 mmol, 1.00 equiv), and hydrogen chloride (16 mL). To this solution was added NaNO 2  (904 mg, 13.10 mmol, 1.10 equiv) at −10° C., and the resulting mixture was stirred for 1 h. To this solution was added SnCl 2 .2 H 2 O (5.45 g, 24.15 mmol, 2.20 equiv) dissolved in HCl. The resulting solution was stirred for 30 min at −25° C. The solids were collected by filtration. The solids of the solution were dissolved in potassium hydroxide (25%). This resulted in 1.3 g (60%) of the title compound as a red solid. 
     LC-MS: (ES, m/z): RT=0.34 min, LCMS 45: m/z=184.07 [M+1].  1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=2.9 Hz, 1H), 7.55 (dd, J=8.8, 2.9 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.65 (s, 1H), 4.17 (s, 2H), 3.90 (s, 3H). 
     Step 2: Synthesis of tert-butyl 1-(2-methoxy-5-nitrophenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 
     Into a 50-mL round-bottom flask was placed (2-methoxy-5-nitrophenyl)hydrazine (200 mg, 1.09 mmol, 1.00 equiv), HOAc (197 mg, 3.28 mmol, 3.00 equiv), tert-butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate (278 mg, 1.09 mmol, 1.00 equiv), and methanol (10 mL). The resulting solution was stirred for 3 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of H 2 O. The resulting solution was extracted with 3×20 mL of chloromethane and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (20% B). This resulted in 240 mg (59%) of the title compound as a yellow solid. 
     LC-MS: (ES, m/z): RT=1.43 min, LCMS 31: m/z=375.16 [M+1]. 
     Step 3: Synthesis of tert-butyl 1-(5-amino-2-methoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 
     Into a 50-mL round-bottom flask was placed tert-butyl 1-(2-methoxy-5-nitrophenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.53 mmol, 1.00 equiv), methanol (20 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 130 mg (71%) of as yellow oil. 
     LC-MS: (ES, m/z): RT=1.00 min, LCMS 33: m/z=345.16 [M+1]. 
     Step 4: Synthesis of 5-fluoro-2-N-(4-methoxy-3-[2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask was placed tert-butyl 2-(5-amino-2-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (110 mg, 0.32 mmol, 1.00 equiv), trifluoroacetic acid (180.7 mg, 1.60 mmol, 5.00 equiv), IPA (5 mL), and 2-chloro-5-fluoro-N,6-dimethylpyrimidin-4-amine (56 mg, 0.32 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (110 mg) was purified by flash-prep-HPLC; mobile phase, H 2 O (TFA):CH 3 CN increasing to H 2 O (TFA):CH 3 CN=20% within 20 min, detector, UV 254 nm. This resulted in 18.3 mg (12%) of the title compound as a light yellow solid. 
     Example 14: Synthesis of Compound 28 
     Synthesis of 5-fluoro-2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl 1-(5-amino-2-methoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 
     Into a 50-mL round-bottom flask was placed tert-butyl 1-(2-methoxy-5-nitrophenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.53 mmol, 1.00 equiv), methanol (20 mL), Raney-Ni, and hydrogen. The resulting solution was stirred for 1 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 130 mg (71%) of tert-butyl 1-(5-amino-2-methoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate as a yellow oil. 
     LC-MS: (ES, m/z): RT=0.99 min, LCMS 15: m/z=345.19 [M+1]. 
     Step 2: Synthesis of 5-fluoro-2-N-(4-methoxy-3-[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask was placed tert-butyl 1-(5-amino-2-methoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), IPA (10 mL), 2-chloro-5-fluoro-N,6-dimethylpyrimidin-4-amine (50.9 mg, 0.29 mmol, 1.00 equiv), trifluoroacetic acid (98.5 mg, 0.87 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (0.05% TFA) and ACN (5.0% ACN up to 73.0% in 7 min), detector, UV 254/220 nm. This resulted in 78.6 mg (54%) of the title compound as a light yellow solid. 
     Example 15: Synthesis of Compound 33 
     Synthesis of 2-N-[3-(1H-indol-4-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-[3-(1H-indol-4-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 30-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), dioxane (10 mL), water (3 mL), potassium carbonate (336 mg, 2.43 mmol, 3.00 equiv), Pd(dppf)Cl2CH2Cl2 (66 mg), and 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (295 mg, 1.21 mmol, 1.50 equiv). The resulting solution was stirred for 3 h at 80° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% HCl, Mobile Phase B: ACN. This resulted in 44.1 mg (14%) of the title compound as a solid. 
     Example 16: Synthesis of Compound 35 
     Synthesis of 2-N-(4-methoxy-3-[1H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-(4-methoxy-3-[1H-pyrazolo[4,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 30-mL round-bottom flask was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), DMSO (4 mL), CuI (61 mg, 0.32 mmol, 0.40 equiv), K 3 PO 4  (516 mg, 2.43 mmol, 3.00 equiv), 1H-pyrazolo[4,3-c]pyridine (385 mg, 3.23 mmol, 3.99 equiv), and 1-N,2-N-dimethylcyclohexane-1,2-diamine (92 mg, 0.65 mmol, 0.80 equiv). The resulting solution was stirred for 12 h at 120° C. The crude product was purified by prep-HPLC; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN. This resulted in 102.7 mg (27%) of the title compound as a white solid. 
     Example 17: Synthesis of Compound 36 
     Synthesis of 2-N-(4-methoxy-3-[1H-pyrrolo[2,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-(4-methoxy-3-[1H-pyrrolo[2,3-c]pyridin-1-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 1H-pyrrolo[2,3-c]pyridine (289 mg, 2.45 mmol, 3.02 equiv), CuI (61.6 mg, 0.32 mmol, 0.40 equiv), K 3 PO 4  (516 mg, 2.43 mmol, 3.00 equiv), DMSO (5 mL), 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (92.1 mg, 0.65 mmol, 0.80 equiv). The resulting solution was stirred for 1 overnight at 100° C. The crude product was purified by Prep-HPLC; mobile phase, Water (10 mmol/L NH 4 HCO 3 ) and ACN (25.0% ACN up to 31.0% in 12 min), detector, UV 254/220 nm. This resulted in 114.5 mg (39%) of the title compound as a white solid. 
     Example 18: Synthesis of Compound 37 
     Synthesis of 2-N-[3-(1H-indazol-4-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     Synthesis of 2-N-[3-(1H-indazol-4-yl)-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.54 mmol, 1.00 equiv), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (224 mg, 0.92 mmol, 1.70 equiv), potassium carbonate (224 mg, 1.62 mmol, 3.00 equiv), dioxane (10 mL), water (2 mL), and Pd(dppf)Cl 2 CH 2 Cl 2  (49 mg, 0.07 mmol, 0.10 equiv). The resulting solution was stirred for 1 overnight at 80° C. in an oil bath, then concentrated under vacuum. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of water and 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; detector, 254 nm. This resulted in 37.8 mg (15%) of the title compound as an off-white solid. 
     Example 19: Synthesis of Compound 56 
     Synthesis of N2-(4-methoxy-3-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine hydrochloride 
     
       
         
         
             
             
         
       
     
     Synthesis of N2-(4-methoxy-3-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask, was placed tert-butyl 2-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridine-4-carboxylate (100 mg, 0.21 mmol, 1.00 equiv), trifluoroacetic acid (73 mg, 0.65 mmol, 3.00 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 24 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H 2 O (0.05% TFA):ACN (1:1). This resulted in 16.1 mg (9%) of the title compounds as a light yellow solid. 
     Example 20: Synthesis of Compound 108 
     Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 500-mL round-bottom flask, was placed 3-iodo-4-methoxyaniline (20 g, 80.31 mmol, 1.00 equiv), IPA (240 mL), trifluoroacetic acid (17.6 g, 155.70 mmol, 2.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (12.7 g, 80.58 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 26 g (87%) of the title compound as a brown solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.058 min; LCMS 33: m/z=371 [M+1]. 2. 
     Step 2: Synthesis of 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde 
     Into a 50-mL round-bottom flask, was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (1 g, 2.70 mmol, 1.00 equiv), Tol (10 mL), CuI (154 mg, 0.81 mmol, 0.30 equiv), K3PO4 (1.72 g, 8.10 mmol, 3.00 equiv), 1H-pyrazole-4-carbaldehyde (262 mg, 2.73 mmol, 1.00 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (230 mg, 1.62 mmol, 0.60 equiv). The resulting solution was stirred for 24 h at 140° C. The residue was applied onto a silica gel column with water/ACN (1:50-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 550 mg (60%) of the title compound as an off-white solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.981 min; LCMS 33: m/z=339 [M+1].  1 H NMR (300 MHz, Methanol-d4) δ 9.91 (s, 1H), 8.77 (d, J=0.6 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 5.82 (s, 1H), 3.91 (s, 3H), 2.89 (s, 3H), 2.18 (s, 3H). 
     Step 3: Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask, was placed 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde (140 mg, 0.41 mmol, 1.00 equiv), NaBH 3 CN (5 g, 79.57 mmol, 192.30 equiv), methanol (233 mg, 7.27 mmol, 6.00 equiv), methanamine (104 mg, 3.35 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um; mobile phase, Water (0.05% TFA) and ACN (10.0% ACN up to 30.0% in 7 min); Detector, uv 254/220 nm. This resulted in 47.5 mg (25%) of the title compound as a trifluoroacetic acid salt as a white solid. 
     Example 21: Synthesis of Compound 109 
     Synthesis of N2-(3-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)-4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of N2-(3-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)-4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask, was placed 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde (160 mg, 0.47 mmol, 1.00 equiv), NaBH 3 CN (5 g, 79.57 mmol, 168.27 equiv), methanol (240 mg, 7.49 mmol, 4.00 equiv), dimethylamine (119 mg, 2.64 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um; mobile phase, Water (0.05% TFA) and ACN (15.0% ACN up to 35.0% in 7 min); Detector, uv 254/220 nm. This resulted in 89.2 mg (39%) of the title compound as the trifluoroacetic acid salt as a white solid. 
     Example 22: Synthesis of Compound 113 
     Synthesis of N2-(4-methoxy-3-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 
     Into a 100-mL round-bottom flask, was placed tert-butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate (500 mg, 1.87 mmol, 1.00 equiv), AcOH (225 mg, 3.75 mmol, 2.00 equiv), methanol (10 mL), 2-N-(3-hydrazinyl-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (580 mg, 1.87 mmol, 1.00 equiv). The resulting solution was stirred for 15 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H 2 O (0.05% TFA):ACN (1:1). This resulted in 300 mg (26%) of as a yellow oil. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.18 min, LCMS 33: m/z=466 [M+1]. 
     Step 2: Synthesis of N2-(4-methoxy-3-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed tert-butyl 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (300 mg, 0.64 mmol, 1.00 equiv), trifluoroacetic acid (290 mg, 1.92 mmol, 3.00 equiv), dichloromethane (10 mL). The resulting solution was stirred for 24 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H 2 O (0.05% NH 4 HCO 3 ):ACN (3:1). This resulted in 16.5 mg (7%) of the title compound as a light yellow solid. 
     Example 23: Synthesis of Compound 137 
     Synthesis of N2-(4-methoxy-3-(4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl 2-[1-(2-methoxy-5-nitrophenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate 
     Into a 100-mL round-bottom flask, was placed 2-azido-1-methoxy-4-nitrobenzene (1 g, 5.15 mmol, 1.00 equiv), tert-butanol (10 mL), water (20 mL), dioxo(sulfonylidene)copper (80 mg, 0.50 mmol, 0.10 equiv), tert-butyl 2-ethynylpyrrolidine-1-carboxylate (1.1 g, 5.53 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 550 mg (25%) of the title compound as a yellow solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.12 min, LCMS 53: m/z=390 [M+1]. 
     Step 2: Synthesis of tert-butyl 2-[1-(5-amino-2-methoxyphenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate 
     Into a 25-mL round-bottom flask, was placed tert-butyl 2-[1-(2-methoxy-5-nitrophenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate (50 mg, 0.13 mmol, 1.00 equiv), palladium carbon (10 mg), ethyl acetate (2 mL). The resulting solution was stirred for 12 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 30 mg (62%) of the title compound as a yellow solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.02 min, LCMS 33: m/z=360 [M+1]. 
     Step 3: Synthesis of tert-butyl 2-[1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate 
     Into a 50-mL round-bottom flask, was placed tert-butyl 2-[1-(5-amino-2-methoxyphenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate (400 mg, 1.21 mmol, 1.00 equiv), trifluoroacetic acid (400 mg, 3.64 mmol, 3.00 equiv), IPA (10 mL), 2-chloro-N,6-dimethylpyrimidin-4-amine (174 mg, 1.20 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (36%) of the title compound as a pink solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.32 min, LCMS 27: m/z=481 [M+1]. 
     Step 4: Synthesis of tert-butyl 2-[1-(2-methoxy-5-nitrophenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate 
     Into a 50-mL round-bottom flask, was placed tert-butyl 2-[1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate (200 mg, 0.42 mmol, 1.00 equiv), trifluoroacetic acid (200 mg, 1.27 mmol, 3.00 equiv), dichloromethane (8 mL). The resulting solution was stirred for 24 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 20.0% in 8 min); Detector, UV 254/220 nm. This resulted in 21.8 mg of the title compound as the trifluoroacetic acid salt as a white solid. 
     Example 24: Synthesis of Compound 157 
     Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl N-(4-iodopyridin-3-yl)carbamate 
     Into a 100-mL round-bottom flask, was placed 4-iodopyridin-3-amine (2 g, 9.09 mmol, 1.00 equiv), Boc 2 O (2.4 g, 11.00 mmol, 1.21 equiv), 4-dimethylaminopyridine (1 g, 8.19 mmol, 0.90 equiv), dichloromethane (50 mL). The resulting solution was stirred for 1 overnight at room temperature. The resulting solution was extracted with of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.9 g (65%) of the title compound as an off-white solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.719 min, LCMS 45: m/z=321 [M+1]. 
     Step 2: Synthesis of tert-butyl N-[4-[2-(2-methoxy-5-nitrophenyl)ethynyl]pyridin-3-yl]carbamate 
     Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(4-iodopyridin-3-yl)carbamate (700 mg, 2.19 mmol, 1.00 equiv), Pd(PPh 3 ) 2 Cl 2  (144 mg, 0.21 mmol, 0.09 equiv), CuI (83 mg, 0.44 mmol, 0.20 equiv), TEA (1.1 g, 10.87 mmol, 4.97 equiv), DMSO (5 mL), [2-(2-methoxy-5-nitrophenyl)ethynyl]trimethylsilane (544 mg, 2.18 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 50° C. The resulting solution was extracted with of ethyl acetate and the organic layers combined. This resulted in 420 mg (52%) of the title compound as a yellow solid. 
     Analytical Data: LC-MS: (ES, m/z): RT 0.880=min, LCMS 45: m/z=370 [M+1]. 
     Step 3: Synthesis of 2-(2-methoxy-5-nitrophenyl)-1H-pyrrolo[2,3-c]pyridine 
     Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[4-[2-(2-methoxy-5-nitrophenyl)ethynyl]pyridin-3-yl]carbamate (30 mg, 0.08 mmol, 1.00 equiv), EtONa (11 mg), ethanol (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 65° C. The crude product was used in the next reaction without further purification. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.715 min, LCMS 30: m/z=270 [M+1]. 
     Step 4: Synthesis of 4-methoxy-3-[1H-pyrrolo[2,3-c]pyridin-2-yl]aniline 
     Into a 50-mL 3-necked round-bottom flask, was placed 2-(2-methoxy-5-nitrophenyl)-1H-pyrrolo[2,3-c]pyridine (109 mg, 0.40 mmol, 1.00 equiv), ethyl acetate (20 mL), Palladium carbon (30 mg), hydrogen. The resulting solution was stirred for 1 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 100 mg of the title compound as a brown solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.041 min, LCMS 31: m/z=270 [M+1]. 
     Step 5: Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 40-mL vial, was placed 4-methoxy-3-[1H-pyrrolo[2,3-c]pyridin-2-yl]aniline (100 mg, 0.42 mmol, 1.00 equiv), IPA (15 mL, 1.09 equiv), trifluoroacetic acid (156 mg, 1.38 mmol, 3.30 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (71.6 mg, 0.45 mmol, 3.30 equiv). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The crude product (100 g) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um; mobile phase, Water (0.05% TFA) and ACN (10.0% ACN up to 35.0% in 7 min); Detector, UV 254/220 nm. 19.2 mg product was obtained and concentrated under vacuum. This resulted in 19.2 mg (10%) of the title compound as the trifluoroacetic acid salt as an off-white solid. 
     Example 25: Synthesis of Compound 159 
     Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of [1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazol-4-yl]methanol 
     Into a 50-mL round-bottom flask, was placed 1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazole-4-carboxylic acid (700 mg, 1.97 mmol, 1.00 equiv), BH 3 /THF (15 mL). The resulting solution was stirred for 20 h at 20° C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 5 mL of. The residue was applied onto a silica gel column with methanol/H 2 O (0.05% TFA) (1/1). This resulted in 350 mg (52%) of the title compound as an off-white solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.856 min; LCMS 53: m/z=342 [M+1].  1 H NMR (300 MHz, Methanol-d4) δ 8.42-8.28 (m, 2H), 7.58 (d, J=9.0 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 6.01 (q, J=0.9 Hz, 1H), 4.78 (d, J=0.7 Hz, 2H), 3.96 (s, 3H), 3.01 (s, 3H), 2.44-2.28 (m, 3H). 
     Step 2: Synthesis of 2-N-[3-[4-(chloromethyl)-1H-1,2,3-triazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine 
     Into a 100-mL round-bottom flask, was placed [1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazol-4-yl]methanol (200 mg, 0.59 mmol, 1.00 equiv), dichloromethane (40 mL), thionyl chloride (346 mg, 5.00 equiv), N,N-dimethylformamide (2 drop). The resulting solution was stirred for 1 h at 20° C. The resulting solution was diluted with 30 mL of H 2 O. The resulting solution was extracted with 3×80 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 137 mg (65%) of the title compound as an off-white solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.994 min; LCMS 15: m/z=360 [M+1]. 
     Step 3: Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 2-N-[3-[4-(chloromethyl)-1H-1,2,3-triazol-1-yl]-4-methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (137 mg, 0.38 mmol, 1.00 equiv), methanamine hydrochloride (127 mg, 1.88 mmol, 5.00 equiv), potassium carbonate (420 mg, 3.04 mmol, 8.00 equiv), ACN (15 mL). The resulting solution was stirred for 2 days at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 20.0% in 7 min); Detector, UV 254/220 nm. This resulted in 62.8 mg (35%) of the title compound as the trifluoroacetic acid salt as a white solid. 
     Example 26: Synthesis of Compound 175 
     Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-N4-methylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 6-(2-methoxy-5-nitrophenyl)-1H-pyrrolo[3,2-c]pyridine 
     Into a 30-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 6-chloro-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.28 mmol, 1.00 equiv), 2-(2-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 3.94 mmol, 1.20 equiv), Pd(dppf)Cl 2  (270 mg, 0.37 mmol, 0.11 equiv), potassium carbonate (1.36 g, 9.84 mmol, 3.00 equiv), Dioxane (10 mL), water (1 mL). The resulting solution was stirred for 4 h at 80° C. in an oil bath. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (60%). This resulted in 280 mg (crude) of the title compound as a yellow solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.543 min, LCMS 30: m/z=270 [M+1]. 
     Step 2: Synthesis of 4-methoxy-3-[1H-pyrrolo[3,2-c]pyridin-6-yl]aniline 
     Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of H2, was placed 6-(2-methoxy-5-nitrophenyl)-1H-pyrrolo[3,2-c]pyridine (280 mg, 1.04 mmol, 1.00 equiv), methanol (5 mL), Palladium on carbon (190 mg). The resulting solution was stirred for 2 h at 20° C. The solids were filtered out. This resulted in 190 mg (76%) of the title compound as a brown solid. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.702 min, LCMS 15: m/z=240 [M+1].  1 H NMR (300 MHz, Methanol-d4) δ 8.82 (d, J=1.1 Hz, 1H), 7.74 (t, J=1.0 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.32 (s, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.67 (s, 1H), 3.75 (s, 3H). 
     Step 3: Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-N4-methylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[1H-pyrrolo[3,2-c]pyridin-6-yl]aniline (180 mg, 0.75 mmol, 1.00 equiv), 2-chloro-N-methylpyrimidin-4-amine (107 mg, 0.75 mmol, 0.99 equiv), trifluoroacetic acid (171.7 mg, 1.52 mmol, 2.02 equiv), IPA (5 mL). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The crude product was purified by Prep-HPLC with the following conditions: Column: X Select C18, 19*250 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 64% B in 15 min. This resulted in 67.8 mg (20%) of the title compound as the trifluoroacetic acid salt as a white solid. 
     Example 27: Synthesis of Compound 181 
     Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4-methylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of N2-(4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4-methylpyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask, was placed 1-(2-methoxy-5-[[4-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde (80 mg, 0.25 mmol, 1.00 equiv), methanol (2 mL), methanamine (34 mg, 1.09 mmol, 2.00 equiv) and stirred for 15 min. Then NaBH 3 CN (93 mg, 1.48 mmol, 6.00 equiv), acetic acid (0.002 mL). The resulting solution was stirred for 2 h at 25° C. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHIPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, CH 3 CN: Water (0.05% HCl)=1/9; Detector, UV 254/220 nm. This resulted in 36.6 mg (37%) of the title compound as the hydrochloride salt as a white solid. 
     Example 28: Synthesis of Compound 200 
     Synthesis of N2-(4-methoxy-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 1-methoxy-4-nitro-2-(prop-1-yn-1-yl)benzene 
     Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-iodo-1-methoxy-4-nitrobenzene (2.8 g, 10.03 mmol, 1.00 equiv), tributyl(prop-1-yn-1-yl)stannane (5 g, 15.19 mmol, 1.51 equiv), Pd(PPh 3 ) 2 Cl 2  (200 mg, 0.28 mmol, 0.03 equiv), dioxane (30 mL). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5%). This resulted in 1.06 g (55%) of the title compound. 
     Step 2: Synthesis of 2-(2-methoxy-5-nitrophenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine 
     Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 1-methoxy-4-nitro-2-(prop-1-yn-1-yl)benzene (500 mg, 2.62 mmol, 1.00 equiv), 4-iodopyridin-3-amine (1.1 g, 5.00 mmol, 1.91 equiv), Pd(OAc) 2  (110 mg, 0.49 mmol, 0.19 equiv), KOAc (750 mg, 7.64 mmol, 2.92 equiv), LiCl (0.11 g), N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 100° C. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, mobile phase, Detector, Xbridge C18 OBD 19*150 mm. This resulted in 167 mg (23%) of the title compound. 
     Step 3: Synthesis of 4-methoxy-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)aniline 
     Into a 20-mL vial, was placed 2-(2-methoxy-5-nitrophenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridine (150 mg, 0.53 mmol, 1.00 equiv), Zn (300 mg), AcOH (8 mL). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 115 mg (86%) of the title compound as a yellow solid. 
     Step 4: Synthesis of N2-(4-methoxy-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 4-methoxy-3-[3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl]aniline (100 mg, 0.39 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (50 g, 317.26 mmol, 803.61 equiv), trifluoroacetic acid (150 g, 1.33 mol, 3361.19 equiv), IPA (8 mL). The resulting solution was stirred for 1 h at 80° C. The resulting mixture was concentrated under vacuum. This resulted in 22 mg (11%) of the title compound as the trifluoroacetyl fluoride salt. 
     Example 29: Synthesis of Compound 206 
     Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 6-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine 
     Into a 50-mL round-bottom flask, was placed 6-chloro-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.28 mmol, 1.00 equiv), tetrahydrofuran (20 mL), sodium hydride (473 mg, 19.71 mmol, 6.00 equiv), 4-methylbenzene-1-sulfonyl chloride (937 mg, 4.91 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 80° C. The resulting solution was extracted with 200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 900 mg (crude) of the title compound that was used without further purification. 
     Step 2: Synthesis of 6-(2-methoxy-5-nitrophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine 
     Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-chloro-1-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridine (500 mg, 1.63 mmol, 1.00 equiv), 2-(2-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1094.1 mg, 3.92 mmol, 2.40 equiv), Pd(dppf)Cl 2  (676.5 mg, 0.92 mmol, 3.00 equiv), potassium carbonate (133.3 mg, 0.96 mmol, 0.10 equiv), water (20 mL), dioxane (2 mL). The resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 600 mg (crude) of the title compound. 
     Step 3: Synthesis of 4-methoxy-3-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-6-yl)aniline 
     Into a 50-mL vial, was placed 6-(2-methoxy-5-nitrophenyl)-1-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridine (400 mg, 0.94 mmol, 1.00 equiv), Palladium carbon (200 mg), methanol (20 mL), hydrogen. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 250 mg (crude) of the title compound. 
     Step 4: Synthesis of N2-(4-methoxy-3-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[1-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]aniline (200 mg, 0.51 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (80 mg, 0.51 mmol, 1.00 equiv), trifluoroacetic acid (147 mg, 1.30 mmol, 2.00 equiv), IPA (10 mL). The resulting solution was stirred for 5 h at 80° C. The resulting mixture was concentrated under vacuum. This resulted in 250 mg (96%) of the title compound. 
     Step 5: Synthesis of N2-(4-methoxy-3-(1H-pyrrolo[3,2-c]pyridin-6-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 2-N-(4-methoxy-3-[1-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]phenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.39 mmol, 1.00 equiv), sodium hydroxide (156 mg, 3.90 mmol, 10.00 equiv), ethanol (20 mL). The resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; mobile phase, Water (10 mmol/L NH 4 HCO 3 ) and ACN (30.0% ACN up to 43.0% in 7 min); Detector, UV 254220 nm. This resulted in 24 mg (17%) of the title compound as a white solid. 
     Example 30: Synthesis of Compound 212 
     Synthesis of (S)—N2-(4-methoxy-3-(4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl (S)-2-(1-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate 
     Into a 20-mL vial, was placed tert-butyl (S)-2-(1-(5-amino-2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (prepared as for compound 137 starting with tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate, 1 g, 2.78 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (525 mg, 3.33 mmol, 1.20 equiv), trifluoroacetic acid (958 mg, 8.47 mmol, 3.05 equiv), IPA (9 mL). The resulting solution was stirred for 1 h at 80° C. The solids were collected by filtration. This resulted in 800 mg (60%) of title compound. 
     Step 2: Synthesis of (S)—N2-(4-methoxy-3-(4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 20-mL vial, was placed tert-butyl (2S)-2-[1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-1,2,3-triazol-4-yl]pyrrolidine-1-carboxylate (200 mg, 0.42 mmol, 1.00 equiv), trifluoroacetic acid (3 mL), dichloromethane (3 mL). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 57.8 mg (37%) of the title compound. 
     Synthesis of Compound 238 
     Synthesis of 5′-methoxy-N-methyl-6′-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)spiro[cyclobutane-1,3′-indol]-2′-amine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of 5′-methoxy-N-methyl-6′-(prop-1-yn-1-yl)spiro[cyclobutane-1,3′-indol]-2′-amine 
     Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 6-romo-5-ethoxy-N-methylspiro[cyclobutane-1,3-ndole]-2-amine (300 mg, 1.02 mmol, 1.00 equiv), Pd(PPh 3 ) 2 Cl 2  (142 mg, 0.20 mmol, 0.20 equiv), dioxane (8 mL), tributyl(prop-1-yn-1-yl)stannane (500 mg, 1.52 mmol, 1.49 equiv). The resulting solution was stirred overnight at 80° C. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/hexane (30%). This resulted in 193 mg (75%) of the title compound. 
     Step 2: Synthesis of 5′-methoxy-N-methyl-6′-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)spiro[cyclobutane-1,3′-indol]-2′-amine 
     Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 5-ethoxy-N-methyl-6-prop-1-yn-1-yl)spiro[cyclobutane-1,3-ndole]-2-mine (50 mg, 0.20 mmol, 1.00 equiv), Pd 2 (dba) 3  (40 mg, 0.04 mmol, 0.22 equiv), Ad 2 (n-Bu)P (38 mg), K 3 PO 4  (80 mg, 0.38 mmol, 1.92 equiv), dioxane (5 mL), 4-iodopyridin-3-amine (90 mg, 0.41 mmol, 2.08 equiv). The resulting solution was stirred overnight at 120° C. The resulting solution was extracted with of ethyl acetate and the organic layers combined. This resulted in 29.7 mg (33%) of the title compound as the trifluoroacetic acid salt as a yellow solid. 
     Synthesis of Compound 262 
     Synthesis of N2-(4-chloro-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: 1. Synthesis of (2-chloro-5-nitrophenyl)hydrazine 
     Into a 250-mL round-bottom flask, was placed 2-chloro-5-nitroaniline (3 g, 17.38 mmol, 1.00 equiv), hydrogen chloride (60 mL), NaNO 2  (1.5 g, 21.74 mmol, 1.25 equiv), SnCl 2  (10 g, 52.74 mmol, 3.03 equiv). The resulting solution was stirred for 1.5 h at 0° C. in an ice/salt bath. The solids were collected by filtration. This resulted in 8 g (crude) of the title compound as a yellow solid. 
     Step 2: Synthesis of ethyl 1-(2-chloro-5-nitrophenyl)-1H-pyrazole-4-carboxylate 
     Into a 100-mL round-bottom flask, was placed (2-chloro-5-nitrophenyl)hydrazine (1 g, 5.33 mmol, 1.00 equiv), ethanol (40 mL), methyl 2-formyl-3-oxopropanoate (760 mg, 5.34 mmol, 1.00 equiv). The final reaction mixture was irradiated with microwave radiation for 2 h at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 600 mg (crude) of the title compound that was used without further purification. 
     Analytical Data: 1H NMR (300 MHz, Methanol-d4) δ 8.69 (d, J=0.6 Hz, 1H), 8.52 (d, J=2.6 Hz, 1H), 8.39 (q, J=2.7 Hz, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H). 
     Step 3: Synthesis of ethyl 1-(5-amino-2-chlorophenyl)-1H-pyrazole-4-carboxylate 
     Into a 100-mL round-bottom flask, was placed ethyl 1-(2-chloro-5-nitrophenyl)-1H-pyrazole-4-carboxylate (900 mg, 3.04 mmol, 1.00 equiv), Fe (900 mg, 5.00 equiv), NH 4 Cl (900 mg, 15.13 mmol, 5.00 equiv), ethanol/H2O (15 mL). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The solids were filtered out. The residue was applied onto a silica gel column with H 2 O (0.05% NH 4 HCO 3 ):ACN (1:1). This resulted in 600 mg (67%) of the title compound. 
     Step 4: Synthesis of ethyl 1-(2-chloro-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazole-4-carboxylate 
     Into a 100-mL round-bottom flask, was placed ethyl 1-(5-amino-2-chlorophenyl)-1H-pyrazole-4-carboxylate (532 mg, 2.00 mmol, 1.00 equiv), trifluoroacetic acid (458 mg, 4.05 mmol, 2.00 equiv), IPA (15 mL), 2-chloro-N,6-dimethylpyrimidin-4-amine (316 mg, 2.01 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 60° C. in an oil bath. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 500 mg (61%) of the title compound as a light yellow 
     Step 5: Synthesis of (1-(2-chloro-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-4-yl)methanol 
     Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 1-(2-chloro-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carboxylate (500 mg, 1.29 mmol, 1.00 equiv), LAH (450 mg, 11.86 mmol, 9.00 equiv), tetrahydrofuran (30 mL). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of. The resulting solution was extracted with 2×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 300 mg (61%) of the title compound. 
     Step 6: Synthesis of 1-(2-chloro-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazole-4-carbaldehyde 
     Into a 50-mL round-bottom flask, was placed [1-(2-chloro-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazol-4-yl]methanol (500 mg, 1.45 mmol, 1.00 equiv), MnO 2  (500 mg, 5.75 mmol, 3.97 equiv), dichloromethane (10 mL). The resulting solution was stirred for 14 h at 40° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (54%) of the title compound. 
     Step 7: Synthesis of N2-(4-chloro-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 1-(2-chloro-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde (300 mg, 0.88 mmol, 1.00 equiv), NaBH 3 CN (150 mg, 2.59 mmol, 3.00 equiv), methanol (10 mL), AcOH (0.01 mL), methanamine (300 mg, 4.46 mmol, 5.00 equiv). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHIPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 15.0% in 12 min); Detector, UV 254220 nm. This resulted in 88.8 mg (22%) of the title compound as the trifluoroacetic acid salt as a white solid. 
     Synthesis of Compound 286 
     Synthesis of N4,6-dimethyl-N2-(4-methyl-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)pyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
     
