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US 8,946,430 B2Granted
Quinolinone carboxamide inhibitors of endothelial lipase
AssigneeBristol-Myers Squibb Company
InventorsJennifer X. Qiao, Carol Hui Hu, Tammy C. Wang
Life of this patent
Estimating the term…
Abstract
The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.
Claims14
A compound of Formula (I):
- or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
- R1 is independently selected from the group consisting of:
- H, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, and —(CH2)—W—(CH2)m—R1a;
- W is independently selected from the group consisting of:
- a bond, NH, O, S, N(C1-4 alkyl), CO, CONH, CON(C1-4 alkyl), NHCO, SO2, NHSO2, SO2NH, NHCO2, and CHRf;
- R1a is independently selected from the group consisting of:
- C3-10 carbocycle and a 5- to 10-membered heterocycle comprising:
- carbon atoms and 1-4 heteroatoms selected from N, NRe, O, and S(O)p;
- and wherein said carbocycle and heterocycle are substituted with 0-3 Rc;
- R2a, R2b, R2c, and R2d are, independently at each occurrence, selected from the group consisting of:
- H, halogen, OH, C1-4 alkyl, C1-2 alkenyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, CF3, OCF3, OCF2CHF2, CN, NH2, NO2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), CONH2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, NHSO2(C1-4 alkyl), SO2(C1-4 alkyl), SO2NH2, and phenyl substituted with 0-2 Rb;
- R4 is independently selected from the group consisting of:
- C3-10 carbocycle and a 5- to 10-membered heterocycle comprising:
- carbon atoms and 1-4 heteroatoms selected from N, NRe, O, and S(O)p;
- wherein said carbocycle and heterocycle are substituted with 0-3 Rd;
- R5 is independently selected from the group consisting of:
- OR6, CN, and NR7R8;
- R6 is independently selected from the group consisting of:
- H and C1-6 alkyl substituted with 0-1 CO2H;
- R7 is independently selected from the group consisting of:
- H, C1-6 alkyl substituted with 0-1 Ra, —(CH2)n-(phenyl substituted with 0-3 Rb), and —(CH2)n-(5- to 6-membered heterocycle comprising:
- carbon atoms and 1-4 heteroatoms selected from N, NRe, O, and S(O)p);
- and wherein said heterocycle is substituted with 0-3 Rc;
- R8 is independently selected from the group consisting of:
- H and C1-6 alkyl;
- alternatively, NR7R8 is a 5- to 6-membered heterocycle comprising:
- carbon atoms and 1-4 heteroatoms selected from N, NRe, O, and S(O)p;
- L is independently a hydrocarbon or hydrocarbon-heteroatom linker optionally substituted with 0-2 Rg;
- wherein said hydrocarbon linker has one to eight carbon atoms and may be straight or branched, saturated or unsaturated;
- and said hydrocarbon-heteroatom linker has one to seven carbon atoms and one group selected from O, —CO—, S, —SO—, —SO2—, NH, and N(C1-4 alkyl);
- alternatively, L is X1—Y—X2;
- X1, and X2 are, independently at each occurrence, selected from the group consisting of:
- a bond, a hydrocarbon linker and a hydrocarbon-heteroatom linker;
- wherein said hydrocarbon linker and hydrocarbon-heteroatom linker may be substituted with 0-2 Rg;
- said hydrocarbon linker has one to six carbon atoms and may be saturated or unsaturated;
- and said hydrocarbon-heteroatom linker may be saturated or unsaturated and has zero to four carbon atoms and one group selected from O, —CO—, S, —SO—, —SO2—, NH, and N(C1-4 alkyl);
- Y is independently selected from the group consisting of:
- C3-10 carbocycle and a 4- to 10-membered heterocycle comprising:
- carbon atoms and 1-4 heteroatoms selected from N, NRe, O, and S(O)p;
- wherein each said carbocycle and heterocycle may be optionally substituted with one, two or three substituents independently selected from:
- halogen, OH, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkyoxy;
- alternatively, R4-L- is
- Ra is, independently at each occurrence, selected from the group consisting of:
- halogen, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CF3, OCF3, CN, NH2, NO2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHCO(C1-4 alkyl substituted with 0-1 NH2), N(C1-4 alkyl)CO(C1-4 alkyl), NHCO2(C1-4 alkyl), CONHSO2(C1-4 alkyl), SO2(C1-4 alkyl), CONH2, CONH(C1-4 alkyl), NHSO2(C1-4 alkyl), N(C1-4 alkyl)SO2(C1-4 alkyl), and phenoxy;
- Rb is, independently at each occurrence, selected from the group consisting of:
- halogen, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CF3, OCF3, OCF2CHF2, OCH2CF3, CN, NH2, NO2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), CONH2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, NHCO2(C1-4 alkyl), NHSO2(C1-4 alkyl), N(C1-4 alkyl)SO2(C1-4 alkyl), SO2(C1-4 alkyl), SO2NH2, phenyl, benzyl, and phenoxy;
- Rc is, independently at each occurrence, selected from the group consisting of:
- ═O and Rb;
- Rd is, independently at each occurrence, selected from the group consisting of:
- ═O, halogen, OH, C1-6 alkyl substituted with 0-10H, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CF3, OCF3, OCF2CF2H, OCH2CF3, CN, NH2, NO2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), CO(C1-4 alkyl), NHCO(C1-4 alkyl), —CH2NHCO(C1-4 alkyl), CONH2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, SO2(C1-4 alkyl), SO2NH2, —SO2NH(C1-4 alkyl), —SO2NH(C3-6 cycloalkyl), —NHSO2(C1-4 alkyl), —CH2NHSO2(C1-4 alkyl), Si(C1-4 alkyl)3, and phenyl optionally substituted with one or two substituents independently selected from:
- halogen, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyoxy, and NHCO(C1-4 alkyl);
- Re is, independently at each occurrence, selected from the group consisting of:
- H, C1-4 alkyl, CO(C1-4 alkyl), CO2(C1-4 alkyl), CO2(benzyl), and —(CH2)n-(phenyl optionally substituted with 0-2 halogens);
- Rf is, independently at each occurrence, selected from the group consisting of:
- C1-4 alkyl, C2-4 alkenyl, CO2(C1-4 alkyl), CONH2, C3-6 cycloalkyl, phenyl, and benzyl;
- Rg is, independently at each occurrence, selected from the group consisting of:
- halogen, OH, C1-4 alkyl, C2-4 alkenyl, C1-4 haloalkyl, C1-4 alkyoxy, CO2(C1-4 alkyl), C3-6 cycloalkyl, and phenyl;
- m is, independently at each occurrence, selected from 0, 1, and 2;
- n is, independently at each occurrence, selected from 0, 1, 2, 3, and 4;
- and
- p is, independently at each occurrence, selected from 0, 1, and 2;
- provided that:
- when L is CH2, R1 is H and R5 is OH, then R4 is other than an unsubstituted phenyl.
60 more elements
Dependencies are inferred from the claim text.