Oxopyrrolidine FPR2 agonists
AssigneeBristol-Myers Squibb Company
InventorsPravin Sudhakar Shirude, Chandrasekhar Reddy Rachamreddy, Amit Kumar Chattopadhyay, Balaji Seshadri, Vishweshwaraiah Baligar, Sudhakara Reddy Madduri, Ellen K. Kick, Nicholas R. Wurtz
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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.
Claims10
A compound, having Formula (IVa):
- or a pharmaceutically acceptable salt thereof, wherein:
- Ar2 is
- R1 is Cl, —CF3, —OCHF2, or —OCF3;
- R2 is F, Cl, CH2OH, CH3, CF3, or CHF2;
- and
- R2a is —CH3, —CH2CH3, —CH2CHF2, —CH2CF3, —CH2CH2OCH3, —CH2CH(OH)CF3, —CH2CH(OH)CH3, —CH2CH2OH, —CH2CH(CH3)OH, —CH2CH(CF3)OH, —CH2CH2CF3, —CH(CH2OH)CH2OCH3, —CH(CH2NH2)OCH3, —CH2CH(CH3)OCH3, or —CH2CH(CF3)OCH3,
- R5a is hydrogen, F, or Cl;
- R5b is hydrogen, F, or Cl;
- R5c is Cl or —OCH3;
- and
- R7 is hydrogen or CH3.
A compound, having Formula (IVb):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is Cl, —CF3, —OCHF2, or —OCF3;
- R2 is cyano, F, Cl, —CH3, —CF3, —CHF2, —CF3, or —NHC(O)CH3;
- R2a is —CH3, CHF2, —CH2CH3, —CH2CN, —CH2CHF2, —CH2CH2OCH3, —CH2CH(OH)CF3, —CH2CH(OH)CH3, —CH2CH2OH, —CF2CH2OH, —CH2CH(CH3)OH, —CH2CH2CF3, —CH(CH2OH)CH2OCH3, —CH(CH2NH2)OCH3, —CH2CH(CH3)OCH3, —CH2CH(CF3)OCH3, —CH(CH2NH2)CH2OCH3, —CH(C(O)N(CH3)2)CH2OCH3, —CH2C(CH3)(CH2OH)2, —CH2CH2N(CH3)2, —CH2CH2S(O)2C1-4 alkyl, —CHRdC(O)NR3R4, —(CH2)0-1—C3-6 cycloalkyl, —(CH2)0-3-heterocyclyl selected from
- R3 and R4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
- R5a is hydrogen or F;
- R5b is hydrogen or F;
- R5c is Cl or —OCH3;
- R7 is hydrogen or CH3;
- and
- Rd is —CH2OCH3.
A compound, having Formula (IVc):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is Cl, —CF3, —OCHF2, or —OCF3;
- R2 is cyano, F, Cl, —CH2OH, —CH3, —CHF2, —CF3, —OCH3, —OCH(CH3)2, —N3R4, (CH3)2(O)P—, C3-6 cycloalkyl,
- R3 is hydrogen or C1-4 alkyl substituted with 0-1 S(O)2C1-3 alkyl,
- R4 is hydrogen;
- alternatively, R3 and R4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
- R5a is hydrogen or F;
- R5b is hydrogen or F;
- R5c is Cl or —OCH3;
- R6 is hydrogen, halo, oxo, —CH3, —CH2CH3, or —CH2OH;
- R7 is hydrogen or CH3;
- and
- R8 is hydrogen, C1-2 alkyl, or —S(O)2C1-3 alkyl.
A compound, having Formula (IVd):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is Cl, —CF3, —OCHF2, or —OCF3;
- R2 is —ORb or (C1-2 alkyl)2(O)P—;
- R5a is hydrogen or F;
- R5b is hydrogen or F;
- R5c is Cl or —OCH3;
- R7 is hydrogen or CH3;
- Rb is hydrogen, C1-4 alkyl substituted with 0-3 Re, or
- Re is F, Cl, or —ORg;
- and
- Rg is hydrogen or C1-3 alkyl.
A compound, having Formula (IVe):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is Cl, —CF3, —OCHF2, or —OCF3;
- R2 is cyano, F, Cl, —CH2OH, —CH3, —CHF2, —CF3, —OCH3, —OCH(CH3)2, or —NR3R4;
- R3 is hydrogen or C1-4 alkyl;
- R4 is hydrogen or C1-2 alkyl;
- alternatively, R3 and R4 together with the nitrogen to which they are both attached form a heterocyclyl selected from
- R5a is hydrogen or F;
- R5b is hydrogen or F;
- R5c is Cl or —OCH3,
- R6 is hydrogen, halo, oxo, —CH3, —CH2CH3, or —CH2OH;
- R7 is hydrogen or CH3;
- and
- R8 is hydrogen, C1-2 alkyl, or —S(O)2C1-3 alkyl.
A compound, having Formula (IVf):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is Cl, —CF3, —OCH3, —OCHF2, or —OCF3;
- R2 is cyano, F, Cl, —CH2OH, —CH3, —CHF2, or —CF3;
- R2a is —CH3, —CH2CH3, —CH2CHF2, —CH2CH2OCH3, —CH2CH(OH)CF3, —CH2CH(OH)CH3, —CH2CH2OH, —CH2CH(CH3)OH, or —CH2CH2CF3;
- R5a is hydrogen, F, or Cl;
- R5b is hydrogen, F, or Cl;
- and
- R5c is Cl or —OCH3;
- and
- R7 is hydrogen or CH3.
Dependencies are inferred from the claim text.