GUANIDINE AND AMINE SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS AS FACTOR XIA INHIBITORS

摘要

The present invention provides compounds of Formula (I): (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 according to formula or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
ring A is C3-12carbocycle;L is selected from a bond, —CHR7—, and —CHR7CHR7—;ring B is phenyl or 5- to 6-membered heterocycle containing carbon atoms and 1-3 heteroatoms selected from the group consisting of N, NR6, O, and S(O)p, wherein said phenyl or heterocycle is substituted with 0-3 R5;---- is an optional bond;R1, at each occurrence, is selected from —(CH2)nNH2, —(CH2)nC(═NH)NH2, —(CH2)nC(═NOR6)NH2, and —(CH2)nNHC(═NH)NH2;R3 is selected from C1-6 alkyl substituted with 1-3 R3a, C3-10 carbocycle substituted with 1-3 R3a, and 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRa, O, and S(O)p; wherein said heterocycle is substituted with 1-3 R3a;R3a, at each occurrence, is selected from H, halogen, C1-4 alkyl, —OH, C1-4 alkoxy, —CN, —NH2, —NH(C1-4 alkyl), —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO2—C1-4 alkylene-O(C1-4 alkyl), —CO2—C1-4 alkylene-N(C1-4 alkyl)2, —CONH2, —CONH(C1-6 alkyl), —CON(C1-4 alkyl)2, —CONHCO2C1-4 alkyl, —NHCOC1-4 alkyl, —NHCO2(C1-4 alkyl), SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, Rc, —CONHRc, and —CO2Rc;R4, at each occurrence, is selected from H, F, and C1-4 alkyl;R5 is selected from H, halogen, C1-4 alkyl, C1-4alkoxy, C1-4haloalkoxy, OH, CN, NH2, —N(C1-4 alkyl)2, NO2, —OCO(C1-4 alkyl), —O—C1-4 alkylene-O(C1-4 alkyl), —O—C1-4 alkylene-N(C1-4 alkyl)2, —CO2H, —CO2(C1-4 alkyl), —(CH2)nCONH2, SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6—(CH2)n—C3-10 carbocycle and —(CH2)n-5- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRa, O, and S(O)p; wherein said carbocycle or heterocycle is substituted with 1-3 Rb;R6, at each occurrence, is selected from H and C1-4 alkyl;R7, at each occurrence, is selected from H, halo, OH, and C1-4 alkyl;Ra, at each occurrence, is selected from H, C1-4 alkyl, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4 alkyl), Rc, CO2Rc, and CONHRc;Rb, at each occurrence, is selected from H, CN, ═O, —OH, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —NHCO2(C1-4 alkyl), SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, —Rc, CORc, CO2Rc, and CONHRc; optionally, Rb and Rb together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring;Rc, at each occurrence, is selected from —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)p; wherein each ring moiety is substituted with 0-2 Rd;Rd, at each occurrence, is selected from ═O, F, —OH, C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl), and heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)p;n, at each occurrence, is selected from 0, 1, 2, 3, and 4; andp, at each occurrence, is selected from 0, 1, and 2;provided the following compound is excluded: