US 10,093,683 B2 · Factor XIa inhibitors

Abstract

The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more compounds of Formula (I), and methods for using the compounds of Formula (I) for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.

A compound of Formula I:

wherein X is absent, CH2, CH2O, O or NH;
Y1 is CR3 or N,
Y2 is CR3 or N,
Y3 is CR3 or N,
Y4 is CR3 or N,
with the proviso that three of Y1, Y2, Y3 and Y4 are not simultaneously N, and all four of Y1, Y2, Y3 and Y4 are not simultaneously N;
Z is S, SO, SO2 or C═O;
L is NHC(═O);
M is phenyl, wherein said phenyl group is optionally substituted with one to three substituents independently selected from halo, cyano, hydroxy, oxo, C1-6 alkyl or NR6R7;
R1a is hydrogen, halo, cyano, hydroxy, C1-4 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, C1-4 alkyl-C3-6 cycloalkyl, C1-4 alkyl-aryl, C1-4 alkyl-heteroaryl or C1-4 alkyl-heterocyclyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from halo, hydroxy, methoxy, SR4, SOR4, SO2R4, C(═O)R9, C(═O)NHR9, C(═O)NHCH2R9, C(═O)NHSO2R9 or NHC(═O)R4, and said cycloalkyl, aryl, heteraryl and heterocyclyl groups are optionally substituted with one to three groups independently selected from halo, hydroxy, oxo, cyano, C1-4 alkyl, C2-4 alkenyl-OR4, OR4, C(═O)NR6R7, NHC(═O)R4, NHC(═O)R9, NHC(═O)OR9, C(═O)R9, R9, OR9, NHSO2R4, SO2R4 or NR6R7;
R1b is hydrogen, halo, cyano, hydroxy or C1-4 alkyl, wherein said alkyl is optionally substituted with one to three groups independently selected from halo or hydroxy;
or R1a and R1b can be taken together with the atom between them to form a C3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl ring system wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl ring systems are optionally substituted with one to three groups independently selected from halo, hydroxy or aryl;
R2 is hydrogen, halo, cyano, OR4, R4, R9, C(═O)OR4, C1-3 alkyl-C(═O)OR5, NR4R7, NR6R9, NHC(═O)R4, NHC(═O)OR4, NHC(═O)O—C1-3 alkyl-OR5, NHC(═O)O(C1-3 alkyl)R9, NHC(═O)O(R4)C(═O)OH, C1-3 alkyl-NHC(═O)OR5, NHC(═O)NR6R7, NH(C═NH)NR6R7, C(═O)NR6R7, CH2C(═O)NR6R7, C(CH3)(NR6R7)C(═O)R4, NHC(═O)NH—C1-3 alkyl-R9, SO2R4, NHSO2R4, NHSO2R9, SO2NR6R7, P(═O)(OCH2CH3)2, P(═O)(OH)2;
or B(OH)2;
each R3 is independently hydrogen, R4, C3-6 cycloalkyl, halo, cyano or OR4, wherein said alkyl and cycloalkyl groups are optionally substituted with one to three groups independently selected from halo or hydroxy;
each R4 is independently hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo or hydroxy;
each R5 is independently hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo;
each R6 is independently hydrogen or C1-6 alkyl;
each R7 is independently hydrogen or C1-6 alkyl;
each R8 is independently hydrogen, halo or methyl;
each R9 is independently aryl, heteroaryl, heterocyclyl or C3-8 cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, cyclopropyl, R4, OR4, C(═O)OR4 or NR6R7;
n is an integer from zero to three;
or a pharmaceutically acceptable salt thereof.

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Factor XIa inhibitors

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Factor XIa inhibitors

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Abstract

Claims13