Bicyclic amide compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11607396-B2
Application number	US-202117141070-A
Country	US
Kind code	B2
Filing date	Jan 4, 2021
Priority date	Dec 2, 2016
Publication date	Mar 21, 2023
Grant date	Mar 21, 2023

Abstract

The invention provides novel compounds having the general formula I:wherein R1, R2, the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A method for the treatment of a disease or disorder in a human, the method comprising administering to the human in need thereof an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 :
(a) are each independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, C 1 -C 6 alkyl-N(R N ) 2 , phenyl, 5 to 6 membered heteroaryl, and 4 to 5 membered heterocyclyl;
(b) together with the adjacent amide N, form a 4 to 7 membered unsaturated heterocyclic ring optionally substituted by one or two R 3 , wherein the unsaturated heterocyclic ring contains zero or one additional heteroatom selected from the group consisting of NR N , O and S; or
(c) together with the adjacent amide N, form a bicyclic heteroaryl moiety optionally substituted by one or two R 3 , wherein the bicyclic heterocyclic moiety contains zero to three additional heteroatoms selected from the group consisting of N, O and S, wherein only one of the additional heteroatoms is 0 or S;

each R 3 is independently selected from the group consisting of F, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, and phenoxy; or, when R 1 and R 2 together with the adjacent amide N form a 6 membered ring, two R 3 may together form a 1 to 2 carbon bridge or a C 3 -C 5 spirocycloalkyl;
each R N is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkyl; or two R N may together with the adjacent N form a 4-6 membered ring;

is selected from the group consisting of:

R 4 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl, wherein the heteroaryl has one or two heteroatoms selected from O, S and N, and phenyl may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and cyano;
each R 5a and R 5b is independently selected from the group consisting of H, F, Cl, C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy; and
R 8 is selected from the group consisting of H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy;
wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease and ulcerative colitis.

2. The method of claim 1 , wherein R 1 and R 2 together with the adjacent amide N, form a 4 to 6 membered unsaturated heterocyclic ring optionally substituted by one or two R 3 , containing zero or one additional heteroatom selected from the group consisting of O and S.

3. The method of claim 1 , wherein the compound has Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; and n is 1, 2 or 3.

4. The method of claim 3 , wherein n is 1.

5. The method of claim 3 , wherein each R 3 is independently selected from the group consisting of methyl, ethyl, F and Cl.

6. The method of claim 5 , wherein each R 3 is methyl or F.

7. The method of claim 3 , wherein

is selected from the group consisting of:

8. The method of claim 3 , wherein

is selected from the group consisting of:

9. The method of claim 1 , wherein the compound has Formula (Ib) or (Ic):

or a pharmaceutically acceptable salt thereof, wherein, in each instance,
the C ring is phenyl or a 5 to 6 membered heteroaryl ring;
Z is C or N;
each R 3 is independently selected from the group consisting of F, Cl, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy;
n is 1 or 2; and
m is 0, 1 or 2.

10. The method of claim 9 , wherein the compound has Formula (lb) and

is selected from the group consisting of:

11. The method of claim 1 , wherein R 1 is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl and C 1 -C 3 haloalkyl; and R 2 is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, phenyl and 4 to 5 membered heterocyclyl.

12. The method of claim 11 , wherein R 1 is selected from the group consisting of methyl, cyclopropyl, —CH 2 CF 2 H and —CH 2 CF 3 ; and R 2 is selected from the group consisting of methyl, cyclopropyl, —CH 2 CH 2 OCH 3 , phenyl and oxetan-3-yl.

13. The method of claim 1 , wherein

is selected from the group consisting of:

14. The method of claim 1 , wherein

is selected from the group consisting of:

15. The method of claim 9 , wherein the compound has Formula (Ic) and

is selected from the group consisting of:

16. A method for the treatment of a disease or disorder in a human, the method comprising administering to the human in need thereof an effective amount of a compound selected from:

Assignees

• Genentech Inc

Inventors

• Patel Snahel
• Hamilton Gregory
• Zhao Guiling
• Chen Huifen

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/416

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

• C07D491/04

  Ortho-condensed systems · CPC title

• A61K31/16 Primary

  Amides, e.g. hydroxamic acids · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title