Cyclic P1 linkers as factor XIa inhibitors

摘要

The present invention provides compounds of Formula (Ia):;
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

主权项

1. A compound of Formula (I):or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
G1 is selected from the group consisting of a 6-membered aryl and a 5- to 6-membered heteroaryl wherein said aryl and heteroaryl are optionally substituted with 1-4 R8; ring A is selected from the group consisting of a 6-membered aryl and a 5- to 6-membered heterocycle, wherein said aryl and heterocycle are optionally substituted with 1-3 R13; X1 is selected from the group consisting of C1-4 alkylene, and C2-4 alkenylene; optionally one or more of the carbon atoms of said alkylene may be replaced by O, S(O)p, NH, and N(C1-4 alkyl); X2 is selected from the group consisting of CHR11, O, NH, and N(C1-4 alkyl); X3 is CR12 or N, provided when X2 is O, NH, and N(C1-4 alkyl), X3 is CR12; R1 is selected from the group consisting of H, halogen, CF3, C1-6 alkyl, and hydroxyl; R2 is selected from the group consisting of H and C1-6 alkyl; R3 is selected from the group consisting of H, haloalkyl, C(O)OH, C(O)O—C1-4 alkyl, and C(O)NR9R10; R4 is selected from the group consisting of H and C1-6 alkyl; optionally, R3 and R4 together are ═O; R5 is selected from the group consisting of H, halogen, NHC(O)O—C1-4 alkyl, CONH2, CO2—C1-4 alkyl, COOH, CN, OH, and O—C1-4 alkyl; R6 is selected from the group consisting of H, C1-6 alkyl, and OH; R7 is selected from the group consisting of H, F, methyl, ethyl, and isopropyl; R8 is selected from the group consisting of H, halogen, OH, CN, C1-6 alkyl, haloalkyl, alkoxy, and haloalkoxy; R9 is selected from the group consisting of H and C1-6 alkyl; R10 is selected from the group consisting of H and C1-6 alkyl; alternatively, R9 and R10 are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle optionally substituted with R14; R11 is selected from the group consisting of H and C1-6 alkyl; R12 is selected from the group consisting of H and C1-6 alkyl; R13 is selected from the group consisting of H, halogen, C1-6 alkyl, CF3 and CN; R14 is selected from the group consisting of H, OH, halogen, and C1-6 alkyl; and p, at each occurrence, is selected from 0, 1, and 2.