THERAPEUTIC INHIBITORY COMPOUNDS - LIFESCI PHARMACEUTICALS INC

Title:

THERAPEUTIC INHIBITORY COMPOUNDS

Document Type and Number:

WIPO Patent Application WO/2018/229543

Kind Code:

Abstract:

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.

Inventors:

MCDONALD ANDREW (US)
QIAN SHAWN (US)

Application Number:

PCT/IB2018/000702

Publication Date:

December 20, 2018

Filing Date:

June 14, 2018

Export Citation:

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Assignee:

LIFESCI PHARMACEUTICALS INC (BB)

International Classes:

A61K31/53; C07D487/04

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Claims:

CLAIMS

We Claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula

(I):

wherein,

W, X, and Z are each independently selected from N or C-R¹;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R⁴ is selected from hydrogen, -CN, -(CH₂)_n-C0₂H, -(CH₂)_n-CO(NR²¹)₂, -(CH₂)_n-C0₂-R²⁰, - (CH₂)_n-NR²¹CO-R²⁰, -(CH₂)_n-NR²¹C0₂-R²⁰, -(CH₂)_n-S0₂(NR²¹)₂, -(CH₂)_n-OH, -(CH₂)_n-NH₂;

R⁵ is selected from -NRⁿCO-R¹⁰, -NRⁿC0₂-R¹⁰, -NR¹ CO-N(R¹²)₂, -NR¹ S0₂-N(R¹²)₂, -O- CO-R¹⁰, -O-CO-R²⁰, -0-C0₂-R¹⁰, -0-C0₂-R²⁰, optionally substituted aralkoxy, optionally substituted heteroarylalkoxy, optionally substituted (carbocyclyl)-O-, optionally substituted heterocyclylalkoxy;

R¹⁰ is optionally substituted carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R¹¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, R¹⁰ and R¹¹ join to form a ring;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; or two R¹² groups join to form a N-linked heterocyclyl;

R¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R¹² and R¹³ join to form a ring;

each R⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

2. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

U is NH and V is CH, or U is CH₂ and V is N;

W, X, and Z are each independently selected from N or C-R¹;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

each R⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein U is NH and V is CH.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein U is CH₂ and V is N.

5. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):

wherein,

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

W, X, and Z are each independently selected from N or C-R¹;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

each R⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein V is N, T is N, and U is C.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein V is C, T is CH, and U is N.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is hydrogen.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

11. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-H.

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

13. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-H.

14. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein both X and W are N; Z is C-H.

15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein both Z and W are N; W is C-H.

16. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H.

17. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z is C-H.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

21. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

23. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein m is 0.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound of any one of claims 1 -24, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰.

29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂.

30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂.

31. The compound of any one of claims 1 -26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰.

32. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰.

33. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰.

34. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰.

35. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy.

36. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy.

37. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-.

38. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

39. The compound of any one of claims 27-28, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen.

40. The compound of any one of claims 29-30, or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

41. A compound, or a pharmaceuticall acceptable salt thereof, having the structure of Formula (VII):

wherein,

Ring A is an optionally substituted bicyclic heteroaryl;

U is C(R⁷⁰)(R⁷¹), or NH;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R⁶¹, R⁶², R⁶³, R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted alkoxy;

each R⁷⁰ or R⁷¹ is independently selected from hydrogen, cyano, optionally substituted alkyl, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted carbocyclyl or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 10-membered bicyclic heteroaryl.

43. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 9-membered bicyclic heteroaryl.

44. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.

45. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted isoquinolyl.

46. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted benzofuranyl, optionally substituted benzooxazolyl, optionally substituted benzonaphthoiuranyl, optionally substituted benzopyranyl, optionally substituted benzopyranonyl, optionally substituted benzofuranyl, optionally substituted benzofuranonyl, optionally substituted benzotriazolyl, optionally substituted

benzo[4,6]imidazo[l,2-a]pyridinyl, optionally substituted furo[3,2-c]pyridinyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyrido[3,2-d]pyrimidinyl, or optionally substituted pyrido [3 ,4 -d] pyrimidinyl .

47. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted benzo[d]thiazolyl, optionally substituted benzothienyl, optionally substituted benzothieno[3,2-d]pyrimidinyl, optionally substituted 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, optionally substituted

thieno[2,3-d]pyrimidinyl, optionally substituted thieno[3,2-d]pyrimidinyl, or optionally substituted thieno [2,3 -c]pridinyl .

48. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (Vila):

wherein,

W, X, Y and Z are each independently selected from N, C-R¹, or C-R⁵, provided that at least one of W, X, Y, and Z is C-R⁵;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂; each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

49. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vllb):

R^ (Vllb)

wherein,

U is NH and V is CH; or U is C(R ^U)(R ¹) and V is N;

W, X, Y and Z are each independently selected from N, C-R¹, or C-R⁵, provided that at least one of W, X, Y, and Z is C-R⁵;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

C0₂H, -S(0)-R , -S-R , -S(0)₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl) -0-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted 21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²°, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂;

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

50. The compoundof claim 49, or a pharmaceutically acceptable salt thereof, wherein U is NH and V is CH.

51. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹) and V is N.

52. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (VIIc):

* 3

^C0R (VIIc)

wherein,

V is N, T is N, and Q is C; or V is C, T is CH, and Q is N; W, X, Y and Z are each independently selected from N, C-R¹, or C-R⁵, provided that at least one of W, X, Y, and Z is C-R⁵;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted

dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein V is N, T is N, and Q is C.

54. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein V is C, T is CH, and Q is N.

55. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein only one of W, X, Y and Z is C-R⁵.

56. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein only X is C-R⁵.

57. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein X is C-R⁵, and W, Y, and Z are C-R¹.

58. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl.

59. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

61. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R³ is NH₂.

62. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

63. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein m is 0.

64. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

65. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

66. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿCO-R¹⁰.

67. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿC0₂-R¹⁰.

68. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹¹ is hydrogen.

69. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NR¹ CO-N(R¹²)₂.

70. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NR¹ S0₂-N(R¹²)₂.

71. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹³ is hydrogen.

72. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R¹⁰.

73. The compound of claim 41, or a pharmaceutically acceptable salt thereof,, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R²⁰.

74. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R¹⁰.

75. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R²°.

76. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted aralkoxy.

77. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heteroarylalkoxy.

78. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted (carbocyclyl)-O-.

79. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heterocyclylalkoxy.

80. A compound, or a pharmaceutically acceptable salt thereof, selected from:

7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-methyl- lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-fluoro- 1 H-indazole-3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-cyano- 1 H-indazole-3 -carboxamide ,

7-(aminomethyl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

methyl 3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-

2- oxoethyl)-lH-indazole-7-carboxylate,

methyl 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxylate ,

l-(2 -((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-3H-imidazo[4,5-c]pyridin-4-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-5-cyanopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-5-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloroisoquinolin-l-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide,

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((5-chloro-lH-pyrazolo[3,4-c]pyridin-7-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((3-chloronaphthalen-l-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((5-chloro-lH-indazol-7-yl)carb^

indazole-3-carboxamide,

5-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (nicotinamido)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- phenylacetamido)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(l- hydroxyethyl) - 1 H-indazole -3 -carboxamide ,

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-lH-indazol-l-yl)acetyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide,

7-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)acetyl)-lH- indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(2- hydroxypropan-2 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((3-chloro-2-fluorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-

