IP Library › Granted Patent US 8,828,996

Granted Patent B2

US 8,828,996 · App. 13/418,737 · Granted Sep 9, 2014

Morpholine-spirocyclic piperidine amides as modulators of ion channels

Inventors: Sara Sabina Hadida-Ruah (La Jolla, CA); Hayley Marie Binch (Encinitas, CA); Michael Paul DeNinno (San Diego, CA); Lev Tyler Dewey Fanning (San Marcos, CA); Bryan A. Frieman (La Jolla, CA); Peter Diederik Jan Grootenhuis (San Diego, CA); Nicole Hilgraf (San Diego, CA); Pramod Joshi (San Diego, CA); Edward Adam Kallel (Escondido, CA); Mark Thomas Miller (San Diego, CA); Joseph Pontillo (San Diego, CA); Alina Silina (San Diego, CA); Urvi Jagdishbhai Sheth (San Diego, CA); Dennis James Hurley (San Marcos, CA); Vijayalaksmi Arumugam (San Marcos, CA)

Assignee: Vertex Pharmaceuticals Incorporated

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Quick Facts

Patent No.: US 8,828,996
App. No.: 13/418,737
Granted: Sep 9, 2014
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims (439)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R 1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, halo, NR 8 SO 2 R 8 , SO 2 R 8 , SR 8 , SOR 8 , NR 8 COR 8 , NR8CO 2 R 8 , CN, CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , optionally substituted heterocycloalkyl, phenyl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 2 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, COR 8 , CO 2 R 8 , CON(R 8 ) 2 , CF 3 , CHF 2 , or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 3 is C1-C6 alkyl or halo;

R 8 is H, C1-C6 alkyl, or C3-C8 cycloalkyl, a straight chain, branched, or cyclic (C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR, or 2 R 8 taken together with the atoms to which they are attached form a ring;

R 9 is H, CF 3 , CHF 2 , CH 2 F, CO 2 R, OH, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R) 2 , NRCOR, CON(R) 2 , CN, or SO 2 R;

R is H, C1-C6 alkyl, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl;

A is an aryl, heteroaryl or heterocyclic in which each is optionally substituted with C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy , C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

n is an integer from 0 to 4 inclusive; and

o is an integer from 0 to 4 inclusive.

2. The compound of claim 1 , wherein R 1 is optionally substituted aryl, heteroaryl, C1-C6 alkyl, C1-C6 fluoroalkyl, a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, or NR 8 .

3. The compound of claim 1 , wherein R 1 is F, or optionally substituted phenyl, pyridyl, oxazole, thiazole, pyrazole, oxadiazole, CH 2 OCH 3 , CH 2 F, CH 2 OCH(CH 3 ) 2 , CH 2 OCHF 2 , CH 3 , CH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, CH 2 CH 2 OH, CH 2 OCH 2 CH 3 , CH(CH 2 ) 2 ,

4. The compound of claim 1 , wherein R 2 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, CF 3 , cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, or NR 8 .

5. The compound of claim 1 , wherein R 2 is H, CH 2 CHF 2 , CH 2 CF 3 , CH(CH 3 )CH 2 F, CH 2 CH(CH 3 ) 2 , CH 3 , CH 2 CH 3 , tBu, CH 2 CN, CH(CH 3 ) 2 , CH 2 C(CH 3 ) 2 OH, CH 2 CH 2 CH(CH 3 ) 2 , CH 2 CH 2 OH, C(O)CH 2 CH 3 , C(O)CH(CH 3 ) 2 , CH(CH 3 )CH 2 F, CH 2 CH(CH 3 ) 2 , CH(CH 2 CH 3 ) 2 , CH 2 C(CH 3 ) 2 OH, CH 2 CH 2 CH(CH 3 ) 2 , CH 2 CH 2 OH, C(O)CH 3 , C(O)CH 2 CH 3 , C(O)CH(CH 3 ) 2 , CH 2 CF 2 CH 3 , CH 2 CCCH 3 , CH 2 C(O)tBu, CH 2 CH 2 OCH 3 , CH 2 OCH 3 , CH 2 C(O)CH 3 , CH 2 C(O)OCH 3 , CH 2 CH 2 OCH 2 CH 2 CH 3 , CH 2 CCCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 SCH 3 , CH 2 CH 2 CH 2 OCH 3 , CH 2 CH(CH 2 CH 3 ) 2 , n-butyl, n-propyl,

6. The compound of claim 1 , wherein n is 0, 1, 2, or 3.

7. The compound of claim 1 , wherein n is 1 or 2.

8. The compound of claim 1 , wherein n is 1.

9. The compound of claim 1 , wherein o is 0 or 1.

10. The compound of claim 1 , wherein o is 0.

11. The compound of claim 1 , wherein A is

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

12. The compound of claim 11 , wherein R 4 is H, C1-C6 alkyl, halo, or OCHF 2 .

13. The compound of claim 11 , wherein R 4 is H, F, CH 3 , or OCHF 2 .

14. The compound of claim 11 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF 3 , CN, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, or NR 8 .

