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1. (WO2019046318) SPIROCYCLE COMPOUNDS AND METHODS OF MAKING AND USING SAME
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CLAIMS

What is claimed is:

1. A compound having the structure of Formula III):


Formula (III);

wherein:

X is -CH2- or -C(0)-;

Y is a bond,
Ci-6haloalkyl, or C3-8cycloalkyl;

R1 is H or Ci-ealkyl;

R2 is H or Ci-6alkyl;

R3 is a 5- to 6-membered heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring; wherein the 5- to 6-membered heteroaryl ring and the 9- to 10-membered bicyclic heteroaryl ring are optionally substituted with one, two, or three R4;

each R4 is independently selected from
halogen, -CN, Ci-6haloalkyl, C3- 8cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-(C2-9heterocycloalkyl), phenyl, -CH2- phenyl, Ci-9heteroaryl, -OR7, -C02R6, -CH2C02R6, and -CH2C(0)N(H)S02R8; wherein C2-9heterocycloalkyl, -Ci-6alkyl(C2-9heterocycloalkyl), phenyl, and Ci.gheteroaryl are optionally substituted with one or two R5; or two adjacent R4 form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, wherein the cycloalkyl and

heterocycloalkyl ring are optionally substituted with one or two R5;

each R5 is independently selected from halogen,
Ci-ehaloalkyl, Ci-6heteroalkyl, Ci.

6alkoxy, C3-8cycloalkyl, -Ci-6alkyl(C3-8cycloalkyl), C2-9heterocycloalkyl, -C02R6, - CH2C02R6, and -Ci-6alkyl(C2-9heterocycloalkyl) optionally substituted with Ci-6alkyl; each R6 is independently selected from H and Ci-6alkyl;

each R7 is independently selected from Ci-6haloalkyl, and C3-8cycloalkyl;

each R8 is independently selected from
-6haloalkyl, and C3-8cycloalkyl;

n is 0 or 1; and

m is 1 or 2; provided that when n is 0, then m is 2; and when n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is a bond.

3. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is a Ci-6alkyl.

4. The compound of claim 3, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -CH2-.

5. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is Ci-6haloalkyl.

6. The compound of claim 5, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -CF2-.

7. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is C3-8cycloalkyl.

8. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is cyclopropyl.

9. A compound having the structure of Formula (I):


Formula (I);

wherein:

X is -CH2- or -C(0)-;

R1 is H or Ci-ealkyl;

R2 is H or Ci-ealkyl;

R3 is a 5- to 6-membered heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring; wherein the 5- to 6-membered heteroaryl ring and the 9- to 10-membered bicyclic heteroaryl ring are optionally substituted with one, two, or three R4;

each R4 is independently selected from
halogen, -CN, Ci-6haloalkyl, C3- scycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-(C2-9heterocycloalkyl), phenyl, -CH2- phenyl, Ci-9heteroaryl, -OR7, -C02R6, and -CH2C02R6; wherein C2-9heterocycloalkyl, - Ci-6alkyl(C2-9heterocycloalkyl), phenyl, and Ci-9heteroaryl are optionally substituted with one or two R5; or two adjacent R4 form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl ring are optionally substituted with one or two R5;

each R5 is independently selected from halogen, Ci-6alkyl, Ci-6haloalkyl, Ci-6heteroalkyl, Ci. 6alkoxy, C3-8cycloalkyl, -Ci-6alkyl(C3-8cycloalkyl), C2-9heterocycloalkyl, -C02R6, - CH2C02R6, and -Ci.6alkyl(C2-9heterocycloalkyl) optionally substituted with

each R6 is independently selected from H and

each R7 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, and C3-8cycloalkyl;

n is 0 or 1; and

m is 1 or 2; provided that when n is 0, then m is 2; and when n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-9, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is H.

