Dihydrobenzoxazine and tetrahydroquinoxaline sodium channel inhibitors

Patent metadata

Field	Value
Publication number	US-9346798-B2
Application number	US-201314377478-A
Country	US
Kind code	B2
Filing date	Feb 12, 2013
Priority date	Feb 13, 2012
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. 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:
R a is hydrogen, C 1-6 alkyl or a three to eight membered cycloalkyl group, where the cycloalkyl group may be unsubstituted or substituted with from 1 to 3 substitutents independently selected from halo, C 1-6 alkyl, —CN, —CF 3 , —OH, —OCF 3 or —OC 1-6 alkyl;
X is O;
Each of W, Y and Z are independently CR 5 ;
U is absent;
V is absent, —C(R d ) 2 —, (C═O) or —(C═O)N(R d )—;
R b is hydrogen, C 1-6 alkyl, —(C═O)NR d R d , —S(═O) 2 NR d or —(C═O)C 1-6 alkyl;
R 1 is a five to six membered heteroaryl group having from one to three heteroatoms independently selected from O, N or S, where the heteroaryl group may be unsubstituted or substituted with from 1 to 3 substituents independently selected from a B group, halo, C 1-6 alkyl, —CN, —CF 3 , —OH, —OCF 3 , —OC 1-6 alkyl or —(CH 2 ) n NR d R d ;
R 2 is a five to ten membered aryl group or a five to ten membered heteroaryl group having from one to three heteroatoms independently selected from O, N or S, where the aryl or heteroaryl group may be unsubstituted or substituted with from 1 to 3 substituents independently selected from an A group, halo, —N 3 , —CF 3 , —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , —O(CH 2 ) m OR c , —NR d five to ten membered aryl, —NR d five to ten membered heteroaryl, —CO 2 H, —SR d , —S(═O) 2 R d , —O-three to eight membered cycloalkyl or —NR d (CH 2 ) m OR c , and heteroaryl group having from one to three heteroatoms independently selected from O, N or S, and the aryl, heteroaryl or cycloalkyl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from halo, C 1-6 alkyl, —CN, —CF 3 , —OH, —OCF 3 , —OC 1-6 alkyl or —(CH 2 ) n NR d R d ;
A is a five to six membered aryl group, a five to six membered heteroaryl group, a three to six membered cycloalkyl group or a three to six membered heterocycloalkyl group, wherein the heteroaryl or heterocycloalkyl group has from one to three heteroatoms independently selected from O, N or S, and where the aryl, heteroaryl cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , —O(CH 2 ) m OR c , —(C═O)NR d R d , —S(═O) 2 NR d , NR d (C═O)NR d R d , —NR d S(═O) 2 NR d , —(C═N)OC 1-6 alkyl, —S(═O) 2 R d or —NR d (CH 2 ) m OR c ;
B is a five to six membered aryl group, a five to six membered heteroaryl group, a three to six membered cycloalkyl group or a three to six membered heterocycloalkyl group, wherein the heteroaryl or heterocycloalkyl group has from one to three heteroatoms independently selected from O, N or S, and where the aryl, heteroaryl cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , —O(CH 2 ) m OR c , —(C═O)NR d R d , —S(═O) 2 NR d , —NR d (C═O)NR d R d , —NR d S(═O) 2 NR d , —(C═N)OC 1-6 alkyl, —S(═O) 2 R d or —NR d (CH 2 ) m OR c ;
each R c is independently hydrogen, C 1-6 alkyl, a three to eight membered cycloalkyl group, a five to 10 membered aryl group, a five to ten membered heteroaryl group or a three to eight membered heteroacylcoalkyl group; where the heteroaryl or heterocycloalkyl group has from one to three heteroatoms independently selected from O, N or S, and where the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —OCF 3 , —OH, C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , —O(CH 2 ) m OR c , —(C═O)NR d R d , —S(═O) 2 NR d , —N(R d ) 2 —NR d (C═O)NR d R d , —NR d S(═O) 2 NR d , —(C═N)OC 1-6 alkyl, —S(═O) 2 R d or —NR d (CH 2 ) m OR c ;
each R d is independently hydrogen or C 1-6 alkyl, -aryl, —Oaryl, heteroaryl, —Oheteroaryl, cycloalkyl or heterocycloalkyl group, where the —Oaryl, heteroaryl, —Oheteroaryl, cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —CH 2 F, —CF 2 H, —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, or —CN;
each R 3 is independently hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 haloalkyl, —OC 1-6 haloalkyl, a five or six membered aryl or —Oaryl group, or a five or six membered heteroaryl or —Oheteroaryl group, a three to eight membered cycloalkyl group or a three to eight membered heterocycloalkyl group, where the heteroaryl, —Oheteroaryl or heterocycloalkyl group has from one to three heteroatoms independently selected from O, N or S, and where the aryl, —Oaryl, heteroaryl, —Oheteroaryl, cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —CH 2 F, —CF 2 H, —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , or R 3 together with the ring carbon to which it is attached can be a (C═O) group;
each R 4 is independently hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 haloalkyl, —OC 1-6 haloalkyl, a five or six membered aryl or —Oaryl group, or a five or six membered heteroaryl or —Oheteroaryl group, a three to eight membered cycloalkyl group or a three to eight membered heterocycloalkyl group, where the heteroaryl, —Oheteroaryl or heterocycloalkyl group has from one to three heteroatoms independently selected from O, N or S, and where the aryl, —Oaryl, heteroaryl, —Oheteroaryl, cycloalkyl or heterocycloalkyl group may be unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, —CF 3 , —OH, —CH 2 F, —CF 2 H, —OH, —OCF 3 , C 1-6 alkyl, —OC 1-6 alkyl, —CN, —(CH 2 ) n NR d R d , or R 3 together with the ring carbon to which it is attached can be a (C═O) group;
each R 5 is independently hydrogen, halo, —CN, —OC 1-6 alkyl, C 1-6 alkyl, —CF 3 , —OH, —CF 2 H, —OCF 3 ,—OCF 2 H, or —OCFH 2 ;
each n is independently 0 to 3;
each m is independently 1 to 3, and
each p is independently 0 to 3,
provided that the compound of Formula I is not N-(5-chloro-1,3-thiazol-2yl)-4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(3-cyano-1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(5-methyl-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)-1,3-thiazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-1,3-thiazol-5-yl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(5-methyl-3-isoxazolyl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1-methyl-1H-imidazol-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-difluorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-4-isoxazolyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-1,3,4-oxadiazol-2-yl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
4-(2-bromo-4-(trifluoromethyl)phenyl)-N-1,3-thiazol-5-yl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide; or
4-(2-(1,2,3,6-tetrahydro-4-pyridinyl)-4-(trifluoromethyl)phenyl)-N-1,3-thiazol-5-yl-

Assignees

• Amgen Inc

Inventors

• Boezio Christiane
• Boezio Alessandro
• Bregman Howard
• Chakka Nagasree
• Coats James R
• Copeland Katrina Woodin
• Dimauro Erin F
• Dineen Thomas
• Gao Hua
• La Daniel
• Marx Isaac E
• Nguyen Hanh Nho
• Peterson Emily Anne
• Weiss Matthew

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P29/00

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

• C07D417/12

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

• C07D417/14 Primary

  containing three or more hetero rings · CPC title