Fused Piperidine Amides as Modulators of Ion Channels

Patent metadata

Field	Value
Publication number	US-2016159815-A1
Application number	US-201414903475-A
Country	US
Kind code	A1
Filing date	Jul 8, 2014
Priority date	Jul 10, 2013
Publication date	Jun 9, 2016
Grant date	—

Abstract

The invention relates to fused piperidine amides useful as inhibitors of ion channels for the treatment of pain. 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.

First claim

We claim:

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence,
ring A is a fused cycloalkyl or heterocycloalkyl ring;
ring B is a substituted or unsubstituted aryl or heteroaryl ring;
ring C is a substituted or unsubstituted aryl or heteroaryl ring;
R 1 is C1-C6 alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo;
R 2 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , CO 2 R 7 , SO 2 N(R 7 ) 2 , or (C1-C8)-R 8 wherein up to two CH 2 units may be replaced with O, CO, CF 2 , or NR 7 ;
R 3 is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy;
n, o, and p are integers from 0 to 4 inclusive;
R 7 is H, C1-C6 alkyl, CHF 2 , CF 3 , or C3-C8 cycloalkyl; and
R 8 is H, CF 3 , CO 2 R 7 , OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R 7 ) 2 , NR 7 COR 7 , CON(R 7 ) 2 , CN, or SO 2 R 7 .

2 . The compound of claim 1 , wherein R 1 is C1-C6 alkyl, halo, or oxo.

3 . The compound of claim 1 or 2 , wherein R 1 is CH 3 , F, or oxo.

4 . The compound of any one of claims 1 to 3 , wherein R 2 is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN, or (C1-C8)-R 8 wherein up to two CH 2 units may be replaced with O, CO, CF 2 , or NR 7 .

5 . The compound of any one of claims 1 to 4 , wherein R 2 is CH 3 , OCH 3 , CF 3 , F, Cl, Br, CN, OCH 2 CH 2 OtBu, OCH 2 CH(CH 3 ) 2 .

6 . The compound of any one of claims 1 to 5 , wherein R 3 is C1-C6 alkyl.

7 . The compound of any one of claims 1 to 6 , wherein R 3 is CH 3 .

8 . The compound of any one of claims 1 to 7 , wherein ring A is a fused cycloalkyl ring.

9 . The compound of any one of claims 1 to 7 , wherein ring A is a fused heterocycloalkyl ring.

10 . The compound of claim 8 , wherein ring A is

11 . The compound of claim 9 , wherein ring A is

12 . The compound of any one of claims 1 to 11 , wherein ring B is an aryl ring.

13 . The compound of any one of claims 1 to 11 , wherein ring B is a heteroaryl ring.

14 . The compound of claim 12 , wherein ring B is a phenyl ring.

15 . The compound of claim 14 , wherein ring B is

16 . The compound of claim 13 , wherein ring B is a pyridyl, thiazole, pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole, pyridazine, or pyrazine ring.

17 . The compound of claim 16 , wherein ring B is

18 . The compound of any one of claims 1 to 17 , wherein ring C is a substituted or unsubstituted aryl ring.

19 . The compound of any one of claims 1 to 18 , wherein ring C is

wherein:
R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH;
R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , CO 2 R 7 , SO 2 N(R 7 ) 2 , fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy;
R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SR 7 , SOR 7 , SO 2 R 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 8 or fluoro-(C1-C8)-R 8 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 ; 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.

20 . The compound of claim 19 , wherein R 4 is H, C1-C6 alkoxy, or halo.

21 . The compound of claim 19 or 20 , wherein R 4 is H, OCH 3 , or F.

22 . The compound of any one of claims 19 to 21 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, or fluoro-C1-C6 alkyl.

23 . The compound of any one of claims 19 to 22 , wherein R 5 is H, CH 3 , OCH 3 , F, Cl, CN, OH, or CF 3 .

24 . The compound of any one of claims 19 to 23 , wherein R 6 is H, C1-C6 alkoxy, fluoro-C1-C6 alkoxy, SO 2 R 7 , SO 2 N(R 7 ) 2 , or a straight chain, branched, or cyclic (C1-C8)-R 8 or fluoro-(C1-C8)-R 8 wherein up to three CH 2 units may be replaced with 0, CO, S, SO, SO 2 , or NR 7 .

25 . The compound of any one of claims 19 to 24 , wherein R 6 is H, OCH 2 CH 2 CF 3 , OCH 2 CF(CH 3 ) 2 , C(CH 3 ) 2 CH 2 OH, OCH 2 CH 2 CH(CH 3 ) 2 , OCH(CH 3 )CF 3 , CH 2 OCH 2 CH 2 CF 3 , C(CH 3 ) 2 OH, OCH 2 CH 2 OtBu, CH 2 C(CH 3 ) 2 OH, OCH(CH 3 ) 2 , OCH 2 C(CH 3 ) 2 OH, OCH 2 CF 2 CHF 2 , OCH 2 CF 3 , OCH 2 CH 2 OCF 3 , OCH(CH 3 )CF 2 CHF 2 , SO 2 CHF 2 , OCH 2 CF 2 CH 3 , OCH 2 CH 2 OCH 2 CF 3 , OCH 2 CF 3 , OCH 2 C(CH 3 ) 3 , OCH 2 CH(CH 3 )CH 2 CF 3 , SO 2 CH 2 CH 3 , OCH(CH 3 )CH 2 CF 3 , OCH 2 CF 2 CHF 2 ,

26 . The compound of claim 19 , wherein R 4 and R 5 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

27 . The compound of claim 26 , wherein ring C is

28 . The compound of claim 19 , wherein R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

29 . The compound of claim 28 , wherein ring C is

30 . The compound of claim 19 , wherein

is selected from:

31 . The compound of any one of claims 1 to 17 , wherein ring C is a substituted or unsubstituted heteroaryl ring.

32 . The compound of claim 31 , wherein ring C is a pyridyl or quinoline ring.

33 . The compound of claim 31 , wherein ring C is selected from:

Assignees

• Vertex Pharma

Inventors

• Deninno Michael Paul
• Anderson Corey
• Conroy Erica Lynn
• Frieman Bryan A
• Grootenhuis Peter Drederik Jan
• Hadida-Ruah Sara Sabina
• Hurley Dennis James
• Pierre Fabrice Jean Denis
• Silina Alina
• Uy Johnny
• Zhou Jinglan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title