Piperidinone formyl peptide 2 receptor and formyl peptide 1 receptor agonists

Patent metadata

Field	Value
Publication number	US-10717708-B2
Application number	US-201615776933-A
Country	US
Kind code	B2
Filing date	Dec 8, 2016
Priority date	Dec 10, 2015
Publication date	Jul 21, 2020
Grant date	Jul 21, 2020

Abstract

The disclosure relates to compounds of formula I, which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1) receptor agonists. The disclosure also provides compositions and methods of using the compounds, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

First claim

What is claimed is:

1. A compound of formula I

where:
Ar 1 is pyridinyl substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, and SO 2 R 6 ;
Ar 2 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 3 is aryl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (NR 1 R 2 )alkyl, (CO 2 R 3 )alkyl, (CONR 4 R 5 )alkyl, (SO 2 R 6 )alkyl, hydroxy, alkoxy, haloalkoxy, cycloalkoxy, NR 1 R 2 , CO 2 R 3 , CONR 4 R 5 , SO 2 R 6 , oxo, aryl, and heteroaryl;
R 1 is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, or haloalkylsulfonyl;
R 2 is hydrogen or alkyl;
R 3 is alkyl or haloalkyl;
R 4 is hydrogen, alkyl, or (R 7 R 8 N)alkyl;
R 5 is hydrogen or alkyl;
R 6 is alkyl or R 7 R 8 N;
R 7 is hydrogen or alkyl;
R 8 is hydrogen or alkyl;
X is hydrogen, halo, hydroxy, or alkoxy;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where:
Ar 1 is pyridinyl substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, and SO 2 R 6 ;
Ar 2 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (NR 1 R 2 )alkyl, hydroxy, alkoxy, haloalkoxy, cycloalkoxy, NR 1 R 2 , CO 2 R 3 , CONR 4 R 5 , and SO 2 R 6 ;
R 1 is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, or haloalkylsulfonyl;
R 2 is hydrogen or alkyl;
R 3 is hydrogen or alkyl;
R 4 is hydrogen, alkyl, or (R 7 R 8 N)alkyl;
R 5 is hydrogen or alkyl;
R 6 is alkyl or R 7 R 8 N;
R 7 is hydrogen or alkyl;
R 8 is hydrogen or alkyl;
X is hydrogen, halo, hydroxy, or alkoxy;
or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 where Ar 1 is pyridinyl substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylthio; Ar 2 is phenyl substituted with 0-3 substituents selected from cyano and halo; Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (NR 1 R 2 )alkyl, alkoxy, haloalkoxy, NR 1 R 2 , CO 2 R 3 , CONR 4 R 5 , and SO 2 R 6 .

4. A compound of claim 1 where Ar 1 is pyridinyl-1,4-substituted with 1 halo, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio substituent with respect to the nitrogen attached to Ar 1 and also is substituted with 0-2 fluoro substituents.

5. A compound of claim 1 where Ar 2 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

6. A compound of claim 1 where Ar 2 is -1,4-substituted with respect to the nitrogen and the Ar 3 to which it is attached.

7. A compound of claim 1 where Ar 2 is phenyl -1,4-substituted with respect to the nitrogen and the Ar 3 to which it is attached and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

8. A compound of claim 1 where Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (NR 1 R 2 )alkyl, alkoxy, haloalkoxy, NR 1 R 2 , CO 2 R 3 , CONR 4 R 5 , and SO 2 R 6 .

9. A compound of claim 1 where Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (NR 1 R 2 )alkyl, alkoxy, haloalkoxy, NR 1 R 2 , CO 2 R 3 , CONR 4 R 5 , and SO 2 R 6 .

10. A compound of claim 1 where X is hydrogen.

11. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

12. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

Assignees

• Bristol Myers Squibb Co

Inventors

• Wurtz Nicholas R
• Shirude Pravin Sudhakar

Classifications

• C07D413/12

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

• C07D211/76 Primary

  attached in position 2 or 6 · 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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title