# Patent

## Title
Amide compounds for treatment of complement mediated disorders

## Abstract

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R12 or R13 on the A group is an amide substituent (R32) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional U.S. Application No. 61/944,189 filed Feb. 25, 2014, provisional U.S. Application No. 62/022,916 filed Jul. 10, 2014, and provisional U.S. Application 62/046,783 filed Sep. 5, 2014. The entirety of each of these applications is hereby incorporated by reference for all purposes.


BACKGROUND
The complement system is a part of the innate immune system which does not adapt to changes over the course of the host's life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phaogytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together).
The complement system has three pathways: classical, alternative and lectin. Complement factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within C3 to produce C3(H2O), which associates with factor B to form the C3(H2O)B complex. Complement factor D acts to cleave factor B within the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H2O) to form the alternative pathway C3 convertase C3(H2O)Bb. Additionally, C3b generated by any of the C3 convertases also associates with factor B to form C3bB, which factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b. C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell.
The dysfunction of or excessive activation of complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway. Some examples of disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.
Age-related macular degeneration (AMD) is a leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of the link between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a fivefold increased risk of macular degeneration and individuals with mutations in other complement factor genes also have an increased risk of AMD. Individuals with mutant factor H also have increased levels of C-reactive protein, a marker of inflammation. Without adequate functioning factor H, the alternative pathway of the complement cascade is overly activated leading to cellular damage. Inhibition of the alternative pathway is thus desired.
Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins. PNH erythrocytes are not capable of modulating their surface complement activation, which leads to the typical hallmark of PNH—the chronic activation of complement mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the U.S. for treatment of PNH. However, many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions. In addition, treatment with eculizumab requires life-long intravenous injections. Thus, there is an unmet need to develop novel inhibitors of the complement pathway.
Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex.
While initial attempts have been made to develop inhibitors of factor D, there are currently no small molecule factor D inhibitors in clinical trials. Examples of factor D inhibitors or prolyl compounds are described in the following disclosures.
Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compounds useful in the complement, coagulat and kallikrein pathways and method for their preparation” describes fused bicyclic ring compounds that are potent inhibitors of factor D. Development of the factor D inhibitor BCX1470 was discontinued due to lack of specificity and short half-life of the compound.
Novartis PCT patent publication WO2012/093101 titled “Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration” describes certain factor D inhibitors.
Novartis PCT patent publications WO2014/002057 titled “Pyrrolidine derivatives and their use as complement pathway modulators” and WO2014/009833 titled “Complement pathway modulators and uses thereof” describe additional factor D inhibitors with heterocyclic substituents. Additional factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002058, WO2014/002059, and WO2014/005150.
Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Open chain prolyl urea-related modulators of androgen receptor function” describes open chain prolyl urea and thiourea related compounds for the treatment of androgen receptor-associated conditions, such as age-related diseases, for example, sarcopenia.
Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amide derivatives and nociceptin antagonists” describes compounds with a proline-like core and aromatic substituents connected to the proline core through amide linkages useful for the treatment of pain.
Ferring B. V. and Yamanouchi Pharmaceutical Co. lTD. PCT patent publication WO1993/020099 titled “CCK and/or gastrin receptor ligands” describes compounds with a proline-like core and heterocyclic substituents connected to the proline core through amide linkages for the treatment of, for example, gastric disorders or pain.
Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled “Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases” discloses antibodies directed to C5 of the complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathologic activation of the complement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab (Soliris®) is currently the only complement-specific antibody on the market, and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).
Compounds which mediate the complement pathway, and for example, act as factor D inhibitors are needed for treatment of disorders in a host, including a human, associated with misregulation of the complement cascade.
SUMMARY
In one aspect, the present invention includes a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R12 or R13 on the A group is an amide substituent, is a superior inhibitor of complement factor D.
In one embodiment, a method for the treatment of a disorder associated with a dysfunction, including increased activity, of the complement pathway is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.
In one embodiment, the disorder is associated with the alternative complement cascade pathway. In yet another embodiment, the disorder is associated with the complement classical pathway. In a further embodiment, the disorder is associated with the complement lectin pathway. The factor D inhibitors provided herein can thus dampen or inhibit detrimental complement activity in a host, by administration of an effective amount in a suitable manner to a host in need thereof.
Specific embodiments of this invention are directed to certain disease indications. In one embodiment, a method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of age-related macular degeneration (AMD) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of rheumatoid arthritis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of multiple sclerosis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
In other embodiments of the invention, an active compound provided herein can be used to treat or prevent a disorder in a host mediated by complement factor D, or by an excessive or detrimental amount of the C3 amplification loop of the complement pathway. As examples, the invention includes methods to treat or prevent complement associated disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder or by ischemic injury. The invention also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by factor D.
The disclosure provides compounds of Formula I




and the pharmaceutically acceptable salts and compositions thereof, wherein:

Q1 is N(R1) or C(R1R1′);
Q2 is C(R2R2′), C(R2R2′)—C(R2R2′), S, O, N(R2) or C(R2R2′)O;
Q3 is N(R3), S, or C(R3R3′);
X1 and X2 are independently N, CH, or CZ, or X1 and X2 together are C═C; and
wherein Q1, Q2, Q3, X1, and X2 are selected such that a stable compound results.
Non-limiting examples of the




ring are illustrated below (any of which can be otherwise substituted with R1, R1′, R2, R2′, R3 and R3′) as described in more detail below.











wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3.

R and R′ are independently chosen from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted or any other substituent group herein that provides the desired properties. In some embodiments, the ring includes one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon can be provided as an enantiomer, or mixtures of enantiomers, including a racemic mixture. Where the ring includes more than one stereocenter, all of the enantiomers and diastereomers are included in the invention as individual species.
Z is F, Cl, NH2, CH3, CH2D, CHD2, or CD3.
R1, R1′, R2, R2′, R3, and R3′ are independently chosen at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, —C0-C4alkylNR9R10, —C(O)OR9, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)OR10, C1-C2haloalkyl, and C1-C2haloalkoxy, where R9 and R10 are independently chosen at each occurrence from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), and —O—C0-C4alkyl(C3-C7cycloalkyl).
In alternative embodiments, R1 and R1′ or R3 and R3′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, or S; R2 and R2′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or R2 and R2′ may be taken together to form a 3- to 6-membered heterocyclic spiro ring; each of which spiro ring each of which ring may be unsubstituted or substituted with 1 or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, —COOH, C1-C4alkyl (including in particular methyl), C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
In alternative embodiments, R1 and R2 may be taken together to form a 3-membered carbocyclic ring; R1 and R2 may be taken together to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or R2 and R3, if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring; each of which ring may be unsubstituted or substituted with 1 or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, —COOH, C1-C4alkyl (including in particular methyl), C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
In alternative embodiments, R1 and R1′, R2 and R2′, or R3 and R3′ can be taken together to form a carbonyl group. In alternative embodiments, R1 and R2 or R2 and R3 can be taken together to form a carbon-carbon double bond.
A is a group chosen from:







R4 is chosen from —CHO, —CONH2, C2-C6alkanoyl, hydrogen, —SO2NH2, —C(CH2)2F, —CH(CF3)NH2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C2alkyl(C3-C7cycloalkyl),




each of which R4 other than hydrogen, —CHO, and —CONH2, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C1-C2alkyl, C1-C2alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy.

R5 and R6 are independently chosen from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, vinyl, C1-C6alkyl (including methyl), C2-C6alkenyl, C1-C6alkoxy, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C4alkyl(C3-C7cycloalkyl), —P(O)(OR9)2, —OC(O)R9, —C(O)OR9, —C(O)N(CH2CH2R9)(R10), —NR9C(O)R10, phenyl, or 5- to 6-membered heteroaryl.
Each R5 and R6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted. For example, R5 and R6 other than hydrogen, hydroxyl, cyano, and —COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C1-C2alkyl, C1-C4alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy.
R6′ is hydrogen, halogen, hydroxyl, C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), or C1-C4alkoxy; or R6 and R6′ may be taken together to form an oxo, vinyl, or imino group.
R7 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl).
R8 and R8′ are independently chosen from hydrogen, halogen, hydroxyl, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, and (C1-C4alkylamino)C0-C2alkyl; or R8 and R8′ are taken together to form an oxo group; or R8 and R8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring.
R16 is absent or may include one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
R19 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, —SO2C1-C6alkyl, (mono- and di-C1-C6alkylamino)C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkyl(C3-C7heterocycloalkyl), —C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and wherein R19 other than hydrogen is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, —COOH, and —C(O)OC1-C4alkyl.
X11 is N or CR11.
X12 is N or CR12.
X13 is N or CR13.
X14 is N or CR14.
No more than 2 of X11, X12, X13, and X14 are N.
One of R12 and R13 is chosen from R31 and the other of R12 and R13 is chosen from R32:
R31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C2-C6alkenyloxy, —C(O)OR9, C1-C6thioalkyl, —C0-C4alkylNR9R10, —C(O)NR9R10, —SO2R9, —SO2NR9R10, —OC(O)R9, and —C(NR9)NR9R10, each of which R31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl, and C1-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2C1-C2haloalkyl, and C1-C2haloalkoxy, and each of which R31 is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, 3 or 4 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl)(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R32 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted;
In an alternative embodiment, R12 and R13 are each independently selected from an R32 moiety.
In one embodiment, when R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, B is not C2-C6 alkenyl; (C0-C4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
R11, R14, and R15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR9)2, —(PO)(OR9)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkenyl(aryl), C2-C6alkenyl(cycloalkyl), C2-C6alkenyl(heterocycle), C2-C6alkenyl(heteroaryl), C2-C6alkynyl, C2-C6alkynyl(aryl), C2-C6alkynyl(cycloalkyl), C2-C6alkynyl(heterocycle), C2-C6alkynyl(heteroaryl), C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkoxy(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
R21 and R22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, —C1-C4alkylOC(O)OC1-C6alkyl, —C1-C4alkylOC(O)C1-C6alkyl, —C1-C4alkylC(O)OC1-C6alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R21 and R22 can be optionally substituted.
R23 is independently chosen at each occurrence from C1-C6alkyl, C1-C6haloalkyl, (C3-C7cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.
R24 and R25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings and each R24 and R25 can be optionally substituted.
R37 is chosen at each occurrence from hydroxyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, —C1-C4alkylOC(O)OC1-C6alkyl, —C1-C4alkylOC(O)C1-C6alkyl, —C1-C4alkylC(O)OC1-C6alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each can be optionally substituted.
L is a bond or is chosen from the formulas




where R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl) and R18 and R18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C6alkenyl; C2-C6alkynyl; —(C0-C4alkyl)(aryl); —(C0-C4alkyl)(heteroaryl); or —(C0-C4alkyl)(biphenyl).
Each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36.
R33 is independently chosen from halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
R34 is independently chosen from nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23, -JOSO2OR21, —C(O)(CH2)1-4S(O)R21, —O(CH2)1-4S)NR21R22, -JOP(O)(OR21)(OR22), -JP(O)(OR21)(OR22), -JOP(O)(OR21)R22, JP(O)(OR21)R22, -JOP(O)R21R22, -JP(O)R21R22, -JSP(O)(OR21)(OR22), -JSP(O)(OR21)(R22), -JSP(O)(R21)(R22), -JNR9P(O)(NHR2)(NHR22), -JNR9P(O)(OR2)(NHR22), -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JNR9S(O)NR10R22, -JNR9SO2NR10R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)NR22, -JC(NH2)NR9S(O)2R22, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21OC(O)R22, —(CH2)1-4C(O)NR21R22, -JC(O)R24R25, -JNR9C(O)R21, -JC(O)R21, -JNR9C(O)NR10R22, —CCR21, —(CH2)1-4OC(O)R21, and -JC(O)OR23; each of which R34 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.
R35 is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7-ring atoms in each ring; each of which R35 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy.
R36 is independently chosen from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R36 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, —OSi(CH3)2C(CH3)3, —Si(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy.
J is independently chosen at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.
Pharmaceutical compositions comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier are also disclosed.
Methods of treating or preventing disorders mediated by complement cascade factor D, including but not limited to age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), arthritis including rheumatoid arthritis (RA), a respiratory disease or a cardiovascular disease, are provided, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a host, including a human, in need of such treatment are also disclosed.
In another embodiment, an effective amount of an active factor D inhibiting compound is provided to treat an inflammatory or immune disorder, including an autoimmune disorder, that is meadited or affected by factor D. In an alternative embodiment, the compound of Formula I can be used to treat a disorder mediated by the complement pathway, regardless whether it is acting through Factor D.
The present invention includes at least the following features:
(a) a compound of Formula I as described herein, and pharmaceutically acceptable salts and prodrugs thereof (each of which and all subgenuses and species thereof considered individually and specifically described);
(b) Formula I as described herein, and pharmaceutically acceptable salts and prodrugs thereof, for use in treating or preventing disorders mediated by the complement pathway, and for example, cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein;
(c) use of Formula I, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for use in treating or preventing disorders mediated by complement cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein;
(d) a process for manufacturing a medicament intended for the therapeutic use for treating or preventing treating or preventing disorders mediated by complement cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein characterized in that Formula I as described herein is used in the manufacture;
(e) a pharmaceutical formulation comprising an effective host-treating amount of the Formula I or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent;
(f) Formula I as described herein in substantially pure form, including substantially isolated from other chemical entities (e.g., at least 90 or 95%);
(g) processes for the manufacture of the compounds of Formula I and salts, compositions, dosage forms thereof; and
(h) processes for the preparation of therapeutic products that contain an effective amount of Formula I, as described herein.


