Bicyclic sulfonamide compounds as sodium channel inhibitors

Patent metadata

Field	Value
Publication number	US-9776995-B2
Application number	US-201414898070-A
Country	US
Kind code	B2
Filing date	Jun 11, 2014
Priority date	Jun 12, 2013
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

The present invention provides compounds of Formula I or 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 treatable by inhibition of sodium channels such as pain disorders. 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:

is

wherein each R a is independently H, halo, —NR c R c , —OH, hydroxyC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl or —CN, and
R a1 is H, —C 1-6 alkyl or acetyl;
R 1 is a 6 membered aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with from 1 to 4 substituents independently selected from halo, OH, —NR b R b , —C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkylCF 3 ,—OC 1-6 alkylCN, —(CR e R e ) m CN,—C 1-6 alkylOC 1-6 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —(CR e R e ) m A, —N(R e )(CR e R e ) m A, —O(CR e R e ) m A, —O(CR e R e ) m OA or —C(═O)A, provided at least one substituent on R 1 is —(CR e R e ) m A, —N(R e )(CR e R e ) m A, —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 3 to 5 membered cycloalkyl group that can be unsubstituted or substituted with from 1 to 4 substituents independently selected from Cl, F, Br, —NHCH 3 , —N(CH 3 ) 2 , —C 1-4 alkyl, —OC 1-4 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F or —CN;
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 and 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, —(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;
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 or —OC 1-6 alkyl;
each n is independently 0, 1, 2, 3 or 4; and
each m is independently 0, 1, 2, 3 or 4;
provided that the compound is not
1-(4-fluoro-2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide;
1-(4-fluoro-2-(pyrimidin-2-yloxy)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide;
5-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide;
N-3-isoxazolyl-1-(3-methoxy-1-phenyl-1H-pyrazol-4-yl)-6-isoquinolinesulfonamide;
1-(2-methoxy-6-(tetrahydro-2H-pyran-4-yloxy)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(2-(cyclohexylamino)-6-methoxy-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(2-((4,4-difluorocyclohexyl)amino)-6-methoxy-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(2-methoxy-6-(tetrahydro-2H-pyran-4-ylamino)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(2-(4,4-difluoro-1-piperidinyl)-6-methoxy-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(6-methoxy-2-(1-pyrrolidinyl)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(2-methoxy-6-(4-morpholinyl)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(6-methoxy-2-(4-morpholinyl)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(6-methoxy-2-(1-piperidinyl)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(6-methoxy-2-(tetrahydro-2H-pyran-4-ylamino)-3-pyridinyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide;
1-(3′,5′-difluoro-3-methoxy-4-biphenylyl)-N-(5-methoxy-4-pyrimidinyl)-6-isoquinolinesulfonamide; or
1-(2-methyl-5-(3-oxetanylmethoxy)phenyl)-N-4-pyrimidinyl-6-isoquinolinesulfonamide.

2. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

3. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

4. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

5. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

6. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

7. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

8. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

9. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

10. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

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

12. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is a ring sele

Assignees

• Amgen Inc

Inventors

• Weiss Matthew
• Dimauro Erin F
• Dineen Thomas
• Graceffa Russell
• Guzman-Perez Angel
• Huang Hongbing
• Kreiman Charles
• Marx Isaac E
• Nguyen Hanh Nho
• Peterson Emily Anne
• Deak Holly L

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

• A61P25/04

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

• A61P29/00

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

• C07D471/04

  Ortho-condensed systems · CPC title