Pyrrolidinone derivatives as formyl peptide 2 receptor agonists
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, and related diseases.
1. A compound of formula I
where:
R 1 is absent, Ar 3 , cycloalkyl substituted with 0-2 halo and 0-1 Ar 4 substituents, or ((Ar 5 )alkyl)(H)NCO;
R 2 is hydrogen, alkyl, or CH 2 CO 2 H;
Ar 1 is isoxazolyl, oxadiazolyl, thiadiazolyl, benzoisoxazolyl, isoxazolopyridinyl, or benzooxazolyl, and is substituted with 0-2 halo, alkyl, alkoxy, fluoroalkyl, or fluoroalkoxy substituents;
Ar 2 is phenyl, pyridinyl, or pyridazinyl, and is substituted with 1 alkoxy, halo, haloalkyl or haloalkoxy substituent in the 4-position and 0-2 additional halo substituents;
Ar 3 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, OAr 6 , alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, and pyrazolyl;
Ar 4 is phenyl or pyridinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 5 is phenyl or pyridinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and
Ar 6 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Provided when Ar 1 is oxadiazolyl or thiadiazolyl, Ar 1 is substituted with 0-1 halo, alkyl, alkoxy, fluoroalkyl, or fluoroalkoxy substituent;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 where R 1 is Ar 3 ; R 2 is hydrogen; Ar 1 is oxadiazolyl or thiadiazolyl, and is substituted with 0-1 halo, alkyl, alkoxy, fluoroalkyl, or fluoroalkoxy substituent; Ar 2 is phenyl substituted with 1 alkoxy, halo, haloalkyl or haloalkoxy substituent in the 4-position and 0-2 additional halo substituents; Ar 3 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, OAr 6 , alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, and pyrazolyl; and Ar 6 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 where R 1 is Ar 3 .
4. A compound of claim 1 where R 2 is hydrogen.
5. A compound of claim 1 where Ar 1 is oxadiazolyl or thiadiazolyl, and is substituted with 0-1 halo, alkyl, alkoxy, fluoroalkyl, or fluoroalkoxy substituent; Ar 2 is phenyl substituted with 1 alkoxy substituent in the 4-position and 0-2 additional halo substituents.
6. A compound of claim 1 where Ar 3 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, OAr 6 , alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, and pyrazolyl.
7. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.