Oxopyrrolidine FPR2 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, chronic obstructive pulmonary disease (COPD), and related diseases.
1 . A compound, having Formula (IVa):
or a pharmaceutically acceptable salt thereof, wherein:
Ar 2 is
R 1 is Cl, —CF 3 , —OCHF 2 , or —OCF 3 ;
R 2 is F, Cl, CH 2 OH, CH 3 , CF 3 , or CHF 2 ; and
R 2a is —CH 3 , —CH 2 CH 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CF 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH 2 OH, —CH 2 CH(CH 3 )OH, —CH 2 CH(CF 3 )OH, —CH 2 CH 2 CF 3 , —CH(CH 2 OH)CH 2 OCH 3 , —CH(CH 2 NH 2 )OCH 3 , —CH 2 CH(CH 3 )OCH 3 , or —CH 2 CH(CF 3 )OCH 3 ,
R 5a is hydrogen, F, or Cl;
R 5b is hydrogen, F, or Cl;
R 5c is Cl or —OCH 3 ; and
R 7 is hydrogen or CH 3 .
2 . A compound, having Formula (IVb):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cl, —CF 3 , —OCHF 2 , or —OCF 3 ;
R 2 is cyano, F, Cl, —CH 3 , —CF 3 , —CHF 2 , —CF 3 , or —NHC(O)CH 3 ;
R 2a is —CH 3 , CHF 2 , —CH 2 CH 3 , —CH 2 CN, —CH 2 CHF 2 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CF 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH 2 OH, —CF 2 CH 2 OH, —CH 2 CH(CH 3 )OH, —CH 2 CH 2 CF 3 , —CH(CH 2 OH)CH 2 OCH 3 , —CH(CH 2 NH 2 )OCH 3 , —CH 2 CH(CH 3 )OCH 3 , —CH 2 CH(CF 3 )OCH 3 , —CH(CH 2 NH 2 )CH 2 OCH 3 , —CH(C(O)N(CH 3 ) 2 )CH 2 OCH 3 , —CH 2 C(CH 3 )(CH 2 OH) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 S(O) 2 C 1-4 alkyl, —CHR d C(O)NR 3 R 4 , —(CH 2 ) 0-1 —C 3-6 cycloalkyl, —(CH 2 ) 0-3 -heterocyclyl selected from
R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
R 5a is hydrogen or F;
R 5b is hydrogen or F;
R 5c is Cl or —OCH 3 ;
R 7 is hydrogen or CH 3 ; and
R d is —CH 2 OCH 3 .
3 . A compound, having Formula (IVc):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cl, —CF 3 , —OCHF 2 , or —OCF 3 ;
R 2 is cyano, F, Cl, —CH 2 OH, —CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , —N 3 R 4 , (CH 3 ) 2 (O)P—, C 3-6 cycloalkyl,
R 3 is hydrogen or C 1-4 alkyl substituted with 0-1 S(O) 2 C 1-3 alkyl,
R 4 is hydrogen;
alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
R 5a is hydrogen or F;
R 5b is hydrogen or F;
R 5c is Cl or —OCH 3 ;
R 6 is hydrogen, halo, oxo, —CH 3 , —CH 2 CH 3 , or —CH 2 OH;
R 7 is hydrogen or CH 3 ; and
R 8 is hydrogen, C 1-2 alkyl, or —S(O) 2 C 1-3 alkyl.
4 . A compound, having Formula (IVd):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cl, —CF 3 , —OCHF 2 , or —OCF 3 ;
R 2 is —OR b or (C 1-2 alkyl) 2 (O)P—;
R 5a is hydrogen or F;
R 5b is hydrogen or F;
R 5c is Cl or —OCH 3 ;
R 7 is hydrogen or CH 3 ;
R b is hydrogen, C 1-4 alkyl substituted with 0-3 R e , or
R e is F, Cl, or —OR g ; and
R g is hydrogen or C 1-3 alkyl.
5 . A compound, having Formula (IVe):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cl, —CF 3 , —OCHF 2 , or —OCF 3 ;
R 2 is cyano, F, Cl, —CH 2 OH, —CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCH(CH 3 ) 2 , or —NR 3 R 4 ;
R 3 is hydrogen or C 1-4 alkyl;
R 4 is hydrogen or C 1-2 alkyl;
alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
R 5a is hydrogen or F;
R 5b is hydrogen or F;
R 5c is Cl or —OCH 3 ,
R 6 is hydrogen, halo, oxo, —CH 3 , —CH 2 CH 3 , or —CH 2 OH;
R 7 is hydrogen or CH 3 ; and
R 8 is hydrogen, C 1-2 alkyl, or —S(O) 2 C 1-3 alkyl.
6 . A compound, having Formula (IVf):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cl, —CF 3 , —OCH 3 , —OCHF 2 , or —OCF 3 ;
R 2 is cyano, F, Cl, —CH 2 OH, —CH 3 , —CHF 2 , or —CF 3 ;
R 2a is —CH 3 , —CH 2 CH 3 , —CH 2 CHF 2 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CF 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH 2 OH, —CH 2 CH(CH 3 )OH, or —CH 2 CH 2 CF 3 ;
R 5a is hydrogen, F, or Cl;
R 5b is hydrogen, F, or Cl; and
R 5c is Cl or —OCH 3 ; and
R 7 is hydrogen or CH 3 .
7 . A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.
8 . A method for the treatment or prophylaxis of inflammatory diseases, heart diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders, comprising administrating a therapeutically effective amount of the pharmaceutical composition of claim 7 to a patient in need thereof.
9 . The method of claim 8 , wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.
10 . The method of claim 9 , wherein the heart failure results from hypertension, an ischemic heart disease, a non-ischemic heart disease, exposure to a cardiotoxic compound, myocarditis, Kawasaki's disease, Type I and Type II diabetes, thyroid disease, viral infection, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary bypass surgery, pacemaker implantation surgery, starvation, an eating disorder, muscular dystrophies, and a genetic defect.