Therapeutic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11149002-B2
Application number	US-201916702286-A
Country	US
Kind code	B2
Filing date	Dec 3, 2019
Priority date	Jul 7, 2014
Publication date	Oct 19, 2021
Grant date	Oct 19, 2021

Abstract

The invention provides compounds having the general Formula (I);and pharmaceutically acceptable salts thereof; wherein the variables RA, RAA, subscript n, subscript q, ring A, X2, L, subscript m, X1, R1, R2, R3, R4, R5, 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):

or a pharmaceutically acceptable salt thereof; wherein:
the group

in Formula I is selected from the group consisting of:

the group

is selected from the group consisting of:

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, C 3-8 cycloalkyl and C 2-7 heterocyclyl, wherein said C 3-8 cycloalkyl and C 2-7 heterocyclyl 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; and
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, or C 1-8 haloalkyl, wherein if the subscript m is 0 then one of X 1 or X 2 is absent.

2. The method of claim 1 , wherein R 3 is F or Cl; and R 5 is selected from the group consisting of F, Cl, C 1-4 alkyl, C 1-4 alkoxy, and C 3-8 cycloalkyl.

3. The method of claim 1 , wherein R 3 is F or Cl and R 5 is selected from the group consisting of F, Cl, cyclopropyl, cyclobutyl, and cyclopentyl.

4. The method of claim 1 , wherein X 1 is —O— or —N(H)—; X 2 is absent; the subscript m is 1; and -(L)- is an optionally substituted C 1-4 alkylene.

5. The method 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 3 )—CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.

6. The method of claim 1 , wherein X 1 is —O—; the subscript m is 1 and -(L)- is —CH 2 —, —C(H)(CH 3 )—, or —CH 2 —CH 2 —.

7. The method 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 —, or —CH 2 CH 2 CH 2 CH 2 —.

8. The method of claim 1 , wherein X 1 and X 2 are 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 3 )—CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.

9. The method of claim 1 , wherein X 1 and X 2 are absent: the subscript m is 1; and -(L)- is selected from the group consisting of —CH 2 —, —C(═O)—, —C(H)(CH 3 )—, and —CH 2 —CH 2 —.

10. The method of claim 1 , wherein m is 0; X 1 is selected from —O— and —N(H)—; and X 2 is absent.

11. A method of treating pain, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

12. A method of treating pain, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt is:

or a pharmaceutically acceptable salt thereof.

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 Salvatore
• Sun Shaoyi
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• C07D207/16 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D403/12

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

• C07D265/30

  not condensed with other rings · CPC title

• C07D305/08

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms · CPC title