DETAILED DESCRIPTION
I. Terminology
Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
The compounds in any of the Formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described. “Formula I” includes all subgeneric groups of Formula I, such as Formula IA and Formula IB and also includes pharmaceutically acceptable salts of a compound of Formula I, unless clearly contraindicated by the context in which this phrase is used. “Formula I” also includes all subgeneric groups of Formula I, such as Formulas IC-ID, and Formulas II-XXX, and also includes pharmaceutically acceptable salts of all subgeneric groups of Formula I, such as Formulas IA-ID, and Formulas II-XXX, unless contraindicated by the context in which this phrase is used.
The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
The present invention includes compounds of Formula I and the use of compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 125I respectively. The invention includes isotopically modified compounds of Formula I. In one embodiment, isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired result. Alternatively or in addition, isotopes of carbon, e.g., 13C and 14C, may be used. In one embodiment, the isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect).
Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one embodiments deuterium is 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and enough to alter a detectable property of the drug in a human.
In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group substituent on the L-B moiety region. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R18, R18′, R33, R34, R35, and/or R36. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group substituent within the A-carbonyl moiety region. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs at R4, R5, R6, R6′, R7, R8, R8′, R11, R12, R13, R14, R15, R16, R19, R21, R22, R23, R30, and/or R30a. In other embodiments, certain substituents on the proline ring are selectively deuterated. For example, in one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs at R, R′, R1, R1′, R2, R2′, R3, and/or R3′. In one embodiment, for example, when any of the R substituents of the proline ring are methyl or methoxy, the alkyl residue is optionally deuterated, e.g., CD3 or OCD3. In certain other embodiments, when two substituents of the proline ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is deuterated.
The substitution of a hydrogen atom for a deuterium atom occurs within an R group when at least one of the variables within the R group is hydrogen (e.g., 2H or D) or alkyl (e.g., CD3). For example, when any of R groups are, or contain for example through substitution, methyl or ethyl, the alkyl residue is typically deuterated, e.g., CD3, CH2CD3 or CD2CD3.
The compound of the present invention may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules. Examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. A solvate can be in a liquid or solid form.
A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —(C═O)NH2 is attached through carbon of the keto (C═O) group.
The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded. For example, when the substituent is oxo (i.e., ═O) then two hydrogens on the atom are replaced. When an oxo group replaces two hydrogens in an aromatic moiety, the corresponding partially unsaturated ring replaces the aromatic ring. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
A stable compound or stable structure refers to a compound leading to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and advances the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, C1, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having one or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted aromatic); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments “optionally substituted” includes one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, —C1-C6alkoxy, C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1-C6alkylamino)C0-C2alkyl, C1-C2haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide, —C1-C6alkyl(heterocyclo), C1-C6alkyl(heteroaryl), —C1-C6alkyl(C3-C7cycloalkyl), 0-C1-C6alkyl(C3-C7cycloalkyl), B(OH)2, phosphate, phosphonate and C1-C2haloalkoxy.
“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cn alkyl is used herein in conjunction with another group, for example, (C3-C7cycloalkyl)C0-C4 alkyl, or —C0-C4alkyl(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in —O—C0-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In one embodiment, the alkyl group is optionally substituted as described above.
“Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Nonlimiting examples are C2-C8alkenyl, C2-C6alkenyl and C2-C4alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above.
“Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C8alkynyl or C2-C6alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above.
“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C1-C4alkylene, C1-C3alkylene, or C1-C2alkylene.
“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene.
“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene.
“Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (—S—). In one embodiment, the alkoxy group is optionally substituted as described above.
“Alkenyloxy” is an alkenyl group as defined covalently bound to the group it substitutes by an oxygen bridge (—O—).
“Alkanoyl” is an alkyl group as defined above covalently bound through a carbonyl (C═O) bridge. The carbonyl carbon is included in the number of carbons, that is C2alkanoyl is a CH3(C═O)— group. In one embodiment, the alkanoyl group is optionally substituted as described above.
“Alkylester” is an alkyl group as defined herein covalently bound through an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula O(C═O)alkyl or a group of the formula —(C═O)Oalkyl.
“Amide” or “carboxamide” is —C(O)NRaRb wherein Ra and Rb are each independently selected from hydrogen, alkyl, for example, C1-C6alkyl, alkenyl, for example, C2-C6alkenyl, alkynyl, for example, C2-C6alkynyl, —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkyl(C3-C7heterocycloalkyl), —C0-C4alkyl(aryl), and —C0-C4alkyl(heteroaryl); or together with the nitrogen to which they are bonded, Ra and Rb can form a C3-C7heterocyclic ring. In one embodiment, the Ra and Rb groups are each independently optionally substituted as described above.
“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents can have a cycloalkyl group, which is attached as a spiro group. Examples of carbocyclic rings include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings. In one embodiment, the carbocyclic ring is optionally substituted as described above. In one embodiment, the cycloalkyl is a partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms. In another embodiment, the cycloalkyl is a saturated group containing all carbon ring atoms.
“Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- or bi-cyclic carbocyclic group as defined above attached to the group it substitutes via an oxygen, —O—, linker.
“Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
“Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
“Hydroxyalkyl” is an alkyl group as previously described, substituted with at least one hydroxyl subsitutuent.
“Aminoalkyl” is an alkyl group as previously described, substituted with at least one amino subsitutuent.
“Halo” or “halogen” indicates independently any of fluoro, chloro, bromo, and iodo.
“Aryl” indicates aromatic groups containing only carbon in the aromatic ring or rings. In one embodiment, the aryl groups contain 1 to 3 separate or fused rings and is 6 to about 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.
The term “heterocycle,” or “heterocyclic ring” as used herein refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring without aromaticity) carbocyclic radical of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described above. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl, quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group wherein 1 or 2 ring carbon atoms are substituted with oxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
“Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bicyclic heterocyclic group as described previously linked to the group it substitutes via an oxygen, —O—, linker.
“Heteroaryl” indicates a stable monocyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. “Heteroaryloxy” is a heteroaryl group as described bound to the group it substituted via an oxygen, —O—, linker.
“Heterocycloalkyl” is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, with remaining ring atoms being carbon. In a typical embodiment, nitrogen is the heteroatom. Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.
The term “mono- and/or di-alkylamino” indicates secondary or tertiary alkylamino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant.
“Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
“Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.
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 and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n—COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).
The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, and includes, in one embodiment, an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
A “patient” or “host” or “subject” is a human or non-human animal in need of modulation of the complement factor D pathway. Typically the host is a human. A “patient” or “host” or “subject” also refers to for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
A “prodrug” as used herein, means a compound which when administered to a host in vivo is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent. Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein. Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
“Providing a compound of Formula I with at least one additional active agent” means the compound of Formula I and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the compound of Formula I and the at least one additional active agent are within the blood stream of a patient. In certain embodiments the compound of Formula I and the additional active agent need not be prescribed for a patient by the same medical care worker. In certain embodiments the additional active agent or agents need not require a prescription. Administration of the compound of Formula I or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories or topical contact.
A “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a macular degeneration. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of complement factor D in the patient's blood, serum, or tissues.
II. Detailed Description of the Active Compounds
According to the present invention, a compound of Formula I is provided:




as well as the pharmaceutically acceptable salts and compositions thereof. Formula I can be considered to have a central core, an L-B substituent, and a (C═O)A substituent. It has been discovered that a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R12 or R13 on the A group is an amide substituent, is a superior inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation.

Non-limiting examples of compounds falling within Formula I with variations in the variables e.g., A, B, R1-R3′, and L, are illustrated below. The disclosure includes all combinations of these definitions so long as a stable compound results.
Formulas II-XXX
In one aspect, the disclosure includes compounds and salts of Formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXX which are within the scope of Formula I. The variables shown in Formula II-XXX carry the definitions set forth in the SUMMARY section for Formula I or any of the definitions set forth in this disclosure.



















In these embodiments, it should be understood that where R1 or R3 is attached to a carbon, there can be two independent attachments as in R2/R2′ and these formulas should be considered to include all such variations.
Additionally, the disclosure includes compounds and salts of Formula I and pharmaceutically acceptable compositions thereof, and any of its subformulae (II-XXX) in which at least one of the following conditions is met in the embodiments described below.
The R12 and R13 Amide Substituents
It has been discovered that a compound of Formula I, a pharmaceutically acceptable salt or composition thereof, wherein R12 or R13 on the A group is an amide substituent, is a superior inhibitor of complement factor D.
One of R12 and R13 is chosen from R31 and the other of R12 and R13 is chosen from R32. In another embodiment each of R12 and R13 can be independently selected from R32.
R31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C2-C6alkenyloxy, —C(O)OR9, C1-C6thioalkyl, —C0-C4alkylNR9R10, —C(O)NR9R10, —SO2R9, —SO2NR9R10, —OC(O)R9, and —C(NR9)NR9R10, each of which R31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl, and C1-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2C1-C2haloalkyl, and C1-C2haloalkoxy, and each of which R31 is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl)(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R32 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted.
In one embodiment, when R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, B is not C2-C6 alkenyl; (C0-C4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
In certain embodiments, R32 is selected from:







Non-Limiting R12/R13 Embodiments

In one embodiment, R12 is R32.
In one embodiment, R13 is R32.
In one embodiment, R12 is R32, which is —C(O)NR21R37.
In one embodiment, R12 is R32, which is —C(O)NR24R25.
In one embodiment, R12 is R32, which is —C(O)NR9R37.
In one embodiment, R12 is R32, which is —C(O)NR21SO2R22.
In one embodiment, R12 is R32, which is —NR9C(O)OR10.
In one embodiment, R12 is R32, which is —NR9C(O)OR23.
In one embodiment, R12 is R32, which is —NR9C(O)R21.
In one embodiment, R12 is R32, which is —NR9C(O)NR9R10.
In one embodiment, R12 is R32, which is —NR9C(O)NR10R23.
In one embodiment, R12 is R32, which is —NR9C(O)NR24R25.
In one embodiment, R13 is R32, which is —C(O)NR21R37.
In one embodiment, R13 is R32, which is —C(O)NR24R25.
In one embodiment, R13 is R32, which is —C(O)NR9R37.
In one embodiment, R13 is R32, which is —C(O)NR21SO2R22.
In one embodiment, R13 is R32, which is —NR9C(O)OR10.
In one embodiment, R13 is R32, which is —NR9C(O)OR23.
In one embodiment, R13 is R32, which is —NR9C(O)R21.
In one embodiment, R13 is R32, which is —NR9C(O)NR9R10.
In one embodiment, R13 is R32, which is —NR9C(O)NR10R23.
In one embodiment, R13 is R32, which is —NR9C(O)NR24R25.
In one embodiment, the disclosure provides compounds of Formula I, wherein; one of R12 and R13 is H and the other of R12 and R13 is R32, where:
R32 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted;
wherein R9, R10, R21, R22, R23, R24, R25, and R37 are as defined in the summary section above.
In another embodiment, the disclosure provides compounds of Formula I, wherein;
R1, R1′, R2, and R3′ are all hydrogen;
R2 is fluoro and R3 is hydrogen, —C0-C4alkyl(C3-C7cycloalkyl), or —O—C0-C4alkyl(C3-C7cycloalkyl);
R5 is hydrogen, halogen, or C1-C2alkyl;
R11, R13, R14, and R15, if present, are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, —C0-C2alkyl(mono- and di-C1-C2alkylamino), trifluoromethyl, and trifluoromethoxy;
X12 is CR12; and
R12 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted;
wherein R9, R10, R21, R22, R23, R24, R25, and R37 are as defined in the summary section above.
In one embodiment, when R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, B is not C2-C6 alkenyl; (C0-C4 alkyl)(heteroaryl); monocyclic or bicyclic carbocyclic; or monocyclic heterocyclic.
In one embodiment, the disclosure provides compounds of Formula I, wherein;

    
    
        m is 0 or 1;
    
    


R2 is halogen, R2′ is hydrogen or halogen, and R3 is hydrogen, halogen, —C0-C4alkyl(C3-C7cycloalkyl), or —O—C0-C4alkyl(C3-C7cycloalkyl);
R6 is —C(O)C1-C4alkyl, —C(O)NH2, —C(O)CF3, —C(O)(C3-C7cycloalkyl), or -ethyl(cyanoimino);
one of R12 and R13 is selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R12 and R13 is R32, where
R32 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted;
wherein R9, R10, R21, R22, R23, R24, R25, and R37 are as defined in the summary section above.
In one embodiment, the disclosure provides compounds of Formula I, wherein;
one of R12 and R13 is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R12 and R13 is R32, where
R32 is chosen from C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, and —NR9C(O)NR24R25, each of which is optionally substituted;
wherein R9, R10, R21, R22, R23, R24, R25, and R37 are as defined in the summary section above.
In one embodiment, R32 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.
Central Core Moiety
The central core moiety in Formula I is illustrated below:




wherein:

Q1 is N(R1) or C(R1R1′);
Q2 is C(R2R2′), C(R2R2′)—C(R2R2′), S, O, N(R2) or C(R2R2′)O;
Q3 is N(R3), S, or C(R3R3′);
X1 and X2 are independently N or CH, or X1 and X2 together are C═C; and
wherein Q1, Q2, Q3, X1, and X2 are selected such that a stable compound results.
Non-limiting examples of the




ring are illustrated below (any of which can be otherwise substituted with R1, R1′, R2, R2′, R3, and R3′) as described in more detail below.











wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3.

R and R′ are independently chosen from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted or any other substituent group herein that provides the desired properties. In some embodiments, the ring includes one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon can be provided as an enantiomer, or mixtures of enantiomers, including a racemic mixture. Where the ring includes more than one stereocenter, all of the enantiomers and diastereomers are included in the invention as individual species.
Z is F, C1, NH2, CH3, CH2D, CHD2, or CD3.
R1, R1′, R2, R2′, R3, and R3′ are independently chosen at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, —C0-C4alkylNR9R10, —C(O)OR9, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)OR′°, C1-C2haloalkyl, and C1-C2haloalkoxy, where R9 and R10 are independently chosen at each occurrence from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), and —O—C0-C4alkyl(C3-C7cycloalkyl).
Non-Limiting Central Core Embodiments
In alternative embodiments, R1 and R1′ or R3 and R3′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, or S; R2 and R2′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or R2 and R2′ may be taken together to form a 3- to 6-membered heterocyclic spiro ring;
each of which ring may be unsubstituted or substituted with one or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, —COOH, C1-C4alkyl (including in particular methyl), C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
In alternative embodiments, R1 and R2 may be taken together to form a 3-membered carbocyclic ring; le and R2 may be taken together to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or R2 and R3, if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring;
each of which ring may be unsubstituted or substituted with one or more substituents independently chosen from halogen (and in particular F), hydroxyl, cyano, —COOH, C1-C4alkyl (including in particular methyl), C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
In one embodiment, the central core moiety is proline.
In one embodiment, the central core moiety is 4-fluoroproline.
In one embodiment, R1, R1′, R2′, R3, and R3′, if present, are all hydrogen; and R2 is fluoro.
In one embodiment, R1, R1′, R2′, and R3′, if present, are all hydrogen; and R2 is fluoro and R3 is —C0-C4alkyl(C3-C7cycloalkyl) or —O—C0-C4alkyl(C3-C7cycloalkyl).
In one embodiment, R1 and R2 are taken together to form a 3- to 6-membered cycloalkyl group, and R1′, R2′, R3, and R3′, where present, are all hydrogen.
In one embodiment, R1, R1′, R3, and R3′, if present, are all hydrogen, and R2 and R2′ are taken together to form a 5- or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.
In one embodiment, R1 is hydrogen and R2 is fluoro.
In one embodiment, R1 and R2 are joined to form a 3 membered ring.
The disclosure includes compounds of Formula I in which the central pyrrolidine is vinyl substituted, for example:




In one embodiment, the compound of Formula I has the structure:




In one embodiment, the central pyrrolidine is modified by addition of a second heteroatom to a pyrrolidine ring, such as N, O, S, or Si, for example:




Another modification within the scope of the disclosure is joining a substituent on the central pyrrolidine ring to R7 or R8 to form a 5- to 6-membered heterocyclic ring, for example:




Example compounds having the modifications disclosed above include:




Central Core L-B Substituents

The central core L-B substituents in Formula I are illustrated below:




L is a bond or is chosen from the formulas:




where R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl) and R18 and R18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C6alkenyl; C2-C6alkynyl; —(C0-C4alkyl)(aryl); —(C0-C4alkyl)(heteroaryl); or —(C0-C4alkyl)(biphenyl).
Each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36:
R33 is independently chosen from halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
R34 is independently chosen from nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23, -JOSO2OR21, —C(O)(CH2)1-4S(O)R21, —O(CH2)1-4S(O)NR21R22, -JOP(O)(OR21)(OR22), -JP(O)(OR21)(OR22), -JOP(O)(OR21)R22, -JP(O)(OR21)R22, -JOP(O)R21R22, -JP(O)R21R22, -JSP(O)(OR21)(OR22), -JSP(O)(OR21)(R22), -JSP(O)(R21)(R22), -JNR9P(O)(NHR21)(NHR22), -JNR9P(O)(OR21)(NHR22), -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JNR9S(O)NR10R22, -JNR9SO2NR10R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)NR22, -JC(NH2)NR9S(O)2R22, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21C(O)R22, —(CH2)1-4 C(O)NR21R22, -JC(O)R24R25, -JNR9C(O)R21, -JC(O)R21, -JNR9C(O)NR10R22, —CCR21, —(CH2)1-4OC(O)R21, and -JC(O)OR23; each of which R34 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy;
R35 is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7-ring atoms in each ring; each of which R35 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R36 is independently chosen from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R36 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, —OSi(CH3)2C(CH3)3, —Si(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy.
J is independently chosen at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.
In one embodiment, -L-B— is




where

R26 and R27 are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkoxy(C3-C7cycloalkyl), C1-C2haloalkyl, C1-C2haloalkoxy, and C1-C2haloalkylthio.
Non-Limiting L-B Embodiments
In another embodiment, -L-B— is




wherein

R18 and R18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0 or 1; and
R26, R27, and R28 are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C1-C6alkylamino)C0-C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl-, (heteroaryl)C0-C4alkyl-, and —C0-C4alkoxy(C3-C7cycloalkyl); each of which R26, R27, and R28 other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C2alkoxy, C1-C2haloalkyl, (C3-C7cycloalkyl)C0-C4alkyl-, and C1-C2haloalkoxy; and
R29 is hydrogen, C1-C2alkyl, C1-C2haloalkyl or —Si(CH3)2C(CH3)3.
In one embodiment, m is 0.
In one embodiment, the disclosure further includes compounds and salts of Formula I in which B is 2-fluoro-3-chlorophenyl. In another embodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl group such as 2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethyl silylphenyl is used.
In another embodiment, B is phenyl, pyridyl, or indanyl each of which is unsubstituted or substituted with one or more substituents independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C1-C6alkylamino)C0-C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, —C0-C4alkoxy(C3-C7cycloalkyl), (phenyl)C0-C2alkyl, (pyridyl)C0-C2alkyl; each of which substituents other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C2alkyl, C1-C2alkoxy, —OSi(CH3)2C(CH3)3, —Si(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy.
In another embodiment, B is phenyl or pyridyl substituted with 1, 2, or 3 substituents chosen from chloro, bromo, hydroxyl, —SCF3, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of which substituents other than chloro, bromo, hydroxyl, —SCF3, can be optionally substitued.
In certain embodiments, B is a 2-fluoro-3-chlorophenyl or a 2-fluoro-3-trifluoromethoxyphenyl group.
In one embodiment, B is pyridyl, optionally substituted with halogen, C1-C2alkoxy, and trifluoromethyl.
In one embodiment, B is phenyl, substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and optionally substituted phenyl.
In one embodiment, R23 is independently chosen at each occurrence from (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.
In one embodiment, B is selected from


































where is hydrogen, methyl, or trifluoromethyl; R28 is hydrogen or halogen; and R29 is hydrogen, methyl, trifluoromethyl, or —Si(CH3)2C(CH3)3.