     Step 1: Synthesis of tert-butyl methyl((1-(2-methyl-5-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-4-yl)methyl)carbamate 
     Into a 20-mL sealed tube, was placed 2-N-(3-iodo-4-methylphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.28 mmol, 1.00 equiv), tert-butyl N-methyl-N-(1H-pyrrol-3-ylmethyl)carbamate (62 mg, 0.29 mmol, 1.04 equiv), CuI (11 mg, 0.06 mmol, 0.20 equiv), K 3 PO 4  (178 mg, 0.84 mmol, 2.97 equiv), methyl[2-(methylamino)ethyl]amine (10 mg, 0.11 mmol, 0.40 equiv), DMSO (8 mL). The resulting solution was stirred overnight at 120° C. The resulting solution was diluted with of H 2 O. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The resulting mixture was washed with H 2 O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (81%) of the title compound. 
     Analytical Data: LC-MS: (ES, m/z): RT=0.815 min, m/z=438 [M+1]. 
     Step 2: Synthesis of N4,6-dimethyl-N2-(4-methyl-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)pyrimidine-2,4-diamine 
     Into a 25-mL round-bottom flask, was placed tert-butyl N-methyl-N-[[1-(2-methyl-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrrol-3-yl]methyl]carbamate (100 mg, 0.23 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), dichloromethane (5 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 23.0% in 12 min); Detector, UV 254/220 nm. This resulted in 41.7 mg (40%) of the title compound as the trifluoroacetic acid salt as light yellow oil. 
     Synthesis of Compound 317 
     Synthesis of N2-(2-fluoro-4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: Synthesis of ethyl 1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate 
     Into a 100-mL round-bottom flask, was placed (2,6-difluorophenyl)hydrazine (1 g, 6.94 mmol, 1.00 equiv), ethanol (12 mL), ethyl 2-formyl-3-oxopropanoate (1.2 g, 8.33 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The solvent was removed under vacuum. The residue was applied onto a silica gel column with PE/EA=50/1. The collected fractions were combined and concentrated under vacuum. This resulted in 1.18 g (67%) of the title compound. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.269 min; LCMS 53: m/z=253 [M+1]+ 
     Step 2: Synthesis of ethyl 1-(2,6-difluoro-3-nitrophenyl)-1H-pyrazole-4-carboxylate 
     Into a 50-mL 3-necked round-bottom flask, was placed ethyl 1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate (1.1 g, 4.36 mmol, 1.00 equiv), H2SO4 (5 mL), HNO 3  (2 mL) was added dropwise at 0° C. with a water/ice bath. The resulting solution was stirred for 4 h at 25° C. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. Dried over anhydrous Na 2 SO 4 , concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA=3/1. The collected fractions were combined and concentrated under vacuum. This resulted in 1 g (77%) of the title compound. 
     Analytical Data: LC-MS: (ES, m/z): RT=1.264 min; LCMS 15: m/z=298[M+1]+ 
     Step 3: Synthesis of ethyl 1-(2-fluoro-6-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylate 
     Into a 100-mL round-bottom flask, was placed ethyl 1-(2,6-difluoro-3-nitrophenyl)-1H-pyrazole-4-carboxylate (1 g, 3.36 mmol, 1.00 equiv), methanol (20 mL), sodium methoxide in methanol solution (m/z=35%, 0.5 ml, 1.0 equiv) was added dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. Then the resulting mixture was quenched by NH 4 Cl (aq) 10 ml, extracted by EA 20 ml*3, dried over anhydrous Na 2 SO 4 , concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA=10/1. The collected fractions were combined and concentrated under vacuum. This resulted in 500 mg (48%) of the title compound as yellow oil. 
     Step 4: Synthesis of ethyl 1-(3-amino-2-fluoro-6-methoxyphenyl)-1H-pyrazole-4-carboxylate 
     Into a 50-mL round-bottom flask, was placed ethyl 1-(2-fluoro-6-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylate (500 mg, 1.62 mmol, 1.00 equiv), ethanol (10 mL), water (3 mL), Fe (453 mg, 8.08 mmol, 5 equiv), NH 4 Cl (857 mg, 16.02 mmol, 9.91 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The solids were filtered out. The resulting solvent was concentrated under vacuum. The resulting was extracted with 3×20 mL of ethyl acetate and the organic layers combined, dried over anhydrous Na 2 SO 4 , concentrated under vacuum. This resulted in 400 mg (89%) of the title compound. 
     Step 5: Synthesis of ethyl 1-(2-fluoro-6-methoxy-3-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazole-4-carboxylate 
     Into a 50-mL round-bottom flask, was placed ethyl 1-(3-amino-2-fluoro-6-methoxyphenyl)-1H-pyrazole-4-carboxylate (400 mg, 1.43 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (270 mg, 1.71 mmol, 1.20 equiv), IPA (20 mL), trifluoroacetic acid (3 mL). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The resulting mixture was allowed to cooled to r.t. Then filtered, the solid was collected. This resulted in 500 mg (87%) of the title compound. 
     Step 6: Synthesis of (1-(2-fluoro-6-methoxy-3-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-4-yl)methanol 
     Into a 50-mL round-bottom flask, was placed ethyl 1-(2-fluoro-6-methoxy-3-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carboxylate (400 mg, 1.00 mmol, 1.00 equiv), tetrahydrofuran (10 mL), LAH (114 mg, 3.00 mmol, 3.01 equiv) was added batch-wise. The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 114 mg water. Then 114 mg NaOH (aq, m/z=15%) and 342 mg water, 20 ml EA was added. Stirred at r.t. for 30 min. The solids were filtered out, the resulting solution was dried over anhydrous Na2SO4, concentrated under vacuum. This resulted in 300 mg (84%) of the title compound. 
     Step 7: Synthesis of 1-(2-fluoro-6-methoxy-3-((4-methyl-6-(methylamino)pyrimidin-2-yl)amino)phenyl)-1H-pyrazole-4-carbaldehyde 
     Into a 50-mL round-bottom flask, was placed [1-(2-fluoro-6-methoxy-3-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazol-4-yl]methanol (300 mg, 0.84 mmol, 1.00 equiv), chloroform (15 mL), MnO 2  (730 mg, 8.40 mmol, 10.03 equiv). The resulting solution was stirred for 8 h at 70° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (67%) of the title compound. 
     Step 8: Synthesis of N2-(2-fluoro-4-methoxy-3-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine 
     Into a 50-mL round-bottom flask, was placed 1-(2-fluoro-6-methoxy-3-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.28 mmol, 1.00 equiv), DCE (10 mL), methanamine (200 mg, 6.44 mmol, 22.95 equiv), STAB (180 mg, 0.85 mmol, 3.03 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD Column, 19*150 mm Sum; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 23.0% in 10 min); Detector, UV 220/254 nm. This resulted in 66.5 mg (49%) of the title compound. 
     Other compounds were synthesized in the similar manner and the characterization data are listed in Table 2 below. 
     
       
         
           
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Cpd # 
                 Data 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 LC-MS: (ES, m z): RT = 0.958 min, LCMS 33: m/z = 366 [M + 1].  1 H-NMR: (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.18 (s, 1H), 7.87 (s, 1H), 7.54-7.51 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 
               
               
                   
                 5.82 (s, 1H), 4.02 (s, 2H), 3.86 (s, 3H), 3.24 (t, J = 6.0 Hz, 2H), 2.94-2.83 (m, 5H), 
               
               
                   
                 2.19 (s, 3H). 
               
               
                 2 
                 LC-MS: (ES, m/z): RT = 1.504 min, LCMS 33: m/z = 380 [M + 1].  1 H NMR: (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.22-8.10 (m, 2H), 7.59-7.50 (m, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.02 
               
               
                   
                 (d, J = 1.2 Hz, 1H), 4.47 (s, 2H), 3.95 (s, 3H), 3.88-3.52 (m, 2H), 3.20-3.16(m, 2H), 
               
               
                   
                 3.10 (s, 3H), 3.03 (s, 3H), 2.32 (d, J = 2.4 Hz, 3H). 
               
               
                 3 
                 LC-MS: (ES, m/z): RT = 1.022 min, LCMS 33: m/z = 380.2 [M + 1].  1 H NMR (300 
               
               
                   
                 MHz, Methanol-d 4 ) δ 8.15 (d, J = 3.9 Hz, 2H), 7.53 (d, J = 2.7 Hz, 1H), 7.28 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 6.02 (d, J = 0.8 Hz, 1H), 4.62 (s, 2H), 3.95 (s, 3H), 3.82 (s, 1H), 3.77 (s, 1H), 
               
               
                   
                 3.17-2.94 (m, 8H), 2.32 (d, J = 0.9 Hz, 3H). 
               
               
                 4 
                 LC-MS: (ES, m/z): RT = 1.06 min, LCMS28, m/z = 394.2 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.26 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.74-7.65 (m, 1H), 
               
               
                   
                 7.26 (d, J = 9.0 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.48 (s, 2H), 
               
               
                   
                 3.93 (d, J = 5.7 Hz, 3H), 3.65 (s, 2H), 3.30 (d, J = 7.4 Hz, 2H), 3.02 (s, 3H), 2.34-2.29 
               
               
                   
                 (m, 3H), 2.21-2.11 (m, 2H), 2.10-1.99 (m, 2H). 
               
               
                 5 
                 LC-MS: (ES, m/z): RT = 1.020 min, LCMS28, m/z = 394.2 [M + 1]. 
               
               
                   
                   1 H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 7.87 (s, 1H), 
               
               
                   
                 7.61-7.51 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 4.41 (s, 2H), 
               
               
                   
                 3.97 (s, 3H), 3.64-3.56 (m, 2H), 3.30-3.18 (m, 2H), 3.02 (s, 3H), 2.33 (d, J = 1.0 Hz, 
               
               
                   
                 3H), 2.20 (d, J = 7.9 Hz, 2H), 2.12-2.01 (m, 2H). 
               
               
                 6 
                 LC-MS: (ES, m/z): RT = 0.963 min, LCMS27: m/z = 380.1 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.08 (d, J = 2.8 Hz, 1H), 7.54 (s, 2H), 6.98 (d, J = 8.9 Hz, 1H), 5.79 (d, 
               
               
                   
                 J = 0.8 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.92 (s, 3H), 3.71 (s, 2H), 2.99-2.93 (m, 2H), 
               
               
                   
                 2.91 (d, J = 8.0 Hz, 3H), 2.54 (s, 3H), 2.18 (s, 3H). 
               
               
                 7 
                 LC-MS: (ES, m/z): RT = 0.901 min, LCMS15: m/z = 366.2 [M + 1].  1 H NMR (300 
               
               
                   
                 MHz, Methanol-d 4 ) δ 8.06 (d, J = 2.8 Hz, 1H), 7.56-7.53 (m, 2H), 6.98 (d, J = 8.9 Hz, 
               
               
                   
                 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.07-4.03 (m, 4H), 3.91 (s, 3H), 3.28-3.18 (m, 2H), 
               
               
                   
                 2.89 (s, 3H), 2.18 (s, 3H). 
               
               
                 8 
                 LC-MS: (ES, m/z): RT = 2.985 min, LCMS 07: m/z = 367 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.23 (d, J = 2.7 Hz, 1H), 7.64 (d, J = 9.0, 2.8 Hz, 1H), 7.27-7.19 (m, 
               
               
                   
                 1H), 6.06 (d, J = 1.3 Hz, 1H), 4.74 (s, 2H), 4.63 (t, J = 5.7 Hz, 2H), 3.94 (d, J = 5.6 Hz, 
               
               
                   
                 5H), 2.99 (d, J = 3.1 Hz, 3H), 2.42 (s, 3H), 2.32 (s, 3H). 
               
               
                 9 
                 LC-MS: (ES, m/z): RT = 1.696 min, LCMS 07, m/z = 381 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.30 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 9.0, 2.7 Hz, 1H), 7.21 (d, J = 9.1 
               
               
                   
                 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.64-4.52 (m, 4H), 3.93 (d, J = 7.8 Hz, 3H), 3.82 (d, 
               
               
                   
                 J = 5.7 Hz, 2H), 3.11 (s, 3H), 3.02 (s, 3H), 2.31 (d, J = 0.9 Hz, 3H). 
               