11. The compound of any one of claims 1-9, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R2 is H.

12. The compound of any one of claims 1-9, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 and R2 are both H.

13. The compound of any one of claims 1-12, wherein X is -CH2-.

14. The compound of any one of claims 1-12, wherein X is -C(O)-.

15. The compound of any one of claims 1-14, wherein n is 0 and m is 2.

16. The compound of any one of claims 1-14, wherein n is 1 and m is 1.

17. A compound having the structure of Formula II):


Formula (II);

wherein:

Y is -CH2- or -C(O)-;

Z is C3-6Cycloalkyl;

R3 is a 5- to 6-membered heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring; wherein the 5- to 6-membered heteroaryl ring and the 9- to 10-membered bicyclic heteroaryl ring are optionally substituted with one, two, or three R4;

each R4 is independently selected from
halogen, -CN, Ci-6haloalkyl, C3- 8cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-(C2-9heterocycloalkyl), phenyl, -CH2- phenyl, Ci.gheteroaryl, -OR7, -C02R6, and -CH2C02R6; wherein C2-9heterocycloalkyl, - Ci-6alkyl(C2-9heterocycloalkyl), phenyl, and Ci.gheteroaryl are optionally substituted with one or two R5; or two adjacent R4 form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl ring are optionally substituted with one or two R5;

each R5 is independently selected from halogen,
Ci-ehaloalkyl, Ci-6heteroalkyl, Ci.

6alkoxy, C3-8cycloalkyl, -Ci-6alkyl(C3-8cycloalkyl), C2-9heterocycloalkyl, -C02R6, - CH2C02R6, and -Ci-6alkyl(C2-9heterocycloalkyl) optionally substituted with Ci-6alkyl; each R6 is independently selected from H

each R7 is independently selected from H,
ehaloalkyl, and C3-8cycloalkyl;

R11 is H, Ci-6alkyl, or -Ci-6alkyl-0-Ci-6alkyl;

R12 is Ci-6alkyl;

R13 is H or Ci-6alkyl; and

v is 0 or 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

18. The compound of claim 17, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R13 is H.

19. The compound of claim 17 or claim 18, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 0.

20. The compound of claim 17 or claim 18, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 1.

21. The compound of any one of claims 17-20, wherein Y is -C(O)-.

22. The compound of any one of claims 17-19, wherein Y is -CH2-.

23. The compound of any one of claims 17-22, wherein R11 is

24. The compound of any one of claims 17-23, wherein R12 is -CH3.

25. The compound of any one of claims 1-24, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5- to 6- membered heteroaryl ring optionally substituted with one, two, or three R4.

26. The compound of any one of claims 1-25, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with one, two, or three R4.

27. The compound of claim 26, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with two or three R4, wherein two adjacent R4 form a 6-membered heterocycloalkyl ring optionally substituted with one or two R5.

28. The compound of claim 27, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with two adjacent R4, wherein the two adjacent R4 form an unsubstituted 6- membered heterocycloalkyl ring.

29. The compound of claim 27, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with two adjacent R4, wherein the two adjacent R4 form a 6-membered heterocycloalkyl ring substituted with one R5.

30. The compound of claim 29, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R5 is selected from Ci-6alkyl, Ci. 6heteroalkyl, C3-8cycloalkyl, -Ci-6alkyl(C3-8cycloalkyl), C2-9heterocycloalkyl, and - CH2C02H.

31. The compound of any one of claims 1-24, or a solvate, hydrate, tautomer, N-oxide,


32. The compound of any one of claims 1-25, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with one, two, or three R4, wherein each R4 is independently selected from halogen, -CN, Ci-ehaloalkyl, C3-8cycloalkyl, C2-

gheterocycloalkyl, phenyl, -OR7, -C02H, and -CH2C02H, and wherein C2- 9heterocycloalkyl and phenyl are optionally substituted with one or two R5.

33. The compound of claim 32, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring substituted with one or two R4, wherein each R4 is independently selected from halogen, Ci-6alkyl, C2-9heterocycloalkyl, and phenyl, and wherein C2-9heterocycloalkyl and phenyl are optionally substituted with one or two R5, and each R5 is independently selected from halogen,
C2-9heterocycloalkyl, or -C02H.

34. The compound of any one of claims 1-25, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted

5- membered heteroaryl ring.

35. The compound of any one of claims 32-34, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 5-membered heteroaryl ring selected from a pyrazole, thiazole, isoxazole, oxazole, and imidazole ring.

