Bicyclic sulfonamide compounds as sodium channel inhibitors

Patent metadata

Field	Value
Publication number	US-9458152-B2
Application number	US-201514920833-A
Country	US
Kind code	B2
Filing date	Oct 22, 2015
Priority date	Jun 12, 2013
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The present invention provides compounds of Formula I,

and pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav1.7. The compounds are useful for the treatment of diseases associated with the activity of sodium channels such as pain disorders and itch. Also provided are pharmaceutical compositions containing compounds of the present invention.

First claim

What is claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein:

wherein each R a is independently H, halo, —OH, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl or —CN, and
R 1 is a 5 to 10 membered aryl or heteroaryl, wherein the heteroaryl group can have from 1 to 3 heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkylCF 3 , —OC 1-6 alkylCN, —C 1-6 alkylOC 1-6 alkyl, —(SO 2 )C 1-6 alkyl, —(SO 2 )NR b R b , hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —(CR e R e ) m CN, —C(═O)NR b R b , —C(═O)OR b , —N(CR e R e ) m A, —N(R e )(CR e R e ) m A, —(C═N)OC 1-6 alkyl, —(C═O)N(R e )(CR e R e ) m A, (C═O)N(R e )(CR e R e ) m CF 3 , —O(CR e R e ) m A, —O(CR e R e ) m OA or —C(═O)A;
A is a 4 to 9 membered aryl, heteroaryl or heterocycloalkyl group, where the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N or S, or a 3 to 6 membered cycloalkyl group, and the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, —(CR e R e ) m OH, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —C(═O)NR b R b , —O(CR e R e ) m B or —(CR e R e ) m B;
B is a 5 to 6 membered aryl, heteroaryl or heterocycloalkyl group, where the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N or S, or a 3 to 5 membered cycloalkyl group, and the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN or —C(═O)NR b R b ;
R 2 is a 5 to 10 membered aryl or heteroaryl, where the heteroaryl group can have from 1 to 3 heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —(CR c R c ) n NR b R b , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN or —C(═O)NR b R b ;
each R b is independently H or —C 1-6 alkyl;
each R c is independently H or —C 1-6 alkyl; and
each R d is independently H, halo, —CN, —NR c R c , —OH, —C 1-6 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl or —OC 1-6 alkyl;
each R e is independently H, halo, —CN, —NR c R c , —OH, —C 1-6 alkyl, —OC 1-6 alkyl or a 5 to 6 membered heterocycloalkyl group having from 1 to 3 heteroatoms independently selected from O, N or S;
each n is independently 0, 1, 2, 3 or 4;
each m is independently 0, 1, 2, 3 or 4.

2. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R d is independently H, F or Cl.

3. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6 membered aryl or heteroaryl group, where the heteroaryl group can have from 1 to 3 heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, CN, —C(═O)NR b R b , —C(═O)OR b , —OA or A; and
A is a 5 to 6 membered aryl or heteroaryl group, wherein the heteroaryl group can have from 1 to 3 heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, or —C(═O)NR b R b .

4. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a phenyl ring or pyridyl ring, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, CN, —C(═O)NR b R b , —C(═O)OR b , —OA or A.

5. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a ring selected from cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, or —C(═O)NR b R b .

6. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is a phenyl ring or pyridyl ring, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, CN, —C(═O)NR b R b —C(═O)OR b , —OA or A; and
A is a ring selected from cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, pyridyl, pyrimidinyl, pyrazolyl, pyridazolyl, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, or —C(═O)NR b R b .

7. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a ring selected from cyclopropyl or cyclohexyl, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, or —C(═O)NR b R b .

8. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a phenyl ring that can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, CN, —C(═O)NR b R b , —C(═O)OR b , —OA or A; and
A is a ring selected from cyclopropyl, cyclohexyl, piperidinyl, pyrrolidinyl, azetidinyl, pyridyl, pyrimidinyl, wherein the ring can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN or —C(═O)NR b R b .

9. The compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5 to 6 membered aryl or heteroaryl, where the heteroaryl can have from 1 to 3 heteroatoms independently selected from O, N or S, and the aryl or heteroaryl can be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, hydroxyC 1-6 alkyl, —(CR c R c ) n NR b R b , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —CN

Assignees

• Amgen Inc

Inventors

• Weiss Matthew
• Boezio Alessandro
• Boezio Christiane
• Butler John R
• Chu-Moyer Margaret Yuhua
• Dimauro Erin F
• Dineen Thomas
• Graceffa Russell
• Guzman-Perez Angel
• Huang Hongbing
• Kreiman Charles
• La Daniel
• Marx Isaac E
• Milgram Benjamin Charles
• Nguyen Hanh Nho
• Peterson Emily Anne
• Vaida Karina R
• Sparling Brian

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

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

• C07D241/44

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title