15. The compound of claim 11 , wherein R 5 is H, CH 3 , OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , F, Cl, CF 3 , CN, or CH 2 OH.

16. The compound of claim 11 , wherein R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, SO 2 R 8 , SO 2 N(R 8 ) 2 , R 9 , or a straight chain, branched, or cyclic (C3-C8)—R 9 , wherein up to three CH 2 units may be replaced with O, S, SO, SO 2 , N, or NR 8 .

17. The compound of claim 11 , wherein R 6 is H, CH 2 OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OtBu, tBu, OCH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OCH 3 , CH(OH)CH(CH 3 ) 2 , C(OH)(CH 2 CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 OH, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, CCCH 2 OCH 3 , SO 2 CH 3 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH 3 , SO 2 C(CH 3 ) 3 , CON(CH 2 CH 3 ) 2 , C(CH 3 ) 2 CO 2 CH 3 ,

18. The compound of claim 11 , wherein

is:

19. The compound of claim 1 , wherein A is heteroaryl or heterocyclic.

20. The compound of claim 19 , wherein A is a monocyclic heteroaryl comprising 1 to 3 heteroatoms, wherein said heteroatoms are independently N, O, or S.

21. The compound of claim 19 , wherein A is a bicyclic heteroaryl comprising from 1 to 3 heteoratoms, wherein said heteroatoms are independently N, O, or S.

22. The compound of claim 19 , wherein A is

wherein:

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 ,NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

23. The compound of claim 22 , wherein R 4 is H or C1-C6 alkyl.

24. The compound of claim 22 , wherein R 4 is H.

25. The compound of claim 22 , wherein R 5 is H, C1-C6 alkyl, or C1-C6 alkoxy.

26. The compound of claim 22 , wherein R 5 is H, CH 3 , or OCH 3 .

27. The compound of claim 22 , wherein R 6 is H, CN, C1-C6 alkoxy, or CF 3 .

28. The compound of claim 22 , wherein R 6 is H, CN, OCH 3 , or CF 3 .

29. The compound of claim 22 , wherein A is:

30. The compound of claim 1 , wherein the compound has formula IA:

wherein:

R 2 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or a straight chain, branched, or cyclic (C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl , halo, CF 3 , OCF 3 , OCHF 2 , or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, CN, SO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , heterocycloalkyl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR8;

R 7 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , CF 3 , OCF 3 , or OCHF 2 ; and

p is an integer from 0 to 3 inclusive.

31. The compound of claim 30 , wherein R 2 is C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

32. The compound of claim 30 , wherein R 2 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , CH(CH 3 )CH 2 F, CH 2 CN, CH 2 CH 2 OH, CH 2 C(CH 3 ) 2 OH, COCH 2 CH 3 , or COCH(CH 3 ) 2 .

33. The compound of claim 30 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluroroalkyl, halo, or a straight chain, branched, or cyclic (C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

34. The compound of claim 30 , wherein R 5 is H, CH 3 , OCH 3 , OCH 2 CH 3 , CF 3 , Cl, F, or CH 2 OH.

35. The compound of claim 30 , wherein R 6 is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

36. The compound of claim 30 , wherein R 6 is H, CH 2 OH, OCH 2 CH 3 , OtBu, OCH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OCH 3 , CH(OH)CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 OH, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, CCCH 2 OCH 3 , SO 2 CH 3 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH 3 , SO 2 C(CH 3 ) 3 , CON(CH 2 CH 3 ) 2 , C(CH 3 ) 2 CO 2 CH 3 ,

37. The compound of claim 30 , wherein R 7 is halo.

38. The compound of claim 30 , wherein R 7 is F.

39. The compound of claim 30 , wherein the

moiety is:

40. The compound of claim 30 , wherein the compound has formula IB:

wherein:

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 flunronlkyl, halo, CF 3 , OCF 3 , OCHF 2 , or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 7 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , CF 3 , OCF 3 , or OCHF 2 ; and

p is an integer from 0 to 3 inclusive.

41. The compound of claim 40 , wherein R 2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR8.

42. The compound of claim 40 , wherein R 2 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , CH(CH 3 )CH 2 F, CH 2 CN, CH 2 CH 2 OH, CH 2 C(CH 3 ) 2 OH, COCH 2 CH 3 , or COCH(CH 3 ) 2 .

43. The compound of claim 40 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluroroalkyl, halo, or a straight chain, branched, or cyclic (C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

44. The compound of claim 40 , wherein R 5 is H, CH 3 , OCH 3 , OCH 2 CH 3 , CF 3 , Cl, F, or CH 2 OH.

45. The compound of claim 40 , wherein R 6 is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

46. The compound of claim 40 , wherein R 6 is H, CH 2 OH, OCH 2 CH 3 , OtBu, OCH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OCH 3 , CH(OH)CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 OH, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, CCCH 2 OCH 3 , SO 2 CH 3 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH 3 , SO 2 C(CH 3 ) 3 , CON(CH 2 CH 3 ) 2 , C(CH 3 ) 2 CO 2 CH 3 ,

47. The compound of claim 40 , wherein R 7 is halo.

48. The compound of claim 40 , wherein R 7 is F.

49. The compound of claim 40 , wherein the

moiety is:

50. The compound of claim 1 , wherein the compound has formula IC:

wherein,

the Het ring is a mono or bicyclic optionally substituted heterocyclic or heteroaryl ring;

R 2 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted aryl, heteroaryl, or heterocycloalkyl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF 3 , OCF 3 , OCHF 2 , or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 7 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , CF 3 , OCF 3 , or OCHF 2 ; and

p is an integer from 0 to 3 inclusive.

