Pyrimidinone carboxamide inhibitors of endothelial lipase

摘要

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.;

主权项

1. A compound of Formula (I):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from the group consisting of:wherein each moiety is substituted with 0-2 R5;
X1 is independently selected from the group consisting of: a bond, O, CO, straight or branched C1-3 alkylene, —O—C1-3 alkylene-, —C1-3 alkylene-O—, NH, —SO2—, —C1-3 alkylene-NH—, —NHCO—, —CONH—, —CH2NHCO—, —CH2CONH—, —OCONH—, —CH2OCONH—, —NHCONH—, and —SO2NH—; alternatively, R1 and R3 are each independently selected from the group consisting of: H, C1-6 alkyl, C1-6 haloalkyl, —(CH2)2OH, —CH2CO2H, —CH2CO2(C1-4 alkyl), —(CH2)1-3Ph, 3-halo-4-halo-phenyl, 3-halo-5-CF3-phenyl, and R2 is independently selected from the group consisting of: OH and NHR7; R4 is independently selected from the group consisting of: H, C1-4 alkyl, C1-4 alkoxy, halogen, C1-4 haloalkyl, C1-4 haloalkoxy, and a ring moiety substituted with 0-2 Rh and selected from: 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; R5 is, independently at each occurrence, selected from the group consisting of: halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, CO2(C1-4 alkyl), —CH2CO2(C1-4 alkyl), NH2, NH(C1-4 alkyl), and N(C1-4 alkyl)2; R6 is independently selected from the group consisting of: H and C1-4 alkyl substitute with 0-1 CO2H, R7 is independently selected from the group consisting of: H, C1-6 haloalkyl, COCF3, —(CH2)2O(C1-4 alkyl), C1-6 alkyl substituted with 0-1 OH, —(CHRf)n—(C3-6 cycloalkyl substituted with 0-1 OH), —(CHRf)n-(phenyl substituted with 0-2 Rb), 1-tetralinyl, 1-indanyl, tetrahydronaphthalenyl, 1-Bn-pyrrolidin-3-yl, —(CH2)n-(piperidin-1-yl), 1-C1-4 alkyl-piperidiny-4-yl, 1-CO2(C1-4 alkyl)-piperidiny-4-yl, 1-(4-halo-phenyl)-piperidiny-4-yl, —(CH2)n(morpholin-4-yl), —(CH2)n-imidazolyl, —(CH2)n-pyridyl, R8 is independently selected from the group consisting of: CO2H and OH; 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, 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), phenoxy, and —CONH(phenylcyclohexyl); Rb is, independently at each occurrence, selected from the group consisting of: halogen, OH, C1-4 alkyl substituted with 0-1 OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, 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), SO2(C1-4 alkyl), and SO2NH2; 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: CONH2, C1-4 alkyl, —(CH2)2O(CH2)2O(C1-4 alkyl), C3-6 carbocycle substituted with 0-2 Rh, morpholin-1-yl, 1-C1-4 alkyl-piperazin-4-yl, 1-CBz-piperazin-4-yl, pyridyl, indol-3-yl, and benzothiazol-2-yl; 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), CONH(C1-4 alkyl), CONH(phenyl substituted with 0-2 halogens), SO2(C1-4 alkyl), and —(CH2)nRd; Rf is, independently at each occurrence, selected from the group consisting of: H and methyl; 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 alkoxy, CO2(C1-4 alkyl), C3-6 cycloalkyl, and phenyl; Rh is, independently at each occurrence, selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, —(CH2)2O(C1-4 alkyl), CF3, NO2, CONH2, OBn, quinolinyl, 1-C1-4 alkyl-pyrazolyl, 1-(CH2CO2(C1-4 alkyl))pyrazolyl, 1-C1-4 alkyl-3-CF3-pyrazolyl, 1-((CH2)2(morpholin-4-yl))-pyrazolyl, 1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC1-4 alkyl-pyrazolyl, 2-Ph-4-C1-4 alkyl-thiazolyl, NHSO2(phenyl substituted with C1-4 alkyl), and —(CH2)0-2-(phenyl substituted with zero to three substituents independently selected from the group consisting of: halogen, CH2OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, N(C1-4 alkyl)2, CONH2, and NHCO(C1-4 alkyl)); and n is, independently at each occurrence, selected from 0, 1, 2, and 3.