Therapeutic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10526285-B2
Application number	US-201816150070-A
Country	US
Kind code	B2
Filing date	Oct 2, 2018
Priority date	Jul 7, 2014
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

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 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. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. 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.

5. The compound of claim 1 , wherein R 3 is F or C 1 ; 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.

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

7. 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 an optionally substituted C 1-4 alkylene.

8. 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 3 )—CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.

9. The compound 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 —.

10. 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 —, or —CH 2 CH 2 CH 2 CH 2 —.

11. The compound 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 —.

12. The compound 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 —.

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

14. A pharmaceutical composition comprising a compound as described in claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising a compound as described in claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. The compound:

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound as described in claim 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

• A61P5/40

  Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids · CPC title

• A61P43/00

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

• A61P39/02

  Antidotes · 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

• A61P9/06

  Antiarrhythmics · CPC title