Central Core (C═O)A Substituent

The central core (C═O)A substituent in Formula I is illustrated below:




A is a group chosen from:







R4 is chosen from —CHO, —CONH2, C2-C6alkanoyl, hydrogen, —SO2NH2, —C(CH2)2F, —CH(CF3)NH2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C2alkyl(C3-C7cycloalkyl),




each of which R4 other than hydrogen, —CHO, and —CONH2, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C1-C2alkyl, C1-C2alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy.
R5 and R6 are independently chosen from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, vinyl, C1-C6alkyl (including methyl), C2-C6alkenyl, C1-C6alkoxy, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C4alkyl(C3-C7cycloalkyl), —P(O)(OR9)2, —OC(O)R9, —C(O)OR9, —C(O)N(CH2CH2R9)(R10), —NR9C(O)R10, phenyl, or 5- to 6-membered heteroaryl.
Each R5 and R6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted. For example, R5 and R6 other than hydrogen, hydroxyl, cyano, and —COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C1-C2alkyl, C1-C4alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy.
R6′ is hydrogen, halogen, hydroxyl, C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), or C1-C4alkoxy; or R6 and R6′ may be taken together to form an oxo, vinyl, or imino group.
R7 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl).
R8 and R8′ are independently chosen from hydrogen, halogen, hydroxyl, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, and (C1-C4alkylamino)C0-C2alkyl; or R8 and R8′ are taken together to form an oxo group; or R8 and R8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring.
R16 is absent or may include one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
R19 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, —SO2C1-C6alkyl, (mono- and di-C1-C6alkylamino)C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkyl(C3-C7heterocycloalkyl), —C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and wherein R19 other than hydrogen is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, —COOH, and —C(O)OC1-C4alkyl.
X11 is N or CR11.
X12 is N or CR12.
X13 is N or CR13.
X14 is N or CR14.
No more than 2 of X11, X12, X13, and X14 are N.
R11, R14, and R15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR9)2, —(PO)(OR9)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkenyl(aryl), C2-C6alkenyl(cycloalkyl), C2-C6alkenyl(heterocycle), C2-C6alkenyl(heteroaryl), C2-C6alkynyl, C2-C6alkynyl(aryl), C2-C6alkynyl(cycloalkyl), C2-C6alkynyl(heterocycle), C2-C6alkynyl(heteroaryl), C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkoxy(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
In one embodiment, R5 and R6 are independently chosen from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, and hydrogen.
In one embodiment, each R5 and R6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C, —C2alkyl, C, —C4alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy.
In one embodiment, R8 and R8′ are independently hydrogen or methyl.
In one embodiment, R8 and R8′ are hydrogen.
In one embodiment, R7 is hydrogen or methyl.
In one embodiment, R7 is hydrogen.
Embodiments of Formulas IA, IB, IC, and ID
To further illustrate the invention, various embodiments of Formula IA, IB, IC and ID are provided. These are presented by way of example to show some of the variations among presented compounds within the invention and can be applied to any of the Formulas I-XXX.
In one aspect, this disclosure includes compounds and salts of Formula IA:




where R6, R13, and B may carry any of the definitions set forth herein for this variable.

In another aspect, this disclosure includes compounds and salts of Formula IB, IC, and ID.




In Formulas IA, IB, IC, and ID, the variables may include any of the definitions set forth herein that results in a stable compound. In certain embodiments, the following conditions apply for Formula IB and IC.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23. —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is R32, R32 is —C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is amide, R12 is R32, R32 is —C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR2SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 is H, R2 is F, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=0, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, le is H, R2 is F, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23 or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is heteroaryl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, R13 is H, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is alkanoyl, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 is H, R2 is F, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
In some embodiments, structures are provided including Formula IB and IC, wherein m=1, R1 and R2 are joined to form a 3 membered ring, R6 is amide, R12 is H, R13 is R32, R32 is C(O)NR21R37, —C(O)NR24R25, —C(O)NR9R37, —C(O)NR21SO2R22, —NR9C(O)OR10, —NR9C(O)OR23, —NR9C(O)R21, —NR9C(O)NR9R10, —NR9C(O)NR10R23, or —NR9C(O)NR24R25, each of which is optionally substituted, and B is phenyl.
Embodiments of Formula VII
To further illustrate the invention, various embodiments of Formula VII. In one aspect, the disclosure includes compounds and salts of Formula VII:




wherein:

R2, R2′, and R3 are independently chosen from hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, —C0-C2alkylNR9R10, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R8 and R8′ are independently chosen from hydrogen, halogen, and methyl;
R5 is hydrogen, hydroxyl, cyano, —COOH, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl-C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C4alkyl(C3-C7cycloalkyl, C1-C2haloalkyl, or C1-C2haloalkoxy;
R6 is —C(O)CH3, —C(O)NH2, —C(O)CF3, —C(O)(cyclopropyl), or -ethyl(cyanoimino); and
R11 and R14 are independently chosen from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —OC0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy.
Prodrugs of Formula I are also within the scope of the disclosure.
III. Pharmaceutical Preparations
Compounds disclosed herein can be administered as the neat chemical, but can also administered as a pharmaceutical composition, that includes an effective amount for a host in need of treatment of the selected compound of Formula I, as described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt of Formula I, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain a compound or salt of Formula I as the only active agent, or, in an alternative embodiment, Formula I and at least one additional active agent. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of a compound of Formula I and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. The pharmaceutical composition may also include a molar ratio of a compound of Formula I and an additional active agent. For example the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an another anti-inflammatory agent.
Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intraveneous, intra-aortal, intracranial, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
The pharmaceutical compositions/combinations can be formulated for oral administration. These compositions can contain any amount of active compound for Formula I that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of a compound of Formula I and usually at least about 5 wt. % of a compound of Formula I. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound of Formula I.
The complement factor D inhibitors of the present invention can be administered, for example, either systemically or locally. Systemic administration includes, for example, oral, transdermal, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal. Local administration for ocular administration includes: topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, sub-tenon, or via an intraocular device. The inhibitors may be delivered via a sustained delivery device implanted intravitreally or transsclerally, or by other known means of local ocular delivery.
IV. Methods of Treatment
The compounds and pharmaceutical compositions disclosed herein are useful for treating or preventing a disorder that is mediated by the complement pathway, and in particular, a pathway that is modulated by complement factor D. In certain embodiments, the disorder is an inflammatory disorder, an immune disorder, an autoimmune disorder, or complement factor D related disorders in a host. In one embodiment, the disorder is an ocular disorder. Complement mediated disorders that may be treated or prevented by the compounds and compositions of this disclosure include, but are not limited to, inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), ischemia/reperfusion injury (I/R injury), psoriasis, myasthenia gravis, system lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burn injury, capillary leak syndrome, obesity, diabetes, Alzheimer's dementia, stroke, schizophrenia, epilepsy, age-related macular degeneration, glaucoma, diabetic retinopathy, asthma, allergy, acute respiratory distress syndrome (ARDS), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), cystic fibrosis, myocardial infarction, lupus nephritides, Crohn's disease, rheumatoid arthritis, atherosclerosis, transplant rejection, prevention of fetal loss, biomaterial reactions (e.g. in hemodialysis, inplants), C3 glomerulonephritis, abdominal aortic aneurysm, neuromyelitis optica (NMO), vasculitis, neurological disorders, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during I L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, immune complex disorders and autoimmune diseases, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, tissue regeneration and neural regeneration. In addition, other known complement related disease are lung disease and disorders such as dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome, arthritis, autoimmune heart disease, inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, transplantation, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid, MPGN II, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion.
In some embodiments, complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases. In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
In one embodiment, a method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of age-related macular degeneration (AMD) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of rheumatoid arthritis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of multiple sclerosis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of myasthenia gravis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of atypical hemolytic uremic syndrome (aHUS) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of C3 glomerulonephritis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of abdominal aortic aneurysm is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, a method for the treatment of neuromyelitis optica (NMO) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
In some embodiments, the present invention provides methods of treating or preventing an inflammatory disorder or a complement related disease, by administering to a host in need thereof an effective amount of a compound of Formula I of the invention. In some embodiments, the present invention provides methods of treating or preventing an inflammatory disorder more generally, an immune disorder, autoimmune disorder, or complement factor D related disease, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to patient with a factor D mediated inflammatory disorder. A compound or salt of Formula I may be provided as the only active agent or may be provided together with one or more additional active agents.
In one embodiment, a method for the treatment of a disorder associated with a dysfunction in the complement cascade is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, a method of inhibiting activation of the alternative complement pathway in a subject is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, a method of modulating factor D activity in a subject is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
“Prevention” as used in this disclosure means decreasing the likelihood of the appearance of symptoms in a patient administered the compound prophylactically as compared to the likelihood of the appearance of symptoms in patients not administered the compound or decreasing the severity of symptoms in a patient administered the compound prophylactically as compared to the severity of symptoms experienced by patients with the disorder or condition who were not administered the compound. In an alternative embodiment, an effective amount of a compound of Formula I is used to prevent or prophylaxis of a complement factor D related disorder.
An effective amount of a pharmaceutical composition/combination of the invention may be an amount sufficient to (a) inhibit the progression of a disorder mediated by the complement pathway, including an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease; or (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease.
An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or theoretically, by calculating bioavailability.
V. Combination Therapy
In one embodiment, a compound or salt of Formula I may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action. In one embodiment, a compound or salt of Formula I may be provided in combination with a complement C5 inhibitor or C5 convertase inhibitor. In another embodiment, a compound or salt of Formula I may be provided in combination with eculizumab. In one embodiment, a compound or salt of Formula I may be provided in combination with additional inhibitors of factor D.
In one embodiment, a compound or salt of Formula I may be provided together with a compound that inhibits an enzyme that metabolizes protease inhibitors. In one embodiment, a compound or salt of Formula I may be provided together with ritonavir.
In nonlimiting embodiments, a compound or salt of Formula I may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitors, receptor agonists, or siRNAs.
Nonlimiting examples of active agents in these categories are:
Protease inhibitors: plasma-derived C1-INH concentrates, for example Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®; and recombinant human C1-inhibitors, for example Rhucin®;
Soluble complement regulators: Soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLex/TP-20 (Avant Immunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals);
Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S);
Complement component inhibitors: Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix);
Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);
Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals).
In an embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the compositions of the present invention are administered in combination with an anti-VEGF agent. Nonlimiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech/Roche); anecortane acetate, squalamine lactate, and corticosteroids, including, but not limited to, triamcinolone acetonide.
In another embodiment, a compound of Formula I can be combined with a second agent in order to treat a disorder of the eye.
Examples of types of therapeutic agents that can be used in combination for ocular applications include anti-inflammatory drugs, antimicrobial agents, anti-angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs and combinations thereof. Examples of therapeutic agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, pegaptanib, platinum analogues, polymicin B, propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin, voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate, tacrolimus and combinations thereof. Examples of eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, an autoimmune disease of the retina, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open angle glaucoma, closed angle glaucoma, pigmentary glaucoma and combinations thereof.
A compound of Formula I, or a combination of Formula I and another active agent, can be administered into an eye compartment of via injection into the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera, the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial).
In an alternative embodiment, a compound of Formula I, or a combination of Formula I and another active agent, can be administered into an eye compartment via binding to a mucosal penetrating particle to treat a condition located in the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera or the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial). Mucosal penetrating particles are known in the art, and are described in, for example, PCT published application WO 2013166436 to Kala Pharmaceuticals, incorporated in its entirety herein.
In other embodiments, a composition comprising compound of Formula I suitable for topical administration to an eye is provided. The pharmaceutical composition comprises a plurality of coated particles, comprising a core particle comprising a compound of Formula I, wherein Formula I constitutes at least about 80 wt % of the core particle, and a coating comprising one or more surface-altering agents, wherein the one or more surface-altering agents comprise at least one of a poloxamer, a poly(vinyl alcohol), or a polysorbate. The one or more surface-altering agents is present on the outer surface of the core particle at a density of at least 0.01 molecules/nm. The one or more surface-altering agents is present in the pharmaceutical composition in an amount of between about 0.001% to about 5% by weight. The plurality of coated particles have an average smallest cross-sectional dimension of less than about 1 micron. The pharmaceutical composition also includes one or more ophthalmically acceptable carriers, additives, and/or diluents.
It will be appreciated by one of ordinary skill in the art that particles suitable for use with the presently disclosed methods can exist in a variety of shapes, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings, nanorings, rod-shaped particles, arrow-shaped particles, teardrop-shaped particles, tetrapod-shaped particles, prism-shaped particles, and a plurality of other geometric and non-geometric shapes. In some embodiments, the presently disclosed particles have a spherical shape.
In one embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system or another active compound with a different biological mechanism of action. In another embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with eculizumab.
In one embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with an additional inhibitor of the complement system. In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with methotrexate.
In certain embodiments, a compound of Formula I is administered in combination or alternation with at least one anti-rhuematoid arthritis drug selected from: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine), indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors including Celecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex), penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologic drugs including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroids including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), and triamcinolone (Aristocort); gold salts, including Auranofin (Ridaura); Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combination thereof.
In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system. In another embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.
In one embodiment, a compound of Formula I is combined with at least one anti-multiple sclerosis drug selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Extavia (interferon beta-1b), Gilenya (fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH), and combinations thereof.
In one aspect, a compound or salt of Formula I may be provided in combination or alternation with an immunosuppressive agent or an anti-inflammatory agent.
In one embodiment of the present invention, a compound described herein can be administered in combination or alternation with at least one immunosuppressive agent. The immunosuppressive agent as nonlimiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.
Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof. In one embodiment, a compound of Formula I is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.
VI. Process of Preparation of Compounds of Formula I
Abbreviations


