Substituted spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]s as modulators of ion channels

Patent metadata

Field	Value
Publication number	US-9511067-B2
Application number	US-201414578628-A
Country	US
Kind code	B2
Filing date	Dec 22, 2014
Priority date	Feb 2, 2011
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The invention relates to pyrrolopyrazine-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 method of treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, osteoarthritis pain, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or pain associated with cancer in a subject, comprising administering to said subject an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
R 1 is H, C1-C8 alkyl, C3-C8 cycloalkyl, halo, CN, NR 8 SO 2 R 8 , SO 2 R 8 , SR 8 , SOR 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , 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 or NR 8 , or two R 1 taken together form an oxo group;
R 2 is H, C1-C8 alkyl, halo, C1-C8 haloalkyl, CN, OH, SO 2 R 8 , SR 8 , SOR 8 , COR 8 , CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(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 , CF 2 , or NR 8 ;
R 3 is H, C1-C8 alkyl, C3-C8 cycloalkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , CF 3 , CH 2 CF 3 , CH 2 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 or NR 8 ;
R 4 is H, C1-C8 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH 2 units may be replaced by O, CO, S, SO, SO 2 , or NR 8 , or 2 R 4 taken together form a fused 3 to 7 membered cycloalkyl ring;
R 8 is H, C1-C8 alkyl, CF 3 , C3-C8 cycloalkyl, fluoroalkyl, aryl, 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 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 , CO 2 R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R) 2 , NRCOR, CON(R) 2 , CN, halo, or SO 2 R;
R is H, C1-C8 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl;
A is an aryl optionally substituted with one or more of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , OSO 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 ) p wherein p is 1 or 2 and wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 ;
or wherein two adjacent substituents on A together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, or 3; and
o is 0, 1, 2, 3, or 4.

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

wherein:
R 2 is H, C1-C8 alkyl, halo, C1-C8 haloalkyl, CN, OH, SO 2 R 8 , SR 8 , SOR 8 , COR 8 , CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(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 , CF 2 , or NR 8 ;
R 3 is H, C1-C8 alkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , CF 3 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with CF 2 , O, CO, S, SO, SO 2 or NR 8 ;
R 6 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 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 , or NR 8 ; and
R 7 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 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 , or NR 8 .

3. The method of claim 2 , wherein R 2 is H, COCF 3 , COC(CH 3 ) 3 , Cl, COCH 3 , CF 2 CF 3 , CH 2 CF 3 , CF 3 , CN, Br, COCH(CH 3 ) 2 , COCH 2 CH 3 , CH(OH)CF 3 , SO 2 CH 3 ,

COPh, or

4. The method of claim 2 , wherein R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CO 2 CH 2 CH 3 , CH 2 CON(CH 3 ) 2 , CH 2 CONH 2 , CH 2 CN, benzyl, cyclobutyl, CH 2 CH(CH 3 ) 2 , CH(CH 3 ) 2 , CH 2 CF 3 , CH 2 CHF 2 , COCH 3 , COCH 2 CH 3 , CO 2 CH 3 , CO 2 CH 2 CH 3 , COH, CONH(CH 3 ) 2 , or CONHCH 3 .

5. The method of claim 2 , wherein R 6 is is H, CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CF 3 , CN, Ph, SO 2 CH 3 , OH, CH(CH 3 ) 2 , OCH 2 CH 2 CH 2 CH 3 , F, Cl, or CH 2 OH.

6. The method of claim 2 , wherein R 7 is H, CH 3 , CH 2 CH 3 , COC(CH 3 ) 3 , Cl, F, OH, C(═CH 2 )CH 3 , OC(═CH 2 )CH 3 , OCH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OH, OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, OC(CH 3 ) 3 , OCH(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, CH(OH)CH(CH 3 ) 2 , C(CH 3 ) 2 CH 2 OH, OCH 2 CH 2 CH(CH 3 ) 2 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 OCH 3 ,

SO 2 CH 3 , SO 2 C(CH 3 ) 3 , SO 2 CH 2 CH 3 , SO 2 CH 2 CH(CH 3 ) 2 , SO 2 CH(CH 3 ) 2 ,

SO 2 NH(CH 3 ),), SO 2 NH(CH(CH 3 ) 2 ), SO 2 NH(CH 2 CH 3 ), SO 2 NH(CH(CH 3 ) 2 ), SO 2 N(CH 3 ) 2 ,

OPh, Ph,

OCH 2 CH 2 OCH 3 , CH(CH 3 ) 2 , SO 2 N(CH 2 CH 2 CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OPh,

OCH 2 Ph, CH 2 CH 2 CH 2 CH 2 CH 3 , OCH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , CH 2 Ph,

CCCH 2 OCH 3 , SO 2 CHF 2 , OCF 3 ,

OCHF 2 ,

CH 2 CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 3 ,

OCH 2 CF 3 ,

CH 2 OCH 2 CH 2 CF 3 , CH 2 OCH 2 CF 3 , SO 2 CF 3 , C(CH 3 ) 2 CH 2 CH 3 , C(CH 2 CH 3 ) 3 , CH(OCH 2 CF 3 ) 2 ,

Assignees

• Vertex Pharma

Inventors

• Hadida Ruah Sara Sabina
• Kallel Edward Adam
• Miller Mark Thomas
• Arumugam Vijayalaksmi
• Mccartney Jason
• Anderson Corey
• Grootenhuis Peter Diederik Jan
• Jiang Licong

Classifications

• A61P7/06

  Antianaemics · 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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

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