               
                 10 
                 LC-MS: (ES, m/z): RT = 0.863 min, LCMS 07: m/z = 380 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 7.81-7.63 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 
               
               
                   
                 4.34 (s, 2H), 3.89 (s, 3H), 3.46-3.42 (m, 2H), 3.04-3.01 (m, 8H), 2.30 (s, 3H). 
               
               
                 11 
                 LC-MS: (ES, m/z): RT = 1.039 min, LCMS 28, m/z = 326 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.39 (d, J = 2.7 Hz, 1H), 7.75 (dd, J = 9.0, 2.7 Hz, 1H), 7.31 (dd, J = 
               
               
                   
                 16.7, 9.0 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 4.06 (s, 3H), 3.01 (s, 3H), 2.61 (s, 3H), 2.33 
               
               
                   
                 (s, 3H). 
               
               
                 12 
                 LC-MS: (ES, m/z): RT = 1.175 min; LCMS53: m/z = 311 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.03 (s, 2H), 7.92 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 
               
               
                   
                 1H), 5.80 (s, 1H), 3.89 (s, 3H), 2.92 (s, 3H), 2.18 (s, 3H). 
               
               
                 13 
                 LC-MS: (ES, m/z): RT = 1.531 min, LCMS28, m/z = 352 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.10 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.21 (d, J = 8.8 
               
               
                   
                 Hz, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 3.96 (s, 3H), 3.01 (s, 3H), 2.32 (s, 3H), 2.225- 
               
               
                   
                 2.137 (m, 1H), 1.181-1.116 (m, 2H), 1.06-0.94 (m, 2H). 
               
               
                 14 
                 LC-MS: (ES, m/z): RT = 1.463 min, LCMS07: m/z = 351 [M + 1].  1 H NMR: (400 MHz, 
               
               
                   
                 Methanol-d 4 ): δ 8.23-7.98 (m, 1H), 7.83-7.77(m, 1H), 7.53 (d, J = 8.9, 1H), 7.45 (d, 
               
               
                   
                 J = 0.8 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.80 (d, J = 0.8 Hz, 1H), 3.84 (s, 3H), 2.88 (s, 
               
               
                   
                 3H), 2.17 (s, 3H), 1.83-1.77 (m, 1H), 1.09-0.71 (m, 2H), 0.70-0.39 (m, 2H). 
               
               
                 15 
                 LC-MS: (ES, m/z): RT = 1.30 min, LCMS 28: m/z = 311 [M + 1].  1 H NMR: (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.21-8.12 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.78-7.67 (m, 1H), 7.50 
               
               
                   
                 (dd, J = 8.9, 2.7 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.57-6.47 (m, 1H), 6.28-5.98 (m, 
               
               
                   
                 1H), 3.95 (s, 3H), 3.00 (s, 3H), 2.44-2.28 (m, 3H). 
               
               
                 19 
                 LC-MS: (ES, m/z): RT = 1.407 min, LCMS28: m/z = 367.1 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.53 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.54 (s, 1H), 5.85 (d, 
               
               
                   
                 J = 0.8 Hz, 1H), 3.94 (d, J = 2.1 Hz, 5H), 3.12 (t, J = 5.9 Hz, 2H), 2.87 (s, 3H), 2.67 (t, 
               
               
                   
                 J = 5.9 Hz, 2H), 2.19 (s, 3H). 
               
               
                 21 
                 LC-MS: (ES, m/z): RT = 0.834 min, LCMS 07: m/z = 367 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 7.89-7.76 (m, 2H), 7.31 (d, J = 15.3, 9.0 Hz, 1H), 6.06 (d, J = 1.3 Hz, 
               
               
                   
                 1H), 4.77 (d, J = 2.0 Hz, 2H), 4.34 (t, J = 5.7 Hz, 2H), 3.96 (d, J = 2.8 Hz, 3H), 3.78 (d, 
               
               
                   
                 J = 6.5, 4.9 Hz, 2H), 2.99 (d, J = 4.5 Hz, 3H), 2.43 (d, J = 0.9 Hz, 1H), 2.33 (d, J = 1.0 
               
               
                   
                 Hz, 3H). 
               
               
                 22 
                 LC-MS: (ES, m/z): RT = 0.992 min LCMS 33: m/z = 366 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.18-8.07 (m, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 6.04 (d, J = 1.2 Hz, 1H), 4.44 (d, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.55 (t, J = 6.3 Hz, 2H), 
               
               
                   
                 3.11-2.95 (m, 5H), 2.45-2.29 (m, 3H). 
               
               
                 23 
                 LC-MS: (ES, m/z): RT = 0.963 min, LCMS31, m/z = 340.4 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.38 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.29 (s, 
               
               
                   
                 1H), 6.02 (s, 1H), 4.16 (s, 2H), 3.96 (d, J = 1.6 Hz, 3H), 3.01 (d, J = 2.4 Hz, 3H), 2.32 
               
               
                   
                 (s, 3H). 
               
               
                 24 
                 LC-MS: (ES, m/z): RT = 1.357 min; LCMS07: m/z = 340 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 7.88-7.70 (m, 3H), 7.51-7.15 (m, 1H), 6.79-6.53(m, 1H), 6.21 (s, 
               
               
                   
                 1H), 4.10 (s, 2H), 3.89 (s, 3H), 2.86(s, 3H), 2.55 (s, 3H). 
               
               
                 26 
                 LC-MS: (ES, m/z): RT = 2.978 min, LCMS31, m/z = 365.4[M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 7.70-7.58 (m, 2H), 7.45 (d, J = 5.0 Hz, 1H), 7.29-7.17 (m, 1H), 6.00 
               
               
                   
                 (d, J = 1.1 Hz, 1H), 3.85 (d, J = 5.1 Hz, 3H), 2.96 (d, J = 3.6 Hz, 3H), 2.64-2.57 (m, 
               
               
                   
                 2H), 2.51-2.44 (m, 2H), 2.31 (d, J = 1.0 Hz, 3H), 1.88-1.75 (m, 4H). 
               
               
                 27 
                 LC-MS: (ES, m/z): RT = 0.99 min, LCMS28: m/z = 384.19 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.51 (dd, J = 8.9, 2.8 Hz, 
               
               
                   
                 1H), 7.27 (d, J = 9.0 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.62 (t, J = 6.3 Hz, 2H), 3.18- 
               
               
                   
                 3.02 (m, 5H), 2.36 (d, J = 2.9 Hz, 3H). 
               
               
                 28 
                 LC-MS: (ES, m/z): RT = 0.99 min, LCMS15: m/z = 384.19 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d 4 ) δ 7.77-7.71 (m, 2H), 7.68 (s, 1H), 7.35-7.2 (m, 1H), 4.36 (s, 2H), 
               
               
                   
                 3.89 (s, 3H), 3.55 (t, J = 6.2 Hz, 2H), 3.05 (s, 3H), 2.94 (t, J = 6.2 Hz, 2H), 2.37 (d, J = 
               
               
                   
                 2.9 Hz, 3H). 
               
               
                 30 
                 LC-MS: (ES, m/z): RT = 0.929 min, LCMS28, m/z = 380 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.00 (dd, J = 9.0, 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = 
               
               
                   
                 20.3, 9.1 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 4.90-4.73 (m, 2H), 4.35-4.23 (m, 1H), 
               
               
                   
                 4.20-4.05 (m, 1H), 3.89 (d, J = 5.1 Hz, 4H), 3.75-3.63 (m, 1H), 2.98 (d, J = 2.8 Hz, 
               
               
                   
                 3H), 2.35-2.27 (m, 6H). 
               
               
                 31 
                 LC-MS: (ES, m/z): RT = 1.221 min, LCMS 07, m/z = 381 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.02 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.2 Hz, 0H), 7.42 (d, 
               
               
                   
                 J = 8.3 Hz, 1H), 6.07 (s, 1H), 5.05-4.99 (m, 3H), 4.64 (d, J = 12.0 Hz, 2H), 4.01 (d, 
               
               
                   
                 J = 8.4 Hz, 6H), 3.28 (d, J = 5.0 Hz, 4H), 3.00 (s, 3H), 2.35 (s, 3H). 
               
               
                 32 
                 LC-MS: (ES, m/z): RT = 1.81 min, LCMS 33: m/z = 366.2 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 7.87-7.68 (m, 3H), 7.35-7.25 (m, 1H), 6.05-5.98 (m, 1H), 3.89 (s, 
               
               
                   
                 3H), 3.61-3.50 (m, 2H), 2.98 (s, 3H), 2.73 (t, J = 6.3 Hz, 2H), 2.32 (d, J = 1.2 Hz, 3H), 
               
               
                   
                 2.19 (d, J = 6.3 Hz, 2H). 
               
               
                 33 
                 LC-MS: (ES, m/z): RT = 1.375 min, LCMS15, m/z = 360.2 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 12.38 (s, 1H), 11.16 (s, 1H), 10.22 (s, 1H), 8.92 (s, 1H), 7.63-7.52 (m, 
               
               
                   
                 2H), 7.43-7.29 (m, 2H), 7.25-7.07 (m, 2H), 7.04-6.95 (s, 1H), 6.20 (s, 1H), 6.01 (d, 
               
               
                   
                 J = 1.2 Hz, 1H), 3.72 (s, 3H), 2.85 (d, J = 4.6 Hz, 3H), 2.25 (s, 3H). 
               
               
                 35 
                 LC-MS: (ES, m/z): RT = 0.966 min, LCMS15, m/z = 362.2 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.58 (s, 1H), 8.93-8.88 (m, 1H), 8.56 (s, 1H), 8.11-8.05 (m, 1H), 
               
               
                   
                 7.88-7.75 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 6.06-6.00 (m, 1H), 3.89 (s, 3H), 3.00 (s, 
               
               
                   
                 3H), 2.33 (d, J = 0.9 Hz, 3H). 
               
               
                 36 
                 LC-MS: (ES, m/z): RT = 1.045 min, LCMS28, m/z = 362 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.75 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.28 (d, J = 5.7 Hz, 
               
               
                   
                 1H), 8.16 (s, 1H), 7.87 (dd, J = 5.7, 1.3 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.23 (d, 
               
               
                   
                 J = 9.1 Hz, 1H), 5.80 (s, 1H), 3.80 (s, 3H), 2.82 (s, 3H), 2.16 (s, 3H). 
               
               
                 37 
                 LC-MS: (ES, m/z): RT = 1.274 min LCMS 15, m/z = 361 [M + 1].  1 H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.85 (s, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.62-7.39 (m, 3H), 7.26-7.13 
               
               
                   
                 (m, 2H), 5.98 (d, J = 1.3 Hz, 1H), 3.82 (s, 3H), 2.94 (s, 3H), 2.30 (s, 3H). 
               
               
                 38 
                 LC-MS: (ES, m/z): RT = 1.077 min, LCMS 07: m/z = 363 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.37-9.16 (m, 1H), 8.97-8.77 (m, 1H), 8.46 (d, J = 4.9, 2.7 Hz, 1H), 
               
               
                   
                 8.35-8.21 (m, 1H), 7.72-7.49 (m, 1H), 7.33-7.21 (m, 1H), 6.07-5.91 (m, 1H), 3.97 
               
               
                   
                 (d, J = 12.7, 5.6, 2.5 Hz, 3H), 2.98 (d, J = 17.2, 8.0, 4.1 Hz, 3H), 2.35-2.24 (m, 3H). 
               
               
                 39 
                 LC-MS: (ES, m/z): RT = 1.358 min, LCMS45, m/z = 376 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.35 (s, 1H), 8.27 (s, 2H), 8.02 (dd, J = 9.0, 2.7 Hz, 1H), 7.70 (d, J = 2.7 
               
               
                   
                 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.25-5.94 (m, 1H), 3.87 (d, J = 2.1 Hz, 3H), 2.96 (s, 
               
               
                   
                 3H), 2.60 (s, 3H), 2.46-2.23 (m, 3H). 
               
               
                 40 
                 LC-MS: (ES, m/z): RT = 1.028 min, LCMS 28: m/z = 361 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.75 (s, 1H), 9.69 (s, 1H), 8.67 (d, J = 2.7 Hz, 1H), 8.41-8.21(m, 1H), 
               
               
                   
                 8.12 (d, J = 7.0 Hz, 1H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 5.97- 
               
               
                   
                 6.31 (m, 1H), 4.07 (s, 3H), 3.09 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H). 
               
               
                 41 
                 LC-MS: (ES, m/z): RT = 1.041 min, LCMS28, m/z = 362 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.18 (t, J = 1.1 Hz, 1H), 8.82 (d, J = 1.0 Hz, 1H), 8.55 (s, 1H), 8.09 (d, 
               
               
                   
                 J = 6.1 Hz, 1H), 7.77 (dd, J = 6.1, 1.4 Hz, 1H), 7.66 (dd, J = 9.0, 2.7 Hz, 1H), 7.23 (d, J = 
               
               
                   
                 9.1 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 3.91 (s, 3H), 2.91 (s, 3H), 2.18 (s, 3H). 
               
               
                 42 
                 LC-MS: (ES, m/z): RT = 0.847 min; LCMS48: m/z = 361 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 11.58 (s, 1H), 8.85 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.87- 
               
               
                   
                 7.76 (m, 1H), 7.56-7.38 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 6.88 (s, 1H), 6.55-6.41 
               
               
                   
                 (m, 1H), 5.74 (s, 1H), 3.75 (s, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.11 (s, 3H). 
               
               
                 43 
                 LC-MS: (ES, m/z): RT = 1.243 min; LCMS53: m/z = 367 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.14 (s, 1H), 7.82 (s, 1H), 7.52-7.50 (m, 1H), 7.13 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 5.85 (d, J = 0.8 Hz, 1H), 4.76 (d, J = 1.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.86 (s, 3H), 
               
               
                   
                 2.95-2.92 (m, 3H), 2.88-2.80 (m, 2H), 2.20 (s, 3H). 
               
               
                 45 
                 LC-MS: (ES, m/z): RT = 0.911 min, LCMS15: m/z = 280 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.49 (s, 1H), 7.77 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.20-7.10 (m, 2H), 
               
               
                   
                 6.90-6.85 (m, 1H), 5.82 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H), 3.87 (s, 3H), 2.91 (s, 3H), 2.20 
               
               
                   
                 (s, 3H), 2.04 (s, 3H). 
               
               
                 47 
                 LC-MS: (ES, m/z): RT = 0.997 min; LCMS53: m/z = 362 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.91 (d, J = 1.0 Hz, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 5.7 Hz, 
               
               
                   
                 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 5.84 (d, 
               
               
                   
                 J = 0.8 Hz, 1H), 4.09 (s, 3H), 2.94 (s, 3H), 2.21 (s, 3H). 
               
               
                 48 
                 LC-MS: (ES, m/z): RT = 1.092 min; m/z = 361 [M + 1]. 1H NMR (300 MHz, Methanol- 
               
               
                   
                 d4) δ 8.85-8.71 (m, 1H), 8.18-8.09 (m, 1H), 7.78-7.42 (m, 3H), 6.91 (d, J = 6.5 Hz, 
               
               
                   
                 2H), 5.66 (s, 1H), 3.86 (d, J = 2.3 Hz, 3H), 2.85-2.69 (m, 3H), 2.12-1.97 (m, 3H). 
               
               
                 50 
                 LC-MS: (ES, m/z): RT = 0.652 min; LCMS45: m/z = 367 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.73 (d, J = 2.5 Hz, 1H), 8.39-8.27 (m, 2H), 6.02 (d, J = 1.1 Hz, 1H), 
               
               
                   
                 4.38 (d, J = 1.1 Hz, 2H), 4.08 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 
               
               
                   
                 3.03 (s, 3H), 2.32 (s, 3H). 
               
               
                 54 
                 LC-MS: (ES, m/z): RT = 0.397 min, LCMS53: m/z = 382 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.87-7.63 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 
               
               
                   
                 4.19 (d, J = 3.2 Hz, 2H), 3.87 (s, 3H), 3.83-3.42 (m, 2H), 3.11 (s, 5H), 2.98 (d, J = 2.7 
               
               
                   
                 Hz, 3H), 2.44-2.29 (m, 3H). 
               
               
                 56 
                 LC-MS: (ES, m/z): RT = 0.966 min; LCMS 33: m/z = 366 [M + 1].  1 H NMR (300 MHz, 
               
               
                   
                 Methanol-d 4 ) δ 8.48 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.31 (d, 
               
               
                   
                 J = 9.0 Hz, 1H), 6.05 (d, J = 0.9 Hz, 1H), 3.98 (s, 3H), 3.63-3.53 (m, 2H), 3.10 (s, 
               
               
                   
                 3H), 3.00-2.85 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 2H). 
               
               
                 57 
                 LC-MS: (ES, m/z): RT = 0.935 min, LCMS53: m/z = 381.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.67 (s, 1H), 8.35 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 5.85 (d, J = 
               
               
                   
                 0.8 Hz, 1H), 4.02 (s, 3H), 3.74 (s, 2H), 3.06-2.88 (m, 7H), 2.61 (s, 3H), 2.20 (s, 3H). 
               
               
                 60 
                 LC-MS: (ES, m/z): RT = 1.116 min, LCMS 28: m/z = 364 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.33 (d, J = 1.4 Hz, 1H), 8.96-8.88 (m, 2H), 8.47 (d, J = 2.8 Hz, 1H), 
               
               
                   
                 8.30 (d, J = 4.6 Hz, 1H), 6.06 (s, 1H), 4.14 (s, 3H), 3.03 (s, 3H), 2.34 (s, 3H). 
               
               
                 61 
                 LC-MS: (ES, m/z): RT = 0.992 min, LCMS28, m/z = 369 [M + 1]. 1H-NMR: δ 9.08 (s, 
               
               
                   
                 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 
               
               
                   
                 6.01 (q, J = 0.8 Hz, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.02 (d, J = 3.4 Hz, 9H), 2.32 (d, J = 
               
               
                   
                 1.0 Hz, 3H). 
               
               
                 62 
                 LC-MS: (ES, m/z): RT = 0.97 min, LCMS28: m/z = 370.17 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 9.25-9.2 (m, 1H), 8.81-8.57 (m, 1H), 8.54-8.35 (m, 1H), 6.34- 
               
               
                   
                 6.00 (m, 1H), 4.60-4.55 (m, 2H), 4.16-4.13 (m, 3H), 3.05-2.96 (m, 9H), 2.57-2.26 
               
               
                   
                 (m, 3H). 
               
               
                 65 
                 LC-MS: (ES, m/z): RT = 1.412 min; LCMS07: m/z = 381 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.57 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 6.12 (s, 1H), 4.73-4.25 (m, 
               
               
                   
                 2H), 4.12 (s, 3H), 3.93-3.42 (m, 2H), 3.24 (t, J = 6.4 Hz, 2H), 3.18-2.95(m, 6H), 2.67- 
               
               
                   
                 2.36 (m, 3H). 
               
               
                 66 
                 LC-MS: (ES, m/z): RT = 0.974 min, LCMS33: m/z = 369.3 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 
               
               
                   
                 9.1 Hz, 1H), 6.03 (s, 1H), 4.58 (s, 2H), 3.99 (s, 3H), 3.08-2.99 (m, 9H), 2.34 (s, 3H). 
               
               
                 67 
                 LC-MS: (ES, m/z): RT = 1.008 min, LCMS28, m/z = 381 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.04 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.9, 2.3 Hz, 1H), 
               
               
                   
                 7.34 (d, J = 9.0 Hz, 1H), 6.02 (s, 1H), 4.62 (s, 2H), 4.36 (t, J = 8.2 Hz, 4H), 4.00 (s, 3H), 
               
               
                   
                 3.04 (s, 3H), 2.58 (s, 2H), 2.33 (s, 3H). 
               
               
                 68 
                 LC-MS: (ES, m/z): RT = 1.766 min, LCMS28, m/z = 399 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.05 (s, 1H), 8.18 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 9.0, 2.6 Hz, 1H), 
               
               
                   
                 7.34 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 5.63-5.30 (m, 1H), 4.81-4.66 (m, 
               
               
                   
                 4H), 4.59-4.46 (m, 2H), 4.00 (s, 3H), 3.04 (s, 3H), 2.33 (s, 3H). 
               
               
                 69 
                 LC-MS: (ES, m/z): RT = 0.933 min; LCMS07: m/z = 422 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 DMSO-d6) δ 8.93 (s, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.07 (d, 
               
               
                   
                 J = 9.0 Hz, 1H), 6.92 (s, 1H), 5.75 (s, 1H), 4.60 (t, J = 6.5 Hz, 2H), 4.50 (t, J = 6.1 Hz, 
               
               
                   
                 2H), 3.78 (s, 3H), 3.65 (t, J = 6.4 Hz, 1H), 3.37 (s, 2H), 2.84 (d, J = 4.5 Hz, 3H), 2.70 (t, 
               
               
                   
                 J = 5.7 Hz, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.10 (s, 3H). 
               
               
                 70 
                 LC-MS: (ES, m/z): RT = 0.999 min; LCMS33: m/z = 394 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.17 (s, 1H), 7.86 (s, 1H), 7.61-7.48 (m, 1H), 7.11 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 5.82 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.26-2.82 (m, 7H), 2.82-2.7 (m, 2H), 2.18 (s, 
               
               
                   
                 3H), 1.25 (t, J = 7.2 Hz, 3H). 
               
               
                 73 
                 LC-MS: (ES, m/z): RT = 1.663 min, LCMS15: m/z = 369.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.75-7.65 (m, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.05- 
               
               
                   
                 5.98 (m, 1H), 4.49 (s, 2H), 4.08 (s, 3H), 3.01 (s, 9H), 2.32 (d, J = 0.9 Hz, 3H). 
               
               
                 74 
                 LC-MS: (ES, m/z): RT = 0.992 min; LCMS33: m/z = 369 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.86-8.52 (m, 2H), 8.49-8.19 (m, 1H), 8.05-7.73 (m, 1H), 6.15- 
               
               
                   
                 5.79 (m, 1H), 4.34 (s, 2H), 4.11 (s, 3H), 3.02 (d, J = 5.1 Hz, 3H), 2.90 (s, 6H), 2.33 (d, 
               
               
                   
                 J = 1.0 Hz, 3H). 
               