51. The compound of claim 50 , wherein the Het ring is an optionally substituted thiazole, pyridine, pyrazole, oxazole, or oxadiazole.

52. The compound of claim 50 , wherein p is 0 or 1.

53. The compound of claim 50 , wherein, R 7 is C1-C6 alkyl.

54. The compound of claim 50 , wherein, R 7 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or tBu.

55. The compound of claim 50 , wherein the Het ring is

56. The compound of claim 50 , wherein R 2 is C1-C6 alkyl or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

57. The compound of claim 50 , wherein R 2 is CH 2 CH 3 , tBu, CH 2 CHF 2 , CH 2 CF 3 , or

58. The compound of claim 50 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, or halo.

59. The compound of claim 50 , wherein R 5 is H, CH 3 , OCH 3 , F, or Cl.

60. The compound of claim 50 , wherein R 6 is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

61. The compound of claim 50 , wherein R 6 is OCH(CH 3 ) 2 , C(CH 3 ) 2 OH, OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH,

62. The compound of claim 1 , wherein the compound has formula ID:

wherein,

the Het ring is a mono or bicyclic optionally substituted heterocyclic or heteroaryl ring;

R 2 is H, C1-C6 alkyl, C1 -C6 fluoroalkyl, an optionally substituted aryl, heteroaryl, or heterocycloalkyl, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 7 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , CF 3 , OCF 3 , or OCHF 2 ; and

p is an integer from 0 to 3 inclusive.

63. The compound of claim 62 , wherein the Het ring is an optionally substituted thiazole, pyridine, pyrazole, oxazole, or oxadiazole.

64. The compound of claim 62 , wherein p is 0 or 1.

65. The compound of claim 62 , wherein R 7 is C1-C6 alkyl.

66. The compound of claim 62 , wherein R 7 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or tBu.

67. The compound of claim 62 , wherein the Het ring is

68. The compound of claim 62 , wherein R 2 is C1-C6 alkyl or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

69. The compound of claim 62 , wherein R 2 is CH 2 CH 3 , tBu, CH 2 CHF 2 , CH 2 CF 3 , or

70. The compound of claim 62 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, or halo.

71. The compound of claim 62 , wherein R 5 is H, CH 3 , OCH 3 , F, or Cl.

72. The compound of claim 62 , wherein R 6 is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 .

73. The compound of claim 62 , wherein R 6 is OCH(CH 3 ) 2 , C(CH 3 ) 2 OH, OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH,

74. The compound of claim 1 , wherein the compound is selected from the following table:

100

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75. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

76. A method of inhibiting a voltage-gated sodium ion channel in:

a patient; or

a biological sample;

comprising administering to the patient, or contacting the biological sample, with the compound or composition of claim 1 .

77. The method of claim 76 , wherein the voltage-gated sodium ion channel is NaV 1.7.

78. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abormal gastro-intestinal motility, comprising administering an effective amount of a compound of claim 1 .

79. The method of claim 78 , wherein said method is used for treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache pain; migraine; tension headache, including, cluster headaches; chronic and acute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritic, tinnitis, or angina-induced pain.

Assignments (3)

RELEASE OF SECURITY INTEREST Recorded Oct 14, 2016

From: MACQUARIE US TRADING LLC

To: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

Reel/Frame 040357/0001 →

SECURITY INTEREST Recorded Jul 10, 2014

From: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

To: MACQUARIE US TRADING LLC

Reel/Frame 033292/0311 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2013

From: HADIDA-RUAH, SARA SABINA; BINCH, HAYLEY MARIE; DENINNO, MICHAEL PAUL; FANNING, LEV TYLER DEWEY; FRIEMAN, BRYAN A.; GROOTENHUIS, PETER DIEDERIK JAN; HILGRAF, NICOLE; JOSHI, PRAMOD; KALLEL, EDWARD ADAM; MILLER, MARK THOMAS; PONTILLO, JOSEPH; SILINA, ALINA; SHETH, URVI JAGDISHBHAI; HURLEY, DENNIS JAMES; ARUMUGAM, VIJAYALAKSMI; VERTEX PHARMACEUTICALS(SAN DIEGO)

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 031417/0580 →

Continuity (3)

Provisional Application 61452538 · Mar 14, 2011

Provisional Application 61567809 · Dec 7, 2011

Related Publication 20120264749A1 · Oct 18, 2012