2 - oxoethyl)- lH-indazol-5 -yl)carbamate,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- (dimethylamino)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- morpholinoacetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(4- methylpiperazin- 1 -yl)acetamido) - lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (phenylsulfonamido)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(l-methoxyisoquinolin-3-yl)-2-oxoethyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)isoquinoline -3 -carboxamide ,

isopropyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2 -oxoethyl) - 1 H-indazol-5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (tetrahydrofuran-3 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (cyclopentanecarboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (methylsulfonamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(2- fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide, l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(2-(3- fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoy ^^^

fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide,

5-(2-(4-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2^ cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(m- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

5-(4-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- cyanobenzamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (cyclopropanecarboxamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperazine -2 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidine -4-carboxamido) - 1 H-indazole -3 -carboxamide ,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)morpholine-2 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrazole -4-carboxamido) - 1 H-indazole -3 -carboxamide,

5-((S)-2-amino-3-methylbutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide,

5-(2-(2-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

5-(2-(3-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(o- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol -5 -yl)mo holine-3 -carboxamide,

5-(3-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazole -4-carboxamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrrole -3 -carboxamido) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-amino-4-methylpentanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- cyanobenzamido)-lH-indazole-3-carboxamide, 5-(3 -chlorobenzamido)-l -(2-(( 1R,3 S,4S)-3 -((6-cU

yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanobenzamido) - 1 H-indazole -3 -carboxamide,

5-(2-aminoacetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-3-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-2-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- hydroxyacetamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-4-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (thiophene-2-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(2- cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

5-(2-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(3- cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(p- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazol -5 -yl)oxazole -5 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxyacetamido) - 1 H-indazole -3 -carboxamide,

5-((S)-2-aminobutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-

2- yl) -2 -oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-amino-3-hydroxypropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- 1 H-indazole-3 -carboxamide ,

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo [2.2.1 ]heptan-2-yl)-2- oxoethyl)- 1 H-indazol -5 -yl)mo holine-4 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- methylpiperazine - 1 -carboxamido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- isopropylureido)-lH-indazole-3-carboxamide, l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- cyclopentylureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3-(2- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3- cyclopropylureido) - 1 H-indazole -3 -carboxamide ,

5-(3-(2-aminoethyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-

2- yl) -2 -oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (tetrahydrofuran-3 -yl)ureido) - 1 H-indazole -3 -carboxamide,

5-(3-(4-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(m- tolyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperazine - 1 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- hydroxyethyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- methoxyethyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(p- tolyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2 .₁]heptan-2-yl)-2-oxoethyl)-5-(3-(4- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-3 -yl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2 .₁]heptan-2-yl)-2-oxoethyl)-5-(3-(4- cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide,

5-(3-(3-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

5-(4-acetylpiperazine-l-carboxamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(3- cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-2-yl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- methylureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (thiazol -2 -yl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(3- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- phenylureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- (dimethylamino)ethyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-4-yl)ureido) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3-(2- (methylamino)ethyl)ureido) - 1 H-indazole -3 -carboxamide ,

5-(3 -( lH-imidazol-2-yl)ureido)- 1 -(2-(( 1R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

5-(3 -( lH-imidazol-5-yl)ureido)- 1 -(2-(( 1R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

methyl (l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- 3 -carbamoyl - 1 H-indazol -5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5-(2- chlorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5-(3- methylureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- (piperidin- 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- morpholino - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -6- (pyrrolidin- 1 -yl)- lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- pyrazol - 1 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- imidazol - 1 -yl) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(oxazol-

2- yl) - 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- imidazol -2 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide, l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- chlorobenzamido) - 1 H-indazole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazol-5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrazol - 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazol - 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (thiazol -2 -yl) - 1 H-indazole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate,

5-(2-chlorobenzamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

5 -(nicotinamido) -1 -(2 -oxo-2 -((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

5-(3 -methylureido)- 1 -(2-oxo-2-(( 1R,3 S,4S)-3 -((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1] heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazol-5 -yl)carbamate,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2 azabicyclo [2.2.1] heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide, methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)carbamate,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylbenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,4S)-2-(2-(3-acetyl-5-(2-methylnicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-3-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxybenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-5-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)carbamate,

methyl (3-acetyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl) - 1 H-indazol-5 -yl)carbamate ,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2- yl) -2-azabicyclo [2.2.1] heptane -3 -carboxamide ,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