    (Boc)2O di-tert-butyl dicarbonate
    CAN Acetonitrile
    AcOEt, EtOAc ethyl acetate
    CH3OH, MeOH Methanol
    CsF Cesium fluoride
    CuI Cuprous iodide
    DCM, CH2Cl2 Dichloromethane
    DIEA, DIPEA N,N-diisopropylethylamine
    DMA N,N-dimethylacetamide
    DMF N,N-dimethylformamide
    DMSO Dimethylsulfoxide
    DPPA Diphenyl phosphoryl azide
    Et3N, TEA Triethylamine
    EtOAc Ethylacetate
    EtOH Ethanol
    HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
    HCl Hydrochloric acid
    iPr2Net N,N-diisopropylethylamine
    K2CO3 Potassium carbonate
    LiOH Lithium hydroxide
    MTBE Methyl tbutylether
    Na2SO4 Sodium sulfate
    NaCl Sodium chloride
    NaH Sodium hydride
    NaHCO3 Sodium bicarbonate
    NEt3 triethylamine
    Pd(OAc)2 Palaldium acetate
    Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II)
    Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride
    Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)
    Pd2 (dba)3 Tris(dibenzylideneacetone)dipalladium(0)
    PPh3 Triphenylphosphine
    RT Room temperature
    TBuOK potassium tert-butoxide
    TEA triethylamine
    Tf2O trifluoromethanesulfonic anhydride
    TFA Trifluoroacetic acid
    THF Tetrahydrofuran
    TMSBr bromotrimethylsilane
    tR Retention time
    Zn(CN)2 Zinc cyanide


General Methods
All nonaqueous reactions were performed under an atmosphere of dry argon or nitrogen gas using anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the two liquid chromatography (LC) methods listed below. The structure of starting materials, intermediates, and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry.
LC Method A

    
    
        Instrument: Waters Acquity Ultra Performance LC
        Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 μm
        Column Temperature: 40° C.
        Mobile Phase: Solvent A: H2O+0.05% FA; Solvent B: CH3CN+0.05% FA
        Flow Rate: 0.8 mL/min
        Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then 0.5 min @ 85% B.
        Detection: UV (PDA), ELS, and MS (SQ in EI mode)
    
    


LC Method B

    
    
        Instrument: Shimadzu LC-2010A HT
        Column: Athena, C18-WP, 50×4.6 mm, 5 μm
        Column Temperature: 40° C.
        Mobile Phase: Solvent A: H2O/CH3OH/FA=90/10/0.1; Solvent B: H2O/CH3OH/FA=10/90/0.1
        Flow Rate: 3 mL/min
        Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min @ 100% B
        Detection: UV (220/254 nm)
    
    


Example 1. General Route of Synthesis
A compound of the present invention can be prepared, for example, from a central core. In one embodiment, for example, the central core Structure 1 is an N-protected aminoacid where X1 is nitrogen and PG=protecting group. In one embodiment, the central core is coupled to an amine to generate an amide of Structure 2 (wherein L-B includes a C(O)N moiety). Structure 2 can then be deprotected to generate Structure 3. Structure 3 is coupled to Structure 4 (A-COOH) to generate a second amide bond, forming a compound within Formula I. The chemistry is illustrated in Route 1.




In an alternative embodiment, central core Structure 5 is reacted with a heterocyclic or heteroaryl compound to generate a compound of Structure 6. In one embodiment, Structure 6 is deprotected to generate a carboxylic acid, Structure 7. In one embodiment, Structure 7 is coupled to an amine to generate a compound of Formula I. This chemistry is illustrated in Route 2.




In an alternative embodiment, Structure 8 is deprotected to generate an amine which is Structure 9. Structure 9 is then coupled to generate an amide which is Structure 6. Structure 6 is then deprotected to generate a carboxylic acid which is Structure 7. Structure 7 is then coupled to form the amide which falls within Formula I. The chemistry is illustrated in Route 3.




In an alternate embodiment, a heteroaryl compound of Structure 10 is coupled to an activated ester, Structure 11, to generate Structure 12. The ester is hydrolyzed to form acid Structure 13. Structure 13 is coupled to Structure 3 from Route 1 to generate Structure 14. Structure 14 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 15. This chemistry is illustrated in Route 4.




In another embodiment, Structure 15 is treated with diphenylphosphoryl azide (DPPA) to generate the isocyanate, Structure 16. Structure 16 is then treated with an amine or alcohol to generate ureas and carbamates compounds of Formula I, wherein the R12 substituent is NR9C(O)NR9R10, NR9C(O)NR10R23, NR9C(O)R24R25, NR9C(O)OR10 or NR9C(O)OR23. In some embodiments, R9 is hydrogen. Structure 15 can be coupled to amines to generate amides of Formula I, wherein the R12 substituent is, C(O)NR24R25, C(O)NR9R37, or C(O)NR21SO2R22. In some embodiments, R9 is hydrogen. The chemistry is illustrated in Route 5.




In an alternate embodiment, a heteroaryl compound of Structure 17 is coupled to an activated ester to generate Structure 18. The ester is hydrolyzed to form acid Structure 19. Structure 19 is coupled to Structure 3 from Route 1 to generate Structure 20. Structure 20 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 21. This chemistry is illustrated in Route 6.




In one embodiment, Structure 21 from Route 6, is treated with, for example, diphenylphosphoryl azide (DPPA) to generate an isocyanate, Structure 22. Structure 22 is then treated with an amine or alcohol to generate urea and carbamate compounds within Formula I, NR9R10, NR9C(O)NR10R23, NR9C(O)R24R25, wherein the R13 substituent is NR9C(O) NR9C(O)OR10 and NR9C(O)OR23. In some embodiments, R9 is hydrogen. Structure 21 can be coupled to amines to generate amides within Formula I, wherein the R13 substituent is C(O)NR24R25, C(O)NR9R37, or C(O)NR21SO2R22. In some embodiments, R9 is hydrogen. The chemistry is illustrated in Route 7.




In an alternate embodiment, a heteroaryl or aryl moiety 8-1 is coupled to a central core to generate 8-2. The protected acid, 8-2 is deblocked to form the carboxylic acid, 8-3. The carboxylic acid is coupled to form an amide bond (L-B) and 8-4. The heteroaryl or aryl moiety, A′, can then be further derivitized to add substituents at the X11, X12, X13 and X14 positions to generate compounds within Formula I. This chemistry is illustrated in Route 8.




In an alternate embodiment, Structure 9-1 is coupled to an acid, Structure 9-2, to generate Structure 9-3. The carboxylic acid, Structure 9-3, is deblocked to generate carboxylic acid, Structure 9-4. Carboxylic acid Structure 9-4 is coupled to an amine to form an amide bond (L-B) and compounds within Formula I. This chemistry is illustrated in Route 9.




In an alternate embodiment, a heteroaryl compound of Structure 10-1 is treated with a carboxylic acid to generate Structure 10-2. The heteroaryl Structure 10-2 can be treated with an acylating agent to generate Structure 10-3. In an alternate embodiment, Structure 10-2 is treated with coupling conditions to generate R6=CN. The nitrile can be treated with an oxime to generate an amide at the R6 position. Structure 10-3 is treated with an activated ester to generate Structure 10-4. In some embodiments, the leaving group, LG, is a halide. Structure 10-4 is treated with a base to generate the acid, Structure 10-5. Structure 10-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. This chemistry is illustrated in Route 10.




In an alternate embodiment, a heteroaryl compound of Structure 11-1 is treated with a carboxylic acid to generate Structure 11-2. The heteroaryl Structure 11-2 can be treated with an acylating agent to generate Structure 11-3. In an alternate embodiment, Structure 11-2 is treated with coupling conditions to generate R6=CN. The nitrile can be treated with an oxime to generate an amide at the R6 position. Structure 11-3 is treated with an activated ester to generate Structure 11-4. In some embodiments, the leaving group, LG, is a halide. Structure 11-4 is treated with a base to generate the acid, Structure 11-5. Structure 11-5 is coupled to Structure 3 from Route 1 to generate compounds within Formula I. The chemistry is illustrated in Route 11.




In an alternate embodiment, a heteroaryl compound of Structure 12-1 is treated with a carboxylic acid to generate Structure 12-2. The heteroaryl Structure 12-2 can be treated with an acylating agent to generate Structure 12-3. In an alternate embodiment, Structure 12-2 is treated with coupling conditions to generate R6=CN. The nitrile can be treated with an oxime to generate an amide at the R6 position. Structure 12-3 is treated with an activated ester to generate Structure 12-4. In some embodiments, the leaving group, LG, is a halide. Structure 12-4 is treated with a base to generate the acid, Structure 12-5. Structure 12-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. This chemistry is illustrated in Route 12.




In an alternate embodiment, a heteroaryl compound of Structure 13-1 is treated with a carboxylic acid to generate Structure 13-2. The heteroaryl Structure 13-2 can be treated with an acylating agent to generate Structure 13-3. In an alternate embodiment, Structure 13-2 is treated with coupling conditions to generate R6=CN. The nitrile can be treated with an oxime to generate an amide at the R6 position. Structure 13-3 is treated with an activated ester to generate Structure 13-4. In some embodiments, the leaving group, LG, is a halide. Structure 13-4 is treated with a base to generate the acid, Structure 13-5. Structure 13-5 can be coupled to Structure 3 from Route 1 to generate compounds within Formula I. The chemistry is illustrated in Route 13.




In an alternate embodiment, Structure 14-1 is coupled to an amine to generate an amide bond (L-B), and Structure 14-2. Structure 14-2, is coupled to an amine to generate compounds within Formula I. This chemistry is illustrated in Route 14.




Example 2. Examples of Central Synthons







ZA is halogen.

In one embodiment, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, for example, the following compounds:




Structure A can be treated with deuterium oxide to generate Structure B. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO 2014/037480 (p. 103). Structure B can be reduced to generate Structure C. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be treated with Mitsunobu reaction conditions to generate Structure D. Structure B can be treated with DAST to generate Structure E. See, WO 2014/037480. Structure A can be treated with sodium borodeuteride to generate Structure F. See, Dormoy, -J.-R.; Castro, B. Synthesis 1986, 81-82. Compound F can be used to generate Structure K. See, Dormoy, -J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can be treated with a deuterated reducing agent, for example sodium borodeuteride to generate Structure G. Structure G can be treated with DAST to generate Structure H. Structure F can be used to generate Structure K. See, Dormoy, -J.-R.; Castro, B. Synthesis 1986, 81-82. Structure G can be used to generate Structure I. Structure J can be prepared according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101, 202-212. Structures A-J can be used to prepare compounds of Formula I.
Example 3. Preparation of Central-L-B Synthons




Routes 1a, 1b and 1c.

In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(1,1-dimethylethyl) ester, (4S)—, CAS 209269-((8-9, can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treated with an amine protecting reagent. In one embodiment, the amine protecting reagent is di-tert-butyl dicarbonate. In another embodiment, 3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester, (4S)—, is commercially available from JPM2 Pharmaceuticals. In one embodiment the reaction is carried out in an organic solvent in the presence of a base. In one embodiment, the organic solvent is acetonitrile. In one embodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, the protected 4-oxazolidinecarboxylic acid is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
In Route 1c, (S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS 1129634-44-1, is commercially available from Ark Pharm. In Step 2, the carboxylic acid is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.




Routes 2a, 2b, 2c, and 2d.

In Route 2a, commercially available Boc-L-proline is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
In Route 2b, commercially available (1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, from Enamine, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
In Route 2c, commercially available (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid, from Manchester Organics, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
In Route 2d, commercially available (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the coupling reagent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane. This chemistry is illustrated in Scheme 2.
Additional starting materials that can readily be converted to Central-L-B-Synthons include, but are not limited to: (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid, CAS 90104-21-5, available from Ark Pharm; cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid, 1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-((0-3, commercially available from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can be purchased from Chem Impex. The compound,




can be prepared according to the procedures disclosed in WO 2004/111041; (S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the Aldrich Chemical Co.; (1 S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylic acid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylic acid is available from Alfa Aesar; (2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid is available from Arch Bioscience; (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid, 3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester, (2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz group can be removed and the amino group can be alkylated to generate central core compounds of the present invention.

The compound




can be prepared as disclosed by Braun, -J. V.; Heymons, Albrecht Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930) 63B, 502-7.

The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester can be prepared as a mixture according to WO 2012/093101 to Novartis and the regioisomers can be ultimately separated once coupled to generate the central core-L-B synthons. The compound (S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the Aldrich Chemical Co.
Example 4. Preparation of A-C(O)-Moiety
Examples of the preparation of the A-C(O)-Moiety can be found in Example 1 and below.
In an alternate embodiment, a heteroaryl compound of Structure 1 is acylated to generate a compound of Structure 2. Structure 2 is coupled to an activated ester of Structure 3 to generate Structure 4. The ester is hydrolyzed to form acid Structure 5. This chemistry is illustrated in Scheme 4a.




In an alternate embodiment, a heteroaryl compound, Structure 2-1, is treated with a halogen to generate Structure 2-2. In some embodiments, the halogen is iodine. Structure 2-2 is treated with an activated ester to generate Structure 2-3. The halide is treated with zinc cyanide to generate nitrile, Structure 2-4. The nitrile, Structure 2-4 is treated with an oxime to generate the amide Structure 2-5. The ester is treated with an acid to generate acid, Structure 2-6. This chemistry is illustrated in Scheme 4b.




Example 5. Coupling of Central-L-B-Synthons to A—C(O)-Moieties
Examples of the coupling of central-L-B-synthons to A—C(O)-moieties can be found in Example 1.
In an alternate embodiment, Structure 5, from Example 4 Scheme 4a, is coupled to Structure 3 from Route 1 to generate Structure 6. Structure 6 is treated with a base such as, but not limited to, lithium hydroxide to generate Structure 7. This chemistry is illustrated in Scheme 5a.




In one embodiment, Structure 2-6 from Example 4b, is coupled to a central core-L-B to generate Structure 2-7. Structure 2-7 is treated with a base to generate a carboxylic acid, Structure 2-8. In one embodiment, the base is lithium hydroxide. This chemistry is illustrated in Scheme 5b.




Example 6. Synthesis of Amides, Carbamates, and Ureas within Formula I
Examples of the synthesis of amides, carbamates and ureas within Formula I can be found in Example 1 and below.
In one embodiment, Structure 1 is treated with, for example, diphenylphosphoryl azide (DPPA) to generate an isocyanate, Structure 2. Structure 2 is then treated with an amine or alcohol to generate urea and carbamate compounds within Formula I, wherein the R13 substituent is NR9C(O)NR9R10, NR9C(O)NR10R23, NR9C(O)R24R25, NR9C(O)OR10 and NR9C(O)OR23. In some embodiments, R9 is hydrogen. Structure 1 can be coupled to amines to generate amides within Formula I, wherein the R13 substituent is C(O)NR24R25, C(O)NR9R37, or C(O)NR21SO2R22. In some embodiments, R9 is hydrogen. The chemistry is illustrated in Scheme 6a.