               
                 75 
                 LC-MS: (ES, m/z): RT = 1.161 min, LCMS 33: m/z = 408.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 7.74-7.70 (m, 2H), 7.58-7.50 (m, 1H), 7.33-7.28 (m, 1H), 
               
               
                   
                 6.01 (d, J = 2.4 Hz, 1H), 4.56 (d, J = 3.3 Hz, 2H), 3.96-3.75 (m, 5H), 2.97 (d, J = 7.2 
               
               
                   
                 Hz, 3H), 2.79 (t, J = 5.7 Hz, 2H), 2.32 (t, J = 5.8 Hz, 3H), 2.22 (s, 3H). 
               
               
                 76 
                 LC-MS: (ES, m/z): RT = 1.462 min; LCMS28: m/z = 382 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.73-7.61 (m, 3H), 7.45-7.15 (m, 1H), 6.45-6.40 (m, 1H), 5.81(s, 
               
               
                   
                 1H), 4.24 (s, 2H), 3.95 (s, 3H), 2.97 (s, 3H), 2.44 (s, 3H), 1.97-1.73 (m, 3H). 
               
               
                 77 
                 LC-MS: (ES, m/z): RT = 1.290 min, LCMS 07, m/z = 467 [M + 1]. 1H-NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.87-7.75 (m, 2H), 7.22 (d, J = 9.2, 2.5 Hz, 1H), 5.98-5.97 (m, 0H), 
               
               
                   
                 5.96 (s, 1H), 4.868 (s, 2H), 3.98 (d, J = 6.2, 4.5 Hz, 2H), 3.93-3.82 (m, 5H), 2.94 (s, 
               
               
                   
                 3H), 2.27 (s, 3H), 1.54 (s, 10H). 
               
               
                 78 
                 LC-MS: (ES, m/z): RT = 1.426 min, LCMS28, m/z = 366 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.05 (d, J = 2.5 Hz, 1H), 7.94-7.69 (m, 1H), 7.34 (d, J = 9.1 Hz, 1H), 
               
               
                   
                 6.01 (d, J = 1.0 Hz, 1H), 4.42 (s, 2H), 4.07 (d, J = 5.9 Hz, 3H), 3.65 (t, J = 6.0 Hz, 2H), 
               
               
                   
                 3.13 (t, J = 6.0 Hz, 2H), 2.97 (s, 3H), 2.32 (s, 3H). 
               
               
                 79 
                 LC-MS: (ES, m/z): RT = 0.923 min, LCMS28, m/z = 380 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.07 (d, J = 2.6 Hz, 1H), 7.86 (dd, J = 9.0, 2.6 Hz, 1H), 7.33 (d, J = 9.1 
               
               
                   
                 Hz, 1H), 6.01 (d, J = 1.0 Hz, 1H), 4.50 (s, 2H), 4.07 (d, J = 5.8 Hz, 3H), 3.72 (t, J = 6.0 
               
               
                   
                 Hz, 2H), 3.16 (d, J = 14.2 Hz, 5H), 2.98 (d, J = 4.6 Hz, 3H), 2.32 (d, J = 1.0 Hz, 3H). 
               
               
                 81 
                 LC-MS: (ES, m/z): RT = 5.04 min, HPLC 07, m/z = 393.2 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.69 (d, J = 2.7 Hz, 1H), 7.50 (dd, J = 8.9, 2.7 Hz, 1H), 7.04 (d, J = 8.9 
               
               
                   
                 Hz, 1H), 6.47 (d, J = 1.1 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 3.74 (s, 3H), 3.49 (t, J = 1.5 
               
               
                   
                 Hz, 2H), 2.87 (s, 3H), 2.76 (t, J = 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.52 (s, 3H), 
               
               
                   
                 2.18 (s, 3H), 2.01 (d, J = 1.0 Hz, 3H). 
               
               
                 82 
                 LC-MS: (ES, m/z): RT = 1.045 min, LCMS33: m/z = 406.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.82 (s, 1H), 7.54-7.50 (m, 1H), 7.10 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 5.80 (d, J = 0.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 0.9 Hz, 2H), 3.06 (t, J = 6.0 
               
               
                   
                 Hz, 2H), 2.90-2.84 (m, 5H), 2.17 (s, 3H), 2.04-1.91 (m, 1H), 0.67-0.48 (m, 4H). 
               
               
                 83 
                 LC-MS: (ES, m/z): RT = 1.021 min, LCMS28, m/z = 380 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.29 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.9, 2.8 Hz, 1H), 7.13 (d, J = 8.9 
               
               
                   
                 Hz, 1H), 6.84 (s, 1H), 5.97 (s, 1H), 4.65 (s, 2H), 4.52 (t, J = 5.9 Hz, 2H), 3.92 (d, J = 3.6 
               
               
                   
                 Hz, 5H), 3.15 (s, 3H), 3.02 (s, 3H), 2.30 (s, 3H). 
               
               
                 84 
                 LC-MS: (ES, m/z): RT = 1.015 min, LCMS28, m/z = 366 [M + H]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.25 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.9, 2.8 Hz, 1H), 7.18-7.07 (m, 
               
               
                   
                 1H), 6.85 (d, J = 1.0 Hz, 1H), 6.01-5.94 (m, 1H), 4.58 (d, J = 0.9 Hz, 2H), 4.53-4.43 
               
               
                   
                 (m, 2H), 3.93 (s, 3H), 3.88-3.79 (m, 2H), 3.02 (s, 3H), 2.29 (d, J = 1.0 Hz, 3H). 
               
               
                 86 
                 LC-MS: (ES, m/z): RT = 2.172 min, LCMS27: m/z = 426.1 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 9.16 (s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 5.94 (d, J = 0.8 Hz, 1H), 
               
               
                   
                 4.73-4.70 (m, 2H), 4.50 (t, J = 6.1 Hz, 2H), 4.07 (s, 3H), 3.78-3.70 (m, 4H), 2.35 (s, 
               
               
                   
                 7H), 2.21 (s, 3H). 
               
               
                 87 
                 LC-MS: (ES, m/z): RT = 1.376 min, LCMS07: m/z = 451 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.17 (s, 1H), 7.84 (s, 1H), 7.56-7.51(m, 1H) 7.11 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 5.82 (s, 1H), 3.85 (s, 3H), 3.68 (d, J = 6.3 Hz, 2H), 3.59 (s, 2H), 2.95-2.80 (m, 4H), 
               
               
                   
                 2.64 (s, 3H), 2.51 (s, 3H), 2.44-2.40 (m, 2H), 2.16 (s, 3H). 
               
               
                 88 
                 LC-MS: (ES, m/z): RT = 1.24 min, LCMS 33: m/z = 492 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.20-8.13 (m, 2H), 7.39-7.38 (m, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.03 
               
               
                   
                 (d, J = 1.1 Hz, 1H), 4.62 (s, 1H), 4.34 (s, 1H), 3.94 (s, 3H), 3.82 (t, J = 8.2 Hz, 3H), 3.65 
               
               
                   
                 (d, J = 7.2 Hz, 2H), 3.52 (d, J = 5.4 Hz, 3H), 3.31 (s, 2H), 3.16-3.14 (m, 4H), 2.68 (s, 
               
               
                   
                 3H), 2.34 (d, J = 0.9 Hz, 3H). 
               
               
                 93 
                 LC-MS: (ES, m/z): RT = 1.268 min, LCMS28, m/z = 362 [M + H]. 1H NMR (300 MHz, 
               
               
                   
                 DMSO-d6) δ 9.18 (d, J = 1.4 Hz, 1H), 8.93 (s, 1H), 8.81-8.66 (m, 2H), 7.88 (d, J = 4.7 
               
               
                   
                 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 1.0 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 6.96 (s, 1H), 5.76 (s, 1H), 3.89 (s, 3H), 2.91 (s, 3H), 2.12 (s, 3H). 
               
               
                 94 
                 LC-MS: (ES, m/z): RT = 2.462 min, LCMS31, m/z = 396 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.11 (d, J = 2.7 Hz, 1H), 7.91 (d, J = 14.9 Hz, 1H), 7.44 (dd, J = 8.9, 2.7 
               
               
                   
                 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.00 (d, J = 1.1 Hz, 1H), 4.43 (d, J = 6.6 Hz, 2H), 
               
               
                   
                 3.93 (d, J = 5.6 Hz, 3H), 3.00 (d, J = 15.7 Hz, 3H), 2.44-2.28 (m, 3H), 2.13 (d, J = 0.9 
               
               
                   
                 Hz, 3H), 1.99 (s, 3H). 
               
               
                 95 
                 LC-MS: (ES, m/z): RT = 1.113 min; LCMS07: m/z = 382 [M + 1]. 1H-NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.19-8.05 (m, 2H), 7.49-7.39 (m, 1H), 7.51-7.13(m, 1H), 6.61- 
               
               
                   
                 6.29 (m, 1H), 5.85 (s, 1H), 4.61-4.33 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H), 2.54-2.19 
               
               
                   
                 (m, 3H), 2.01 (s, 3H). 
               
               
                 96 
                 LC-MS: (ES, m/z): RT = 3.599 min; LCMS07: m/z = 396 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.23-8.06 (m, 2H), 7.57-7.43 (m, 1H), 7.45-7.06 (m, 1H), 6.48- 
               
               
                   
                 6.36 (m, 1H), 5.87 (s, 1H), 4.63 (s, 2H), 3.97-3.89 (m, 3H), 3.21-2.87 (m, 6H), 2.51- 
               
               
                   
                 2.17 (m, 6H). 
               
               
                 99 
                 LC-MS: RT = 1.04 min, LCMS 28: m/z = 376 [M + 1]. 1H-NMR: (Methanol-d4, ppm): 
               
               
                   
                 δ 9.83 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 7.1 Hz, 
               
               
                   
                 1H), 7.73 (dd, J = 9.0, 2.7 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.04 (s, 1H), 4.06 (s, 3H), 
               
               
                   
                 3.16 (s, 3H), 3.09 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H). 
               
               
                 100 
                 LC-MS: (ES, m/z): RT = 2.13 min, LCMS 28: m/z = 392 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 9.09 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H), 7.85-7.74 (m, 1H), 7.62 (dd, J = 9.0, 
               
               
                   
                 2.7 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 6.6, 1.0 Hz, 1H), 6.02 (s, 1H), 4.25 
               
               
                   
                 (s, 3H), 4.01 (s, 3H), 3.05 (s, 3H), 2.33 (s, 3H). 
               
               
                 102 
                 LC-MS: (ES, m/z): RT = 1.124 min, LCMS45, m/z = 382 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.08 (s, 1H), 7.99 (s, 1H), 7.61 (dd, J = 8.9, 2.9 Hz, 1H), 7.27 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 6.00 (s, 1H), 4.38 (s, 2H), 3.94 (s, 3H), 2.98 (d, J = 7.9 Hz, 9H), 2.31 (s, 3H), 
               
               
                   
                 2.22 (d, J = 0.8 Hz, 3H). 
               
               
                 103 
                 LC-MS: (ES, m/z): RT = 2.178 min, LCMS15: m/z = 382 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.58 (d, J = 6.0 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.47-7.42 (m, J = 5.1 
               
               
                   
                 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.97 (d, J = 6.9 Hz, 3H), 
               
               
                   
                 3.03 (s, 3H), 2.88 (s, 3H), 2.49 (s, 3H), 2.32 (d, J = 0.9 Hz, 3H). 
               
               
                 104 
                 LC-MS: (ES, m/z): RT = 1.16 min, LCMS33: m/z = 368.18 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.87-8.54 (m, 1H), 8.29-7.91 (m, 2H), 7.65-7.4 (m, 1H), 7.39- 
               
               
                   
                 7.12 (m, 1H), 6.35-5.65 (m, 1H), 4.12-3.85 (m, 3H), 2.95-3.18 (m, 3H), 2.92 (s, 3H), 
               
               
                   
                 2.49-2.25 (m, 3H). 
               
               
                 105 
                 LC-MS: (ES, m/z): RT = 0.11 min, LCMS28: m/z = 396.21 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 7.89 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 9.0, 2.7 Hz, 1H), 7.14 (d, 
               
               
                   
                 J = 9.1 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 3.80 (s, 3H), 2.92 (s, 3H), 2.87 (s, 3H), 2.39 (s, 
               
               
                   
                 3H), 2.26 (s, 3H), 2.19 (s, 3H). 
               
               
                 106 
                 LC-MS: (ES, m/z): RT = 0.99 min, LCMS28: m/z = 382.23 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.85 (s, 1H), 7.70 (dd, J = 9.0, 2.8 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 5.82 (d, J = 0.8 Hz, 1H), 3.76 (d, J = 8.2 Hz, 5H), 2.86 (s, 3H), 2.52 (s, 3H), 2.30 (s, 
               
               
                   
                 3H), 2.17 (d, J = 7.9 Hz, 6H). 
               
               
                 108 
                 LC-MS: (ES, m/z): RT = 0.942 min; LCMS53: m/z = 354 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.40 (s, 1H), 8.25-8.15 (m, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.55 (d, J = 
               
               
                   
                 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 4.21 (d, J = 2.1 Hz, 2H), 
               
               
                   
                 3.95 (s, 3H), 3.00 (s, 3H), 2.74 (s, 3H), 2.31 (s, 3H). 
               
               
                 109 
                 LC-MS: (ES, m/z): RT = 0.948; LCMS53: m/z = 368 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.46 (s, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.85 (s, 1H), 7.56 (d, J = 8.9 Hz, 
               
               
                   
                 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.00 (d, J = 1.1 Hz, 1H), 4.34 (s, 2H), 3.95 (s, 3H), 3.01 
               
               
                   
                 (s, 3H), 2.90 (s, 6H), 2.31 (d, J = 0.9 Hz, 3H). 
               
               
                 113 
                 LC-MS: (ES, m/z): RT = 0.85 min, LCMS 27: m/z = 366.0 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 7.89 (d, J = 2.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.48 (s, 1H), 7.12 (d, 
               
               
                   
                 J = 9.0 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 3.91 (s, 2H), 3.79 (s, 3H), 3.08 (t, J = 5.7 Hz, 
               
               
                   
                 2H), 2.86 (s, 3H), 2.61 (t, J = 5.7 Hz, 2H), 2.18 (s, 3H). 
               
               
                 116 
                 LC-MS: (ES, m/z): RT = 1.637 min, LCMS28, m/z = 397 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.50 (s, 1H), 6.74 (s, 1H), 4.16-4.07 (m, 
               
               
                   
                 2H), 3.99 (s, 3H), 3.83-3.72 (m, 4H), 3.47-3.53 (m, 1H), 3.01 (s, 3H), 2.36 (s, 6H), 
               
               
                   
                 1.99-1.77 (m, 4H). 
               
               
                 117 
                 LC-MS: (ES, m/z): RT = 1.659 min; LCMS07: m/z = 369 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.74 (s, 1H), 8.49 (s, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 
               
               
                   
                 1H), 5.71 (s, 1H), 3.91 (s, 3H), 2.98 (s, 3H), 2.90 (s, 3H), 2.18 (s, 3H). 
               
               
                 119 
                 LC-MS: (ES, m/z): RT = 1.22 min, LCMS 33: m/z = 362 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.67 (d, J = 1.2 Hz, 1H), 8.54-8.45 (m, 1H), 8.04-7.88 (m, 2H), 7.75- 
               
               
                   
                 7.51 (m, 2H), 7.37 (d, J = 9.3 Hz, 1H), 6.01 (q, J = 0.9 Hz, 1H), 3.87 (d, J = 5.7 Hz, 
               
               
                   
                 3H), 2.97 (d, J = 7.2 Hz, 3H), 2.32 (d, J = 1.2 Hz, 3H). 
               
               
                 121 
                 LC-MS: (ES, m/z): RT = 1.568 min, LCMS15: m/z = 381.2 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.69-7.67 (m, 1H), 7.36 
               
               
                   
                 (d, J = 9.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 4.62 (s, 2H), 4.30-4.28 (m, 4H), 3.98 (s, 
               
               
                   
                 3H), 3.03 (s, 3H), 2.65-2.45 (m, 2H), 2.33 (s, 3H). 
               
               
                 122 
                 LC-MS: (ES, m/z): RT = 0.912 min, LCMS 28, m/z = 313.2 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.80 (s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.02 (s, 1H), 4.48 (s, 2H), 4.13 
               
               
                   
                 (s, 3H), 3.20 (s, 3H), 2.85 (s, 3H), 2.76 (s, 3H). 
               
               
                 125 
                 LC-MS: (ES, m/z): RT = 0.957 min, LCMS 28, m/z = 339.1 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.79 (s, 1H), 8.42 (s, 1H), 7.68 (s, 1H), 7.01 (s, 1H), 5.07-4.99 (m, 
               
               
                   
                 1H), 4.12 (s, 3H), 3.61-3.46 (m, 2H), 3.20 (s, 3H), 2.76 (s, 3H), 2.66-2.54 (m, 1H), 
               
               
                   
                 2.51-2.32 (m, 2H), 2.31-2.17 (m, 1H). 
               
               
                 134 
                 LC-MS: (ES, m/z): RT = 2.426 min, LCMS34, m/z = 382 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 DMSO-d6) δ 10.52 (s, 1H), 8.85 (q, J = 4.6 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.84-8.87 
               
               
                   
                 (m, 1H), 7.98-7.95 (m, 1H), 7.46 (dd, J = 8.9, 2.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 6.02 (d, J = 1.1 Hz, 1H), 2.90 (d, J = 4.6 Hz, 3H), 2.74 (d, J = 4.7 Hz, 3H), 2.25 (s, 6H). 
               
               
                 136 
                 LC-MS: (ES, m/z): RT = 1.66 min, LCMS 15: m/z = 395.2 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.72 (s, 1H), 8.36 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.36 (d, 
               
               
                   
                 J = 9.0 Hz, 1H), 6.03 (q, J = 0.9 Hz, 1H), 4.74 (t, J = 9.0 Hz, 1H), 3.98 (s, 4H), 3.40 (t, 
               
               
                   
                 J = 9.6 Hz, 1H), 3.03 (d, J = 5.1 Hz, 6H), 2.75-2.51 (m, 2H), 2.33 (d, J = 0.9 Hz, 5H). 
               
               
                 137 
                 LC-MS: (ES, m/z): RT = 1.06 min, LCMS 33: m/z = 381 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.65-8.55 (m, 1H), 8.32 (d, J = 2.7 Hz, 1H), 7.80-7.60 (m, 1H), 7.36 
               
               
                   
                 (d, J = 9.0 Hz, 1H), 6.03 (q, J = 0.9 Hz, 1H), 5.04-4.92 (m, 1H), 3.96 (d, J = 7.2 Hz, 
               
               
                   
                 3H), 3.57-3.43 (m, 2H), 3.03 (s, 3H), 2.67-2.13 (m, 7H). 
               
               
                 138 
                 LC-MS: (ES, m/z): RT = 0.910 min, LCMS 07, m/z = 383 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.04 (s, 1H), 7.75 (d, J = 9.0, 2.8 Hz, 1H), 7.18 (d, J = 9.1 Hz, 1H), 5.83 
               
               
                   
                 (d, J = 0.7 Hz, 1H), 3.79 (s, 3H), 3.48 (s, 2H), 2.85 (s, 3H), 2.42 (s, 3H), 2.18 (s, 3H), 
               
               
                   
                 2.08 (s, 6H). 
               
               
                 139 
                 LC-MS: (ES, m/z): RT = 0.976 min, LCMS 27, m/z = 383 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.02 (s, 1H), 7.75 (d, J = 9.0, 2.8 Hz, 1H), 7.21 (d, J = 9.1 Hz, 1H), 5.83 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 2H), 2.85 (s, 3H), 2.36 (s, 6H), 2.24 (s, 3H), 
               
               
                   
                 2.18 (s, 3H). 
               
               
                 143 
                 LC-MS: (ES, m/z): RT = 1.694 min; LCMS15: m/z = 397 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.42 (s, 1H), 8.30 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 
               
               
                   
                 1H), 5.82 (s, 1H), 3.88 (d, J = 5.7 Hz, 5H), 2.89 (s, 3H), 2.61 (q, J = 7.2 Hz, 4H), 2.18 
               
               
                   
                 (s, 3H), 1.16 (t, J = 7.2 Hz, 6H). 
               
               
                 144 
                 LC-MS: (ES, m/z): RT = 1.381 min, LCMS27: m/z = 375.0 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.57 (d, J = 1.0 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.63-7.46 (m, 
               
               
                   
                 3H), 7.34 (d, J = 9.0 Hz, 1H), 7.28-7.17 (m, 1H), 6.05-5.97 (m, 1H), 3.97 (s, 3H), 
               
               
                   
                 3.00 (s, 3H), 2.47-2.37 (m, 3H), 2.31 (d, J = 0.9 Hz, 3H). 
               
               
                 145 
                 LC-MS: (ES, m/z): RT = 2.711 min, LCMS33: m/z = 401.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.47 (d, J = 1.0 Hz, 1H), 8.37 (s, 1H), 7.63-7.60 (m, 1H), 7.56- 
               
               
                   
                 7.53 (m, 1H), 7.45 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.13-7.10 (m, 1H), 5.81 (s, 1H), 
               
               
                   
                 3.87 (s, 3H), 2.88 (s, 3H), 2.18 (s, 3H), 2.06-1.96 (m, 1H), 1.04-0.88 (m, 2H), 0.83- 
               
               
                   
                 0.68 (m, 2H). 
               
               
                 146 
                 LC-MS: (ES, m/z): RT = 1.094 min, LCMS32: m/z = 361.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.28 (d, J = 3.4 Hz, 1H), 7.78-7.75 (m, 
               
               
                   
                 1H), 7.75-7.53 (m, 2H), 7.45-7.29 (m, 2H), 7.14-7.12 (m, 1H), 6.03 (d, J = 1.2 Hz, 
               
               
                   
                 1H), 4.00 (s, 3H), 3.03 (s, 3H), 2.34 (d, J = 1.0 Hz, 3H). 
               
               
                 148 
                 LC-MS: (ES, m/z): RT = 1.737 min, LCMS33: m/z = 441.1 [M + 1]. 1H-NMR: (CDCl3, 
               
               
                   
                 ppm): 1H NMR (300 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.33 (s, 1H), 8.00 (d, J = 3.0 
               
               
                   
                 Hz, 1H), 7.63-7.58 (m, 2H), 7.49-7.31 (m, 2H), 6.02 (s, 1H), 3.99 (s, 3H), 3.03 (s, 
               
               
                   
                 3H), 2.33 (s, 3H). 
               