6-(2-carbamoylpyrimidin-5-yl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

6-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-

2- oxoethyl) - 1 H-indazol -6 -yl)carbamate,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3- methylureido)- lH-indazole-3 -carboxamide,

6-benzamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

6-acetamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazol-6 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3- methylureido)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2. l]heptane-3-carboxamide, or

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-carbamoylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-

2- azabicyclo [2.2.1 ]heptane-3 -carboxamide .

81. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof.

82. A method of treating an autoimmune, inflammatory, or neurodegenerative disease in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof.

83. The method of claim 82, wherein the autoimmune, inflammatory, or neurodegenerative disease is paraoxvsmal nocturnal hemoglobinuria.

84. The method of claim 82, wherein the autoimmune, inflammatory, or neurodegenerative disease is C3 glomerulopathy.

Description:

THERAPEUTIC INHIBITORY COMPOUNDS

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 62/519,755 filed on June 14, 2017, and U.S. Provisional Patent Application No. 62/520,951 filed on June 16, 2017, each incorporated herein by reference in its entirety.

BACKGROUND

[0002] A need exists in the medicinal arts for the effective treatment of diseases and disorders mediated by complement factor D. Such diseases and disorders include, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.

BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting complement factor D activity.

[0004] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I :

wherein,

W, X, and Z are each independently selected from N or C-R ¹;

each Pv ¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

C0 ₂H, -S(0)-Pv , -S-R , -S(0) ₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0 ₂-R , - CO(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, -S0 ₂(NR ²¹) ₂, -C(=NR ²²)-(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, - NR ²¹CO-N(R ²⁰) ₂, -NR ²¹SO ₂-N(R ²⁰) ₂;

each R ²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R ²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R ² is optionally substituted aryl, or optionally substituted heteroaryl;

R ³ is selected from NH ₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R ⁴ is selected from hydrogen, -CN, -(CH ₂) _n-C0 ₂H, -(CH ₂) _n-CO(NR ²¹) ₂, -(CH ₂) _n-C0 ₂-R ²⁰, - (CH ₂) _n-NR ²¹CO-R ²⁰, -(CH ₂) _n-NR ²¹C0 ₂-R ²⁰, -(CH ₂) _n-S0 ₂(NR ²¹) ₂, -(CH ₂) _n-OH, -(CH ₂) _n-NH ₂;

R ⁵ is selected from -NR ⁿCO-R ¹⁰, -NR ⁿC0 ₂-R ¹⁰, -NR ¹ CO-N(R ¹²) ₂, -NR ¹ S0 ₂-N(R ¹²) ₂, -O- CO-R ¹⁰, -O-CO-R ²⁰, -0-C0 ₂-R ¹⁰, -0-C0 ₂-R ²⁰, optionally substituted aralkoxy, optionally substituted heteroarylalkoxy, optionally substituted (carbocyclyl)-O-, optionally substituted heterocyclylalkoxy;

each R ¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R ¹² and R ¹³ join to form a ring;

each R ⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0005] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

(II)

wherein,

U is NH and V is CH, or U is CH ₂ and V is N;

W, X, and Z are each independently selected from N or C-R ¹;

each R ¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0 ₂-R , - CO(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, -S0 ₂(NR ²¹) ₂, -C(=NR ²²)-(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, - NR ²¹CO-N(R ²⁰) ₂, -NR ²¹SO ₂-N(R ²⁰) ₂;

each R ²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R ² is optionally substituted aryl, or optionally substituted heteroaryl;

