Substituted benzamides useful as sodium channel blockers

Patent metadata

Field	Value
Publication number	US-10899732-B2
Application number	US-201615779065-A
Country	US
Kind code	B2
Filing date	Nov 22, 2016
Priority date	Nov 25, 2015
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The invention provides compounds having the general formula (I): and pharmaceutically acceptable salts thereof, wherein the variables R A , R AA , n, ring A, X 2 , L, m, 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

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-8 carbocycle, C-linked 3-15 membered heterocyclyl, 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, and C 1-8 alkoxy, and wherein R 1A and R 1B are optionally combined to form a 3 to 8 membered heterocyclyl ring optionally comprising 1 additional heteroatom selected from N, O and S; and wherein R 1 is optionally substituted with from 1 to 5 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 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;
R 2 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 3 is selected from the group consisting of F, Cl, Br, I, —CN, C 1-8 haloalkyl and C 1-8 alkoxy;
R 4 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 5 is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, and C 3-8 cycloalkyl, wherein said C 1-8 alkoxy and C 3-8 cycloalkyl is optionally substituted with 1-3 substituents selected from F, Cl, Br and I;
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;
m is 0;
X 2 is absent;
n is 0, 1,2,3,4, or 5;
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;
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;
R A is selected from the group consisting of H, —OR A1 , —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 6-12 membered aryl and 5-12 membered heteroaryl of R A is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 (halo)alkoxy; 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 C 1-8 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo (═O), fluoro, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from the group consisting of 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; and
wherein A is not a pyridine ring.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is H.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is F, Cl, Br, or I.

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is F.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 4 is H.

6. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is C 1-4 alkyl or C 1-4 haloalkyl.

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is methyl.

8. The compound of claim 1 that has the formula (Ic):

or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is methyl, cyclopropyl, or 1-azetidinyl.

10. The compound or pharmaceutically acceptable salt of claim 1 , wherein A is a ring selected from the group consisting of piperidine, pyrrolidine, azetidine, tetrahydronaphthalene, cyclohexane, tetrahydropyran, and adamantane.

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein:

and A is a 3-15 membered heterocyclyl.

12. The compound or pharmaceutically acceptable salt of claim 1 , wherein:

and A is a 3-15 membered heterocyclyl.

13. The compound or pharmaceutically acceptable salt of claim 1 , wherein each R AA is independently selected from the group consisting of F, Cl and C 1-4 haloalkyl.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein:

is selected from the group consisting of:

15. The compound or pharmaceutically acceptable salt of claim 1 , wherein R A is selected from the group consisting of:

16. The compound of claim 1 which is selected from:

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Chen Chien-An
• Chowdhury Sultan
• Decker Shannon Marie
• Dehnhardt Christoph Martin
• Hemeon Ivan William
• Mckerrall Steven
• Safina Brian Salvatore
• Sheng Tao
• Sutherlin Dan

Classifications

• A61P17/04

  Antipruritics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title