               
                 151 
                 LC-MS: (ES, m/z): RT = 1.085 min, LCMS28, m/z = 376 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 9.74 (s, 1H), 9.60 (s, 1H), 8.52 (d, J = 2.7 Hz, 1H), 8.24-8.12 (m, 1H), 
               
               
                   
                 7.61 (dd, J = 9.1, 2.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.93 (s, 
               
               
                   
                 3H), 2.96 (s, 3H), 2.59 (s, 3H), 2.24 (s, 3H). 
               
               
                 155 
                 LC-MS: (ES, m/z): RT = 1.028 min; LCMS27: m/z = 375 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.76 (s, 1H), 7.65 (s, 1H), 7.58-7.46 (m, 2H), 7.54-7.23 (m, 1H), 
               
               
                   
                 7.18-6.89 (m, 1H), 5.80 (s, 1H), 3.78 (s, 3H), 2.90 (s, 3H), 2.60 (s, 3H), 2.19 (s, 3H). 
               
               
                 156 
                 LC-MS: (ES, m/z): RT = 1.58 min, LCMS28: m/z = 374.19 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 7.63 (d, J = 2.7 Hz, 1H), 7.50-7.31 (m, 3H), 7.19-7.00 (m, 2H), 6.29- 
               
               
                   
                 5.75 (m, 1H), 3.88-3.78 (m, 3H), 3.02-2.91 (m, 3H), 2.5-2.36 (m, 3H), 2.28 (d, 
               
               
                   
                 J = 1.0 Hz, 3H). 
               
               
                 157 
                 LC-MS: (ES, m/z): RT = 1.125 min, LCMS28: m/z = 361 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.98 (s, 1H), 8.20 (d, J = 6.7 Hz, 2H), 8.08 (d, J = 6.5 Hz, 1H), 7.79 (d, 
               
               
                   
                 J = 9.4 Hz, 1H), 7.45-7.33 (m, 2H), 6.05 (s, 1H), 4.14 (s, 3H), 3.00 (s, 3H), 2.35 (s, 
               
               
                   
                 3H). 
               
               
                 158 
                 LC-MS: (ES, m/z): RT = 1.090 min; LCMS28: m/z = 375 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.14 (s, 1H), 8.42 (d, J = 6.8, 1.0 Hz, 1H), 8.08 (d, J = 6.8, 0.8 Hz, 1H), 
               
               
                   
                 7.85 (dd, J = 9.0, 2.7 Hz, 1H), 7.69-7.54 (m, 1H), 7.36-7.18 (m, 1H), 7.14-7.05 (m, 
               
               
                   
                 1H), 6.32-5.95 (m, 1H), 3.95-3.79 (m, 3H), 3.83 (s, 3H), 3.24-3.07 (m, 3H), 2.39- 
               
               
                   
                 2.26 (m, 3H). 
               
               
                 159 
                 LC-MS: (ES, m/z): RT = 1.879 min; LCMS33: m/z = 355 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.62 (s, 1H), 8.38-8.31 (m, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.37 (d, J = 
               
               
                   
                 9.1 Hz, 1H), 6.06-6.01 (m, 1H), 4.45 (s, 2H), 3.98 (d, J = 0.8 Hz, 3H), 3.03 (s, 3H), 
               
               
                   
                 2.83 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H). 
               
               
                 160 
                 LC-MS: (ES, m/z): RT = 1.420 min, LCMS 07: m/z = 382 [M + 1]. 1H-NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.46 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.50-7.46(m, 1H), 7.29 (d, J = 
               
               
                   
                 2.4 Hz, 1H), 6.04 (s, 1H), 4.32 (s, 2H), 3.98 (s, 3H), 3.05 (s, 3H), 2.92 (s, 6H), 2.44- 
               
               
                   
                 2.31 (m, 6H). 
               
               
                 161 
                 LC-MS: (ES, m/z): RT = 1.016 min, LCMS28, m/z = 367 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.26 (d, J = 2.7 Hz, 1H), 7.50-7.40 (m, 1H), 7.19-7.03 (m, 2H), 5.99 
               
               
                   
                 (q, J = 0.7 Hz, 1H), 4.41 (d, J = 2.3 Hz, 2H), 3.96 (d, J = 9.6 Hz, 6H), 3.03 (s, 3H), 2.82 
               
               
                   
                 (s, 3H), 2.30 (s, 3H). 
               
               
                 163 
                 LC-MS: (ES, m/z): RT = 1.501 min; LCMS53: m/z = 316 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.18 (s, 1H), 7.45 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.01 (s, 0H), 3.88 (s, 
               
               
                   
                 3H), 3.73 (s, 2H), 3.57 (d, J = 1.3 Hz, 3H), 3.27 (s, 0H), 3.04 (s, 3H), 2.34 (s, 6H). 
               
               
                 164 
                 LC-MS: (ES, m/z): RT = 0.932 min, LCMS27, m/z = 369 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.43 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 
               
               
                   
                 7.20 (dd, J = 9.1, 2.9 Hz, 1H), 5.83 (d, J = 1.0 Hz, 1H), 3.98-4.03 (m, 1H), 3.90 (d, J = 
               
               
                   
                 1.8 Hz, 3H), 2.91 (s, 3H), 2.38 (d, J = 1.5 Hz, 3H), 2.19 (s, 3H), 1.53 (d, J = 6.8 Hz, 
               
               
                   
                 3H). 
               
               
                 165 
                 LC-MS: RT = 1.077 min; m/z = 423.2 [M + 1]. 1H NMR (400 MHz, Methanol-d4) δ 8.77 
               
               
                   
                 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.67 (dd, J = 9.0, 2.7 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 
               
               
                   
                 6.17-6.02 (m, 1H), 5.46 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.03 (s, 3H), 2.73 (s, 3H), 
               
               
                   
                 2.34 (s, 3H). 
               
               
                 166 
                 LC-MS: (ES, m/z): RT = 1.526 min, LCMS 33, m/z = 383 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.62 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.7 Hz, 
               
               
                   
                 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.98 (s, 3H), 3.03 (s, 3H), 2.63 
               
               
                   
                 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 1.86 (s, 6H). 
               
               
                 169 
                 LC-MS: (ES, m/z): RT = 0.95 min, LCMS 33: m/z = 353 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 7.84 (d, J = 2.7 Hz, 1H), 7.63-7.53 (m, 2H), 7.26 (d, J = 9.0 Hz, 1H), 6.92 
               
               
                   
                 (s, 1H), 6.19 (d, J = 7.3 Hz, 1H), 4.38 (s, 2H), 4.02 (s, 3H), 3.05-2.85 (m, 9H). 
               
               
                 170 
                 LC-MS: (ES, m/z): RT = 0.95 min, LCMS 27: m/z = 354 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.10 (s, 1H), 7.77-7.58 (m, 4H), 7.34 (d, J = 9.0 Hz, 1H), 6.21 (d, J = 7.3 
               
               
                   
                 Hz, 1H), 4.33 (s, 2H), 3.93 (s, 3H), 2.97 (d, J = 20.4 Hz, 9H). 
               
               
                 171 
                 LC-MS: (ES, m/z): RT = 0.875 min, LCMS07, m/z = 355.10 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.75 (s, 1H), 8.32 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 
               
               
                   
                 9.0 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.59 (s, 2H), 3.99 (s, 3H), 3.05 (s, 3H), 2.99 (s, 
               
               
                   
                 6H). 
               
               
                 172 
                 LC-MS: (ES, m/z): RT = 0.907 min, LCMS27: m/z = 355.0 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.33 (s, 1H), 7.74 (s, 1H), 7.65-7.60 (m, 1H), 7.21 
               
               
                   
                 (d, J = 9.1 Hz, 1H), 5.95 (d, J = 6.1 Hz, 1H), 3.98-3.90 (m, 5H), 2.92 (s, 3H), 2.76 (q, 
               
               
                   
                 J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H). 
               
               
                 173 
                 LC-MS: (ES, m/z): RT = 1.015 min, LCMS28: m/z = 381.2 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.28 (s, 1H), 7.68-7.60 (m, 2H), 7.40 (d, J = 9.1 
               
               
                   
                 Hz, 1H), 6.23 (d, J = 7.3 Hz, 1H), 4.49 (s, 2H), 4.00 (s, 3H), 3.11-3.02 (m, 5H), 1.24- 
               
               
                   
                 1.12 (m, 1H), 0.82-0.72 (m, 2H), 0.51-0.42 (m, 2H). 
               
               
                 174 
                 LC-MS: (ES, m/z): RT = 0.953 min, LCMS28: m/z = 348.1 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 9.11 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H), 8.03 (s, 1H), 
               
               
                   
                 7.90 (t, J = 1.2 Hz, 1H), 7.71 (d, J = 6.2 Hz, 1H), 7.70-7.65 (m, 1H), 7.09 (d, J = 8.9 
               
               
                   
                 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 2.89 (s, 3H). 
               
               
                 175 
                 LC-MS: (ES, m/z): RT = 1.621 min, LCMS15: m/z = 347.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 9.14 (d, J = 0.7 Hz, 1H), 8.11-8.02 (m, 1H), 7.93-7.73 (m, 
               
               
                   
                 3H), 7.63 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.11-7.09 (m, 1H), 6.20 (d, J = 
               
               
                   
                 7.3 Hz, 1H), 3.96 (s, 3H), 3.00 (s, 3H). 
               
               
                 176 
                 LC-MS: (ES, m/z): RT = 2.222 min, LCMS15: m/z = 338.2 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.21 (s, 1H), 8.16 (s, 1H), 7.65-7.53 (m, 2H), 7.34 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 6.20 (d, J = 7.3 Hz, 1H), 3.97 (s, 3H), 3.04 (s, 3H), 2.08-2.01 (m, 1H), 1.09- 
               
               
                   
                 0.98 (m, 2H), 0.93-0.84 (m, 2H). 
               
               
                 177 
                 LC-MS: (ES, m/z): RT = 1.828 min; LCMS28: m/z = 354 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.46-8.36 (m, 1H), 8.26 (s, 1H), 7.71-7.56 (m, 2H), 7.40-7.27 (m, 
               
               
                   
                 1H), 6.20 (dd, J = 7.3, 1.9 Hz, 1H), 5.10 (dd, J = 8.5, 5.9 Hz, 2H), 4.99-4.90 (m, 2H), 
               
               
                   
                 4.55 (tt, J = 8.5, 7.0 Hz, 1H), 4.03-3.91 (m, 3H), 3.08 (s, 3H). 
               
               
                 178 
                 LC-MS: (ES, m/z): RT = 1.214 min, LCMS27: m/z = 346.0 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 7.71 (s, 2H), 7.61-7.46 (m, 3H), 7.28-7.18 (m, 2H), 7.03 (d, 
               
               
                   
                 J = 8.9 Hz, 1H), 6.51-6.41 (m, 1H), 5.91 (d, J = 6.0 Hz, 1H), 3.78 (s, 3H), 2.92 (s, 3H). 
               
               
                 179 
                 LC-MS: (ES, m/z): RT = 0.790 min; LCMS33: m/z = 301 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.32 (d, J = 0.7 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 
               
               
                   
                 1H), 4.24 (s, 2H), 4.01 (s, 3H), 3.73 (s, 3H), 3.18 (s, 3H), 2.77 (s, 3H). 
               
               
                 181 
                 LC-MS: (ES, m/z): RT = 1.839 min; LCMS33: m/z = 340 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.46 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 1.8 Hz, 
               
               
                   
                 1H), 7.51-7.48 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 4.23 (s, 2H), 
               
               
                   
                 3.99 (s, 3H), 3.04 (s, 3H), 2.76 (s, 3H). 
               
               
                 182 
                 LC-MS: (ES, m/z): RT = 1.47 min, LCMS 31: m/z = 356 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.72 (d, J = 2.4 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.86 (s, 
               
               
                   
                 1H), 6.08-6.01 (m, 1H), 4.23 (s, 2H), 4.12 (s, 3H), 3.02 (s, 3H), 2.76 (s, 3H), 2.34 (s, 
               
               
                   
                 3H). 
               
               
                 184 
                 LC-MS: (ES, m/z): RT = 1.503 min, LCMS 33, m/z = 382.3 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 6.98 (s, 1H), 
               
               
                   
                 4.25 (s, 2H), 4.19-4.10 (m, 5H), 3.86-3.75 (m, 2H), 3.68 (t, J = 11.8 Hz, 1H), 3.20 (s, 
               
               
                   
                 3H), 2.77 (s, 3H), 2.08-1.81 (m, 5H). 
               
               
                 185 
                 LC-MS: (ES, m/z): RT = 1.019 min, LCMS07: m/z = 354 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.47 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.62 (d, 
               
               
                   
                 J = 3.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.34-7.31 (m, 1H), 6.21 (d, J = 2.7 Hz, 1H), 4.23 (s, 
               
               
                   
                 2H), 3.99 (d, J = 1.5 Hz, 3H), 3.22-2.18 (m, 5H), 1.37-1.34 (m, 3H). 
               
               
                 186 
                 LC-MS: (ES, m/z): RT = 0.871 min, LCMS33: m/z = 312.2 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.04 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 
               
               
                   
                 7.14 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 2.76-2.65 (m, 2H), 2.62-2.40 (m, 6H), 2.36- 
               
               
                   
                 2.28 (m, 1H). 
               
               
                 187 
                 LC-MS: (ES, m/z): RT = 1.320 min; LCMS53: m/z = 326 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.40 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 4.21 (s, 2H), 4.03 
               
               
                   
                 (s, 3H), 3.22 (s, 3H), 2.84-2.78 (m, 5H), 2.74-2.62 (m, 3H), 2.37-2.32 (m, 1H). 
               
               
                 188 
                 LC-MS: (ES, m/z): RT = 0.981 min, LCMS15: m/z = 381.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H), 6.05 (s, 1H), 
               
               
                   
                 4.74 (t, J = 7.5 Hz, 1H), 4.11 (s, 3H), 3.50-3.39 (m, 2H), 3.00 (s, 3H), 2.57-2.38 (m, 
               
               
                   
                 1H), 2.36-2.15 (m, 6H). 
               
               
                 191 
                 LC-MS: (ES, m/z): RT = 1.01 min, LCMS28: m/z = 381.21 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.40 (s, 1H), 8.30 (s, 1H), 7.74 (s, 1H), 7.62 (dd, J = 9.0, 2.7 Hz, 1H), 
               
               
                   
                 7.21 (d, J = 9.0 Hz, 1H), 5.95 (d, J = 6.1 Hz, 1H), 3.92-3.86 (m, 5H), 3.43-3.33 (m, 
               
               
                   
                 1H), 2.92 (s, 3H), 2.28-2.18 (m, 2H), 1.92-1.65 (m, 4H). 
               
               
                 192 
                 LC-MS: (ES, m/z): RT = 0.96 min, LCMS 28: m/z = 353 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.60 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.99 (t, J = 7.8 Hz, 1H), 4.05 (s, 3H), 
               
               
                   
                 3.62-3.41 (m, 2H), 3.25 (s, 3H), 2.95-2.84 (m, 2H), 2.84-2.62 (m, 4H), 2.67-2.16 
               
               
                   
                 (m, 4H). 
               
               
                 193 
                 LC-MS: (ES, m/z): RT = 0.86 min, LCMS 07: m/z = 339 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.59 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H), 
               
               
                   
                 3.60-3.43 (m, 2H), 2.96-2.81 (m, 2H), 2.79-2.63 (m, 3H), 2.59-2.53 (m, 1H), 2.49- 
               
               
                   
                 2.16 (m, 4H). 
               
               
                 194 
                 LC-MS: (ES, m/z): RT = 0.94 min, LCMS 28: m/z = 339 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.59 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 
               
               
                   
                 3H), 3.60-3.43 (m, 2H), 2.98-2.82 (m, 2H), 2.79-2.51 (m, 4H), 2.49-2.16 (m, 4H). 
               
               
                 195 
                 LC-MS: (ES, m/z): RT = 0.87 min, LCMS 07: m/z = 339 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.58 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 
               
               
                   
                 3H), 3.60-3.43 (m, 2H), 2.96-2.81 (m, 2H), 2.79-2.63 (m, 3H), 2.67-2.51 (m, 1H), 
               
               
                   
                 2.49-2.32 (m, 3H), 2.35-2.16 (m, 1H). 
               
               
                 196 
                 LC-MS: (ES, m/z): RT = 0.938 min, LCMS07, m/z = 409 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.80 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 18.4 Hz, 1H), 7.77 (d, J = 8.7 Hz, 
               
               
                   
                 1H), 7.05 (s, 1H), 5.08-4.98 (m, 1H), 4.16-4.12 (m, 4H), 4.05 (s, 1H), 3.78-3.85 
               
               
                   
                 (m, 2H), 3.67-3.74 (m, 1H), 3.58-3.47 (m, 2H), 3.21 (d, J = 2.0 Hz, 3H), 2.69-2.57 
               
               
                   
                 (m, 1H), 2.49-2.23 (m, 3H), 2.05-1.97 (m, 2H), 1.84-1.93 (m, 2H). 
               
               
                 199 
                 LC-MS: (ES, m/z): RT = 1.128 min, LCMS28, m/z = 379 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.75 (dd, J = 2.5, 1.1 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 5.7 
               
               
                   
                 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.59 (dd, J = 5.7, 1.1 Hz, 1H), 7.16 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 5.85 (d, J = 0.8 Hz, 1H), 4.00 (s, 3H), 2.92 (s, 3H), 2.22 (s, 3H). 
               
               
                 200 
                 LC-MS: (ES, m/z): RT = 1.180 min, LCMS28: m/z = 375 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.90 (t, J = 0.8 Hz, 1H), 8.20 (dd, J = 6.5, 0.8 Hz, 1H), 8.10 (dd, J = 6.5, 
               
               
                   
                 0.8 Hz, 1H), 7.87 (dd, J = 9.0, 2.7 Hz, 1H), 7.83-7.70 (m, 1H), 7.33 (d, J = 9.0 Hz, 
               
               
                   
                 1H), 6.02 (d, J = 1.1 Hz, 1H), 3.95 (s, 3H), 2.96 (s, 3H), 2.45 (s, 3H), 2.33 (d, J = 1.0 
               
               
                   
                 Hz, 3H). 
               
               
                 201 
                 LC-MS: (ES, m/z): RT = 4.116 min, HPLC06: m/z = 362 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.05 (s, 1H), 8.96 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.82 (dd, J = 9.0, 2.7 
               
               
                   
                 Hz, 1H), 7.44-7.28 (m, 2H), 6.03 (d, J = 1.1 Hz, 1H), 4.13 (s, 3H), 3.01 (s, 3H), 2.34 
               
               
                   
                 (s, 3H). 
               
               
                 202 
                 LC-MS: (ES, m/z): RT = 1.00 min, LCMS53: m/z = 319 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.97 (s, J = 0.9 Hz, 1H), 8.30-8.05 (m, 2H), 7.75 (s, 1H), 7.70 (s, 1H) 7.39 
               
               
                   
                 (s, 1H), 4.22 (s, 3H), 2.97-2.84 (m, 2H), 2.81-2.64 (m, 3H), 2.49-2.35 (m, 1H). 
               
               
                 203 
                 LC-MS: (ES, m/z): RT = 0.579 min, LCMS 07, m/z = 362 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.02 (s, 1H), 8.64-8.56 (m, 2H), 8.23 (d, J = 6.5, 0.8 Hz, 1H), 8.15- 
               
               
                   
                 8.08 (m, 1H), 7.52 (s, 1H), 6.07 (s, 1H), 4.25 (s, 3H), 2.98 (s, 3H), 2.36 (s, 3H). 
               
               
                 204 
                 LC-MS: (ES, m/z): RT = 0.579 min, LCMS 07, m/z = 362 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.02 (s, 1H), 8.64-8.56 (m, 2H), 8.23 (d, J = 6.5, 0.8 Hz, 1H), 8.15- 
               
               
                   
                 8.08 (m, 1H), 7.52 (s, 1H), 6.07 (s, 1H), 4.25 (s, 3H), 2.98 (s, 3H), 2.36 (s, 3H). 
               
               
                 205 
                 LC-MS: (ES, m/z): RT = 0.787 min, LCMS 07: m/z = 324 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 0.8 Hz, 
               
               
                   
                 1H), 6.81 (s, 1H), 6.23 (s, 1H), 4.03 (s, 3H), 3.97 (d, 1H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 
               
               
                   
                 (t, J = 6.3 Hz, 2H), 2.01 (d, 2H), 1.42 (t, J = 5.9 Hz, 2H). 
               
               
                 206 
                 LC-MS: (ES, m/z): RT = 1.018 min, LCMS27: m/z = 361.0 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.34-8.30 (m, 1H), 7.87 
               
               
                   
                 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.48-7.40 (m, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.83 (s, 
               
               
                   
                 1H), 6.57 (s, 1H), 5.73 (s, 1H), 3.78 (s, 3H), 2.83 (d, J = 4.5 Hz, 3H), 2.09 (s, 3H). 
               
               
                 207 
                 LC-MS: (ES, m/z): RT = 0.781 min, LCMS28: m/z = 375 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ8.95 (s, 1H), 8.00-7.74 (m, 3H), 7.42-7.27 (m, 1H), 6.84-6.77 (m, 
               
               
                   
                 1H), 6.06 (d, J = 1.1 Hz, 1H), 3.97 (d, J = 3.3 Hz, 3H), 2.99 (s, 3H), 2.63 (d, J = 1.1 Hz, 
               
               
                   
                 3H), 2.35 (d, J = 1.0 Hz, 3H). 
               
               
                 208 
                 LC-MS: (ES, m/z): RT = 0.739 min, LCMS 07: m/z = 324 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 0.8 Hz, 
               
               
                   
                 1H), 6.81 (s, 1H), 6.23 (s, 1H), 4.03 (s, 4H), 3.97 (d, 2H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 
               
               
                   
                 (t, J = 6.3 Hz, 2H), 2.01 (d, 2H). 
               
               
                 209 
                 LC-MS: (ES, m/z): RT = 1.079 min, LCMS 28: m/z = 308 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.14 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 3.4 Hz, 1H), 7.65 (s, 1H), 7.44 (s, 
               
               
                   
                 1H), 7.15-7.09 (m, 1H), 4.01 (s, 3H), 3.76 (s, 3H), 3.20 (s, 3H). 
               