R ³ is selected from NH ₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R ⁴ is selected from hydrogen, -CN, -(CH ₂) _n-C0 ₂H, -(CH ₂) _n-CO(NR ²¹) ₂, -(CH ₂) _n-C0 ₂-R ²⁰, - (CH ₂) _n-NR ²¹CO-R ²⁰, -(CH ₂) _n-NR ²¹C0 ₂-R ²⁰, -(CH ₂) _n-S0 ₂(NR ²¹) ₂, -(CH ₂) _n-OH, -(CH ₂) _n-NH ₂;

R ⁵ is selected from -NR ⁿCO-R ¹⁰, -NR ⁿC0 ₂-R ¹⁰, -NR ¹ CO-N(R ¹²) ₂, -NR ¹ S0 ₂-N(R ¹²) ₂, -O- CO-R ¹⁰, -O-CO-R ²⁰, -0-C0 ₂-R ¹⁰, -0-C0 ₂-R ²⁰, optionally substituted aralkoxy, optionally substituted heteroarylalkoxy, optionally substituted (carbocyclyl)-O-, optionally substituted heterocyclylalkoxy;

R ¹¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, R ¹⁰ and R ¹¹ join to form a ring; each R ¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R ¹² and R ¹³ join to form a ring;

each R ⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0006] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula III):

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

W, X, and Z are each independently selected from N or C-R ¹;

each R ¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0 ₂-R , - CO(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, -S0 ₂(NR ²¹) ₂, -C(=NR ²²)-(NR ²¹) ₂, -NR ²¹CO-R ²⁰, -NR ²¹C0 ₂-R ²⁰, - NR ²¹CO-N(R ²⁰) ₂, -NR ²¹SO ₂-N(R ²⁰) ₂;

each R ²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R ² is optionally substituted aryl, or optionally substituted heteroaryl; R ³ is selected from NH ₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R ⁴ is selected from hydrogen, -CN, -(CH ₂) _n-C0 ₂H, -(CH ₂) _n-CO(NR ²¹) ₂, -(CH ₂) _n-C0 ₂-R ²⁰, - (CH ₂) _n-NR ²¹CO-R ²⁰, -(CH ₂) _n-NR ²¹C0 ₂-R ²⁰, -(CH ₂) _n-S0 ₂(NR ²¹) ₂, -(CH ₂) _n-OH, -(CH ₂) _n-NH ₂;

R ⁵ is selected from -NR ⁿCO-R ¹⁰, -NR ⁿC0 ₂-R ¹⁰, -NR ¹ CO-N(R ¹²) ₂, -NR ¹ S0 ₂-N(R ¹²) ₂, -O- CO-R ¹⁰, -O-CO-R ²⁰, -0-C0 ₂-R ¹⁰, -0-C0 ₂-R ²⁰, optionally substituted aralkoxy, optionally substituted heteroarylalkoxy, optionally substituted (carbocyclyl)-O-, optionally substituted heterocyclylalkoxy;

each R ¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R ¹² and R ¹³ join to form a ring;

each R ⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0007] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0008] One embodiment provides a method of treating an autoimmune, inflammatory, or neurodegenerative disease in a patient in need thereof comprising administering to the patient a

pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

Definitions

[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0012] "Amino" refers to the -NH ₂ radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -N0 ₂ radical.

[0015] "Oxa" refers to the -O- radical.

[0016] "Oxo" refers to the =0 radical.

[0017] "Thioxo" refers to the =S radical.

[0018] "Imino" refers to the =N-H radical.

[0019] "Oximo" refers to the =N-OH radical.

