Pyran-spirocyclic piperidine amides as modulators of ion channels

Patent metadata

Field	Value
Publication number	US-9403839-B2
Application number	US-201314372353-A
Country	US
Kind code	B2
Filing date	Jan 15, 2013
Priority date	Jan 16, 2012
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The invention relates to pyran 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.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
R 1 is an optionally substituted phenyl, pyridyl, thiazole, or pyrazole,

R 2 is C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, CF 3 , CHF 2 , or a straight chain, branched, or cyclic (C1-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, C3-C8 cycloalkyl, CF 3 , or a straight chain, branched, or cyclic (C1-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, halo, 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;
ring A is

wherein:
R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl halo, CN, OR 8 SO 2 R 8 SO 7 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 (C1-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, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 SO 7 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 (C1-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, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO,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 (C1-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; or

wherein:
R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 ,SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-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, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-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, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 SO 2 N(R 8 ) 2 CHF 2 CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-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;
n is 1 or 2; and
o is 0 or 1.

2. The compound of claim 1 , wherein R 2 is CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 F, OCH 2 CH 2 OCH 3 , or OCH(CH 3 ) 2 .

3. The compound of claim 1 , wherein A is

wherein:
R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , 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 (C1-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, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , 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 (C1-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, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , 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 (C1-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.

4. The compound of claim 3 , wherein R 4 is H, CH 3 , OCH 3 , OCH 2 CH 3 , F, Cl, OCHF 2 , CHF 2 , CF 3 , CH 2 OCH 3 , OCH(CH 3 ) 2 , CH 2 OCH 3 , or

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

6. The compound of claim 3 , wherein R 6 is H, F, Cl, CH 3 , CF 3 , CH 2 CH 3 , OCH 3 , OCH 2 CF 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 CH(CH 3 ) 2 , OCH(CH 3 )CH 2 CH 3 , CH(OH)CH(CH 3 ) 2 , C(OH)(CH 3 )CH 2 CH 3 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 OH, CH 2 C(CH 3 ) 2 OH OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, SO 2 CH 3 , SO 2 CF 3 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH 3 , CH 2 OCH 2 CF 3 , CH 2 OCH 2 CH 2 CF 3 , OCHF 2 , OCH 2 CF(CH 3 ) 2 ,

7. The compound of claim 3 , wherein

is selected from:

8. The compound of claim 1 , wherein A is

wherein:
R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wh

Assignees

• Vertex Pharma

Inventors

• Hadida-Ruah Sara Sabina
• Arumugam Vijayalaksmi
• Deninno Michael Paul
• Frieman Bryan A
• Kallel Edward Adam
• Miller Mark Thomas
• Uy Johnny
• Zhou Jinglan

Classifications

• A61P43/00

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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title