               
                 210 
                 LC-MS: (ES, m/z): RT = 1.000 min, LCMS28: m/z = 362 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.29 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 7.98-7.84 (m, 2H), 7.39-7.27 
               
               
                   
                 (m, 1H), 6.21-6.02 (m, 1H), 3.97 (s, 3H), 2.99 (s, 3H), 2.43 (s, 1H), 2.54-2.15 (m, 
               
               
                   
                 2H). 
               
               
                 212 
                 LC-MS: (ES, m/z): RT = 0.941 min, LCMS07, m/z = 381 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.42 (s, 1H), 8.30 (s, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 7.20 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 4.38 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.22-3.11 (m, 
               
               
                   
                 1H), 3.07-2.96 (m, 1H), 2.91 (s, 3H), 2.38-2.24 (m, 1H), 2.19 (s, 3H), 2.09-1.89 
               
               
                   
                 (m, 3H). 
               
               
                 213 
                 LC-MS: (ES, m/z): RT = 0.952 min, LCMS07, m/z = 381 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.41 (s, 1H), 8.29 (s, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 7.19 (d, J = 9.0 
               
               
                   
                 Hz, 1H), 5.83 (s, 1H), 4.37 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.16-3.19 (m, 1H), 3.07- 
               
               
                   
                 2.96 (m, 1H), 2.91 (s, 3H), 2.38-2.24 (m, 1H), 2.19 (s, 3H), 2.08-1.89 (m, 3H). 
               
               
                 214 
                 LC-MS: (ES, m/z): RT = 1.10 min, LCMS28: m/z = 333 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 9.16 (s, 1H), 8.04 (s, 1H), 7.90 (d, J = 3.3 Hz, 1H), 7.75 (s, 1H), 7.40 (s, 
               
               
                   
                 1H), 7.13 (dd, J = 3.4, 0.8 Hz, 1H), 4.04 (s, 3H), 3.26 (s, 3H), 2.97-2.40 (m, 6H). 
               
               
                 215 
                 LC-MS: (ES, m/z): RT = 1.107 min, LCMS28: m/z = 333 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 5.6, 1.1 
               
               
                   
                 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.95 (d, J = 0.9 Hz, 1H), 4.08 (s, 3H), 3.06 (s, 3H), 
               
               
                   
                 2.71-2.57 (m, 2H), 2.60-2.44 (m, 3H), 2.30 (tq, J = 9.7, 5.6, 4.8 Hz, 1H). 
               
               
                 216 
                 LC-MS: (ES, m/z): RT = 1.148 min, LCMS28: m/z = 367 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.71 (d, J = 1.1 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.58 (dd, J = 5.6, 1.1 
               
               
                   
                 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 3.96 (s, 3H), 3.06 (s, 3H), 2.74-2.62 (m, 2H), 2.64- 
               
               
                   
                 2.43 (m, 3H), 2.35-2.22 (m, 1H). 
               
               
                 217 
                 LC-MS: (ES, m/z): RT = 2.121 min, LCMS28: m/z = 351[M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.05 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.12 (dd, J = 6.6, 0.8 
               
               
                   
                 Hz, 1H), 7.80 (d, J = 1.4 Hz, 2H), 4.19 (s, 3H), 3.25 (s, 3H), 2.93-2.62 (m, 5H), 2.48- 
               
               
                   
                 2.35 (m, 1H). 
               
               
                 218 
                 LC-MS: (ES, m/z): RT = 2.136 min, LCMS53: m/z = 376.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.55-7.51 (m, 1H), 7.27-7.24 (m, 1H), 7.16- 
               
               
                   
                 7.15 (m, 1H), 7.09-6.98 (m, 1H), 7.01 (d, J = 8.9 Hz, 1H), 5.79 (d, J = 0.7 Hz, 1H), 
               
               
                   
                 3.77 (s, 3H), 3.34-3.16 (m, 2H), 2.88 (s, 3H), 2.17 (s, 3H). 
               
               
                 219 
                 LC-MS: (ES, m/z): RT = 0.969 min, LCMS33: m/z = 377.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.47 (s, 1H), 
               
               
                   
                 7.34 (d, J = 9.1 Hz, 1H), 6.02 (s, 1H), 3.96 (s, 3H), 2.97 (s, 3H), 2.33 (s, 3H). 
               
               
                 220 
                 LC-MS: (ES, m/z): RT = 0.977 min, LCMS07: m/z = 391.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.49-7.41 (m, 2H), 6.87 
               
               
                   
                 (d, J = 2.4 Hz, 1H), 6.72 (s, 1H), 5.85 (s, 1H), 3.72 (s, 3H), 3.37 (s, 3H), 2.97 (s, 3H), 
               
               
                   
                 2.21 (s, 3H). 
               
               
                 221 
                 LC-MS: (ES, m/z): RT = 1.022 min, LCMS33: m/z = 379.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 9.23 (s, 1H), 8.03-7.98 (m, 3H), 7.24-7.18 (m, 2H), 6.05 (s, 
               
               
                   
                 1H), 3.94 (s, 3H), 2.94 (s, 3H), 2.34 (s, 3H). 
               
               
                 222 
                 LC-MS: (ES, m/z): RT = 0.926 min, LCMS33: m/z = 384 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.61 (d, J = 2.8 Hz, 1H), 7.79 (s, 2H), 6.92 (d, J = 3.2 Hz, 1H), 5.86 (s, 
               
               
                   
                 1H), 3.90 (s, 2H), 3.76 (s, 3H), 3.44 (s, 3H), 2.95 (s, 3H), 2.54 (s, 3H), 2.20 (s, 3H). 
               
               
                 223 
                 LC-MS: (ES, m/z): RT = 1.757 min, LCMS53: m/z = 361 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.49 (d, J = 1.9 Hz, 1H), 8.05-7.98 (m, 1H), 7.86 (s, 1H), 7.65-7.53 
               
               
                   
                 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.69-6.60 (m, 1H), 5.83 (s, 1H), 3.83 (s, 3H), 2.92 
               
               
                   
                 (s, 3H), 2.21 (s, 3H). 
               
               
                 225 
                 LC-MS: (ES, m/z): RT = 1.022 min, LCMS33: m/z = 352.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.43 (d, J = 1.2 Hz, 1H), 8.10-8.02 (m, 1H), 7.69-7.66 (m, 
               
               
                   
                 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 1.2 Hz, 1H), 5.79 (d, J = 0.7 Hz, 1H), 3.85 (s, 
               
               
                   
                 3H), 2.94 (s, 3H), 2.89 (s, 3H), 2.17 (s, 3H). 
               
               
                 227 
                 LC-MS: (ES, m/z): RT = 0.875 min, LCMS07: m/z = 326 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 6.81 (s, 1H), 4.03 (s, 4H), 3.97 
               
               
                   
                 (d, 2H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 (t, J = 6.3 Hz, 3H), 2.01 (d, 2H), 1.86 (t, J = 5.9 
               
               
                   
                 Hz, 2H), 1.42 (t, J = 6.3 Hz, 2H). 
               
               
                 228 
                 LC-MS: (ES, m/z): RT = 0.668 min, LCMS30: m/z = 375 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 7.66 (dd, J = 8.9, 2.8 Hz, 1H), 7.60 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 2.7 
               
               
                   
                 Hz, 1H), 7.53 (d, J = 3.3 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 3.2, 1.0 Hz, 
               
               
                   
                 1H), 5.83-5.75 (m, 1H), 3.75 (s, 3H), 2.85 (s, 3H), 2.42 (s, 3H), 2.18 (s, 3H). 
               
               
                 229 
                 LC-MS: (ES, m/z): RT = 1.203 min, LCMS28: m/z = 379 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.24 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.96-7.84 (m, 2H), 7.78 (d, J = 
               
               
                   
                 2.9 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 3.96 (s, 2H), 2.99 (s, 
               
               
                   
                 2H), 2.36-2.31 (m, 2H). 
               
               
                 230 
                 LC-MS: (ES, m/z): RT = 1.055 min, LCMS33, m/z = 366 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.05 (s, 1H), 7.67 (dd, J = 8.9, 2.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 
               
               
                   
                 6.69 (s, 1H), 5.80 (d, J = 0.7 Hz, 1H), 3.84 (s, 3H), 2.93 (d, J = 16.2 Hz, 6H), 2.48 (s, 
               
               
                   
                 3H), 2.18 (s, 3H). 
               
               
                 231 
                 LC-MS: (ES, m/z): RT = 0.926 min, LCMS15: m/z = 323 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.96 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.01 (d, 
               
               
                   
                 J = 3.3 Hz, 1H), 6.54-6.46 (m, 2H), 3.94 (m, 3H), 3.84-3.74 (m, 1H), 3.55-3.45 (m, 
               
               
                   
                 2H), 3.27-3.17 (m, 2H), 2.35-2.24 (m, 2H), 1.85-1.69 (m, 2H). 
               
               
                 232 
                 LC-MS: (ES, m/z): RT = 1.356 min, LCMS15: m/z = 363 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.92 (d, J = 4.0 Hz, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.76-7.71 (m, 1H), 
               
               
                   
                 7.11 (d, J = 8.0 Hz, 1H), 5.82 (s, 1H), 3.91 (s, 3H), 2.92 (s, 3H), 2.19-2.05 (m, 4H), 
               
               
                   
                 1.20-1.13 (m, 4H). 
               
               
                 233 
                 LC-MS: (ES, m/z): RT = 1.215 min, LCMS15 m/z = 363 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.01 (s, 1H), 8.01 (s, 1H), 7.95-7.87 (m, 1H), 7.81-7.62 (m, 1H), 
               
               
                   
                 7.33-7.21 (m, 1H), 6.23-5.97 (m, 1H), 3.97-3.90 (d, J = 6.0 Hz, 3H), 3.02-2.96 
               
               
                   
                 (m, 3H), 2.45-2.29 (m, 3H), 2.20-2.11 (m, 1H), 1.41-1.30 (m, 2H), 1.14-1.04 (m, 
               
               
                   
                 2H). 
               
               
                 234 
                 LC-MS: (ES, m/z): RT = 0.98 min, LCMS27: m/z = 361.9 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.14-9.02 (m, 2H), 8.44 (s, 1H), 8.10 (t, J = 1.2 Hz, 1H), 7.83 (d, J = 
               
               
                   
                 1.2 Hz, 1H), 7.66 (q, J = 2.7 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 5.82 (d, J = 0.9 Hz, 1H), 
               
               
                   
                 3.94 (s, 3H), 2.95 (s, 3H), 2.19 (s, 3H). 
               
               
                 235 
                 LC-MS: (ES, m/z): RT = 2.256 min, LCMS15: m/z = 363 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 12.79-11.73(m, 2H), 10.27 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.25 (s, 
               
               
                   
                 1H), 8.13 (s, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 6.01 (s, 1H), 3.88 
               
               
                   
                 (s, 3H), 2.93 (d, J = 4.0 Hz, 3H), 2.26 (s, 3H). 
               
               
                 236 
                 LC-MS: (ES, m/z): RT = 0.942 min, LCMS34: m/z = 325 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.73 (s, 1H), 7.67 (s, 1H), 7.57-7.51(m, 1H), 6.44-6.37(m, 
               
               
                   
                 2H), 3.84 (s, 3H), 3.63-3.51(m, 1H), 3.27-3.15 (m, 2H), 2.88-2.82 (m, 2H), 2.19- 
               
               
                   
                 2.07 (m, 2H), 2.05-1.95(m, 1H), 1.59-1.44 (m, 2H), 1.28-1.16 (m, 2H), 0.99-0.86 
               
               
                   
                 (m, 2H). 
               
               
                 238 
                 LC-MS: (ES, m/z): RT = 1.313 min, LCMS28, m/z = 347 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 
               
               
                   
                 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94-2.80 (m, 
               
               
                   
                 2H), 2.78-2.63 (m, 3H), 2.43 (s, 4H). 
               
               
                 241 
                 LC-MS: (ES, m/z): RT = 3.62 min, HPLC05: m/z = 345 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.01 (q, J = 0.9 Hz, 1H), 8.25 (q, J = 6.6 Hz, 1H), 8.14 (d, J = 6.3 Hz, 
               
               
                   
                 1H), 7.94-7.80 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.19-7.10 (m, 1H), 6.07-6.00 (m, 
               
               
                   
                 1H), 2.99 (s, 3H), 2.52 (s, 3H), 2.34 (s, 3H). 
               
               
                 242 
                 LC-MS: (ES, m/z): RT = 0.971 min, LCMS15: m/z = 335 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.91 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.26-8.35(m, 2H), 7.82-7.87 
               
               
                   
                 (m, 1H), 7.55-7.39 (m, 3H), 5.88 (s, 1H), 2.95 (s, 3H), 2.22 (s, 3H). 
               
               
                 243 
                 LC MS: (ES, m/z): RT = 0.810 min, LCMS28: m/z = 307 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.02 (s, 1H), 8.30 (m, 2H), 8.16-8.06 (m, 1H), 7.12 (d, J = 15.9 Hz, 
               
               
                   
                 1H), 6.97 (s, 1H), 4.12 (s, 1H), 3.54 (d, J = 12.1 Hz, 2H), 3.21 (s, J = 12.5 Hz, 2H), 2.53 
               
               
                   
                 (d, J = 12.3 Hz, 3H), 2.36-2.27 (m, 2H), 1.85 (s, 2H). 
               
               
                 244 
                 LC-MS: (ES, m/z): RT = 1.08 min, LCMS 33: m/z = 363 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Chloroform-d) δ 8.85 (s, 1H), 8.83-8.24 (m, 2H), 8.09 (s, 1H), 7.61 (d, J = 8.7 Hz, 
               
               
                   
                 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 6.3 Hz, 1H), 5.84 (s, 1H), 2.89 (s, 3H), 2.83 
               
               
                   
                 (q, J = 9.0 Hz, 2H), 2.20 (s, 3H), 1.24 (t, J = 0.9 Hz, 3H). 
               
               
                 245 
                 LC-MS: (ES, m/z): RT = 1.122 min, LCMS28: m/z = 370 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 11.18 (s, 1H), 9.42-9.35 (m, 2H), 9.10 (dd, J = 5.9, 1.0 Hz, 1H), 8.33 (s, 
               
               
                   
                 1H), 8.06 (dd, J = 5.9, 2.7 Hz, 1H), 7.93-7.85 (m, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.06 
               
               
                   
                 (s, 1H), 5.84 (s, 1H), 2.78 (d, J = 4.7 Hz, 3H), 2.14 (s, 3H). 
               
               
                 246 
                 LC-MS: (ES, m/z): RT = 1.341 min, LCMS28: m/z = 375 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 12.62 (s, 1H), 9.33 (s, 1H), 8.15 (s, 1H), 7.97 (dd, J = 8.9, 2.6 Hz, 1H), 
               
               
                   
                 7.54 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 3.5 Hz, 1H), 7.05 (s, 1H), 
               
               
                   
                 5.84 (s, 1H), 2.79 (d, J = 4.6 Hz, 3H), 2.14 (s, 3H). 
               
               
                 247 
                 LC-MS: (ES, m/z): RT = 0.760 min, LCMS07: m/z = 308 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 2H), 7.51 (d, J = 0.8 Hz, 
               
               
                   
                 1H), 6.81 (s, 1H), 4.23 (s, 1H), 4.03 (s, 2H), 3.97 (d, 2H), 3.12 (d, J = 7.5 Hz, 5H), 2.86 
               
               
                   
                 (t, J = 6.3 Hz, 2H), 2.01 (d, 1H). 
               
               
                 248 
                 LC-MS: (ES, m/z): RT = 1.183 min, LCMS33: m/z = 370 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.00 (dd, J = 4.8, 1.4 Hz, 1H), 8.66-8.58 (m, 1H), 8.16 (d, J = 2.6 Hz, 
               
               
                   
                 1H), 7.79 (dd, J = 9.1, 4.8 Hz, 1H), 7.71 (dd, J = 8.8, 2.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 
               
               
                   
                 1H), 6.07 (d, J = 1.1 Hz, 1H), 3.02 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H). 
               
               
                 249 
                 LC-MS: (ES, m/z): RT = 1.181 min, LCMS28: m/z = 359 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.25 (s, 1H), 7.79-7.68 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.15 (s, 1H), 
               
               
                   
                 5.88 (s, 1H), 2.92 (s, 3H), 2.21 (s, 3H). 
               
               
                 250 
                 LC-MS: (ES, m/z): RT = 1.274 min, LCMS27: m/z = 368 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.23 (s, 1H), 7.78-7.64 (m, 3H), 7.45-7.32 (m, 3H), 7.24-7.11 (m, 
               
               
                   
                 1H), 5.87 (d, J = 0.7 Hz, 1H), 2.91 (s, 3H), 2.21 (s, 3H). 
               
               
                 251 
                 LC-MS: (ES, m/z): RT = 1.04 min, LCMS27: m/z = 369.9 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.52 (d, J = 1.5 Hz, 1H), 8.47-8.35 (m, 2H), 8.29-8.22 (m, 1H), 7.77 
               
               
                   
                 (q, J = 2.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 5.88 (s, 1H), 2.90 (s, 3H), 2.21 (s, 3H). 
               
               
                 252 
                 LC-MS: (ES, m/z): RT = 1.36 min, LCMS28: m/z = 375 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): 8.86 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 
               
               
                   
                 7.69 (dd, J = 8.8, 2.7 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 6.07 (d, J = 1.1 Hz, 1H), 3.01 (s, 
               
               
                   
                 3H), 2.34 (s, 3H). 
               
               
                 253 
                 LC-MS: (ES, m/z): RT = 2.424 min, LCMS07: m/z = 358.7 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.26 (d, J = 1.1 Hz, 1H), 8.05 (dd, J = 13.5, 1.9 Hz, 2H), 7.69 (dd, J = 
               
               
                   
                 8.8, 2.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 6.07 (s, 1H), 3.01 (s, 3H), 2.34 (s, 3H). 
               
               
                 254 
                 LC-MS: (ES, m/z): RT = 1.10 min, LCMS28: m/z = 371 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): 8.68 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.98-7.85 (m, 1H), 7.60- 
               
               
                   
                 7.49 (m, 2H), 6.06 (d, J = 1.0 Hz, 1H), 3.96 (s, 3H), 3.01 (s, 3H), 2.35 (s, 3H). 
               
               
                 255 
                 LC-MS: (ES, m/z): RT = 2.004 min, LCMS28: m/z = 365 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.24 (d, J = 3.8 Hz, 1H), 8.13-8.05 (m, 2H), 8.01 (d, J = 2.7 Hz, 1H), 
               
               
                   
                 7.94 (d, J = 3.3 Hz, 1H), 7.76-7.64 (m, 1H), 7.17 (dd, J = 3.4, 0.9 Hz, 1H), 6.07 (d, J = 
               
               
                   
                 1.1 Hz, 1H), 2.99 (d, J = 7.7 Hz, 3H), 2.38-2.33 (m, 3H). 
               
               
                 256 
                 LC-MS: (ES, m/z): RT = 1.716 min, LCMS53: m/z = 345 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.19 (d, J = 0.9 Hz, 1H), 7.96 (t, J = 0.8 Hz, 1H), 7.93-7.87 (m, 2H), 
               
               
                   
                 7.85-7.78 (m, 1H), 7.49 (dd, J = 15.3, 8.4 Hz, 1H), 7.15 (dd, J = 3.4, 0.9 Hz, 1H), 6.23- 
               
               
                   
                 6.03 (m, 1H), 2.97 (d, J = 3.5 Hz, 3H), 2.46-2.26 (m, 6H). 
               
               
                 257 
                 LC-MS: (ES, m/z): RT = 1.342 min, LCMS53: m/z = 292 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.20 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 3.4 Hz, 
               
               
                   
                 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.16 (dd, J = 3.4, 0.9 Hz, 1H), 3.73 (s, 3H), 3.20 (s, 3H), 
               
               
                   
                 2.42 (d, J = 0.6 Hz, 3H). 
               
               
                 258 
                 LC-MS: (ES, m/z): RT = 0.91 min, LCMS 27: m/z = 370 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.68 (d, J = 4.8 Hz, 2H), 8.25 (s, 1H), 7.74 (q, J = 2.7 Hz, 1H), 7.37 (d, 
               
               
                   
                 J = 8.7 Hz, 1H), 7.23 (t, J = 4.9 Hz, 1H), 5.87 (d, J = 0.9 Hz, 1H), 2.90 (s, 3H), 2.21 (s, 
               
               
                   
                 3H). 
               
               
                 259 
                 LC-MS: (ES, m/z): RT = 1.02 min, LCMS 53: m/z = 369.9 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.92-8.85 (m, 1H), 8.70 (q, J = 5.7 Hz, 1H), 8.33 (q, J = 5.7 Hz, 1H), 
               
               
                   
                 8.25 (s, 1H), 7.77 (q, J = 2.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 5.88 (d, J = 0.9 Hz, 1H), 
               
               
                   
                 2.90 (s, 3H), 2.21 (s, 3H). 
               
               
                 260 
                 LC-MS: (ES, m/z): RT = 1.797 min, LCMS31: m/z = 381.2 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.33 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 4.3 Hz, 1H), 7.77-7.73 (m, 
               
               
                   
                 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 5.84 (s, 1H), 3.36 (s, 2H), 2.86 (s, 3H), 2.18 
               
               
                   
                 (s, 3H). 
               
               
                 261 
                 LC-MS: (ES, m/z): RT = 0.969 min, LCMS33: m/z = 377.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.47 (s, 1H), 
               
               
                   
                 7.34 (d, J = 9.1 Hz, 1H), 6.02 (s, 1H), 3.96 (s, 3H), 2.97 (s, 3H), 2.33 (s, 3H). 
               
               
                 262 
                 LC-MS: (ES, m/z): RT = 1.03 min, LCMS 27: m/z = 358 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.32-8.15 (m, 2H), 7.95-7.86 (m, 1H), 7.77 (q, J = 8.7 Hz, 1H), 7.65 
               
               
                   
                 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 1.2 Hz, 1H), 4.24 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H), 
               
               
                   
                 2.35 (d, J = 0.9 Hz, 3H). 
               
               
                 263 
                 LC-MS: (ES, m/z): RT = 1.04 min, LCMS28: m/z = 224 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 9.07-9.00 (m, 1H), 8.26 (dd, J = 6.5, 0.8 Hz, 1H), 8.14 (dd, J = 6.4, 0.8 Hz, 
               
               
                   
                 1H), 7.52-7.37 (m, 2H), 7.28 (dd, J = 8.2, 2.4 Hz, 1H), 7.11 (d, J = 0.8 Hz, 1H), 2.49 
               
               
                   
                 (s, 3H). 
               
