Therapeutic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10125098-B2
Application number	US-201815988956-A
Country	US
Kind code	B2
Filing date	May 24, 2018
Priority date	Jul 7, 2014
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

The invention provides compounds having the general Formula (I);

and pharmaceutically acceptable salts thereof; wherein the variables R A , R AA , subscript n, subscript q, ring A, X 2 , L, subscript m, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , D and E 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 method of treating pain, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof; wherein:
each R 1/4 is selected from the group consisting of F, Cl, Br, I, —CN, —OH, —NH 2 , —NO 2 , ═CH—R 1/4a , C 1-6 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylamino and C 1-8 dialkylamino, wherein said R 1/4a is H or C 1-8 alkyl;
R 2 is selected from the group consisting of hydrogen, —CN, —F, —Cl, —Br, —I, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 heteroalkyl;
R 3 is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN, C 1-8 alkyl and C 1-8 haloalkyl;
R 5 is selected from the group consisting of F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, and C 3-8 cycloalkyl wherein said C 3-8 cycloalkyl is optionally substituted with 1-3 substituents selected from F, Cl, Br, I, —OH, —NH 2 , —NH(C 1-4 alkyl)-, —N(C 1-4 dialkyl)-, and C 1-4 alkyl substituted with 1-3 substituents selected from F, Cl, Br, I, —OH, —NH 2 , —NH(C 1-4 alkyl)- and —N(C 1-4 dialkyl)-;
L is C 1-6 alkylene, wherein L is optionally substituted with from 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halo, oxo (═O), and C 1-4 haloalkyl, and wherein any two substituents attached to the same atom on L are optionally combined to form a 3- to 5-membered carbocyclic ring;
the subscript m represents the integer 0 or 1;
X 1 and X 2 are each independently selected from the group consisting of absent, —S—, —O— and —N(R X )— wherein R x is H, C 1-8 alkyl, C 1-8 haloalkyl, and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
the ring “A” is a C 3-12 membered carbocycle; wherein
R A is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, C 1-8 dialkylamino, C 1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , ═O, —(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 , —(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 ), —(X RA ) 0-1 N(R A1 )S(O) 1-2 (R A3 ), and —C(═O)R A1 , 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, 5- to 6 membered heteroaryl and C 2-7 heterocyclyl; R A3 is selected from the group consisting of C 1-8 alkyl, and C 1-8 haloalkyl, wherein R A substituent is optionally substituted with from 1 to 5 R RA substituents 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 alkylamino and C 1-4 dialkylamino; and
q is the integer 0 to 6.

2. The method of claim 1 wherein the compound has a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the group

is selected from the group consisting of:

4. The method of claim 1 , wherein the group

is selected from the group consisting of:

5. The method of claim 1 , wherein the group

is selected from the group consisting of:

6. The method of claim 1 , wherein the group

is selected from the group consisting of:

7. The method of claim 1 , wherein:
R o is hydrogen or C 1-6 alkyl;
each R 1/4 substituent is selected from the group consisting of F and —OH;
R 2 is hydrogen;
R 3 is selected from the group consisting of hydrogen and F;
R 5 is selected from the group consisting of F, Cl, C 1-8 alkyl, and C 3-8 cycloalkyl;
L is C 1-6 alkylene;
the subscript m represents the integer 0 or 1;
X 1 and X 2 are each independently selected from the group consisting of absent and —O—, and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
the ring “A” is a C 3-12 membered carbocycle; wherein
R A is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, F, and —CN; and
q is the integer 0 to 6.

8. The method of claim 1 wherein a compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof is administered.

9. The method of claim 1 wherein a compound selected from the group consisting of:

or a pharmaceutically acceptable salt

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Bergeron Philippe
• Bichler Paul Robert
• Chowdhury Sultan
• Dehnhardt Christoph Martin
• Focken Thilo
• Gong Wei
• Grimwood Michael Edward
• Hasan Abid
• Hemeon Ivan William
• Jia Qi
• Safina Brian
• Sun Shaoyi
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

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

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title