36. The compound of any one of claims 1-25, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 6-membered heteroaryl ring substituted with one, two, or three R4, wherein each R4 is independently selected from halogen, - Ci-6alkyl, Ci-6haloalkyl, and C2-9heterocycloalkyl, wherein C2- gheterocycloalkyl is optionally substituted with one or two R5.

37. The compound of claim 36, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 6-membered heteroaryl ring substituted with one or two R4, wherein each R4 is independently selected from halogen, Ci-6alkyl, Ci-ehaloalkyl, and C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl is optionally substituted with one R5, and R5 is -C02H.

38. The compound of any one of claims 1-25, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted

6- membered heteroaryl ring.

39. The compound of any one of claims 36-38, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 6-membered heteroaryl ring selected from a pyridine, pyrimidine, pyridazine, and pyrazine ring.

40. The compound of any one of claims 1-24, or a solvate, hydrate, tautomer, N-oxide,

stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 9- to 10- membered bicyclic heteroaryl ring optionally substituted with one, two, or three R4.

41. The compound of claim 40, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R4.

42. The compound of claim 41, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R4, wherein each R4 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-8cycloalkyl, -OR7, and -C02R6.

43. The compound of claim 42, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 9-membered bicyclic heteroaryl ring substituted with one or two R4, wherein each R4 is independently selected from halogen,
and Ci-6haloalkyl.

44. The compound of claim 40, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted 9-membered bicyclic heteroaryl ring.

45. The compound of any one of claims 40-44, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is a 9-membered bicyclic heteroaryl ring selected from a benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolpyridine, imidazopyridine, and pyrrolopyridine ring.

46. The compound of claim 40, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is selected from:


-257 -

47. A compound having the structure of Formula (IV):


Formula (IV);

wherein:

X is a bond, -C(O)-, or -S(0)2-;

R1 is selected from
Ci-ehaloalkyl, C3-8cycloalkyl, C2-9heterocycloalkyl, phenyl, and

Ci-gheteroaryl; wherein C3-8cycloalkyl, C2-9heterocycloalkyl, phenyl, and Ci.gheteroaryl are optionally substituted with one, two, or three R2;

each R2 is independently selected from halogen, Ci-6alkyl, and Ci-6haloalkyl; and

R3 is H, Ci-6alkyl, -Ci-6alkyl-OH, or -Ci-6alkyl-0-Ci-6alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

48. The compound of claim 47, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is a bond.

49. The compound of claim 47, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.

50. The compound of claim 47, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-.

51. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is Ci-6alkyl.

52. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is Ci-6haloalkyl.

53. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is C3-8cycloalkyl optionally substituted with one, two, or three R2.

54. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is C2- gheterocycloalkyl optionally substituted with one, two, or three R2.

55. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is phenyl optionally substituted with one, two, or three R2.

56. The compound of any one of claims 47-50, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1 is Ci.gheteroaryl optionally substituted with one, two, or three R2.

57. The compound of any one of claims 47-56, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is H.

58. The compound of any one of claims 47-56, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is Ci-6alkyl.

59. A compound selected from:

-260-


19/046318


-267-
; or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof.

60. A compound selected from:


WO 2019/046318


pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a compound of any one of claims 1-60, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

62. A method of treating pain in a patient, comprising administering a therapeutically

effective amount of a compound of any one of claims 1-60, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat said pain.

63. The method of claim 62, wherein the pain is neuropathic pain.

64. The method of claim 62, wherein the pain is inflammatory pain.

65. A method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt or solvate thereof, wherein the disease or disorder is selected from migraine, epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourette syndrome, persistent motor tic disorder, persistent vocal tic disorder, and abdominal pain associated with irritable bowel syndrome.

66. The method of claim 65, wherein the disease or disorder is migraine.

67. The method of claim 65, wherein the disease or disorder is epilepsy/seizure disorder.

68. The method of claim 65, wherein the disease or disorder is neuromyelitis optica (NMO).

69. The method of claim 65, wherein the disease or disorder is Tourette syndrome.

70. The method of claim 65, wherein the disease or disorder is persistent motor tic disorder.

71. The method of claim 65, wherein the disease or disorder is persistent vocal tic disorder.

72. The method of claim 65, wherein the disease or disorder is abdominal pain associated with irritable bowel syndrome.