Claims for Patent: 9,796,741

Summary for Patent: 9,796,741

Title:	Aryl, heteroaryl, and heterocyclic 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 aryl, heteroaryl or heterocycle (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.
Inventor(s):	Venkat Rao Gadhachanda, Qiuping Wang, Godwin Pais, Akihiro Hashimoto, Dawei Chen, Xiangzhu Wang, Atul Agarwal, Milind Deshpande, Jason Allan Wiles, Avinash S. Phadke
Assignee:	Achillion Pharmaceuticals Inc
Application Number:	US14/631,625
Patent 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, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, —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); 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, —CONH2, C1-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 selected from 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; 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); or —(C0-C4alkyl)(heteroaryl); 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, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21OC(O)R22, —(CH2)1-4C(O)NR21R22, -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)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 method for the treatment of a disorder mediated by complement factor D, comprising administering an effective amount to a host in need thereof of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 3. The method of claim 2, wherein the host is a human. 4. The method of claim 2, wherein the disorder is age-related macular degeneration (AMD). 5. The method of claim 2, wherein the disorder is retinal degeneration. 6. The method of claim 2, wherein the disorder is an ophthalmic disease. 7. The method of claim 2, wherein the disorder is paroxysymal nocturnal hemoglobinuria (PNH). 8. The method of claim 2, wherein the disorder is multiple sclerosis. 9. The method of claim 2, wherein the disorder is arthritis. 10. The method of claim 2, wherein the disorder is rheumatoid arthritis. 11. The method of claim 2, wherein the disorder is a respiratory disease or a cardiovascular disease. 12. The compound of claim 1, wherein the ring is selected from: 13. The compound of claim 1, wherein B is selected from: 14. The compound of claim 1, wherein R32 is selected from 15. The compound of claim 1, wherein B is selected from: 16. The compound of claim 1, wherein B is selected from: 17. The compound of claim 1, wherein B is selected from: 18. The compound of claim 1 of Formula IB or a pharmaceutically acceptable salt thereof. 19. The compound of claim 1 of Formula IC or a pharmaceutically acceptable salt thereof. 20. The compound of claim 1, wherein A is 21. The compound of claim 1, wherein A is 22. The compound of claim 1, wherein B is —(C0-C4alkyl)(aryl) or —(C0-C4alkyl)(heteroaryl) 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. 23. The compound of claim 22, wherein B is —(CH2)(aryl) substituted with two substituents independently chosen from R33 and R34. 24. The compound of claim 23, wherein R33 is halogen. 25. The compound of claim 24, wherein there are two R33 substituents and one is chlorine and the other is fluorine. 26. The compound of claim 22, wherein B is aryl or heteroaryl each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34. 27. The compound of claim 26, wherein B is aryl. 28. The compound of claim 26, wherein B is heteroaryl. 29. The compound of claim 28, wherein heteroaryl is 2-pyridine. 30. The compound of claim 29, wherein 2-pyridine is substituted with one substituent independently chosen from R33. 31. The compound of claim 30, wherein R33 is halogen. 32. The compound of claim 31, wherein A is 33. The compound of claim 31, wherein A is 34. The compound of claim 25, wherein A is 35. The compound of claim 1, wherein A is 36. The compound of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof. 37. The compound of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof. 38. The compound of claim 37, wherein the compound is: or a pharmaceutically acceptable salt thereof. 39. The method of claim 2, wherein the disorder is MPGN II. 40. The method of claim 2, wherein the compound is: or a pharmaceutically acceptable salt thereof. 41. The method of claim 40, wherein the host is a human. 42. The method of claim 40, wherein the disorder is age-related macular degeneration (AMD). 43. The method of claim 40, wherein the disorder is retinal degeneration. 44. The method of claim 40, wherein the disorder is an ophthalmic disease. 45. The method of claim 40, wherein the disorder is paroxysymal nocturnal hemoglobinuria (PNH). 46. The method of claim 40, wherein the disorder is multiple sclerosis. 47. The method of claim 40, wherein the disorder is arthritis. 48. The method of claim 40, wherein the disorder is rheumatoid arthritis. 49. The method of claim 40, wherein the disorder is a respiratory disease or a cardiovascular disease. 50. The method of claim 40, wherein the disorder is MPGN II.