Oxadiazole transient receptor potential channel inhibitors

Patent metadata

Field	Value
Publication number	US-10710994-B2
Application number	US-201916355352-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 19, 2018
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The invention relates to compounds of formula I:

and pharmaceutically acceptable salts thereof wherein A, X, R 1 , R 4 and n are as defined herein. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

First claim

What is claimed is:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof,
wherein:
A is selected from:

X is; a bond; C 1-4 alkylene; —O—; —S—; —SO 2 —; or —N(R a )—;
n is: 0, 1, 2 or 3;
R a is H or C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;
R 1 is: H; or C 1-6 alkyl; and
each R 2 is independently: H; D; —C 1-4 alkyl; —C 1-4 haloalkyl; C 1-4 alkoxy; —CN, halo; halo-C 1-4 alkoxy; —OH; —SO 2 —C 1-4 alkyl; —C 1-4 CN, C 1-4 aldehyde; C 1-4 ketone; benzylamino; or NR 14 R 15 —;
each R 3 is independently: H; D: —C 1-4 alkyl; —C 1-4 haloalkyl; —CN; NR 14 R 15 ; or halo;
R 4 is: substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl;
or R 1 and R 4 may together form an unsubstituted or substituted C 3-6 cylcoalkyl fused to a substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl,
p is 0, 1 or 2;
q is 0 or 1;
R 14 and R 15 are each independently: H; substituted or unsubstituted —C 1-4 alkyl; substituted or unsubstituted —C(O)—C 1-4 alkyl; substituted or unsubstituted C 3-6 cycloalkyl; substituted or unsubstituted 3- to 6-membered heterocycloalkyl; substituted or unsubstituted —C 1-4 heteroalkyl; —C(O)NR 16 R 17 ; substituted or unsubstituted alkyl-C(O)NR 16 R 17 ; substituted or unsubstituted phenyl; or substituted or unsubstituted benzyl;
or R 14 and R 15 together with the atoms to which they are attached may form a 4-, 5-, 6- or 7-membered ring that optionally includes one additional heteroatom selected from O, N and S; and
R 16 and R 17 each are independently H and C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently; H; —CH 3 ; CN; -halo; —NH 2 ; —NHCH 3 ; NHCH 2 CH 3 ; —NHCH 2 CH 2 CH 2 OH; —NHCH 2 CH 2 OCH 3 ; —NHC(O)CH 3 ; —NHCH 2 C(O)N(CH 3 ) 2 ;

and p is 0 or 1.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is methylene.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein:
each R 18 is independently selected from H, halogen, —OH, —C 1-4 alkyl, —C 1-4 haloalkyl, —CN, halo, C 1-4 haloalkoxy, C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C 1-4 CN, C 1-4 aldehyde, —SF 5 , C 1-4 ketone, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, fused aryl, and fused heteroaryl; and
k is from 0 to 3.

11. The compound claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 18 is independently: H; Cl; —OCHF 2 ; —OCF, —OCH 3 ; or —CN.

12. The compound claim 10 , or a pharmaceutically acceptable salt thereof, wherein each R 18 is independently fluoro or chloro.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein:
each R 10 is independently: H; halogen; —CN; —OH; C 1-4 alkyl; substituted or unsubstituted C 3-6 cycloalkyl; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 1-4 alkoxy; —SO 2 —C 1-4 alkyl; C 1-4 CN; C 1-4 aldehyde; C 1-4 ketone; —S—C 1-4 haloalkyl; substituted or unsubstituted 5- to 6-membered heteroaryl; substituted or unsubstituted 4- to 6-membered hetercycloalkyl; or substituted or unsubstituted C 5-6 aryl; and
each u is independently 0, 1, 2 or 3.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II)

16. A compound of formula (IVa) or formula (IVb), or a pharmaceutically acceptable salt thereof,

wherein:
E is a five membered or a six membered heteroaryl ring wherein one ring carbon atom is optionally substituted with oxo;
G is a six membered heteroaryl ring having one ring carbon atom

Assignees

• Genentech Inc

Inventors

• Terrett Jack Alexander
• Chen Huifen
• Constantineau-Forget Lea
• Larouche-Gauthier Robin
• Lépissier Luce
• Beaumier Francis
• Déry Martin
• Grand-Maître Chantal
• Sturino Claudio
• Volgraf Matthew
• Villemure Elisia

Classifications

• C07D473/08

  with methyl radicals in positions 1 and 3, e.g. theophylline · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title