[0020] "Hydrazino" refers to the =N-NH ₂ radical.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-C ₈ alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., Ci-C ₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C ₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C ₅-Ci ₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C ₅-C ₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C ₂-C ₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C ₃-C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (^-propyl), 1-methylethyl (zso-propyl), 1 -butyl («-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1, 1-dimethylethyl (fert-butyl), 1-pentyl («-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a, -SR ^a, -OC(0)-R ^a, -N(R ^a) ₂, -C(0)R ^a, -C(0)OR ^a, -C(0)N(R ^a) ₂, -N(R ^a)C(0)OR ^a, -OC(0)-N(R ^a) ₂, -N(R ^a)C(0)R ^a, -N(R ^a)S(0),R ^a (where t is 1 or 2), -S(0) _tOR ^a (where t is 1 or 2), -S(0) _tR ^a (where t is 1 or 2) and -S(0) _tN(R ^a) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a, -SR ^a, -OC(0)-R ^a, -N(R ^a) ₂, -C(0)R ^a, -C(0)OR ^a, -C(0)N(R ^a) ₂, -N(R ^a)C(0)OR ^a, - OC(0)-N(R ^a) ₂, -N(R ^a)C(0)R ^a, -N(R ^a)S(0),R ^a (where t is 1 or 2), -S(0),OR ^a (where t is 1 or 2), -S(0),R ^a (where t is 1 or 2) and -S(0) _tN(R ^a) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a, -SR ^a, -OC(0)-R ^a, -N(R ^a) ₂, -C(0)R ^a, - C(0)OR ^a, -C(0)N(R ^a) ₂, -N(R ^a)C(0)OR ^a, -OC(0)-N(R ^a) ₂, -N(R ^a)C(0)R ^a, -N(R ^a)S(0),R ^a (where t is 1 or 2), -S(0),OR ^a (where t is 1 or 2), -S(0) _tR ^a (where t is 1 or 2) and -S(0) _tN(R ^a) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

[0025] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C ₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., Ci-C ₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., Ci-C ₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., Ci-C ₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C ₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C ₅-C ₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C ₂-C ₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C ₃-C ₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - OR ^a, -SR ^a, -OC(0)-R ^a, -N(R ^a) ₂, -C(0)R ^a, -C(0)OR ^a, -C(0)N(R ^a) ₂, -N(R ^a)C(0)OR ^a, -OC(0)-N(R ^a) ₂, - N(R ^a)C(0)R ^a, -N(R ^a)S(0) _tR ^a (where t is 1 or 2), -S(0) _tOR ^a (where t is 1 or 2), -S(0) _tR ^a (where t is 1 or 2) and -S(0),N(R ^a) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C ₂-C ₈ alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C ₂-C ₅ alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C ₂-C ₄ alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C ₂-C ₃ alkynylene). In other embodiments, an alkynylene comprises two carbon atom (e.g., C ₂ alkylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C ₅-C ₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C ₃-C ₅ alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a, -SR ^a, -OC(0)-R ^a, -N(R ^a) ₂, -C(0)R ^a, - C(0)OR ^a, -C(0)N(R ^a) ₂, -N(R ^a)C(0)OR ^a, -OC(0)-N(R ^a) ₂, -N(R ^a)C(0)R ^a, -N(R ^a)S(0),R ^a (where t is 1 or 2), - S(0) _tOR ^a (where t is 1 or 2), -S(0) _tR ^a (where t is 1 or 2) and -S(0) _tN(R ^a) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic

hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b- OR ^a, -R ^b-OC(0)-R ^a, -R ^b-OC(0)-OR ^a, -R ^b-OC(0)-N(R ^a) ₂, -R ^b-N(R ^a) ₂, -R ^b-C(0)R ^a, -R ^b-C(0)OR ^a, -R ^b- C(0)N(R ^a) ₂, -R ^b-0-R ^c-C(0)N(R ^a) ₂, -R ^b-N(R ^a)C(0)OR ^a, -R ^b-N(R ^a)C(0)R ^a, -R ^b-N(R ^a)S(0),R ^a (where t is 1 or 2), -R ^b-S(0),R ^a (where t is 1 or 2), -R ^b-S(0),OR ^a (where t is 1 or 2) and -R ^b-S(0),N(R ^a) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -R ^c-aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -R ^d-aryl where R ^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -R ^e-aryl, where R ^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R ^c-aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,