Example 7. Synthesis of Intermediates
7A. (2S,4R)-Tert-Butyl 2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidine-1-Carboxylate




(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.33 gm, 10 mmol) was dissolved in DMF (50 ml) and iPr2NEt (8.6 ml, 5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl) methanamine (3.18 gm 20 mmol) at 5° C. Then HATU (8 gm, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction monitored by HPLC, the reaction mixture was diluted with 1M citric acid solution (200 ml+NaCl solid 20 gm) and extracted with DCM (150 mL×2), the organic layer was then washed with an aqueous solution of NaHCO3 (100 ml) and washed with water (100 ml), brine (100 ml) and dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.
7B. (2S,4R)—N-(3-Chloro-2-Fluorobenzyl)-4-Fluoropyrrolidine-2-Carboxamide Hydrochloride (A)




(2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (500 mg,) was taken in 4N HCl dioxane (30 ml) and resulting reaction mixture was stirred at rt for 3 h. After completion of the reaction monitored by HPLC solvent was removed under reduced pressure. The residue, A, was used for next reaction.
7C. 2-(3-Acetyl-1H-Indol-1-yl)Acetic Acid (B)




A mixture of 3-Acetylindole (10.09 g) and t-butylbromoacetate (13.71 g) were reflux in acetonitrile in presence of potassium carbonate (9.7 g) for 24 h. The reaction mixture was cooled to room temperature and filtered and evaporated to dryness. The residue was purified by chromatography over silica gel and eluted with a mixture of ethylacetate in methylene chloride to give tert-butyl 2-(3-acetyl-1H-indol-1-yl)acetate.
Tert-butyl 2-(3-acetyl-1H-indol-1-yl)acetate was stirred overnight in a mixture of trifluoroacetic acid in methylene chloride and diluted with methanol and evaporated to dryness. The residue was treated with 1M sodium hydroxide and extracted with methylene chloride. The aqueous layer was acidified with 6M HCl and the residue filtered, washed with water and dried to give 2-(3-acetyl-1H-indol-1-yl)acetic acid (B).
7D. 1-(3-Amino-1H-Indol-1-yl)Ethanone Hydrochloride (C)




To a stirred solution of AgNO3 (9.3 g, 1.07 equiv) in acetonitrile was added benzoyl chloride (7.47 g, 1.04 equiv) dropwise at 0° C. The mixture was stirred for 10 min, and then solution of 1H-indole (6 g, 1 equiv) in acetonitrile was added at 0° C. and stirred for 1 h at RT. The reaction mixture was poured into ice to get a dark brown precipitate. The precipitate was filtered washed with water dried. The crude residue was purified by flash column chromatography (ISCO with hexanes/EtOAc) to give 3-nitro-1H-indole.
A stirred solution of 3-nitro-1H-indole (1 g, 1 equiv) in dry THF was cooled to 5° C. Then tBuOK (830 mg, 1.2 equiv) was added slowly, and the resulting mixture was stirred 10 min. Acetyl chloride (525 mg, 1.2 equiv) was added and the reaction mixture was stirred for 30 min. After completion of the reaction as monitored by HPLC, solvent was removed under reduced pressure, diluted with DCM washed with an aqueous solution of NaHCO3. The organic layer was separated washed with brine and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with DCM/EtOAc) to give 1-(3-nitro-1H-indol-1-yl)ethanone.
To a mixture of 1-(3-nitro-1H-indol-1-yl)ethanone (600 mg, 2.942 mmol) and di-tert-butyl dicarbonate (1.925 g, 8.826 mmol) in methanol (50 mL) was added 5% Pd/C (20 mg).
The resulting reaction mixture was stirred under hydrogen 24 h, after completion of the reaction Pd/C was filtered using Celite®, and the filtrate was concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with DCM/EtOAc) to give tert-butyl(1-acetyl-1H-indol-3-yl)carbamate.
Tert-butyl(1-acetyl-1H-indol-3-yl) carbamate (300 mg, 1.1 mmol) was taken in 4N HCl dioxane (10 ml) and resulting reaction mixture was stirred at rt for 3 h. After completion of the reaction solvent was removed under reduced pressure. This material, 1-(3-amino-1H-indol-1-yl)ethanone hydrochloride (C), was used directly in the next synthetic step.
7E. 2-(3-Acetyl-6-Hydroxy-1H-Indol-1-yl)Acetic Acid (D)




6-Benzyloxyindole was acetylated using reported procedure (Eur. J. Med Chem., (2011), 46, 756) and alkylated following the procedure describe for compound B. The benzyl group was removed by hydrogenation over palladium on charcoal and the t-butyl group removed again as described for compound B.
7F. 2-(3-Acetyl-5-Hydroxy-1H-Indol-1-yl)Acetic Acid (E)




To a stirred solution of 5-(benzyloxy)-1H-indole (11.08 g, 1 equiv) in 200 mL DCM was added diethylaluminium chloride (1 M solution in Hexane; 74.6 mL, 1.5 equiv) drop wise at 0° C. The mixture was stirred for 30 min, and then a solution of acetyl chloride (5.3 mL, 1.5 equiv) in 150 mL DCM was added at 0° C. and the reaction was stirred for 1 h at 0° C. A 5% aqueous citric acid solution was added at 0° C. and the reaction was stirred for 15 min at RT. The precipitate was filtered and washed with water, and the organic filtrate was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to give 1-(5-(Benzyloxy)-1H-indol-3-yl)ethanone.
To a suspension of 1-(5-(benzyloxy)-1H-indol-3-yl)ethanone (6.5 gm, 1 equiv) and K2CO3 (3.72 gm, 1.1 equiv) in 50 mL acetonitrile was added tert-butyl 2-bromoacetate (3.92 mL, 1.1 equiv) dropwise at RT. The resulting mixture was then heated to reflux for 18 h. After cooling to RT, the mixture was diluted with DCM (100 mL), and then filtered through the celite pad; filtrate was concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (silica gel eluted with DCM/EtOAc) to give tert-Butyl 2-(3-acetyl-5-(benzyloxy)-1H-indol-1-yl)acetate.
To tert-Butyl 2-(3-acetyl-5-(benzyloxy)-1H-indol-1-yl)acetate (6 g) in THF (80 mL) was added Pd/C (0.05 equiv). The reaction mixture was stirred at RT for 5 h under H2 (1 atm). The reaction mixture was then filtered through a pad of Celite and washed with CH2Cl2 and MeOH. The filtrate was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (silica gel eluted with DCM/EtOAc) to give tert-Butyl 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetate.
Tert-Butyl 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetate (814 mg, 2.8 mmol) was taken up in 4 N HCl dioxane (10 mL) and the resulting reaction mixture was stirred at RT for 48 h. The solvent was then removed under reduced pressure to give 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetic acid (E) which could be used directly in the next synthetic step.
Example 8. Synthesis of (2S,4R)—N2-(1-Acetyl-1H-Indol-3-yl)-N1-(3-Chloro-2-Fluorobenzyl)-4-Fluoropyrrolidine-1,2-Dicarboxamide (Compound F)




To a stirred solution of methyl 1H-indole-5-carboxylate (10 g, 1 equiv) in 200 mL DCM was added diethylaluminium chloride (1 M solution in hexane; 85.71 mL, 1.5 equiv) dropwise at 0° C. The mixture was stirred for 30 min and then a solution of acetyl chloride (6 mL, 1.5 equiv) in 150 mL DCM was added at 0° C. and stirred for 1 h at 0° C. A 5% aqueous citric acid solution was added at 0° C. and the reaction mixture was stirred for 15 min at RT. The precipitate was collected by filtration, washed with water, and dried. The residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to give Methyl 3-acetyl-1H-indole-5-carboxylate.
To a suspension of methyl 3-acetyl-1H-indole-5-carboxylate (6 g, 1 equiv) and K2CO3 (4.19 g, 1.1 equiv) in 50 mL acetonitrile was added tert-butyl 2-bromoacetate (4.42 mL, 1.1 equiv) dropwise at RT. The resulting mixture was then heated to reflux for 18 h. After cooling to RT, the mixture was diluted with DCM (100 mL), filtered through a pad of Celite; and the filtrate was concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (silica gel eluted with DCM/EtOAc) to give Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-5-carboxylate (12).
Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-5-carboxylate (3 g, 9.06 mmol) was taken up in 4 N HCl dioxane (50 mL) and the resulting reaction mixture was stirred at RT for 48 h. The solvent was then removed under reduced pressure and the remaining material 2-(3-Acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid was used directly in the next synthetic step.
2-(3-Acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (2 g, 1 equiv) was dissolved in DMF (50 mL) and iPr2NEt (3.95 mL, 5 equiv) was added, followed by the sequential addition of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride A (2.254 g, 1 equiv) and HATU (5.8 g, 2.1 equiv) slowly at 5° C. The reaction mixture was then stirred for 18 h at RT, diluted with 1 M citric acid solution (100 mL, containing 10 g NaCl), and extracted with DCM (50 mL×2). The organic layer was washed with an aqueous solution of NaHCO3 (40 mL), washed with water (40 mL), washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to give methyl 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.
Methyl 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate (3.86 g, 1 equiv) was taken up in a mixture of THF (20 mL) and methanol (20 mL), and then LiOH (1.832 g, 6 equiv) in water (20 mL) was added. The resulting reaction mixture was stirred at RT for 48 h. The solvent was then removed under reduced pressure and water (30 mL) was added. Acidification with 4 N HCl produced a white precipitate that was collected by filtration and dried in vacuo. This material 3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (F) was used directly in the next synthetic step.
Example 9. Synthesis of Cyclopropyl(3-Acetyl-1-(2-((2S,4R)-2-((3-Cloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-Yl)-2-Oxoethyl)-1H-Indol-5-yl)Carbamate




To a suspension of 3-acetyl-1-(2-(2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (155 mg, 0.3 mmol, 1 equiv) in THF (20 mL) was added Et3N (38 μL, 1 equiv) and the resulting solution was stirred at RT under a nitrogen atmosphere for 15 min. DPPA (64 μL, 1 equiv) was added and the reaction was further stirred at RT under nitrogen for 18 h. The reaction mixture was concentrated under reduced pressure and the residue acyl azide intermediate was suspended in a mixture of toluene (20 mL) and THF (5 mL). This mixture was refluxed under nitrogen for 4 h and evaporated to dryness under reduce pressure. The remaining crude isocyanate (2S,4R)-1-(2-(3-Acetyl-5-isocyanato-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (G) was used directly in the next step.
Compound G was dissolved in a mixture of THF (7 mL), ACN (3 mL), and cyclopropanol (35 mg, 2 equiv), followed by the addition of NEt3 (76 μL, 2 equiv) at 0° C. The reaction mixture was then stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to give product cyclopropyl(3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)carbamate (187). 1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 0.68-0.72 (m, 4H), 2.00-2.17 (m, 1H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 3.89 (ddd, J=22.8, 9.6, 2.8 Hz, 1H), 4.05-4.14 (m, 1H), 4.32 (dd, J=20.8, 6.0 Hz, 1H), 4.42-4.49 (m, 2H), 5.12 (d, J=17.2 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H), 5.50 (d, J=52.8 Hz, 1H), 6.97-7.01 (m, 1H), 7.15-7.45 (m, 4H), 8.18 (s, 1H), 8.31 (s, 1H), 8.59 (t, J=5.6 Hz, 1H), 9.49 (s, 1H). 19F NMR (376 MHz, DMSO-d6, 300 K): (major rotamer) δ −121.8, −176.1. LC (method 1): tR=1.78 min. LC/MS(O) m/z: [M+H]+ calcd for C28H27ClF2N4O5, 573. found, 573.
Example 10. Synthesis of N-(3-Acetyl-1-(2-((2S,4R)-2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-yl)-2-Oxoethyl)-1H-Indol-5-yl)-3,3-Difluoropiperidine-1-Carboxamide




Compound G from the previous reaction was dissolved in a mixture of THF (7 mL), ACN (3 mL), and 3,3-difluoropiperidine hydrochloride (51.81 mg, 1.1 equiv), followed by the addition of NEt3 (76 μL, 2 equiv) at 0° C. The reaction mixture was then stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to give N-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide. 1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.69-1.76 (m, 2H), 2.01-2.17 (m 3H), 2.41 (s, 3H), 3.52 (t, J=5.2 Hz, 1H), 3.78-3.95 (m, 3H), 4.13 (dd, J=9.2, 12.4 Hz, 1H), 4.32 (dd, J=20.4, 6.0 Hz, 1H), 4.42-4.49 (m, 2H), 5.12 (d, J=17.2 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H), 5.50 (d, J=52.8 Hz, 1H), 6.99-7.03 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.48 (m, 3H), 8.16 (s, 1H), 8.19 (d, J=2 Hz, 1H), 8.59 (t, J=6 Hz, 1H), 8.62 (s, 1H). 19F NMR (376 MHz, DMSO-d6, 300 K): (major rotamer) δ −101.06, 121.25, −176.1. LC (method 1): tR=1.82 min. LC/MS (EI) m/z: [M+H]+ calcd for C30H30ClF4N5O4, 636. found, 636.
Example 11. Synthesis of 3-Acetyl-1-(2-((2S,4R)-2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-yl)-2-Oxoethyl)-N-Cyclopropylsulfonyl)-1-1H-Indole-6-Carboxamide







Methyl 3-acetyl-1H-indole-6-carboxylate was prepared according to the procedure published by MacKay et al. (MacKay, -J. A.; Bishop, R.; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)
A mixture of 150 mg (0.68 mmol) of methyl 3-acetyl-1H-indole-6-carboxylate, 0.12 mL (0.76 mmol) of tert-butyl bromoacetate, and 249 mg (0.76 mmol) cesium carbonate in anhydrous acetonitrile (15 mL) was refluxed for 18 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was taken in a 2:1 mixture of EtOAc and water (30 mL: 15 mL). The two layers were separated and the organic layer was washed with brine (2×15 mL). Finally, the organic layer was dried (Na2SO4) and concentrated to obtain 283 mg of product methyl 3-acetyl-1-(2-tert-butoxy)-2-oxoethyl)-1H-indole-6-carboxylate (H) as a yellow solid.
100 mg of methyl 3-acetyl-1-(2-tert-butoxy)-2-oxoethyl)-1H-indole-6-carboxylate (0.3 mmol) was stirred in 4 N HCl in dioxane (15 mL) at RT for 18 h. The volatiles were removed under reduced pressure. The residue (intermediate I) was dissolved in 5 mL of DMF. To this solution was added 140 mg (0.36 mmol) of TFA salt of A, followed by 0.26 mL of N,N-diisopropylethylamine (1.5 mmol). Then 137 mg of (0.36 mmol) HATU was added and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc (20 mL) and water (15 mL). The organic layer was separated, washed with brine (3×15 mL), dried (Na2SO4), concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 0-10% MeOH in CH2Cl2) to give 128 mg of methyl-3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylate as a yellow solid.
A mixture of 128 mg (0.24 mmol) of methyl-3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylate in THF (5 mL) and 1 N LiOH (10 mL) was stirred at RT for 18 h. The solvent (THF) was removed under reduced pressure and the remaining water layer was washed with EtOAc (5 mL), acidified by 2 N HCl, and extracted with EtOAc (20 mL). The organic layer was washed with water, dried, and concentrated to obtain 126 mg of product 3-Acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylic acid as a yellow solid.
To a stirred solution of 177 mg (0.34 mmol) of 3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylic acid in DMF (8 mL) was added 207 mg (1.71 mmol) of cyclopropanesulfonamide, 390 mg (1.03 mmol) of HATU, and 0.4 mL (2.4 mmol) DIEA. The reaction mixture was heated to 60° C. for 36 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give 63 mg of the desired product 3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-cyclopropylsulfonyl)-1H-indole-6-carboxamide (129) as a white solid. 1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.12 (m, 4H), 2.11 (m, 1H), 2.48 (s, 3H), 3.15 (m, 1H), 3.92 (m, 1H), 4.16 (m, 2H), 4.32 (m, 2H), 4.49 (m, 2H), 5.48 (m, 2H), 6.92 (t, 1H), 7.21 (t, 1H), 7.43 (t, 1H), 7.81 (d, 1H), 8.30 (d, 1H), 8.44 (s, 1H), 8.65 (t, 1H). 31F NMR (376 MHz, DMSO-d6, 300 K): (major rotamer) δ −121.6, −176.0. LC (method 1): tR=1.52 min. LC/MS (EI) m/z: [M+H]+ calcd for C28H27C1F2N4O6S, 621.05. found, 621.00.
Example 12. Additional Syntheses of Non-Limiting Examples of Compounds of Formula
2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (D)




