Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists

Patent metadata

Field	Value
Publication number	US-10071078-B2
Application number	US-201715628104-A
Country	US
Kind code	B2
Filing date	Jun 20, 2017
Priority date	Jun 21, 2016
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention provides compounds of Formula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

First claim

What is claimed is:

1. A compound according to Formula (III):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and C 1-4 alkyl;
R 3 is independently selected from H and C 1-4 alkyl;
R 4 is independently selected from C 1-6 alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-6 cycloalkyl substituted with 1-3 R 8 , and —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 ;
R 5 is independently selected from H, F, Cl, CN and C 1-4 alkyl; provided one of R 5 is H;
R 6 is

R 7 is independently selected from H, C 1-4 alkyl, and C 3-6 cycloalkyl; or R 7 and R 7 , together with the carbon atom to which they both attach, form a C 3-6 cycloalkyl ring;
R 8 is independently selected from H, C 1-6 alkyl substituted with 1-5 R 9 , C 3-6 cycloalkyl, F, Cl, Br, CN, ═O, and COOH;
R 9 is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, wherein when R 9 is Cl, NH 2 or OH, it is not substituted on C 1 of the alkyl to which it is attached;
R 10 is independently selected from H, D, C 1-4 alkyl, and F;
R 11 is independently selected from CN, C(═O)R 12 , and tetrazolyl;
R 12 is independently selected from OH, OC 1-4 alkyl, NH 2 , and NHSO 2 C 1-4 alkyl; and
r is independently selected from zero, 1, 2, 3, and 4.

2. The compound of claim 1 , having Formula (IV):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and C 1-4 alkyl;
R 3 is independently selected from H and C 1-4 alkyl;
R 4 is independently selected from C 1-6 alkyl,

R 5 is independently selected from H, F, Cl, and C 1-4 alkyl; provided one of R 5 is H;
R 7 is independently selected from H, C 1-4 alkyl, and C 3-6 cycloalkyl;
R 8 is independently selected from H, C 1-6 alkyl substituted with 1-5 R 9 , C 3-6 cycloalkyl, F, Cl, Br, CN, ═O, and COOH;
R 9 is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, wherein when R 9 is Cl, NH 2 or OH, it is not substituted on C 1 of the alkyl to which it is attached;
R 10 is independently selected from H, D, C 1-4 alkyl, and F;
R 11 is independently selected from CN, —C(═O)R 12 , and

and
R 12 is independently selected from OH and NHSO 2 C 1-4 alkyl.

3. The compound of claim 2 , or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 4 is independently selected from

 and
R 8 is independently selected from H, F, Cl, Br, CN, and C 1-4 alkyl.

4. The compound of claim 3 , having Formula (V):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and CH 3 ;
R 3 is independently selected from H and CH 3 ;
R 4 is independently selected from

R 5 is independently selected from H, F, and C 1-4 alkyl;
R 8 is independently selected from H, F, Cl, Br, CN, and C 1-4 alkyl;
R 10 is independently selected from H, D, and F; and
R 11 is independently selected from —C(═O)OH, and —C(═O)NHSO 2 Me.

5. The compound of claim 1 , wherein said compound is selected from the group of:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. A compound of the formula:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

7. A compound of the formula:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

8. A compound of the formula:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the stereoisomer is an enantiomer or a diastereomer.

10. A compound of the formula:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

11. A compound of the formula:

12. A compound of the formula:

13. A compound of the formula:

14. A compound of the formula:

15. The compound of any one of claims 6 , 7 , 8 , and 10 , wherein the stereoisomer is an enantiomer or a diastereomer.

16. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4 , 5 , 6 , 7 , 8 , and 10 to 14 , or a stereoisomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Assignees

• Bristol Myers Squibb Co
• Syngene International Ltd

Inventors

• Cheng Peter Tai Wah
• Kaltenbach Iii Robert F
• Li Jun
• Shi Jun
• Shi Yan
• Tao Shiwei
• Zhang Hao
• Dhanusu Suresh
• Selvakumar Kumaravel
• Reddigunta Ramesh Babu
• Walker Steven J
• Kennedy Lawrence J
• Corte James R
• Fang Tianan
• Jusuf Sutjano

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/27 Primary

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K31/4192 Primary

  1,2,3-Triazoles · CPC title