US 7,453,002 B2 · Five-membered heterocycles useful as serine protease inhibitors

Abstract

The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, R4, R6, R11, X1, X2, and X3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

A compound of Formula (I):

or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
A is C3-10 carbocycle substituted with 0-1 R1 and 0-3 R2;
L is —C(O)NH—
R1 is, independently at each occurrence, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, —C(═NH)NH2, —C(O)NR8R9, —S(O)pNR8R9, —CH2)rNR7R8, —(CH2)rNR7CO2Ra, —CH2NH2, —CH2NH(C1-3 alkyl), —CH2N(C1-3 alkyl)2, —CH2CH2NH2, —CH2CH2NH(C1-C3 alkyl), —CH2CH2N(C1-3alkyl)2, —CH(C1-4 alkyl)NH2, —C(C1-4 alkyl)2NH2, —C(═NR8a)NR7R8, —NHC(═NR8a)NR7R8, ═NR8, —NR8CR8(═NR8a), F, Cl, Br, I, OCF3, CF3, —(CH2)rORa, —(CH2)rSRa, CN, 1-NH2-1-cyclopropyl, or C1-6 alkyl substituted with 0-1 R1a;
R1a is H, —C(═NR8a)NR7R8, —NHC(═NR8a)NR7R8, —NR8CH(═NR8a), —NR7R8, —C(O)NR8R9, F, OCF3, CF3, ORa, SRa, CN, —NR9SO2NR8R9,—NR8SO2Rc, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, or —(CF2)rCF3;
R2 is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)2NR8R9, —NR8S(O)2Rc, —S(O)Rc, —S(O)2Rc, C1-6 alkyl substituted with 0-2 R2a, C2-6 alkenyl substituted with 0-2 R2a, C2-6 alkynyl substituted with 0-2 R2a, —(CH2)r—C3-10 carbocycle substituted with 0-3 R2b,or —(CH2)r—5-to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R2b;
R2a is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR8, CN, OCF3, CF3, ORa, SRa, —NR7R8, —C(O)NR8R9, —NR7C(O)Rb, —S(O)pNR8R9, —NR8SO2Rc, —S(O)Rc, or —S(O)2Rc;
R2b is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR8, CN, NO2, ORa, SRa, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)2NR8R9, —S(O)2Rc, —NR8SO2NR8R9, —NR8SO2Rc, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, or C1-4 haloalkoxy-;
R3 is a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)p, wherein said heterocycle is substituted with 0-3R3a and 0-1 R3d;
R3a is, independently at each occurrence, ═O, F, Cl, Br, I, OCF3, CF3, NO2, CN, —(CH2)rOR3b, —(CH2)rSR3b, —(CH2)rNR7R8, C(═NR8a) NR8R9, —NHC(═NR8a)NR7R8, —NR8CR8(═NR8a), —(CH2)rNR8C(O)R3b, ═NR8, —(CH2)rNR8C(O)R3b, —(CH2)rNR8C(O)2R3b, —(CH2)rS(O)pNR8R9, —(CH2)rNR8S(O)pR3c, —S(O)pR3c, —S(O)pR3c, —C(O)—C1- C4 alkyl, —(CH2)rCO2R3b, —(CH2)rC(O)NR8R9, —(CH2)rOC(O)NR8R9, —NHCOCF3, —NHSO2CF3, —SO2NHR3b, —SO2NHCOR3c, —SO2NHCO2R3c, —CONHSO2R3c, —NHSO2R3c, —CONHOR3b, C1-4 haloalkyl, C1-4 haloalkoxy-, C1-6 alkyl substituted by R3d, C2-6 alkenyl substituted by R3d, C2-6 alkynyl substituted by R3d, C3-6 cycloalkyl substituted by 0-1 R3d, —(CH2)r—C3-10 carbocycle substituted with 0-3 R3d, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R3d;
R3b is, independently at each occurrence, H, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, —(CH2)r—C3-10 carbocycle substituted with 0-3 R3d, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R3d;
R3c is, independently at each occurrence, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, —(CH2)r—C3-10 carbocycle substituted with 0-3 R3d, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R3d;
R3d is, independently at each occurrence, H, ═O, —(CH2)rORa, F, Cl, Br, CN, NO2, —(CH2)rNR7R8, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7C(O)Rb, —C(O)NR8R9, —SO2NR8R9, —NR8SO2NR8R9, —NR8SO2Rc, —S(O)pRc, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rd, or —(CH2)r-5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rd;
R4 is H, F, Cl, Br, I, CF3, CN, —C(O)ORa, —C(O)NR8R9, or C1-6 alkyl;
R6is H;
R7 is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n—C3-10 carbocycle, —(CH2)n-(5-10 membered heteroaryl), —C(O)Rc, —CHO, —C(O)2Rc, —S(O)2Rc, —CONR8Rc, —OCONHRc, —C(O)O—(C1-4 alkyl)OC(O)—(C1-4 alkyl), or —C(O)O—(C1-4 alkyl)OC(O)—(C6-10 aryl);
wherein said alkyl, carbocycle, heteroaryl, and aryl are optionally substituted with 0-2 Rf;
R8 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)r-phenyl, or —(CH2)n-5-10 membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
wherein said alkyl, phenyl and heterocycle are optionally substituted with 0-2 Rf;
alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rd;
R8a is, independently at each occurrence, H, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl)-C1-4 alkoxy, —(CH2)n-phenyl, —(CH2)n-(5-10 membered heteroaryl), —C(O)Rc, —C(O)2Rc, —C(O)O—(C1-4 alkyl)OC(O)—(C1-4 alkyl), or —C(O)O—(C1-4 alkyl)OC(O)—(C6-10 aryl);
wherein said phenyl, aryl, and heteroaryl is optionally substituted with 0-2 Rf;
R9 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)r-phenyl;
wherein said alkyl and phenyl are optionally substituted with 0-2 Rf;
R9a is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
alternatively, R8 and R9, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rd;
R11 is C1-6 alkyl or —(C14R15)r—C3-C10 aromatic carbocycle substituted with 0-3 R11.
R11b is, independently at each occurrence, H, F, Cl, Br, CN, NO2, CF3, OCF3, OCHF2, —C(O)Ra, —C(O)ORa, —SORc, —SO2Rc, —NR7R8, —C(O)NR7R8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy-, or —(CH2)r—C3-10 carbocycle ;
R14 and R15 are, independently at each occurrence, H, F, or C1-4 alkyl;
C2-6 alkynl, or (CH2)n-phenyl;
Rg is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
and
s, at each occurrence, is selected from 1, 2, 3, and 4.

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Five-membered heterocycles useful as serine protease inhibitors

Life of this patent

Five-membered heterocycles useful as serine protease inhibitors

Life of this patent

Abstract

Claims17