N-substituted benzamides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2017002017-A1
Application number	US-201615017282-A
Country	US
Kind code	A1
Filing date	Feb 5, 2016
Priority date	May 22, 2012
Publication date	Jan 5, 2017
Grant date	—

Abstract

The invention provides novel compounds having the general formula:

and pharmaceutically acceptable salts thereof, wherein the variables R A , subscript n, ring A, X 2 , L, subscript m, X 1 , B, R 1 , R 2 , R 3 , R 4 , R 5 and R N have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

1 . A compound selected from a compound of Formula I:

and pharmaceutically acceptable salts thereof, wherein in Formula I:
R 1 is C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-12 cycloalkyl, C-linked C 2-11 heterocycloalkyl, heteroaryl, or —NR 1A R 1B , wherein R 1A and R 1B are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, (6-10 membered aryl)-(X R1 ) 0-1 —, (5-10 membered heteroaryl)-(X R1 ) 0-1 —, and wherein R 1A and R 1B are optionally combined to form a 3 to 9 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S and optionally fused thereto is a benzene or pyridine ring; X R1 is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene, C 2-4 alkynylene; and wherein the aliphatic and aromatic portions of R 1 are optionally substituted with from 1 to 5 R R1 substituents selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , ═O, —(X 1R ) 0-1 NR R1a R R1b , —(X 1R ) 0-1 OR R1a , —(X 1R ) 0-1 SR R1a , —(X 1R ) 0-1 N(R R1a )C(═O)OR R1c , —(X 1R ) 0-1 OC(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)N(R R1a )(R R1b ), —(X 1 R) 0-1 C(═O)N(R R1a )(R Rb ), —(X 1R ) 0-1 N(R R1a )C(═)R R1b , —(X 1R ) 0-1 C(═O)OR R1a , —(X 1R ) 0-1 OC(═O)R R1a , —(X 1R ) 0-1 —P(═O)(OR R1a )(OR R1b ), —(X 1R ) 0-1 S(O) 1-2 R R1c , —(X 1R ) 0-1 S(O) 1-2 N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and —(X 1R ) 0-1 N(R R1a )S(O) 1-2 (R R1c ), wherein X 1R is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R R1a and R Rib are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C 2-7 heterocycloalkyl; R R1c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C 2-7 heterocycloalkyl;
R N is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl;
B is C or N;
R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 alkoxy, and R 3 is absent when B is nitrogen;
R 5 is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl, C 1-8 alkyl, C 3-8 cycloalkyl or C 2-7 heterocycloalkyl is further optionally substituted with from 1 to 3 R 5a substituents selected from F, Cl, Br, I, —OH, ═O, C 3-6 cycloalkyl, —CN, C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
L is a linker selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and C 1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 R L substituents selected from the group consisting of ═O, —OH, —OCH2.phenyl, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 acyl;
the subscript m represents the integer 0 or 1;
X 1 and X 2 are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O) 2 — and —N(R X )— wherein R X is H, C 1-8 alkyl, C 1-8 acyl or —S(O) 2 (C 1-8 alkyl), and wherein if the subscript m is 0 then at least one of X 1 or X 2 is absent;
the subscript n is an integer from 0 to 5;
A is selected from the group consisting of hydrogen, C 3-12 cycloalkyl, C 2-11 heterocycloalkyl, phenyl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto or a 5 to 6 membered heteroaryl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto, and wherein if A is hydrogen then the subscript n is 0; and
R A is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , ═O, heteroaryl, —(X RA ) 0-1 NR A1 R A2 , —(X RA ) 0-1 OR A1 , —(X RA ) 0-1 SR A1 , —(X RA ) 0-1 N(R A1 )C(═O)OR A3 , —(X RA ) 0-1 OC(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)R A2 , —(X RA ) 0-1 C(═O)OR A1 , —(X RA ) 0-1 OC(═O)R A1 , —P(═O)(OR A1 )(OR A2 ), —(X RA ) 0-1 S(O) 1-2 R A3 , —(X RA ) 0-1 S(O) 1-2 N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )S(O) 1-2 N(R A1 )(R A2 ) and —(X RA ) 0-1 N(R A1 )S(O) 1-2 (R A3 ), wherein X RA is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R A1 and R A2 are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C 2-7 heterocycloalkyl; R A3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C 2-7 heterocycloalkyl; wherein if A is a monocyclic C 3-12 carbocycloalkyl or monocyclic C 2-11 heterocycloalkyl, then any two R A substituents attached to adjacent atoms on the A ring are optionally combined to form a benzene or a 5 to 6 membered heteroaryl ring; and wherein the aliphatic and aromatic portions of a R A substitutent is optionally substituted with from 1 to 5 R R1 substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkyl-C(═O)—, C 1-4 (halo)alkyl-S(O) 0-2 —, C 1-4 (halo)alkyl-C(═O)N(H)—, C 1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4 alkylamino, C 1-4 dialkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-5 heterocycloalkoxy, tetrahydronaphthalene and phenyl wherein phenyl is optionally substituted with 1-3 fluoro, chloro, bromo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkylamino, or C 1-6 dialkylamino;
with the proviso that a compound of Formula I is not 4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide; 4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or 4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.

2 . The compound of claim 1 wherein the compound has the formula

3 . The compound of claim 1 wherein B is N and R 3 is absent.

4 . The compound of claim 1 wherein B is C.

5 . The compound of claim 1 wherein R 2 , R 3 and R 4 are each independently selected from H, F, or Cl.

6 . The compound of claim 1 wherein R 2 is H, F or Cl; R 3 and R 4 are each H; and R 5 is an optionally substituted group selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, and C 1-8 alkoxy.

7 . The compound of claim 1 wherein R 1 is C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl or —NR 1A R 1 .

8 . The compound of claim 7 , wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl.

9 . The compound of claim 1 wherein, R 1 is selected from the group consisting of: —NH(CH 3 ), —N(CH 3 ) 2 ,

10 . The compound of claim

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Chowdhury Sultan
• Decker Shannon Marie
• Dehnhardt Christoph Martin
• Focken Thilo
• Grimwood Michael Edward
• Hemeon Ivan William
• Jia Qi
• Li Jun
• Ortwine Daniel F
• Safina Brian
• Sheng Tao
• Sun Shaoyi
• Sutherlin Daniel P
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/06

  Antimigraine agents · CPC title