To a stirred solution of methyl 1H-indole-5-carboxylate, (A, 10 g, 1 eq.) in 200 mL DCM, was added diethylaluminium chloride (1M solution in Hexane; 85.71 mL, 1.5 eq.) dropwise at 0° C. The mixture was stirred for 30 min, and then a solution of acetyl chloride (6 mL, 1.5 eq.) in 150 mL DCM was added at 0° C. and stirring continued for 1 h at 0° C. A 5% aqueous citric acid solution was added at 0° C. and the reaction mixture was stirred for 15 min at RT. The precipitate was filtered washed with water dried. The residue was purified by flash column chromatography over silica gel (eluent: DCM/CH3OH to give compound B.
tButyl bromoacetate (4.42 mL, 1.1 eq.) was added dropwise to a suspension of methyl 3-acetyl-1H-indole-5-carboxylate B (6 g, 1 eq.) and K2CO3 (4.19 g, 1.1 eq.) in 50 mL acetonitrile at RT. The resulting mixture was refluxed for 18 h. After cooling to RT, the mixture was diluted with DCM (100 mL), filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: DCM/EtOAc) to give compound C.
Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-5-carboxylate, (C, 3 g, 9.06 mmol) was taken in 4N HCl in dioxane (50 mL) and resulting reaction mixture stirred at RT for 48 h. After completion of the reaction, solvent was removed under reduced pressure and the residue, compound D, was used directly in the next synthetic step.
2-(3-acetyl-6-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (E)




To a solution of acetyl chloride (22.3 mL, 1.1 eq.) and aluminum chloride (83.7 g, 2.2 eq.) in methylene chloride (3 L) was added indole-5-carboxylic acid methyl ester (AD, 50 g, 1 eq.) at RT. The reaction mixture was stirred at RT for 2 h, then poured over ice and solid obtained was collected by filtration. The solid was washed with water, and dried. The resultant solid was again slurried with methanol, filtered and dried under vacuum to give compound AE.
Methyl 3-acetyl-1H-indole-6-carboxylate (AE, 32 g, 1 eq.) and potassium carbonate (24.2 g, 1.2 eq.) in acetonitrile (320 mL) was added tert-butyl bromoacetate (26 mL, 1.2 eq.) drop wise at room temperature. The reaction mixture was heated at 85° C. for 12 h, concentrated and the residue dissolved in DCM. The organic layer was washed with water, 1M aqueous HCl, saturated aqueous NaHCO3 and brine. The organic layer was concentrated under vacuum. The solid obtained was again slurried with MTBE, filtered and dried to give compound AF.
Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-6-carboxylate (AF, 3 g, 9.06 mmol) was taken in 4N HCl in dioxane (50 mL) and resulting reaction mixture was stirred at RT for 48 h. After completion of the reaction, solvent was removed under reduced pressure and the residue, E, was used directly in the next synthetic step.
2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (F)







To a solution of methyl 1H-indazole-5-carboxylate (AG, 10 g, 1 eq.) in THF (100 mL) was added iodine (21.6 g, 1.5 eq.) and potassium tert-butoxide (16 g, 2.5 eq.) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with 10% sodium thiosulfate in water and extracted twice with EtOAc. The combined organic extracts were washed with brine, and dried evaporated to dryness. The resultant solid was slurried with MTBE, filtered and dried to give compound AH (13 g)
To a mixture of Methyl 3-iodo-1H-indazole-5-carboxylate (AH, 30 g, 1 eq.) and potassium carbonate (34.3 g, 2.5 eq.) in DMF (300 mL) was added tert-butyl bromoacetate (17.6 mL, 1.2 eq.) drop wise at room temperature. The resulting mixture was stirred at 50° C. for 3 h. Then reaction mixture was poured into water and extracted with EtOAc (2×100 mL), the combined organic extracts were concentrated under vacuum. The material thus obtained (compound AI) was used without further purification in the next step.
A mixture of methyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-iodo-1H-indazole-5-carboxylate (AI, 40 g, 1 eq.), Zn (CN)2 (13.5 g, 1.2 eq.), Pd (dppf) C12 (7.9 g, 0.1 eq.), Pd2(dba) 3 (8.8 g, 0.1 eq.), water (80 mL) and DMF (400 mL) was stirred at 80° C. for 5 h under nitrogen. The reaction mixture was diluted with EtOAc and then successively washed with water, sat. aqueous NaHCO3 and brine. The organic layer was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: Hexane/EtOAc) to give compound AJ.
A mixture of methyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-cyano-1H-indazole-5-carboxylate (A, 20 g, 1 eq.), acetaldoxime (7.5 g, 2 eq.), Pd (OAc)2 (0.7 g, 0.05 eq.) and PPh3 (1.7 g, 0.1 eq.) in aqueous ethanol (500 mL, H2O/EtOH (100 mL/400 mL) was refluxed for 3 h under nitrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was removed under vacuum. The crude residue was purified by column chromatography over silica gel (eluent: Hexane/EtOAc) to give compound AK.
Methyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylate (AK, 3 g, 9.06 mmol) was taken in 4N HCl in dioxane (50 mL) and resulting reaction mixture was stirred at RT for 48 h. After completion of the reaction, solvent was removed under reduced pressure and the product (compound F) was used directly in the next synthetic step.
(2S,4R)—N-(2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (L)




A mixture of 4-bromo-5-fluoroaniline, (G, 30 g), 2-chlorophenylboronic acid (H, 60 g), K2CO3 (91 g) and Pd(dppf)2C12 (19.25 g) in aq. dioxane (dioxane 400 mL, H2O 100 mL) was purged with argon in a pressure vessel for 5 min and stirred for 15 h at 100° C. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel. The purified material was then dissolved in MeOH and treated with HCl/MeOH. The solvent was removed and the solid was washed with IPA-heptane (1/1) to afford compound I.
To an ice-cold solution of N-Boc-4-fluoroproline (J, 530 mg) in 20 mL of DCM, 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) was added dropwise with stirring. Stirring was continued for 3 h at this temperature, then compound I (640 mg, 1.1 eq.) was added, followed by 1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reaction mixture stirred overnight at RT. After completion of the reaction the reaction mixture was added to water (20 mL) and extracted with DCM (2×25 mL). The organic layer was washed successively with an aqueous NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (ISCO eluent: Hexanes/EtOAC) to give compound K.
(2S,4R)-tert-Butyl 2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoro pyrrolidine-1-carboxylate (K, 700 mg) was taken in 4N HCl in dioxane (25 mL) and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction the solvent was removed under reduced pressure. The residue, compound L was used directly in the next synthetic step.
(2S,4R)—N-(3-Chloro-2-Fluorobenzyl)-4-Fluoropyrrolidine-2-Carboxamide Hydrochloride (O)




(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid J (2.33 g, 10 mmol) was dissolved in DMF (50 mL) and DIEA (8.6 mL, 5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl) methanamine (M, 3.18 g, 20 mmol) at 5° C. Then HATU (8 g, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction, the reaction mixture was diluted with 1M citric acid solution (200 mL+NaCl solid 20 g) and extracted with DCM (150 mL×2). The organic layer was then washed with an aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate, compound N.
(2S,4R)-tert-Butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (500 mg,) was taken in 4N HCl in dioxane (30 mL) and resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction, solvent was removed under reduced pressure and the residue, compound O, was used for next reaction without further purification.
(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (R)




To an ice-cold solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (P, 516 mg) in 20 mL of DCM, 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then compound I (640 mg, 1.1 eq.) was added, followed by 1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at RT. After completion of the reaction the reaction mixture was added to water (20 mL) and extracted with DCM (2×25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (ISCO eluent: Hexanes/EtOAC) to give compound Q.
(2S,4R)-tert-Butyl 2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (Q, 700 mg) was taken in 4N HCl in dioxane (25 mL) and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction the solvent was removed under reduced pressure. The residue, compound R was used directly in the next synthetic step.
(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (T)




(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (P, 2.27 g, 10 mmol) was dissolved in DMF (50 mL) and DIEA (8.6 mL, 5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl) methanamine (M, 3.18 g, 20 mmol) at 5° C. HATU (8 g, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction the reaction mixture was diluted with 1M citric acid solution (200 mL+NaCl solid 20 g) and extracted with DCM (150 mL×2), the organic layer was then washed with an aqueous solution of NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: DCM/EtOAc) to give (1R,3S,5R)-tert-butyl 3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, compound S.
(2S,4R)-tert-butyl(1R,3S,5R)-tert-butyl 3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (S, 500 mg,) was taken in 4N HCl in dioxane (30 mL) and resulting reaction mixture stirred at RT for 3 h. After completion of the reaction, solvent was removed under reduced pressure. The residue, compound T, was used for the next reaction without any purification.
(2S,4R)—N-(3-(3-chloropyridin-2-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (X)




A mixture of 3-bromo-2-fluoroaniline (G, 10 g), (3-chloropyridin-2-yl)boronic acid (U, 20 g), K2CO3 (30 g) and Pd(dppf)2C12 (6.42 g) in solvent (dioxane 130 mL, H2O 33 mL) was purged with argon in a pressure vessel for 5 min and stirred for 15 h at 100° C. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel. The purified material was then dissolved in MeOH and treated with HCl/MeOH. The solvent was removed and the solid was washed with IPA-heptane (1/1) to afford 3-(3-chloropyridin-2-yl)-2-fluoroaniline hydrochloride, compound V.
To an ice-cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (J, 530 mg) in 20 mL of DCM, 1-chloro-N,N,-2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then 3-(3-chloropyridin-2-yl)-2-fluoroaniline hydrochloride (V) (642 mg, 1.1 eq.) was added, followed by 1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with DCM (2×25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (ISCO eluted with Hexanes/EtOAC) to give (2S,4R)-tert-butyl 2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate, compound W.
(2S,4R)-tert-butyl 2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (W, 700 mg) was taken in 4N HCl dioxane (25 mL) and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction, the solvent was removed under reduced pressure. The residue, compound X was used directly in the next synthetic step.
(2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (AA)




To an ice-cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (J, 530 mg) in 20 mL of DCM, 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then 6-bromopyridin-2-amine (Y, 427 mg) was added, followed by 1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with DCM (2×25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent Hexanes/EtOAC) to give (2S,4R)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate, compound Z.
(2S,4R)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (Z, 700 mg) was taken in 4N HCl dioxane (25 mL) and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction, the solvent was removed under reduced pressure. The residue, compound AA was used directly in the next synthetic step.
3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AC)




Compound D (2 g, 1 eq.) from previous reaction was dissolved in DMF (50 mL) and DIEA (3.95 mL, 5 eq.) was added followed by the addition of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (0, 2.254 g, 1 eq.) at 5° C. Then HATU (5.8 g, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction the reaction mixture was diluted with 1M citric acid solution (100 mL+NaCl solid 10 g) and extracted with DCM (50 mL×2), the organic layer was then washed with an aqueous solution of NaHCO3 (40 mL) and washed with water (40 mL), brine (40 mL) and dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography over silica gel (eluent: DCM/CH3OH) to give compound AB.
Methyl 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate (AB, 3.86 g, 1 eq.) was taken in THF (20 mL), methanol (20 mL), and LiOH (1.832 gm, 6 eq.) in water (20 mL) was added, resulting reaction mixture was stirred at RT for 48 h. After completion of the reaction, solvent was removed under reduced pressure. Water (30 mL) was added and acidified with 4N HCl. The precipitated solid was filtered and dried. This material, compound AC was used directly in the next synthetic step.
3-acetyl-1-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AM)




Compound AM was prepared from 2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (D, 275 mg) and (1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (T, 305 mg) to give compound AL and then hydrolyzed following procedures described in Scheme 10.
3-acetyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AO)




Compound AO was prepared from 2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (D, 275 mg) and (2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (L, 373 mg)) to give compound AN and then hydrolyzed following procedures described in Scheme 10.
3-acetyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-6-carboxylic acid (AQ)




Compound AQ was prepared from 2-(3-acetyl-6-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (E, 275 mg) and (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (O, 311 mg) to give compound AP and then hydrolyzed following procedures described in Scheme 10.
3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AS)




Compound AS was prepared from 2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (F, 277 mg) and (2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (L, 373 mg) to give compound AR and then hydrolyzed following procedures described in Scheme 10.
3-carbamoyl-1-(2-((1R,3S,5R)-3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AU)




Compound AU was prepared from 2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (F, 277 mg) and (1R,3S,5R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (R, 367 mg) to give compound AT and then hydrolyzed following procedures described in Scheme 10.
3-Carbamoyl-1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AW)




Compound AW was prepared from 2-(3-Carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (F, 277 mg) and (2S,4R)—N-(3-(3-chloropyridin-2-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (X, 374 mg) to give compound AT and then hydrolyzed following procedures described in Scheme 10.
1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylic acid (AY)




1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylic acid (AY)
Compound AY was prepared from 2-(3-Carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (F, 277 mg) and (2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (AA, 325 mg) to give compound AX and then hydrolyzed following procedures described in Scheme 10.
(2S,4R)-1-(2-(3-acetyl-5-(3-cyclopropylureido)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (1)




(To a suspension of 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (W, 517 mg, 1 mmol, 1 eq.) in THF (60 mL) was added Et3N (127 μL, 1 eq.) and the resulting solution was stirred at RT under nitrogen for 15 min. DPPA (213 μl, 1 eq.) was added and the reaction was further stirred at RT under nitrogen for 18 h. After completion of the reaction, THF was evaporated and the residue was suspended in toluene (60 mL) and THF (15 mL). The mixture was refluxed under nitrogen for 4 h until completion of the reaction to give crude isocyanate, Y which was directly used in the next step.
Isocyanate, Y from previous reaction was dissolved in THF (20 mL), ACN (10 mL) and cyclopropylamine (17 mg, 2 eq.), which was followed by the addition of Et3N (253 μL, 2 eq.) at 0° C. The reaction mixture was then stirred for 24 h at RT. After completion of the reaction the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluant DCM/CH3OH) to give compound 1. 1H-NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 0.40-0.66 (m, 4H) 2.00-2.17 (m, 1H), 2.40 (s, 3H), 2.46-2.58 (m, 1H), 3.85-3.95 (m, 1H), 4.09-4.18 (m, 1H), 4.15 (dd, J=21.2, 12.4 Hz, 1H), 4.25-4.49 (m, 2H), 5.06 (d, J=17.2 Hz, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.50 (d, J=53.2 Hz, 1H), 6.21 (s, 1H), 6.99-7.07 (m, 1H), 7.15-7.45 (m, 4H), 8.15 (s, 2H), 8.27 (s, 1H), 8.59 (t, J=5.6 Hz, 1H), 10.05 (s, 1H). LC (method 1): tR=1.24 min. LC/MS (APCI) m/z: [M+H]+, 572
(1R,3S,5R)-2-(2-(3-acetyl-5-(3-cyclopropylureido)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (3)




3-Acetyl-1-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AM, 512 mg) was converted to the isocyanate, compound AX and the reacted with cyclopropanamine (114 mg) to give compound 3 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 0.42-1.07 (m, 6H) 1.88 (m, 1H), 2.18-2.63 (m, 2H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 3.7 (m, 1H), 4.27-4.40 (m, 3H), 5.23 (d, J=17.2 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 6.21 (d, J=2 Hz, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.32-7.44 (m, 3H), 8.14 (s, 1H), 8.21 (s, 1H), 8.43 (s, 1H), 8.45 (m, 1H). LC (method 1): tR=1.52 min. LC/MS (APCI) m/z: [M+H]+566
N-(3-acetyl-1-(2-((2S,4R)-2-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide (18)




3-Acetyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AO, 580 mg) was converted to the isocyanate, compound AY and the reacted with and 3,3-difluoropiperidine (242 mg) to give compound 18 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.71 (m, 2H) 2.01-2.09 (m, 2H), 2.36 (s, 3H), 2.49-2.65 (m, 1H), 3.27 (m, 1H), 3.51 (m, 2H), 3.79 (m, 2H), 3.80-4.25 (m, 2H), 4.77 (m, 1H), 5.17 (d, J=17.2 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H), 5.50 (d, J=52.8 Hz, 1H), 7.04-7.59 (m, 8H), 8.01 (m, 1H), 8.17 (s, 2H), 8.61 (s, 1H), 10.02 (s, 1H). LC (method 1): tR=2.25 min. LC/MS (APCI) m/z: [M+H]+ 698.
1-(2-((2S,4R)-2-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide (24)




3-Carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AS, 582 mg) was converted to the isocyanate, compound AZ and the reacted with and 3,3-difluoropiperidine (242 mg) to give compound 24 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.71 (m, 2H) 2.01-2.3 (m, 3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H), 5.39-5.75 (m, 4H), 7.04-7.70 (m, 8H), 8.01 (m, 1H), 8.18 (s, 1H), 8.77 (s, 1H), 10.00 (s, 1H). LC (method 1): tR=2.09 min. LC/MS (APCI) m/z: [M+H]+ 700.
1-(2-((1R,3S,5R)-3-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide (28)




3-Carbamoyl-1-(2-((1R,3S,5R)-3-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AU, 576 mg) was converted to the isocyanate, compound BA and the reacted with and 3,3-difluoropiperidine (242 mg) to give compound 28 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 0.74-1.30 (m, 3H) 1.72-2.35 (m, 7H), 3.30 (s, 1H), 3.55 (m, 2H), 3.80 (m, 3H), 4.55 (m, 1H), 5.45 (d, J=17.2 Hz, 1H), 5.74 (d, J=17.2 Hz, 1H), 7.15-7.70 (m, 8H), 7.92 (m, 1H), 8.19 (s, 1H), 8.75 (s, 1H), 9.75 (s, 1H). LC (method 1): tR=2.17 min. LC/MS (APCI) m/z: [M+H]+ 694.
1-(2-((2S,4R)-2-(3-(3-chloropyridin-2-yl)-2-fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide (29)




3-Carbamoyl-1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylic acid (AW, 583 mg) was converted to the isocyanate, compound BB and the reacted with and 3,3-difluoropiperidine (242 mg) to give compound 29 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.72 (m, 2H) 2.01-2.3 (m, 3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H), 5.39-5.75 (m, 4H), 7.18-7.65 (m, 5H), 8.00 (m, 1H), 8.07 (m, 1H), 8.19 (s, 1H), 8.64 (m, 1H), 8.75 (s, 1H), 10.05 (s, 1H). LC (method 1): tR=1.65 min. LC/MS (APCI) m/z: [M+H]+ 701
1-(2-((2S,4R)-2-(6-bromopyridin-2-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide (33)




1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylic acid (AY) 533 mg was converted to the isocyanate, compound BC and the reacted with and 3,3-difluoropiperidine (242 mg) to give compound 33 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.72 (m, 2H) 2.01-2.3 (m, 3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H), 5.39-5.75 (m, 4H), 7.30-7.75 (m, 4H), 8.02 (d, J=8.0 Hz, 1H), 8.28 (s, 1H), 8.74 (s, 1H), 11.00 (s, 1H). LC (method 1): tR=1.59 min. LC/MS (APCI) m/z: [M+H]+ 651.
(2S,4R)-1-(2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetyl)-N-(2′-chloro-2-fluorobiphenyl-3-yl)-4-fluoropyrrolidine-2-carboxamide (35)







The mixture of 1H-indol-5-amine (220 mg), 3,3-difluorocyclopentanecarboxylic acid, (250 mg), HATU (1.2 eq), DIEA (5.0 eq) in DMF (20 mL) was stirred overnight at rt. The solvent was removed and residue purified by chromatography over silica gel to afford 3,3-difluoro-N-(1H-indol-5-yl)cyclopentanecarboxamide (BD).
3,3-difluoro-N-(1H-indol-5-yl)cyclopentanecarboxamide (BD, 287 mg), acetyl chloride (1.5 eq) in DCM was added diethylaluminum chloride (1.5 eq) at 0° C. The reaction mixture was stirred for 3 h and pour in to ice-water and extracted with DCM. Solvent was removed and the residue was purified by chromatography over silica gel to afford N-(3-acetyl-1H-indol-5-yl)-3,3-difluorocyclopentanecarboxamide (BE).
N-(3-acetyl-1H-indol-5-yl)-3,3-difluorocyclopentanecarboxamide (BE, 8 mg), tert-butyl 2-bromoacetate (5.6 mg) and K2CO3 (4.1 mg) in ACN (10 mL) was stirred at 60° C. for 5 h. Solvent was removed and residue purified by chromatography over silica gel to afford tert-butyl 2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetate (BF).
2-(3-Acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetate (BF, 7 mg) in DCM (3 mL) was added TFA (3 mL) and stirred for 3 h at RT. The solvent was removed and the crude product, BG, was directly used in the next step.
2-(3-Acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetic acid (BG, 5 mg) and (2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (L, 6.3 mg) using HATU as a coupling reagent as described in scheme 14 to give compound 35.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.92-2.70 (m, 10H) 3.19 (m, 1H), 3.88-4.18 (m, 2H), 4.77 (m, 1H), 5.19 (d, J=17.2 Hz, 1H), 5.35 (d, J=17.2 Hz, 1H), 5.48 (m, 1H), 5.61 (m, 1H), 7.04-7.59 (m, 8H), 8.01 (m, 1H), 8.17 (s, 2H), 8.61 (s, 1H), 10.02 (s, 1H). LC (method 1): tR=2.61 min. LC/MS (APCI) m/z: [M+H]+ 683.
(2S,4R)-1-(2-(3-acetyl-5-(3,3,3-trifluoropropanamido)-1H-indol-1-yl)acetyl)-N-(2′-chloro-2-fluorobiphenyl-3-yl)-4-fluoropyrrolidine-2-carboxamide (36)




2-(3-Acetyl-5-(3,3,3-trifluoropropanamido)-1H-indol-1-yl)acetic acid (BH, 10 mg) and (2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (L, 10 mg) using HATU as a coupling agent following procedure described in scheme 14 to get compound 36.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 2.16-2.70 (m, 4H) 3.28 (m, 1H), 3.49 (ddd, J=22.4, 11.2, Hz, 2H), 3.89-4.01 (m, 1H), 4.13-4.22 (m, 1H), 4.75 (m, 1H), 5.16 (d, J=17.2 Hz, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.43 (d, J=35.6 Hz, 1H), 7.04-7.59 (m, 8H), 8.01 (m, 1H), 8.17 (s, 2H), 8.61 (s, 1H), 10.27 (s, 1H). LC (method 1): tR=2.70 min. LC/MS (APCI) m/z: [M+H]+ 661.
tert-Butyl 3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4-fluoro pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-6-ylcarbamate (37)




To a solution of 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AQ, 56 mg) was dissolved in DCM (20 mL) was added TEA (0.02 mL, 1 eq.), stirred for 15 min., followed by addition of DPPA (0.02 mL, 1 eq.). The reaction mixture was stirred for 16 h at RT, DCM was removed, the residue refluxed in toluene, (15 mL) and tBuOH (excess) for 16 h. Solvent was evaporated and the residue was purified by chromatography over silica gel (MeOH in DCM gradient) to obtain tert-butyl 3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-6-ylcarbamate (37) (46 mg, 0.08 mmol).
LC (method 1): tR=1.90 min. LC/MS (APCI) m/z: [M+H]+ 589.
(2S,4R)-1-(2-(3-acetyl-5-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (39)




3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (AC, 518 mg) was converted to the isocyanate and the reacted with 2-azabicyclo[2.2.1]heptane (194 mg) to give compound 39 following procedures described in scheme 18.
1H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 1.38-1.77 (m, 6H), 2.00-2.17 (m, 1H), 2.45 (s, 3H), 2.62 (s, 1H), 3.10 (d, J=10.8 Hz, 1H), 3.46-3.48 (m, 1H), 3.80-4.00 (m, 1H), 4.05-4.55 (m, 5H), 5.21 (d, J=17.2 Hz, 1H), 5.42 (d, J=53.2 Hz, 1H), 5.58 (s, 1H), 6.99-7.07 (m, 1H), 7.15-7.45 (m, 4H), 8.15 (s, 2H), 8.27 (s, 1H), 8.59 (t, J=5.6 Hz, 1H). LC (method 1): tR=1.76 min. LC/MS (APCI) m/z: [M+H]+ 597.
3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-1H-indole-6-carboxamide (48)




To a stirred solution of 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylic acid (AQ, 177 mg 0.34 mmol) in DMF (8 mL) was added cyclopropanesulfonamide, (207 mg, 1.71 mmol), HATU (390 mg, 1.03 mmol), and DIEA (0.4 mL, 2.4 mmol). The reaction mixture was heated to 60° C. for 36 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give 63 mg of the desired product 3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-cyclopropylsulfonyl)-1H-indole-6-carboxamide (48) as a white solid.
1H NMR (400 MHz, CD3OD, 300 K): (major rotamer) δ 1.12 (m, 4H), 2.11 (m, 1H), 2.48 (s, 3H), 3.15 (m, 1H), 3.92 (m, 1H), 4.16 (m, 2H), 4.32 (m, 2H), 4.49 (m, 2H), 5.48 (m, 2H), 6.92 (t, 1H), 7.21 (t, 1H), 7.43 (t, 1H), 7.81 (d, 1H), 8.30 (d, 1H), 8.44 (s, 1H), 8.65 (t, 1H). LC (method 1): tR=1.52 min. LC/MS (EI) m/z: [M+H]+ 621.00.
3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(phenylsulfonyl)-1H-indole-6-carboxamide (53)




Was prepared from 3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-6-carboxylic acid (AQ, 518 mg) and benzenesulfonamide (786 mg) using HATU as a coupling agent to give compound 53 following procedure described in scheme 29.
1H NMR (400 MHz, CD3OD, 300 K): (major rotamer) δ 2.06-2.25 (m, 1H), 2.41 (s, 3H), 2.51-2.59 (m, 1H), 3.82-4.15 (2H), 4.32 (m, 2H), 4.49 (m, 1H), 5.13-5.45 (m, 3H), 6.62 (t, J=7.0 Hz, 1H), 7.15 (dt, J=6.4 Hz, J=7.0 Hz 2H), 7.45 (t, 2H), 7.55 (m, 2H), 7.82 (d, 2H), 7.88 (s, 1H), 8.25 (m, 2H), 8.59 (t, J=5.6 Hz, 1H). LC (method 1): tR=1.71 min. LC/MS (EI) m/z: [M+H]+ 657.
Example 13. Non-Limiting Examples of Compounds of Formula I
Table 1 shows illustrative compounds of Formula I with characterizing data. The assay of Example 14 was used to determine the IC50's of the compounds. Other standard factor D inhibition assays are also available. Three ***s are used to denote compounds with an IC50 less than 1 micromolar; two **s indicate compound with an IC50 between 1 micromolar and 10 micromolar, and one * denotes compounds with an IC50 greater than 10 micromolar.












TABLE 1









RT min



Cmp



(Method
MS


No.
Structure
Name
IC50
A or B)
(M + 1)




















1




(2S,4R)-1-(2-(3-acetyl-5- (3-cyclopropylureido)-1H- indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.24 (A)
572


 


2




(2S,4R)-1-(2-(5-(3-((2H- tetrazol-5-yl)methyl)ureido)-3- acetyl-1H-indo-1-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)- 4-fluoropyrrolidine-2- carboxamide
***
1.01 (A)
614


 


3




(1R,3S,5R)-2-(2-(3-acetyl- 5-(3-cyclopropylureido)- 1H-indol-1-yl)acetyl)-N- (3-chloro-2-fluorobenzyl)- 2-azabicyclo[3.1.0]hexane- 3-carboxamide
***
1.52 (A)
566


 


4




(2S,4R)-1-(2-(3-acetyl-5- (3-(1-methylcyclopropyl) ureido)-1H-indol-1-yl) acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.66 (A)
586


 


5




(1R,3S,5R)-2-(2-(3-acetyl- 5-(3-cyclopropylureido)- 1H-indol-1-yl)acetyl)-N- ((R)-1-(3-chloro-2- fluorophenyl)ethyl)-2- azabicyclo[3.1.0]hexane- 3-carboxamide
***
1.74 (A)
580


 


6




(2S,4R)-1-(2-(3-acetyl-5- (3-isopropylureido)-1H- indol-1-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.65 (A)
574


 


7




(2S,4R)-1-(2-(3-acetyl-5- (3-(isoxazol-3-ylmethyl) ureido)-1H-indol-1-yl) acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.49 (A)
613


 


8




(2S,4R)-1-(2-(3-acetyl-5- (3-(pyrimidin-2-ylmethyl) ureido)-1H-indol-1-yl) acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.35 (A)
624


 


9




N-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5- yl)pyrrolidine-1- carboxamide
***
1.61 (A)
586


 


10




(2S,4R)-1-(2-(3-acetyl-5- (3-cyclopropylureido)-1H- indol-1-yl)acetyl)-4-fluoro- N-(2-fluoro-3- (trifluoromethoxy)phenyl) pyrrolidine-2-carboxamide
***
1.80 (A)
608


 


11




(1R,3S,5R)-2-(2-(3-acetyl- 5-(3-cyclopropylureido)- 1H-indol-1-yl)acetyl)-N- (2-fluoro-3- (trifluoromethoxy)phenyl)- 2-azabicyclo[3.1.0]hexane- 3-carboxamide
***
1.88 (A)
602


 


12




(1R,3S,5R)-2-(2-(3-acetyl- 5-(pyrrolidine-1- carboxamido)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-2- azabicyclo[3.1.0]hexane- 3-carboxamide
***
1.72 (A)
581


 


13




(N-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5-yl)- 3,3-difluoropyrrolidine-1- carboxamide
***
1.77 (A)
622


 


14




cyclopropyl 2-acetyl-1-(2- ((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5- ylcarbamate
***
1.78 (A)
573


 


15




cyclopropylmethyl 3- acetyl-1-(2-((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5- ylcarbamate
***
1.96 (A)
587


 


16




N-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5-yl)- 3,3-difluoropiperidine-1- carboxamide
***
1.82 (A)
636


 


17




N-(3-acetyl-1-(2-((2S,4R)- 4-fluoro-2-(2-fluoro-3- (trifluoromethoxy) phenylcarbamoyl)pyrrolidin- 1-yl)-2-oxoethyl)-1H-indol-5- yl)-3,3-difluoropiperidine- 1-carboxamide
***
2.06 (A)
672


 


18




N-(3-acetyl-1-(2-((2S,4R)- 2-(2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5-yl)- 3,3-difluoropiperidine-1- carboxamide
***
2.25 (A)
698


 


19




(2S,4R)-1-(2-(3-acetyl-5- (3-isoxazol-3-ylureido)- 1H-indol-1-yl)acetyl)-N- (3-chloro-2-fluorobenzyl)- 4-fluoropyrrolidine-2- carboxamide
***
1.60 (A)
599


 


20




N-(3-acetyl-1-(2-((2S,4R)- 4-fluoro-2-(6- (trifluoromethyl)pyridin- 2-ylcarbamoyl)pyrrolidin- 1-yl)-2-oxoethyl)-1H- indol-5-yl)-3,3- difluoropiperidine-1- carboxamide
***
1.89 (A)
639


 


21




(2S,4R)-1-(2-(3-acetyl-5- (3-(2,2,2-trifluoroethyl) ureido)-1H-indol-1-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)- 4-fluoropyrrolidine-2- carboxamide
***
1.72 (A)
614


 


22




N-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-5-yl)- 5H-pyrrolo[3,4- d]pyrimidine-6(7H)- carboxamide
***
1.38 (A)
636


 


23




(2S,4R)-1-(2-(3-acetyl-5- (3-pyrimidin-5-ylureido)- 1H-indol-1-yl)acetyl)-N- (3-chloro-2-fluorobenzyl)- 4-fluoropyrrolidine-2- carboxamide
***
1.40 (A)
610


 


24




1-(2-((2S,4R)-2-(2′- chloro-2-fluorobiphenyl- 3-ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(3,3- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
2.09 (A)
700


 


25




1-(2-((2S,4R)-4-fluoro-2- (2-fluoro-3- (trifluoromethoxy) phenylcarbamoyl)pyrrolidin- 1-yl)-2-oxoethyl)-5-(3- isoxazol-3-ylureido)-1H- indazole-3-carboxamide
***
1.71 (A)
637


 


26




5-(3,3-difluoropiperidine- 1-carboxamido)-1-(2- ((2S,4R)-4-fluoro-2-(2- fluoro-3-(trifluoromethoxy) phenylcarbamoyl)pyrrolidin- 1-yl)-2-oxoethyl)-1H- indazole-3-carboxaide
***
1.90 (A)
674


 


27




5-(3,3-difluoropiperidine- 1-carboxamido)-1-(2- ((1R,3S,5R)-3-(2-fluoro-3- (trifluoromethoxy) phenylcarbamoyl)-2- azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-1H- indazole-3-carboxamide
***
1.97 (A)
668


 


28




1-(2-((1R,3S,5R)-3-(2′- chloro-2-fluorobiphenyl- 3-ylcarbamoyl)-2- azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-(3,3- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
2.17 (A)
694


 


29




1-(2-((2S,4R)-2-(3-(3- chloropyridin-2-yl)-2- fluorophenylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(3,3- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
1.65 (A)
701


 


30




1-(2-((2S,4R)-2-(2′- chloro-2-fluorobiphenyl- 3-ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(3,3- difluoropyrrolidine-1- carboxamido)-1H- indazole-3-carboxamide
***
2.03 (A)
686


 


31




1-(2-((2S,4R)-2-(2′- chloro-2-fluorobiphenyl- 3-ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(4,4- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
2.11 (A)
700


 


32




1-(2-((2S,4R)-2-(2′-chloro- 2-fluorobiphenyl-3- ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(3-(pyrimidin- 2-ylmethyl)ureido)-1H- indazole-3-carboxamide
***
1.69 (A)
688


 


33




1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-5-(3,3- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
1.59 (A)
651


 


34




1-(2-((1R,3S,5R)-3-(6- bromopyridin-2- ylcarbamoyl)-2- azabicyclo[3.1.0]hexan-2- yl)-2-oxoethyl)-5-(3,3- difluoropiperidine-1- carboxamido)-1H- indazole-3-carboxamide
***
1.75 (A)
645


 


35




(2S,4R)-1-(2-(3-acetyl-5-(3,3- difluorocyclopentanecarboxamido)- 1H-indol-1-yl)acetyl)-N-(2′-chloro- 2-fluorobiphenyl-3-yl)-4- fluoropyrrolidine-2- carboxamide
***
2.61 (A)
683


 


36




(2S,4R)-1-(2-(3-acetyl-5-(3,3,3- trifluoropropanamido)-1H-indol- 1-yl)acetyl)-N-(2′-chloro-2- fluorobiphenyl-3-yl)-4- fluoropyrrolidine-2- carboxamide
***
2.70 (A)
661


 


37




tert-butyl 3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indol-6-ylcarbamate
***
1.90 (A)
589


 


38




1-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indole-5-carbonyl)- 1,2,3,6-tetrahydropyridin-4- ylboronic acid
***
0.93 (A)
627


 


39




(2S,4R)-1-(2-(3-acetyl-5- (2-azabicyclo[2.2.1]heptane-2- carbonyl)-1H-indol-1-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide
***
1.76 (A)
597


 


40




(2S,4R)-1-(2-(3-acetyl-5- (3,3-difluoropiperidine-1- carbonyl)-1H-indol-1- yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2- carboxamide
***
1.83 (A)
621


 


41




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N-cyclopropyl-1H-indole-5- carboxamide
***
1.54 (A)
557


 


42




(2S,4R)-1-(2-(3-acetyl-6-(3- (aminomethyl)pyrrolidine-1- carbonyl)-1H-indol-1-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide
***
1.02 (A)
600


 


43




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N-(methylsulfonyl)-1H-indole-6- carboxamide
***
1.60 (A)
595


 


44




(S)-tert-butyl 3-(3-acetyl-1-(2- ((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- 1H-indole-6-carboxamido) pyrrolidine-1-carboxylate
***
1.92 (A)
686


 


45




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N-((S)-pyrrolidin-3-yl)-1H-indole- 6-carboxamide
***
1.10 (A)
586


 


46




3-acetyl-N-((S)-1-acetylpyrrolidin- 3-yl)-1-(2-((2S,4R)-2-(3-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- 1H-indole-6-carboxamide
***
1.30 (A)
628


 


48




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N-(cyclopropylsulfonyl)-1H- indole-6-carboxamide
***
1.52 (A)
621


 


49




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N-(pyrrolidin-3-ylmethyl)-1H- indole-6-carboxamide
***
0.70 (A)
600


 


50




tert-butyl 3-((3-acetyl-1-(2- ((2S,4R)-2-(2-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indole-6- carboxamido)methyl) pyrrolidine-1-carboxylate
***
1.77 (A)
700


 


51




methyl 1-(3-acetyl-1-(2-((2S,4R)- 2-(3-chloro-2- fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- 1H-indole-6-carbonyl)pyrrolidine- 3-carboxylate
***
1.28 (A)
629


 


52




1-(3-acetyl-1-(2-((2S,4R)-2(3- chloro-2-fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-indole-6-carbonyl) pyrrolidine-3-carboxylic acid
***
1.14 (A)
615


 


53




3-acetyl-1-(2-((2S,4R)-2-(3-chloro- 2-fluorobenzylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl- N-(phenylsulfonyl)-1H-indole-6- carboxamide
***
1.71 (A)
657


 


54




1-(2-((2S,4R)-2-(2′-chloro-2- fluorobiphenyl-3-ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)- N6-(cyclopropylsulfonyl)-1H- indazole-3,6-dicarboxamide
***
2.00 (A)
685









Example 14. Human Factor D Assay
Human factor D (purified from human serum, Complement Technology, Inc.) at 80 nM final concentration is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl, pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent) are added to final concentrations of 100 μM each. The increase in color is recorded at OD405 nm in a microplate in kinetic mode over 30 minutes with 30 second time points in a spectrofluorimeter. IC50 values are calculated by non-linear regression from the percentage of inhibition of complement factor D activity as a function of test compound concentration.
Example 15. Hemolysis Assay
The hemolysis assay was previously described by G. Ruiz-Gomez, et al., -J. Med. Chem. (2009) 52: 6042-6052. In the assay red blood cells (RBC), rabbit erythrocyctes (purchased from Complement Technologies), are washed using GVB Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3) plus 10 mM final Mg-EGTA. Cells are used at a concentration of 1×108 cells/mL. Prior to the hemolysis assay, the optimum concentration of Normal Human Serum (NHS) needed to achieve 100% lysis of rabbit erythrocytes is determined by titration. NHS (Complement Technologies) is incubated with inhibitor for 15 min at 37° C., rabbit erythrocytes in buffer were added and incubated for an additional 30 min at 37° C. Positive control (100% lysis) consists of serum and RBC and negative control (0% lysis) of Mg-EGTA buffer and RBC only. Samples are centrifuged at 2000 g for 5 min, and supernatants collected. Optical density of the supernatant is monitored at 405 nm using a UV/visible spectrophotometer. Percentage lysis in each sample is calculated relative to positive control (100% lysis).
This specification has been described with reference to embodiments of the invention. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

## Claims

1. A compound of Formula I




or a pharmaceutically acceptable salt thereof, wherein:
Q1 is C(R1R1′);
Q2 is C(R2R2′);
Q3 is C(R3R3′);
X1 is N and X2 is CH;
R1, R1′, R2, R2′, R3, and R3′ are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, —C0-C4alkylNR9R10, —C(O)OR9, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)OR10, C1-C2haloalkyl, and C1-C2haloalkoxy,
R9 and R10 are independently chosen at each occurrence from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), and —O—C0-C4alkyl(C3-C7cycloalkyl);
or R1 and R2 form a 3- to 6-membered carbocyclic or aryl ring;
or R2 and R3 form a 3- to 6-membered carbocyclic ring;
or R1 and R1′, or R2 and R2′, or R3 and R3′ form a 3- to 6-membered carbocyclic spiro ring;
or R1 and R1′, or R2 and R2′, or R3 and R3′ form a 3- to 6-membered heterocyclic spiro ring;
each of which ring is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, —COOH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
or R1 and R1′, R2 and R2′, or R3 and R3′ form a carbonyl group;
or R1 and R2 or R2 and R3 form a carbon-carbon double bond;
A is a group selected from:




R5 and R6 are independently selected from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, vinyl, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C4alkyl(C3-C7cycloalkyl), —P(O)(OR9)2, —OC(O)R9, —C(O)OR9, —C(O)N(CH2CH2R9)(R10), —NR9C(O)R10, phenyl, or 5- to 6-membered heteroaryl;
R8 and R8′ are independently chosen from hydrogen, halogen, hydroxyl, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, and (C1-C4alkylamino)C0-C2alkyl; or R8 and R8′ are taken together to form an oxo group; or R8 and R8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring;
X11 is N or CR11;
X12 is CR12;
X13 is CR13;
X14 is N or CR14;
one of R12 and R13 is chosen from R31 and the other of R12 and R13 is chosen from R32;
R31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C2-C6alkenyloxy, —C(O)OR9, C1-C6thioalkyl, —C0-C4alkylNR9R10, —C(O)NR9R10, —SO2R9, —SO2NR9R10, —OC(O)R9, and —C(NR9)NR9R10, each of which R31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl, and C1-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2C1-C2haloalkyl, and C1-C2haloalkoxy, and each of which R31 is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl)(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R32 is —C(O)NR21SO2R22;
R11 and R14 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR9)2, —(PO)(OR9)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkoxy(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R21 and R22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, —C1-C4alkylOC(O)OC1-C6alkyl, —C1-C4alkylOC(O)C1-C6alkyl, —C1-C4alkylC(O)OC1-C6alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
R23 is independently chosen at each occurrence from C1-C6alkyl, C1-C6haloalkyl, (aryl)C0-C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
R24 and R25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings;
L is




 where R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl), and R18 and R18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3;
B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C6alkenyl; C2-C6alkynyl; —(C0-C4alkyl)(aryl); —(C0-C4alkyl)(heteroaryl); or —(C0-C4alkyl)(biphenyl) each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36;
R33 is independently chosen from halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
R34 is independently chosen from nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23, -JOSO2OR21, —C(O)(CH2)1-4S(O)R21, —O(CH2)1-4S(O)NR21R22, -JOP(O)(OR21)(OR22), -JP(O)(OR21)(OR22), -JOP(O)(OR21)R22, -JP(O)(OR21)R22, -JOP(O)R21R22, -JP(O)R21R22, -JSP(O)(OR21)(OR22), -JSP(O)(OR21)(R22), -JSP(O)(R21)(R22), -JNR9P(O)(NHR21)(NHR22), -JNR9P(O)(OR21)(NHR22), -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JNR9S(O)NR10R22, -JNR9SO2NR10R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)NR22, -JC(NH2)NR9S(O)2R22, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21OC(O)R22, —(CH2)1-4C(O)NR21R22, -JC(O)R24R25, -JNR9C(O)R21, -JC(O)R21, -JNR9C(O)NR10R22, —CCR21, —(CH2)1-4OC(O)R21, and -JC(O)OR23; each of which R34 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy;
R35 is independently chosen from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7-ring atoms in each ring; each of which R35 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R36 is independently chosen from tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which R36 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, —OSi(CH3)2C(CH3)3, —Si(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy; and
J is independently selected at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.

2. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

3. The compound of claim 1, wherein the




ring is selected from:

4. The compound of claim 1, wherein R1 and R1′ or R3 and R3′ can together form a 3- to 6-membered carbocyclic Spiro ring or a 3- to 6-membered heterocyclic Spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, or S.

5. The compound of claim 1, wherein R2 and R2′ can together to form a 3 to 6-membered carbocyclic spiro ring; or R2 and R2′ are taken together to form a 3- to 6-membered heterocyclic Spiro ring.

6. The compound of claim 1, wherein B is selected from:

7. The compound of claim 1, wherein R32 selected from:

8. The compound of claim 1, wherein B is selected from:

9. The compound of claim 1, wherein B is selected from:

10. The compound of claim 1, wherein B is selected from:

11. The compound of claim 1, wherein B is selected from:

12. The compound of claim 1, wherein B is selected from:

13. The compound of claim 1 of Formula IB




or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 of Formula IC




or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein A is

16. The compound of claim 1, wherein B is —(C0-C4alkyl)(aryl), —(C0-C4alkyl)(heteroaryl), or —(C0-C4alkyl)(biphenyl) each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36.

17. The compound of claim 16, wherein B is aryl, heteroaryl, or biphenyl each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36.

18. The compound of claim 17, wherein R33 is halogen.

19. The compound of 17, wherein there are two substituents chosen from R33 and wherein one is halogen and the other is C1-C6alkyl.

20. The compound of 19, wherein C1-C6alkyl is methyl.

21. The compound of claim 6, wherein A is

22. The compound of claim 6, wherein A is

23. The compound of claim 6, wherein A is

24. The compound of claim 16, wherein

25. The compound of claim 24, wherein

26. The compound of claim 16, wherein

27. The compound of claim 26, wherein

28. The compound of claim 16, wherein R22 is selected from hydroxyl, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and (phenyl)C0-C4alkyl.

29. The compound of claim 16, wherein R22 is selected from C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, and (phenyl)C0-C4alkyl.

30. The compound of claim 16, wherein R22 is selected from hydroxyl and amino.

31. The compound of claim 16, wherein A is

32. The compound of claim 16, wherein A is

33. The compound of claim 16, wherein A is

34. The compound of claim 33, wherein

35. The compound of claim 34, wherein

36. The compound of claim 33, wherein

37. The compound of claim 36, wherein

38. The compound of claim 3, wherein R21 is H and R22 is selected from hydroxyl, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and (phenyl)C0-C4alkyl.

39. The compound of claim 38, wherein R22 is hydroxyl or amino.

40. The compound of claim 38, wherein R22 is C1-C6alkyl.

41. The compound of claim 38, wherein R22 is C1-C6haloalkyl or C1-C6alkoxy.

42. The compound of claim 38, wherein R22 is (C3-C7cycloalkyl)C0-C4alkyl.

43. The compound of claim 42, wherein (C3-C7cycloalkyl)C0-C4alkyl is cyclopropyl.

44. The compound of claim 38, wherein R22 is (phenyl)C0-C4alkyl.

45. The compound of claim 44, wherein (phenyl)C0-C4alkyl is phenyl.

46. The compound of claim 38, wherein R21 is methyl and R22 is selected from hydroxyl, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and (phenyl)C0-C4alkyl.

47. The compound of claim 46, wherein R22 is hydroxyl or amino.

48. The compound of claim 46, wherein R22 is C1-C6alkyl.

49. The compound of claim 46, wherein R22 is C1-C6haloalkyl or C1-C6alkoxy.

50. The compound of claim 46, wherein R22 is (C3-C7cycloalkyl)C0-C4alkyl.

51. The compound of claim 46, wherein R22 is (phenyl)C0-C4alkyl.

52. The compound of claim 37, wherein R32 selected from:

53. The compound of claim 1 of structure:




or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1 of structure:




or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1 of structure:




or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1 of structure:




or a pharmaceutically acceptable salt thereof.