Substituted 1,2,3,4-tetrahydro-2,6-naphthyridines as factor XIa inhibitors

摘要

The present invention provides compounds of Formula (I):;
or stereoisomers, pharmaceutically acceptable salts thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of factor XIa and/or plasma kallikrein which may be used as medicaments.

主权项

1. A compound of Formula (I):or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl; L is selected from the group consisting of: a bond, —CHR10CHR10—, —CR10═CR10—, and —C≡C—; R1, at each occurrence, is selected from the group consisting of: H, halo, C1-2 alkyl, —O(C1-4 alkyl), CN, —CH2NH2, and —C(═NH)NH2; R2 is selected from the group consisting of: H, halo, CN, OH, C1-6 alkyl, C1-4 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, CO(C1-4 alkyl), CONH2, CO2H and a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)p, wherein said heterocycle is substituted with 1-2 R2a; R2a, at each occurrence, is selected from the group consisting of: H, halo, C1-4 alkyl, CO2H, —CO2(C1-4 alkyl), —CONH2, —CH2OH, —CH2OC1-4alkyl, and —CH2NH2; R3 is selected from the group consisting of: C1-6 alkyl substituted with 1-3 R3a, C3-10 carbocycle substituted with 1-3 R3a, and 5-10 membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR7, O, and S(O)p; wherein said heterocycle is substituted with 1-3 R3a; R3a, at each occurrence, is selected from the group consisting of: H, ═O, halo, C1-4 alkyl, —OH, C1-4 alkoxy, —CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO2—C1-4 alkylene-O(C1-4 alkyl), —CO2—C1-4 alkylene-N(C1-4 alkyl)2, —CO2—C1-4 alkylene-O—C1-4 alkylene-N(C1-4 alkyl)2, —CO2—C1-4alkylene-O—C1-4 alkylene-O(C1-4 alkyl), —CONH2, —CONH(C1-6alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), —CONHCO2C1-4 alkyl, —CONH—C1-4 alkylene-NHCO(C1-4 alkyl), —CONH—C1-4 alkylene-CONH2, —NHCOC1-4 alkyl, —NHCO2(C1-4 alkyl), —CH2NHCO2(C1-4 alkyl), Rc, —CONHRc, and —CO2Rc; R4, at each occurrence, is selected from the group consisting of: H, halo, and C1-4 alkyl; R5 is selected from the group consisting of: H, halo, C1-4 alkyl substituted with 0-2 Rb, C2-4 alkenyl substituted with 0-2 Rb, C2-4 alkynyl substituted with 0-2 Rb, —OH, —CN, NO2, —NH2, —N(C1-4 alkyl)2, —O(C1-4 alkyl), —OCO(C1-4 alkyl), —O—C1-4 alkylene-O(C1-4 alkyl), —O—C1-4 alkylene-N(C1-4 alkyl)2, —CO2H, —CO2(C1-4alkyl), —CONH2, —(CH2)2CONH2, —CONR9(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONR9—C1-4 alkylene-O(C1-4 alkyl), —CONR9—C1-4 alkylene-N(C1-4 alkyl)2, —CONR9—C1-4 alkylene-CO2(C1-4 alkyl), —NR9COC1-4 alkyl, —NR9CO2C1-4 alkyl, —NR9CONH(C1-4 alkyl), —NR9CONR9—C1-4 alkylene-CO2C1-4 alkyl, —NR9—C1-4 alkylene-N(C1-4 alkyl)2, —NR9SO2(C1-4 alkyl), —SO2NH2, R8, —OR8, —COR8, —CO2R8, —CONR9R8, —NR9COR8, —NR9CO2R8, and —NR9CONR9R8; R7, at each occurrence, is selected from the group consisting of: H, C1-4 alkyl, COC1-4 alkyl, CO2(C1-4 alkyl), CO2CH2-phenyl, CONH—C1-4 alkylene-CO2C1-4 alkyl, phenyl, benzyl, and —CO2—C1-4 alkylene-aryl; R8 is, independently at each occurrence, selected from the group consisting of: —(CH2)n—C3-10 carbocycle and —(CH2)n-5- to 10-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NRa, O, and S(O)p; wherein said carbocycle or heterocycle is substituted with 0-3 Rb; R9 is, independently at each occurrence, selected from the group consisting of: H and C1-4alkyl; R10, at each occurrence, is selected from the group consisting of: H, halo, OH, and C1-4 alkyl; Ra is selected from the group consisting of: H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4alkyl), Rc, CO2Rc, and CONHRc; Rb is selected from the group consisting of: ═O, halo, C1-4alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, —NHCO2(C1-4 alkyl), —Rc, CORc, CO2Rc, and CONHRc; Rc is, independently at each occurrence, selected from the group consisting of: —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NH, N(C1-4 alkyl), N(CO2C1-4 alkyl), O, and S(O)p; wherein each ring moiety is substituted with 0-2 Rd; Rd is selected from the group consisting of: ═O, halo, —OH, C1-4 alkyl, N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl), and heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NH, N(C1-4 alkyl), O, and S(O)p; n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is selected from 0, 1, and 2.