               
                 264 
                 LC-MS: (ES, m/z): RT = 0.970 min, LCMS 27: m/z = 225.0 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.95 (s, 1H), 8.22 (d, J = 6.5 Hz, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.25 (d, 
               
               
                   
                 J = 8.5 Hz, 1H), 7.08-7.02 (m, 2H), 6.91 (dd, J = 8.3, 2.7 Hz, 1H), 2.41 (s, 3H). 
               
               
                 266 
                 LC-MS: (ES, m/z): RT = 1.137 min, LCMS 07: m/z = 280 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.82 (s, 1H), 7.45 (d, J = 9.0, 2.8 Hz, 2H), 6.91 (d, J = 9.1 Hz, 2H), 6.73 
               
               
                   
                 (d, J = 0.8 Hz, 1H), 4.61 (s, 2H), 2.21 (s, 3H). 
               
               
                 267 
                 LC-MS: (ES, m/z): RT = 0.74 min, LCMS33: m/z = 210.15 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.75 (s, 1H), 8.68 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.13 (d, J = 5.6 Hz, 
               
               
                   
                 1H), 7.67 (dd, J = 5.6, 1.1 Hz, 1H), 7.47 (d, J = 5.3 Hz, 1H), 6.79 (d, J = 0.8 Hz, 1H), 
               
               
                   
                 2.70-2.42 (m, 3H). 
               
               
                 268 
                 LC-MS: (ES, m/z): RT = 0.659 min, LCMS 07, m/z = 210 [M + H]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.95 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.40 
               
               
                   
                 (d, 1H), 6.72 (s, 1H), 2.35 (s, 3H). 
               
               
                 271 
                 LC-MS: (ES, m/z): RT = 1.849 min, LCMS33: m/z = 370 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.26 (s, 1H), 8.53 (d, J = 6.4 Hz, 1H), 8.32 (d, J = 6.4 Hz, 1H), 7.93- 
               
               
                   
                 7.90 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 6.04 (s, 1H), 2.99 (s, 3H), 2.47-2.34 (m, 6H). 
               
               
                 273 
                 LC-MS: (ES, m/z): RT = 1.428 min, LCMS53: m/z = 231 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.87 (s, 1H), 8.17 (d, J = 6.5 Hz, 1H), 8.05 (d, J = 6.5 Hz, 1H), 7.13 (s, 
               
               
                   
                 1H), 2.61 (s, 3H). 
               
               
                 274 
                 LC-MS: (ES, m/z): RT = 1.806 min, LCMS53: m/z = 344 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 7.91 (s, 1H), 7.62-7.50 (m, 2H), 7.44-7.34 (m, 1H), 7.21 (d, J = 8.3 
               
               
                   
                 Hz, 1H), 7.16-7.04 (m, 1H), 7.07-6.95 (m, 1H), 6.52 (d, J = 0.9 Hz, 1H), 5.81 (d, J = 
               
               
                   
                 0.7 Hz, 1H), 2.89 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H). 
               
               
                 275 
                 LC-MS: (ES, m/z): RT = 1.062 min, LCMS28: m/z = 231 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.91-8.84 (m, 1H), 8.26-8.15 (m, 1H), 8.08-8.97 (m, 1H), 7.06 (d, 
               
               
                   
                 J = 0.8 Hz, 1H), 2.55 (s, 3H). 
               
               
                 276 
                 LC-MS: (ES, m/z): RT = 0.975 min, LCMS33: m/z = 365.3 [M + 1]. 1H NMR (300 
               
               
                   
                 MHz, Methanol-d4) δ 7.52-7.40 (m, 2H), 7.36-7.20 (m, 3H), 5.98 (s, 1H), 3.21- 
               
               
                   
                 3.18 (m, 2H), 2.97 (s, 3H), 2.31-2.19 (m, 6H), 1.34-1.29 (m, 3H). 
               
               
                 278 
                 LC-MS: (ES, m/z): RT = 1.130 min, LCMS28: m/z = 292 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.04-8.98 (m, 1H), 8.26 (d, J = 6.4 Hz, 1H), 8.15 (d, J = 6.5 Hz, 1H), 
               
               
                   
                 7.63 (s, 1H), 7.58 (s, 1H), 7.13 (d, J = 0.7 Hz, 1H), 3.72 (s, 3H), 3.20 (s, 3H), 2.62 (s, 
               
               
                   
                 3H). 
               
               
                 279 
                 LC-MS: (ES, m/z): RT = 1.948 min, LCMS 27: m/z = 346.0 [M + 1]. 1H NMR (400 
               
               
                   
                 MHz, Methanol-d4) δ 8.93 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 2.4 
               
               
                   
                 Hz, 1H), 7.77-7.71 (m, 1H), 7.67 (dd, J = 5.6, 1.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 
               
               
                   
                 5.83 (s, 1H), 2.87 (s, 3H), 2.48 (s, 3H), 2.19 (s, 3H). 
               
               
                 280 
                 LC-MS: (ES, m/z): RT = 2.2 min, LCMS33: m/z = 355.15 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.85 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.3 Hz, 
               
               
                   
                 1H), 7.58 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 
               
               
                   
                 3.002-2.98(m, 3H), 2.5-2.42 (m, 3H), 2.33 (s, 3H). 
               
               
                 282 
                 LC-MS: (ES, m/z): RT = 2.054 min, LCMS28: m/z = 346 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.28 (d, J = 1.3 Hz, 1H), 8.84 (d, J = 1.0 Hz, 1H), 8.32-8.21 (m, 2H), 
               
               
                   
                 7.74-7.62 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 5.85 (d, J = 0.7 Hz, 1H), 2.84 (s, 3H), 2.18 
               
               
                   
                 (d, J = 7.7 Hz, 6H). 
               
               
                 284 
                 LC-MS: (ES, m/z): RT = 1.313 min, LCMS28: m/z = 347 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 
               
               
                   
                 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94-2.80 (m, 
               
               
                   
                 2H), 2.78-2.63 (m, 3H), 2.43 (s, 4H). 
               
               
                 285 
                 LC-MS: (ES, m/z): RT = 0.942 min; LCMS53: m/z = 354 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.40 (s, 1H), 8.25-8.15 (m, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.55 (d, J = 
               
               
                   
                 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 4.21 (d, J = 2.1 Hz, 2H), 
               
               
                   
                 3.95 (s, 3H), 3.00 (s, 3H), 2.74 (s, 3H), 2.31 (s, 3H). 
               
               
                 286 
                 LC-MS: (ES, m/z): RT = 1.290 min, LCMS 28: m/z = 338.1 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.10-8.07 (m, 1H), 7.90-7.86 (m, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.75- 
               
               
                   
                 7.62 (m, 1H), 7.47-7.39 (m, 1H), 6.25-6.02 (m, 1H), 4.24 (s, 2H), 2.98 (d, J = 1.4 
               
               
                   
                 Hz, 3H), 2.77 (d, J = 2.4 Hz, 3H), 2.44-2.30 (m, 3H), 2.23 (d, J = 6.9 Hz, 3H). 
               
               
                 287 
                 LC-MS: (ES, m/z): RT = 2.288 min, LCMS 07: m/z = 350 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 9.53 (s, 1H), 7.58 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 10.1 
               
               
                   
                 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 3.7 Hz, 1H), 5.81 (s, 1H), 2.93 (s, 3H), 
               
               
                   
                 2.41 (s, 3H), 2.17 (s, 3H). 
               
               
                 288 
                 LC-MS: (ES, m/z): RT = 1.107 min, LCMS28: m/z = 333 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 5.6, 1.1 
               
               
                   
                 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.95 (d, J = 0.9 Hz, 1H), 4.08 (s, 3H), 3.06 (s, 3H), 
               
               
                   
                 2.71-2.57 (m, 2H), 2.60-2.44 (m, 3H), 2.30 (tq, J = 9.7, 5.6, 4.8 Hz, 1H). 
               
               
                 289 
                 LC-MS: (ES, m/z): RT = 1.313 min, LCMS28, m/z = 347 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 
               
               
                   
                 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94-2.80 (m, 
               
               
                   
                 2H), 2.78-2.63 (m, 3H), 2.43 (s, 4H). 
               
               
                 292 
                 LC-MS: (ES, m/z): RT = 1.39 min, LCMS28: m/z = 386 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.33-8.24 (m, 2H), 7.68 (d, J = 3.3 Hz, 1H), 7.48 (dd, J = 8.8, 2.8 Hz, 1H), 
               
               
                   
                 7.22 (d, J = 8.8 Hz, 1H), 6.82-6.74 (m, 1H), 6.01 (d, J = 1.1 Hz, 1H), 3.96 (s, 3H), 3.11 
               
               
                   
                 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H). 
               
               
                 293 
                 LC-MS: (ES, m/z): RT = 1.01 min, LCMS33: m/z = 432 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.03-7.75 (m, 4H), 7.32 (dd, J = 12.6, 8.9 Hz, 1H), 7.19 (dd, J = 3.4, 0.9 
               
               
                   
                 Hz, 1H), 6.02 (s, 1H), 5.00 (s, 2H), 3.97 (d, J = 4.7 Hz, 3H), 2.98 (s, 3H), 2.34 (d, J = 
               
               
                   
                 0.9 Hz, 3H), 2.07 (s, 3H). 
               
               
                 294 
                 LC-MS: (ES, m/z): RT = 0.98 min, LCMS33: m/z = 333.17 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.75 (d, J = 1.5 Hz, 1H), 8.69 (t, J = 1.2 Hz, 1H), 8.20 (d, J = 3.3 Hz, 
               
               
                   
                 1H), 7.70 (s, 1H), 7.30 (s, 1H), 6.94 (dd, J = 3.3, 1.0 Hz, 1H), 4.00 (s, 3H), 3.25 (s, 3H), 
               
               
                   
                 2.9-2.82 (m, 2H), 2.75-2.62 (m, 3H), 2.48-2.34 (m, 1H). 
               
               
                 295 
                 LC-MS: (ES, m/z): RT = 0.90 min, LCMS33: m/z = 308.16 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.73 (d, J = 1.5 Hz, 1H), 8.66 (s, 1H), 8.16 (d, J = 3.3 Hz, 1H), 7.54 (s, 
               
               
                   
                 1H), 7.38 (s, 1H), 6.92 (dd, J = 3.3, 0.9 Hz, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 3.19 (s, 3H). 
               
               
                 296 
                 LC-MS: (ES, m/z): RT = 1.30 min, LCMS07: m/z = 390 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.11 (d, J = 1.0 Hz, 1H), 8.02-7.86 (m, 2H), 7.74 (d, J = 3.4 Hz, 1H), 
               
               
                   
                 7.32-7.18 (m, 1H), 7.01 (dd, J = 3.4, 1.0 Hz, 1H), 6.00 (d, J = 1.0 Hz, 1H), 4.75 (s, 
               
               
                   
                 2H), 3.95 (s, 3H), 2.99 (s, 3H), 2.33 (d, J = 0.9 Hz, 3H). 
               
               
                 297 
                 LC-MS: (ES, m/z): RT = 1.163 min, LCMS28, m/z = 296 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.84 (t, J = 0.8 Hz, 1H), 8.15 (dd, J = 6.5, 0.8 Hz, 1H), 8.02 (dd, J = 6.5, 
               
               
                   
                 0.7 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 
               
               
                   
                 1H), 3.92 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H). 
               
               
                 298 
                 LC-MS: (ES, m/z): RT = 1.138 min, LCMS28, m/z = 311 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.80 (d, J = 0.8 Hz, 1H), 8.14 (dd, J = 6.5, 0.8 Hz, 1H), 8.01 (dd, J = 
               
               
                   
                 6.5, 0.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 
               
               
                   
                 Hz, 1H), 3.93 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H). 
               
               
                 299 
                 LC-MS: (ES, m/z): RT = 1.56 min, LCMS33: m/z = 353.18 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.26 (s, 1H), 7.94 (s, 1H), 7.57 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (d, J = 8.3 
               
               
                   
                 Hz, 1H), 6.04 (s, 1H), 4.14 (s, 3H), 3.00 (s, 3H), 2.47 (s, 3H), 2.33 (s, 3H). 
               
               
                 300 
                 LC-MS: (ES, m/z): RT = 0.941 min, LCMS07: m/z = 347 [M + 1]. 1H-NMR-PH-EPI-K- 
               
               
                   
                 1211-200: 1H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 7.58 (s, 1H), 8.07 (s, 1H), 
               
               
                   
                 7.65 (s, 1H), 7.13 (s, 1H), 6.87 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H), 3.21 (s, 3H), 2.87 (d, 
               
               
                   
                 J = 9.1 Hz, 2H), 2.65 (d, J = 10.3 Hz, 3H), 2.57 (s, 3H), 2.33 (s, J = 10.3 Hz, 1H). 
               
               
                 301 
                 LC-MS: RT = 0.623 min, LCMS 32: m/z = 282 [M + 1]. 1H NMR (400 MHz, Methanol- 
               
               
                   
                 d4) δ 8.92 (s, 1H), 8.20 (d, J = 6.5 Hz, 1H), 8.09 (d, J = 6.5 Hz, 1H), 7.73-7.61 (m, 
               
               
                   
                 2H), 7.41-7.28 (m, 1H), 4.26 (s, 2H), 3.96 (s, 3H), 2.76 (s, 3H), 2.43 (s, 3H). 
               
               
                 302 
                 LC-MS: (ES, m/z): RT = 1.029 min, LCMS53: m/z = 352 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 DMSO-d6) δ 10.42 (s, 1H), 8.97 (s, 1H), 8.00-7.75 (m, 2H), 7.41-7.32 (m, 2H), 7.07 
               
               
                   
                 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.77 (s, 1H), 3.65 (s, 3H), 2.79 (d, J = 4.0 Hz, 3H), 
               
               
                   
                 2.25 (s, 3H), 2.12 (s, 3H). 
               
               
                 306 
                 LC-MS: (ES, m/z): RT = 0.856 min, LCMS27: m/z = 352 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.10 (s, 1H), 7.91 (s, 1H), 7.79-7.69 (m, 1H), 7.06 (d, J = 8.9 Hz, 1H), 
               
               
                   
                 6.45 (d, J = 6.2 Hz, 1H), 5.81 (s, 1H), 3.83 (s, 3H), 2.97 (s, 3H), 2.89 (s, 3H), 2.19 (s, 
               
               
                   
                 3H). 
               
               
                 307 
                 LC-MS: (ES, m/z): RT = 0.868 min, LCMS07: m/z = 360 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 8.47-8.43 (m, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.14-7.11 (m, 1H), 
               
               
                   
                 5.88 (d, J = 1.2 Hz, 1H), 3.74 (s, 2H), 2.88 (s, 3H), 2.43 (s, 3H), 2.19 (s, 3H). 
               
               
                 308 
                 LC-MS: (ES, m/z): RT = 1.94 min, LCMS07: m/z = 376 [M + 1]. 1H-NMR: 
               
               
                   
                 (Methanol-d4, ppm): δ 8.22 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.68 (d, 
               
               
                   
                 J = 2.5 Hz, 2H), 7.30 (dd, J = 3.3, 0.8 Hz, 1H), 4.06 (s, 3H), 3.25 (s, 3H), 
               
               
                   
                 2.87 (s, 2H), 2.68 (d, J = 8.6 Hz, 3H), 2.41 (d, J = 13.8 Hz, 1H). 
               
               
                 309 
                 LC-MS: RT = 1.014 min, LCMS 07: m/z = 376 [M + 1]. 1H NMR (400 MHz, Methanol- 
               
               
                   
                 d4) δ 9.14 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 3.3 Hz, 1H), 7.75 (s, 1H), 7.39 (s, 1H), 7.11 
               
               
                   
                 (d, J = 3.3 Hz, 1H), 4.37 (s, 2H), 4.04 (s, 3H), 3.03-2.85 (m, 2H), 2.79-2.65 (m, 3H), 
               
               
                   
                 2.48-2.34 (m, 1H). 
               
               
                 310 
                 LC-MS: (ES, m/z): RT = 1.063 min, LCMS28: m/z = 337 [M + 1]. 1H NMR (400 MHz, 
               
               
                   
                 Methanol-d4) δ 8.73 (s, 1H), 8.08 (dd, J = 6.6, 0.8 Hz, 1H), 7.95-7.88 (m, 1H), 7.41 
               
               
                   
                 (d, J = 8.3 Hz, 1H), 6.52-6.44 (m, 2H), 3.91 (s, 3H), 3.85-3.73 (m, 1H), 3.47-3.52 
               
               
                   
                 (m, 2H), 3.18-3.25 (m, 2H), 2.42 (s, 3H), 2.30 (dd, J = 14.7, 3.8 Hz, 2H), 1.72-1.82 
               
               
                   
                 (m, 2H). 
               
               
                 317 
                 LC-MS: (ES, m/z): RT = 1.68 min, LCMS07: m/z = 372 [M + 1]. 1H-NMR: (Methanol- 
               
               
                   
                 d4, ppm): δ 8.04 (s, 1H), 7.91 (s, 1H), 7.82-7.65 (m, 1H), 7.18-7.12 (m, 1H), 6.03 (s, 
               
               
                   
                 1H), 4.23 (s, 2H), 3.88 (s, 3H), 2.94 (s, 3H), 2.76 (s, 3H), 2.32 (s, 3H). 
               
               
                 386 
                 LC-MS: (ES, m/z): RT = 0.784 min, LCMS28: m/z = 375 [M + 1]. 1H NMR (300 MHz, 
               
               
                   
                 Methanol-d4) δ 9.09 (s, 1H), 8.01-7.98 (m, 1H), 7.94-7.74 (m, 2H), 7.64 (d, J = 1.3 
               
               
                   
                 Hz, 1H), 7.41-7.27 (m, 1H), 6.07 (d, J = 1.2 Hz, 1H), 3.97 (d, J = 3.3 Hz, 3H), 2.99 (s, 
               
               
                   
                 3H), 2.53 (d, J = 1.2 Hz, 3H), 2.39-2.32 (m, 3H). 
               
               
                   
               
            
           
         
       
     
     Example 20: Bioactivity Assays 
     Materials and Equipment: 
     Recombinant purified human EHMT2 913-1193 (55 μM) synthesized by Viva was used for all experiments. Biotinylated histone peptides were synthesized by Biopeptide and HPLC-purified to &gt;95% purity. Streptavidin Flashplates and seals were purchased from PerkinElmer and 384 Well V-bottom Polypropylene Plates were from Greiner.  3 H-labeled S-adenosylmethionine (3H-SAM) was obtained from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. Unlabeled SAM and S-adenosylhomocysteine (SAH) were obtained from American Radiolabeled Chemicals and Sigma-Aldrich respectively. Flashplates were washed in a Biotek ELx-405 with 0.1% Tween. 384-well Flashplates and 96-well filter binding plates were read on a TopCount microplate reader (PerkinElmer). Compound serial dilutions were performed on a Freedom EVO (Tecan) and spotted into assay plates using a Thermo Scientific Matrix PlateMate (Thermo Scientific). Reagent cocktails were added by Multidrop Combi (Thermo Scientific). 
     MDA-MB-231 cell line was purchased from ATCC (Manassas, Va., USA). RPMI/Glutamax medium, Penicillin-Streptomycin, Heat Inactivated Fetal Bovine Serum, and D-PBS were purchased from Life Technologies (Grand Island, N.Y., USA). Odyssey blocking buffer, 800CW goat anti-mouse IgG (H+L) antibody, and Licor Odyssey Infrared Scanner were purchased from Licor Biosciences, Lincoln, Nebr., USA. H3K9me2 mouse monoclonal antibody (Cat #1220) was purchased from Abcam (Cambridge, Mass., USA). 16% Paraformaldehyde was purchased from Electron Microscopy Sciences, Hatfield, Pa., USA). MDA-MB-231 cells were maintained in complete growth medium (RPMI supplemented with 10% v/v heat inactivated fetal bovine serum) and cultured at 37° C. under 5% CO 2 . UNC0638 was purchased from Sigma-Aldrich (St. Louis, Mo., USA). 
     Various In vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. 
     General Procedure for EHMT2 Enzyme Assay on Histone Peptide Substrate. 
     10-point curves of test compounds were made on a Freedom EVO (Tecan) using serial 3-fold dilutions in DMSO, beginning at 2.5 mM (final top concentration of compound was 50 μM and the DMSO was 2%). A 1 μL aliquot of the inhibitor dilution series was spotted in a polypropylene 384-well V-bottom plate (Greiner) using a Thermo Scientific Matrix PlateMate (Thermo Scientific). The 100% inhibition control consisted of 1 mM final concentration of the product inhibitor S-adenosylhomocysteine (SAH, Sigma-Aldrich). Compounds were incubated for 30 minutes with 40 μL per well of 0.031 nM EHMT2 (recombinant purified human EHMT2 913-1193, Viva) in 1× assay buffer (20 mM Bicine [pH 7.5], 0.002% Tween 20, 0.005% Bovine Skin Gelatin and 1 mM TCEP). 10 μL per well of substrate mix comprising assay buffer,  3 H-SAM (3H-labeled S-adenosylmethionine, American Radiolabeled Chemicals, specific activity of 80 Ci/mmol), unlabeled SAM (American Radiolabeled Chemicals), and peptide representing histone H3 residues 1-15 containing C-terminal biotin (appended to a C-terminal amide-capped lysine, synthesized by Biopeptide and HPLC-purified to greater than 95% purity) were added to initiate the reaction (both substrates were present in the final reaction mixture at their respective K m  values, an assay format referred to as “balanced conditions”). Reactions were incubated for 60 minutes at room temperature and quenched with 10 μL per well of 400 μM unlabeled SAM, then transferred to a 384-well streptavidin Flashplate (PerkinElmer) and washed in a Biotek ELx-405 well washer with 0.1% Tween after 60 minutes. 384-well Flashplates were read on a TopCount microplate reader (PerkinElmer). 
     General Procedure for MDA-MB-231 HEK9me2 In-Cell Western Assay. 
     Compound (100 nL) was added directly to 384-well cell plate. MDA-MB-231 cells (ATCC) were seeded in assay medium (RPMI/Glutamax supplemented with 10% v/v heat inactivated fetal bovine serum and 1% Penicillin/Streptomycin, Life Technologies) at a concentration of 3,000 cells per well to a Poly-D-Lysine coated 384-well cell culture plate with 50 μL per well. Plates were incubated at 37° C., 5% CO 2  for 48 hours (BD Biosciences 356697). Plates were incubated at room temperature for 30 minutes and then incubated at 37° C., 5% CO 2  for additional 48 hours. After the incubation, 50 μL per well of 8% paraformaldehyde (Electron Microscopy Sciences) in PBS was added to the plates and incubated at room temperature for 20 minutes. Plates were transferred to a Biotek 406 plate washer and washed 2 times with 100 μL per well of wash buffer (1×PBS containing 0.3% Triton X-100 (v/v)). Next, 60 μL per well of Odyssey blocking buffer (Licor Biosciences) was added to each plate and incubated for 1 hour at room temperature. Blocking buffer was removed and 20 μL of monoclonal primary antibody α-H3K9me2 (Abcam) diluted 1:800 in Odyssey buffer with 0.1% Tween 20 (v/v) were added and plates were incubated overnight (16 hours) at 4° C. Plates were washed 5 times with 100 μL per well of wash buffer. Next 20 μL per well of secondary antibody was added (1:500 800CW donkey anti-mouse IgG (H+L) antibody (Licor Biosciences), 1:1000 DRAQ5 (Cell Signaling Technology) in Odyssey buffer with 0.1% Tween 20 (v/v)) and incubated for 1 hour at room temperature. The plates were washed 5 times with 100 μL per well wash buffer then 2 times with 100 μL per well of water. Plates were allowed to dry at room temperature then imaged on a Licor Odyssey Infrared Scanner (Licor Biosciences) which measured integrated intensity at 700 nm and 800 nm wavelengths. Both 700 and 800 channels were scanned. 
     % Inhibition Calculation. 
     First, the ratio for each well was determined by 
     
       
         
           
             
               ( 
               
                 
                   H 
                   ⁢ 
                   3 
                   ⁢ 
                   K 
                   ⁢ 
                   9 
                   ⁢ 
                   me 
                   ⁢ 
                   2 
                   ⁢ 
                       
                   800 
                   ⁢ 
                       
                   nm 
                   ⁢ 
                       
                   value 
                 
                 
                   DRAQ 
                   ⁢ 
                   5 
                   ⁢ 
                       
                   700 
                   ⁢ 
                       
                   nm 
                   ⁢ 
                       
                   value 
                 
               
               ) 
             
             . 
           
