Substituted benzamides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10766858-B2
Application number	US-201716088417-A
Country	US
Kind code	B2
Filing date	Mar 28, 2017
Priority date	Mar 30, 2016
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The invention provides compounds having the general formula I: (i) and pharmaceutically acceptable salts thereof, wherein the variables R A , R AA , subscript n, ring A, X 2 , L, subscript m, X 1 , ring B, R 1 , and R N have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

We claim:

1. A compound of formula I:

or a salt thereof wherein:
R 1 is C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, 3-20 membered carbocycle, C-linked 3-20 membered heterocycle, or —NR 1A R 1B , herein R 1A and R 1B are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, and wherein R 1A and R 1B are optionally combined to form a 3-20 membered heterocycle; and wherein R 1 is optionally substituted with from 1 to 5 substituents selected from the group consisting of C 1-4 alkyl, C 3-4 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , —NR R1a R R1b , —OR R1a , —SR R1a , —Si(R R1a ) 3 and C 3-6 carbocycle; wherein R R1a and R R1b are independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl;
R N is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl;
L is a linker selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene, wherein L is optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, C 1-4 alkyl, halo, and C 1-4 haloalkyl;
the subscript m is 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 alkanoyl, or —S(O) 2 (C 1-8 alkyl), and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
the subscript n is 0, 1, 2, 3, 4, or 5;
the ring A is a 3-20 membered carbocyclyl, a 6-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocyclyl;
each R AA is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, CN, F, Cl, Br and I; and
R A is selected from the group consisting of absent, CN, F, Cl, Br, I, R A1 O—(X RB )—, (3-20 membered aryl)-(X RA )—, (3-20 membered heteroaryl)-(X RA )—, (3-20 membered carbocycle)-(X RA )—, (3-20 membered heterocycle)-(X RA )—, —R A2 , and —S(O) 2 —R A2 , wherein said 3-20 membered aryl, 3-20 membered heteroaryl, 3-20 membered carbocycle and 3-20 membered heterocycle of R A is optionally substituted with from 1 to 5 substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkanoyl, C 1-4 akyl-OC(═O)—, C 1-4 alkyl-S(O) 2 —, C 3-6 carbocycle, and phenyl that is optionally substituted with one or more substituents selected from fluoro, chloro, and bromo; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is a C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo (═O), fluoro, amino, C 1-4 alkylamino and C 1-4 dialkylamino; X RA is selected from the group consisting of absent, —O—, —S—, —N(H)—, —N(C 1-4 alkyl)-, —S(O)—, —S(O) 2 —, —C(═O)—, C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; X RB is selected from the group consisting of absent, C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein any C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene of X RA or X RB is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl, oxo (═O), hydroxy, and phenyl that is optionally substituted with 1 to 5 substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; or wherein X RA or X RB is optionally substituted with 2 substituents that combine to form a 3-5 membered carbocycle or a 3-5 membered heterocycle;
the ring B is selected from:

D 1 is N or C(R D1 );
D 3 is N or C(R D3 );
R D1 , R D2 , R D3 and R D4 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
R 22 and R 23 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;
R 24 is selected from the group consisting of H, F, CL, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, 3-12 membered carbocycle, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R 5 substituents selected from F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
R 32 and R 33 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;
R 34 is selected from the group consisting of H, F, Cl, Br, 1, —CN, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, 3-12 membered carbocycle, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
R 42 is 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;
R 43 is 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;
R 44 is 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 45 is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, and 3-12 membered cycloalkyl, wherein said C 1-8 alkoxy, and 3-12 membered cycloalkyl are optionally substituted with 1-3 substituents selected from F, Cl, Br and I.

2. The compound of claim 1 wherein R 1 is methyl, cyclopropyl, cyclopropylmethyl, 1-azetidinyl, 1-methylcycloprop-1-yl, difluoromethyl, N-methylamino, ethyl, 2-methoxyeth-1-yl, 2-trimethylsilyleth-1-yl, propyl, 1,1,1-trifluoroprop-3-yl, butyl, morpholino, pyrrolidino, or 3-fluoroazetidin-1-yl.

3. The compound of claim 1 , wherein X 1 is —O— or —N(H)—; X 2 is absent; the subscript m is 1; and -(L)- is selected from the group consisting of —CH 2 —, —C(═O)—, —C(H)(CH 3 )—, —CH 2 —CH 2 —, —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—C(H 2 )—, —CH 2 CH 2 CH 2 —, —CH 2 —C(H)(CH 13 )—CH 2 — or —CH 2 CH 2 CH 2 CH 2 —.

4. The compound of claim 1 , wherein X 1 is absent; X 2 is —O— or —N(H)—; the subscript m is 1; and -(L)- is selected from the group consisting of —CH 2 —, —C(═O)—, —C(H)(CH 3 )—, —CH 2 —CH 2 —, —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—C(H 2 )—, —CH 2 CH 2 CH 2 —, —CH 2 —C(H)(CH 3 )—CH 2 —, and —CH 2 CH 2 CH 2 CH 2 —.

5. The compound of claim 1 , wherein the ring A is a 3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl.

6. The compound of claim 1 , wherein A is optionally substituted and is selected from azetidine, pyrrolidine, piperidine, morpholine, homopiperazine, and piperazine.

7. Th

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Chowdhury Sultan
• Dehnhardt Christoph Martin
• Focken Thilo
• Grimwood Michael Edward
• Hemeon Ivan William
• Mckerrall Steven
• Sutherlin Daniel

Classifications

• C07C381/10 Primary

  Compounds containing sulfur atoms doubly-bound to nitrogen atoms · CPC title

• C07D401/12

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

• C07D213/69

  Two or more oxygen atoms · CPC title

• C07D211/42

  attached in position 3 or 5 · CPC title

• C07D211/22

  by oxygen atoms · CPC title