7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR ^a, -R ^b-OC(0)-R ^a, -R ^b-OC(0)-OR ^a, -R ^b-OC(0)-N(R ^a) ₂, -R ^b-N(R ^a) ₂, -R ^b- C(0)R ^a, -R ^b-C(0)OR ^a, -R ^b-C(0)N(R ^a) ₂, -R ^b-0-R ^c-C(0)N(R ^a) ₂, -R ^b-N(R ^a)C(0)OR ^a, -R ^b-N(R ^a)C(0)R ^a, -R ^b- N(R ^a)S(0),R ^a (where t is 1 or 2), -R ^b-S(0),R ^a (where t is 1 or 2), -R ^b-S(0),OR ^a (where t is 1 or 2) and -R ^b- S(0) _tN(R ^a) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -R ^c-carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -R ^c-carbocyclyl where R ^c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -

0-R ^c-carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of

and the like.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,

2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR ^a, -R ^b-OC(0)-R ^a, -R ^b-OC(0)-OR ^a, -R ^b-OC(0)-N(R ^a) ₂, -R ^b- N(R ^a) ₂, -R ^b-C(0)R ^a, -R ^b-C(0)OR ^a, -R ^b-C(0)N(R ^a) ₂, -R ^b-0-R ^c-C(0)N(R ^a) ₂, -R ^b-N(R ^a)C(0)OR ^a, -R ^b- N(R ^a)C(0)R ^a, -R ^b-N(R ^a)S(0),R ^a (where t is 1 or 2), -R ^b-S(0),R ^a (where t is 1 or 2), -R ^b-S(0),OR ^a (where t is 1 or 2) and -R ^b-S(0) _tN(R ^a) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0040] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1 -piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0041] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0042] "Heterocyclylalkyl" refers to a radical of the formula -R ^c -heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen -containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -

0-R ^c-heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,

benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,

6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl,

5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9, 10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,

5.6.7.8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR ^a, -R ^b-OC(0)-R ^a, -R ^b-OC(0)-OR ^a, -R ^b- OC(0)-N(R ^a) ₂, -R ^b-N(R ^a) ₂, -R ^b-C(0)R ^a, -R ^b-C(0)OR ^a, -R ^b-C(0)N(R ^a) ₂, -R ^b-0-R ^c-C(0)N(R ^a) ₂, -R ^b- N(R ^a)C(0)OR ^a, -R ^b-N(R ^a)C(0)R ^a, -R ^b-N(R ^a)S(0) _tR ^a (where t is 1 or 2), -R ^b-S(0) _tR ^a (where t is 1 or 2), -R ^b- S(0),OR ^a (where t is 1 or 2) and -R ^b-S(0),N(R ^a) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0045] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "Heteroarylalkyl" refers to a radical of the formula -R ^c-heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-

R ^c-heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹ C- or ¹⁴C-enriched carbon are within the scope of the present disclosure.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Isotopic substitution with ²H, ⁿC, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶0, ¹⁷0, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S,

36 35 37 79 81 125

S, CI, CI, Br, Br, I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the ^l atoms replaced with ²H atoms. The methods of synthesis for deuterium -containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;

George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic

Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commerically from chemical vendors, such as Aldrich Chemical Co.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d ₃ (CD ₃I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD ₃I is illustrated, by way of example only, in the reaction schemes below.

^ base ^ D

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD ₄), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD ₄ is illustrated, by way of example only, in the reaction schemes below.

^R ¾N ^LiAID4. ^{R AI P}4 , ^Dv ^R'

D D ^Nh2 ρΌ¾Η

R V^OH R A ^Li

R' " _R^ _{O H}

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example onl in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable ^l hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the kallikrein inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, p -toluene sulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,

monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,

methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.

Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,

2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, NN- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0065] "Prodrug" is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0066] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery

Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0067] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

Complement Factor D Inhibitory Compounds

[0068] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting complement factor D activity.

[0069] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):