         
       
     
     Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells (background wells) for maximum inhibition treated with control compound UNC0638 (Background wells). 
     The average of the ratio values for each well was calculated and used to determine the percent inhibition for each test well in the plate. Control compound was serially diluted three-fold in DMSO for a total of 10 test concentrations beginning at 1 μM. Percent inhibition was calculated as: 
     
       
         
           
             
               Percent 
               ⁢ 
                   
               Inhibition 
             
             = 
             
               100 
               - 
               
                 ( 
                 
                   
                     ( 
                     
                       
                         
                           ( 
                           
                             Individual 
                             ⁢ 
                                 
                             Test 
                             ⁢ 
                                 
                             Sample 
                             ⁢ 
                                 
                             Ratio 
                           
                           ) 
                         
                         - 
                         
                           ( 
                           
                             Background 
                             ⁢ 
                                 
                             Avg 
                             ⁢ 
                                 
                             Ratio 
                           
                           ) 
                         
                       
                       
                         
                           ( 
                           
                             Minimum 
                             ⁢ 
                                 
                             Inhibition 
                             ⁢ 
                                 
                             Ratio 
                           
                           ) 
                         
                         - 
                         
                           ( 
                           
                             Background 
                             ⁢ 
                                 
                             Average 
                             ⁢ 
                                 
                             Ratio 
                           
                           ) 
                         
                       
                     
                     ) 
                   
                     
                   ⋆ 
                   100 
                 
                 ) 
               
             
           
         
       
     
     IC 50  curves were generated using triplicate wells per concentration of compound. The IC 50  is the concentration of compound at which measured methylation is inhibited by 50% as interpolated from the dose response curves. IC 50  values were calculated using a non-linear regression (variable slope-four parameter fit model) with by the following formula 
     
       
         
           
             
               
                 % 
                 ⁢ 
                     
                 inhibition 
               
               = 
               
                 Bottom 
                 + 
                 
                   ( 
                   
                     
                       Top 
                       - 
                       Bottom 
                     
                     
                       ( 
                       
                         1 
                         + 
                         
                           
                             ( 
                             
                               
                                 IC 
                                 50 
                               
                               / 
                               
                                 [ 
                                 l 
                                 ] 
                               
                             
                             ) 
                           
                           n 
                         
                       
                       ) 
                     
                   
                   ) 
                 
               
             
             , 
           
         
       
     
     where Top is fixed at 100% and Bottom is fixed to 0%, [I]=concentration of inhibitor, IC 50 =half maximal inhibitory concentration and n=Hill Slope. 
     The IC 50  values are listed in Table 3 below (“A” means IC 50 &lt;100 nM; “B” means IC 50  ranging between 100 nM and 1 μM; “C” means IC 50  ranging between &gt;1 μM and 10 μM; “D” means IC 50 &gt;10 μM; “-” or “ND” means not determined). 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                 Compound 
                 EHMT2 PEP 
                 EHMT1 PEP 
                 EHMT2 ICW 
               
               
                   
                 No. 
                 (IC50 μM) 
                 (IC50 μM) 
                 (IC50 μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 A 
                 A 
                 B 
               
               
                   
                 2 
                 A 
                 A 
                 B 
               
               
                   
                 3 
                 C 
                 B 
                 D 
               
               
                   
                 4 
                 C 
                 C 
                 C 
               
               
                   
                 5 
                 C 
                 B 
                 C 
               
               
                   
                 6 
                 D 
                 D 
                 D 
               
               
                   
                 7 
                 C 
                 B 
                 C 
               
               
                   
                 8 
                 D 
                 C 
                 D 
               
               
                   
                 9 
                 D 
                 D 
                 D 
               
               
                   
                 10 
                 B 
                 B 
                 B 
               
               
                   
                 11 
                 D 
                 D 
                 D 
               
               
                   
                 12 
                 D 
                 D 
                 D 
               
               
                   
                 13 
                 C 
                 B 
                 C 
               
               
                   
                 14 
                 C 
                 B 
                 C 
               
               
                   
                 15 
                 D 
                 D 
                 D 
               
               
                   
                 19 
                 C 
                 C 
                 C 
               
               
                   
                 21 
                 D 
                 D 
                 D 
               
               
                   
                 22 
                 D 
                 C 
                 D 
               
               
                   
                 23 
                 A 
                 A 
                 C 
               
               
                   
                 24 
                 C 
                 C 
                 D 
               
               
                   
                 26 
                 D 
                 C 
                 D 
               
               
                   
                 27 
                 B 
                 B 
                 C 
               
               
                   
                 28 
                 C 
                 C 
                 C 
               
               
                   
                 30 
                 D 
                 D 
                 D 
               
               
                   
                 31 
                 D 
                 D 
                 D 
               
               
                   
                 32 
                 D 
                 D 
                 D 
               
               
                   
                 33 
                 D 
                 D 
                 D 
               
               
                   
                 35 
                 C 
                 C 
                 C 
               
               
                   
                 36 
                 D 
                 C 
                 D 
               
               
                   
                 37 
                 D 
                 D 
                 D 
               
               
                   
                 38 
                 D 
                 C 
                 D 
               
               
                   
                 39 
                 D 
                 D 
                 D 
               
               
                   
                 40 
                 B 
                 A 
                 B 
               
               
                   
                 41 
                 D 
                 C 
                 D 
               
               
                   
                 42 
                 D 
                 D 
                 D 
               
               
                   
                 43 
                 D 
                 C 
                 D 
               
               
                   
                 45 
                 D 
                 D 
                 D 
               
               
                   
                 47 
                 C 
                 C 
                 D 
               
               
                   
                 48 
                 B 
                 A 
                 C 
               
               
                   
                 49 
                 D 
                 D 
                 D 
               
               
                   
                 50 
                 B 
                 B 
                 D 
               
               
                   
                 54 
                 D 
                 D 
                 D 
               
               
                   
                 56 
                 D 
                 C 
                 D 
               
               
                   
                 57 
                 C 
                 B 
                 C 
               
               
                   
                 60 
                 D 
                 C 
                 C 
               
               
                   
                 61 
                 D 
                 C 
                 D 
               
               
                   
                 62 
                 D 
                 C 
                 D 
               
               
                   
                 65 
                 D 
                 C 
                 D 
               
               
                   
                 66 
                 B 
                 A 
                 B 
               
               
                   
                 67 
                 D 
                 C 
                 D 
               
               
                   
                 68 
                 D 
                 D 
                 D 
               
               
                   
                 69 
                 D 
                 D 
                 D 
               
               
                   
                 70 
                 B 
                 B 
                 C 
               
               
                   
                 73 
                 D 
                 C 
                 D 
               
               
                   
                 74 
                 B 
                 A 
                 B 
               
               
                   
                 75 
                 D 
                 D 
                 D 
               
               
                   
                 76 
                 D 
                 D 
                 D 
               
               
                   
                 77 
                 D 
                 D 
                 D 
               
               
                   
                 78 
                 C 
                 C 
                 D 
               
               
                   
                 79 
                 C 
                 C 
                 D 
               
               
                   
                 81 
                 C 
                 C 
                 C 
               
               
                   
                 82 
                 B 
                 B 
                 C 
               
               
                   
                 83 
                 D 
                 D 
                 D 
               
               
                   
                 84 
                 C 
                 C 
                 C 
               
               
                   
                 86 
                 D 
                 D 
                 D 
               
               
                   
                 87 
                 B 
                 A 
                 B 
               
               
                   
                 88 
                 B 
                 B 
                 D 
               
               
                   
                 93 
                 D 
                 C 
                 D 
               
               
                   
                 94 
                 D 
                 C 
                 D 
               
               
                   
                 95 
                 D 
                 D 
                 D 
               
               
                   
                 96 
                 D 
                 D 
                 D 
               
               
                   
                 99 
                 C 
                 C 
                 C 
               
               
                   
                 100 
                 D 
                 D 
                 C 
               
               
                   
                 102 
                 C 
                 B 
                 C 
               
               
                   
                 103 
                 D 
                 D 
                 D 
               
               
                   
                 104 
                 D 
                 C 
                 D 
               
               
                   
                 105 
                 D 
                 D 
                 D 
               
               
                   
                 106 
                 D 
                 D 
                 D 
               
               
                   
                 108 
                 A 
                 A 
                 A 
               
               
                   
                 109 
                 A 
                 A 
                 A 
               
               
                   
                 113 
                 A 
                 A 
                 B 
               
               
                   
                 116 
                 C 
                 C 
                 C 
               
               
                   
                 117 
                 D 
                 D 
                 D 
               
               
                   
                 119 
                 D 
                 C 
                 D 
               
               
                   
                 121 
                 B 
                 B 
                 B 
               
               
                   
                 122 
                 C 
                 B 
                 C 
               
               
                   
                 125 
                 B 
                 A 
                 B 
               
               
                   
                 134 
                 D 
                 D 
                 D 
               
               
                   
                 136 
                 B 
                 B 
                 B 
               
               
                   
                 137 
                 A 
                 A 
                 B 
               
               
                   
                 138 
                 D 
                 D 
                 D 
               
               
                   
                 139 
                 D 
                 D 
                 D 
               
               
                   
                 143 
                 B 
                 B 
                 C 
               
               
                   
                 144 
                 C 
                 C 
                 D 
               
               
                   
                 145 
                 D 
                 D 
                 D 
               
               
                   
                 146 
                 D 
                 B 
                 C 
               
               
                   
                 148 
                 C 
                 B 
                 C 
               
               
                   
                 151 
                 B 
                 B 
                 B 
               
               
                   
                 155 
                 D 
                 D 
                 D 
               
               
                   
                 156 
                 D 
                 D 
                 C 
               
               
                   
                 157 
                 A 
                 A 
                 B 
               
               
                   
                 158 
                 B 
                 A 
                 B 
               
               
                   
                 159 
                 A 
                 A 
                 B 
               
               
                   
                 160 
                 A 
                 A 
                 B 
               
               
                   
                 161 
                 C 
                 B 
                 C 
               
               
                   
                 163 
                 C 
                 C 
                 C 
               
               
                   
                 164 
                 B 
                 B 
                 B 
               
               
                   
                 165 
                 D 
                 D 
                 D 
               
               
                   
                 166 
                 D 
                 C 
                 D 
               
               
                   
                 169 
                 C 
                 B 
                 C 
               
               
                   
                 170 
                 B 
                 A 
                 B 
               
               
                   
                 171 
                 A 
                 A 
                 B 
               
               
                   
                 172 
                 B 
                 B 
                 C 
               
               
                   
                 173 
                 C 
                 A 
                 C 
               
               
                   
                 174 
                 D 
                 D 
                 C 
               
               
                   
                 175 
                 A 
                 A 
                 B 
               
               
                   
                 176 
                 C 
                 B 
                 C 
               
               
                   
                 177 
                 D 
                 C 
                 D 
               
               
                   
                 178 
                 D 
                 D 
                 D 
               
               
                   
                 179 
                 B 
                 B 
                 C 
               
               
                   
                 181 
                 A 
                 A 
                 B 
               
               
                   
                 182 
                 B 
                 A 
                 B 
               
               
                   
                 184 
                 B 
                 B 
                 C 
               
               
                   
                 185 
                 B 
                 B 
                 C 
               
               
                   
                 186 
                 A 
                 A 
                 B 
               
               
                   
                 187 
                 A 
                 A 
                 B 
               
               
                   
                 188 
                 B 
                 B 
                 C 
               
               
                   
                 191 
                 C 
                 B 
                 D 
               
               
                   
                 192 
                 A 
                 A 
                 B 
               
               
                   
                 193 
                 A 
                 A 
                 B 
               
               
                   
                 194 
                 A 
                 A 
                 B 
               
               
                   
                 195 
                 B 
                 B 
                 C 
               
               
                   
                 196 
                 B 
                 B 
                 C 
               
               
                   
                 199 
                 A 
                 A 
                 C 
               
               
                   
                 200 
                 A 
                 A 
                 A 
               
               
                   
                 201 
                 C 
                 C 
                 D 
               
               
                   
                 202 
                 A 
                 A 
                 C 
               
               
                   
                 203 
                 C 
                 B 
                 C 
               
               
                   
                 204 
                 C 
                 C 
                 D 
               
               
                   
                 205 
                 D 
                 C 
                 D 
               
               
                   
                 206 
                 A 
                 A 
                 A 
               
               
                   
                 207 
                 A 
                 A 
                 B 
               
               
                   
                 208 
                 C 
                 C 
                 D 
               
               
                   
                 209 
                 C 
                 B 
                 D 
               
               
                   
                 210 
                 C 
                 A 
                 C 
               
               
                   
                 212 
                 A 
                 A 
                 B 
               
               
                   
                 213 
                 B 
                 A 
                 B 
               
               
                   
                 214 
                 A 
                 A 
                 B 
               
               
                   
                 215 
                 A 
                 A 
                 B 
               
               
                   
                 216 
                 A 
                 A 
                 B 
               
               
                   
                 217 
                 A 
                 A 
                 B 
               
               
                   
                 218 
                 D 
                 D 
                 C 
               
               
                   
                 219 
                 C 
                 B 
                 D 
               
               
                   
                 220 
                 D 
                 C 
                 D 
               
               
                   
                 221 
                 B 
                 A 
                 B 
               
               
                   
                 222 
                 B 
                 A 
                 B 
               
               
                   
                 223 
                 A 
                 A 
                 B 
               
               
                   
                 225 
                 C 
                 A 
                 C 
               
               
                   
                 227 
                 C 
                 C 
                 D 
               
               
                   
                 228 
                 A 
                 A 
                 B 
               
               
                   
                 229 
                 B 
                 A 
                 B 
               
               
                   
                 230 
                 B 
                 A 
                 C 
               
               
                   
                 231 
                 C 
                 C 
                 D 
               
               
                   
                 232 
                 D 
                 C 
                 C 
               
               
                   
                 233 
                 C 
                 B 
                 C 
               
               
                   
                 234 
                 D 
                 B 
                 C 
               
               
                   
                 235 
                 D 
                 D 
                 D 
               
               
                   
                 236 
                 D 
                 D 
                 D 
               
               
                   
                 237 
                 A 
                 A 
                 B 
               
               
                   
                 238 
                 A 
                 A 
                 A 
               
               
                   
                 239 
                 D 
                 D 
                 D 
               
               
                   
                 240 
                 D 
                 C 
                 D 
               
               
                   
                 241 
                 A 
                 A 
                 B 
               
               
                   
                 242 
                 D 
                 D 
                 D 
               
               
                   
                 243 
                 C 
                 B 
                 D 
               
               
                   
                 244 
                 D 
                 D 
                 D 
               
               
                   
                 245 
                 D 
                 D 
                 D 
               
               
                   
                 246 
                 C 
                 B 
                 C 
               
               
                   
                 247 
                 C 
                 C 
                 D 
               
               
                   
                 248 
                 D 
                 C 
                 D 
               
               
                   
                 249 
                 C 
                 B 
                 C 
               
               
                   
                 250 
                 D 
                 C 
                 D 
               
               
                   
                 251 
                 C 
                 B 
                 C 
               
               
                   
                 252 
                 C 
                 B 
                 C 
               
               
                   
                 253 
                 D 
                 C 
                 D 
               
               
                   
                 254 
                 D 
                 D 
                 D 
               
               
                   
                 255 
                 A 
                 A 
                 B 
               
               
                   
                 256 
                 A 
                 A 
                 B 
               
               
                   
                 257 
                 C 
                 B 
                 C 
               
               
                   
                 258 
                 C 
                 B 
                 C 
               
               
                   
                 259 
                 D 
                 C 
                 D 
               
               
                   
                 260 
                 C 
                 B 
                 D 
               
               
                   
                 261 
                 C 
                 B 
                 D 
               
               
                   
                 262 
                 A 
                 A 
                 A 
               
               
                   
                 263 
                 D 
                 D 
                 D 
               
               
                   
                 264 
                 D 
                 D 
                 D 
               
               
                   
                 266 
                 D 
                 D 
                 D 
               
               
                   
                 267 
                 D 
                 D 
                 D 
               
               
                   
                 268 
                 D 
                 D 
                 D 
               
               
                   
                 269 
                 A 
                 A 
                 B 
               
               
                   
                 270 
                 D 
                 D 
                 D 
               
               
                   
                 271 
                 C 
                 C 
                 D 
               
               
                   
                 273 
                 D 
                 D 
                 D 
               
               
                   
                 274 
                 D 
                 C 
                 D 
               
               
                   
                 275 
                 D 
                 D 
                 D 
               
               
                   
                 276 
                 C 
                 C 
                 C 
               
               
                   
                 278 
                 A 
                 A 
                 B 
               
               
                   
                 279 
                 A 
                 A 
                 C 
               
               
                   
                 280 
                 D 
                 C 
                 D 
               
               
                   
                 282 
                 A 
                 A 
                 A 
               
               
                   
                 284 
                 A 
                 A 
                 A 
               
               
                   
                 285 
                 A 
                 A 
                 A 
               
               
                   
                 286 
                 A 
                 A 
                 A 
               
               
                   
                 287 
                 C 
                 B 
                 C 
               
               
                   
                 288 
                 A 
                 A 
                 B 
               
               
                   
                 289 
                 A 
                 A 
                 A 
               
               
                   
                 291 
                 C 
                 C 
                 C 
               
               
                   
                 292 
                 B 
                 A 
                 B 
               
               
                   
                 293 
                 B 
                 A 
                 C 
               
               
                   
                 294 
                 A 
                 A 
                 C 
               
               
                   
                 295 
                 C 
                 B 
                 C 
               
               
                   
                 296 
                 B 
                 A 
                 C 
               
               
                   
                 297 
                 D 
                 D 
                 D 
               
               
                   
                 298 
                 D 
                 D 
                 D 
               
               
                   
                 299 
                 D 
                 C 
                 D 
               
               
                   
                 300 
                 B 
                 A 
                 B 
               
               
                   
                 301 
                 C 
                 C 
                 D 
               
               
                   
                 302 
                 D 
                 D 
                 D 
               
               
                   
                 303 
                 C 
                 C 
                 D 
               
               
                   
                 304 
                 B 
                 B 
                 D 
               
               
                   
                 305 
                 B 
                 C 
                 D 
               
               
                   
                 306 
                 C 
                 C 
                 D 
               
               
                   
                 307 
                 A 
                 A 
                 B 
               
               
                   
                 308 
                 C 
                 B 
                 D 
               
               
                   
                 309 
                 C 
                 B 
                 D 
               
               
                   
                 310 
                 C 
                 C 
                 D 
               
               
                   
                 311 
                 D 
                 D 
                 D 
               
               
                   
                 312 
                 D 
                 D 
                 D 
               
               
                   
                 313 
                 B 
                 B 
                 C 
               
               
                   
                 314 
                 A 
                 A 
                 B 
               
               
                   
                 315 
                 B 
                 B 
                 C 
               
               
                   
                 316 
                 A 
                 A 
                 B 
               
               
                   
                 317 
                 A 
                 A 
                 A 
               
               
                   
                 318 
                 B 
                 B 
                 B 
               
               
                   
                 319 
                 A 
                 A 
                 A 
               
               
                   
                 320 
                 A 
                 A 
                 B 
               
               
                   
                 321 
                 A 
                 A 
                 A 
               
               
                   
                 322 
                 A 
                 A 
                 B 
               
               
                   
                 323 
                 A 
                 A 
                 B 
               
               
                   
                 324 
                 B 
                 B 
                 C 
               
               
                   
                 325 
                 A 
                 A 
                 B 
               
               
                   
                 326 
                 A 
                 A 
                 A 
               
               
                   
                 327 
                 A 
                 A 
                 A 
               
               
                   
                 328 
                 A 
                 A 
                 A 
               
               
                   
                 329 
                 A 
                 A 
                 A 
               
               
                   
                 330 
                 A 
                 A 
                 A 
               
               
                   
                 331 
                 A 
                 A 
                 B 
               
               
                   
                 332 
                 A 
                 A 
                 ND 
               
               
                   
                 333 
                 A 
                 A 
                 ND 
               
               
                   
                 334 
                 A 
                 A 
                 ND 
               
               
                   
                 386 
                 A 
                 A 
                 A 
               
               
                   
                   
               
            
           
         
       
     
     The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.