US 8,410,155 B2 · Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIA inhibitors

Abstract

The present invention provides compounds of Formula (I) or (II): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, R3, R4, R8a, R11 and M are as defined herein. The compounds of Formula (I) or (II) are 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 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.

A compound of Formula (I):

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
A is a C3-10 carbocycle substituted with 0-1 R1 and 0-3 R2, or a 5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-1 R1 and 0-3 R2;
provided that when A is a heterocycle containing one or more nitrogen atoms, A is not attached to L1 via any of the nitrogen atoms on the A ring;
L1 is —CHR5CH2—, —CH(NR7R8)CH2—, —CR5═CH—, —C≡C—, —OCH2—, —C(R5R6)NH—, —CH2O—, —SCH2—, —S(O)CH2—, —SO2CH2—, —CH2NR10—, or —NHNH—;
provided that when L1 is —CH2O—, then A is other than an unsubstituted phenyl;
R1 is, independently at each occurrence, F, Cl, Br, I, OCF3, CF3, —(CH2)rORa, —(CH2)rSRa, CN, —(CH2)rNR7R8, —C(═NR8) NR8R9, —C(O)NR8R9, —S(O)pNR8R9, or C1-6 alkyl substituted with 0-1 R1a;
R1a is F, OCF3, CF3, ORa, SRa, CN, —NR7R8, —C(O)NR8R9, —NR8C(O)Rc, —S(O)pNR8R9, —NR8SO2Rc, or —(CF2)rCF3;
R2 is, independently at each occurrence, ═O, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, —(CH2)rORa, —(CH2)rSRa, —(CH2)rC(O)Ra, —(CH2)rC(O)ORa, —(CH2)rOC(O)Ra, —(CH2)rNR7R8, —(CH2)rC(O)NR8R9, —(CH2)rNR8C(O)Rc, —(CH2)rNR8C(O)ORc, —NR8C(O)NR8Rc, —S(O)pNR8R9, —NR8S(O)pRc, —S(O)Rc, —S(O)2Rc, C1-6 alkyl substituted with 0-1 R2a, —(CH2)r-3-7 membered carbocycle optionally substituted with 0-2 R2b, or —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-2 R2b;
alternately, when R1 and R2 groups are substituents on adjacent atoms they may be taken together with the atoms to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising carbon atoms and 0-4 heteroatoms selected from N, O, and S(O)p and substituted with 0-2 Rg;
R2a is F, OCF3, CF3, ORa, SRa, CN, —NR7R8, —C(O)NR8R9, —NR8C(O)Rc, —NR8C(O)ORc, —NR8C(O)NR8Rc, —S(O)pNR8R9, —NR8SO2Rc, or —(CF2)rCF3;
R2b is, independently at each occurrence, ═O, F, Br, Cl, OCF3, CF3, —(CH2)rORa, —(CH2)rSRa, —(CH2)rCN, —(CH2)rNR7R8, —(CH2)rC(O)ORa, —(CH2)rOC(O)Ra, —(CH2)rC(O)NR8R9, —(CH2)rNR8C(O)Rc, —(CH2)rNR8C(O)ORc, —(CH2)rS(O)pNR8R9, —(CH2)rNR8SO2Rc, C1-4 alkyl or —(CF2)rCF3;
R3 is —(CH2)r—C3-10 carbocycle substituted with 0-3 R3a and 0-1 R3d, or —(CH2)r-5- to 12-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 R3a and 0-1 R3d;
R3a is, independently at each occurrence, ═O, ═NR8, F, Cl, Br, I, OCF3, CF3, —(CH2)rCN, NO2, —(CH2)rOR3b, —(CH2)rSR3b, —(CH2)rNR7R8, —NHC(O)NR8R9, —(CH2)rC(O)OR3b, —C(O)C1-4 alkyl, —SO2NHR3b, —SO2NHCOR3c, —SO2NHCO2R3c, —CONHSO2R3c, —(CH2)rNR8C(O)R3b, —(CH2)rNR8CO2R3c, —(CH2)rS(O)pNR8R9, —(CH2)rNR8S(O)pR3c, —NHSO2CF3, —S(O)R3c, —S(O)2R3c, —(CH2)rOC(O)R3b, —(CH2)rC(O)NR8R9, —(CH2)rOC(O)NR8R9, —NHCOCF3, —NHSO2R3c, —CONHOR3b, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-6 alkyl substituted by R3e, C2-6 alkenyl substituted by R3e, C1-6 alkynyl substituted by R3e, C3-6 cycloalkyl substituted by 0-1 R3d, —(CH2)r—C6-10 carbocycle substituted by 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;
alternately, when two R3a groups are substituted on adjacent atoms, they can be taken together with the atoms to which they are attached to form a C3-10 carbocycle substituted with 0-2 R3d, or 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 0-2 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, F, Cl, Br, CN, NO2, —(CH2)rNR7R8, —(CH2)rORa, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR8C(O)Rc, —C(O)NR8R9, —S(O)2NR8R9, —NR7R8, —NR8S(O)2NR8R9, —NR8S(O)2Rc, —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;
R3e is, independently at each occurrence, H, —(CH2)rORa, F, ═O, CN, NO2, —(CH2)rNR7R8, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR8C(O)Rc, —C(O)NR8R9, —S(O)2NR8R9, —NR8S(O)2NR8R9, NR8S(O)2Rc, —S(O)pRc, —(CF2)rCF3, —(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, OCF3, CF3, CN, NO2, —(CH2)rORa, —(CH2)rSRa, —(CH2)rC(O)Ra, —(CH2)rC(O)ORa, —OC(O)Ra, —(CH2)rNR7R8, —NR8(CH2)rC(O)ORa, —(CH2)rC(O)NR8R9, —(CH2)rNR8C(O)Rc, —(CH2)rNR8C(O)2Rb, —(CH2)rNR8C(O)NR8R9, —S(O)pNR8R9, —NR8S(O)pRc, —S(O)2Rc, or C1-4 alkyl substituted with 0-2 R4a;
R4a is, independently at each occurrence, H, F, ═O, C1-6 alkyl, ORa, SRa, CF3, CN, NO2, —C(O)Ra, —C(O)ORa, —NR7R8, —C(O)NR8R9, —NR8C(O)Rc, —S(O)pNR8R9, —NR8S(O)pRc, —S(O)Rc, or —S(O)2Rc;
R5 is, independently at each occurrence, H, F, CF3, —(CH2)rORa, ═O, —(CH2)rNR7R8, —S(O)pNR8R9, —(CH2)rCO2Ra, —(CH2)rCONR8R9, or C1-4 alkyl;
R6 is, independently at each occurrence, H, F, or C1-4 alkyl;
R7 is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n—C3-10 carbocycle, —(CH2)n-(5- to 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 substituted with 0-2 Rf;
wherein said heteroaryl comprises, carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
R8 is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n-phenyl, or —(CH2)n-5- to 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 heterocycle comprising:
carbon atoms and 0-3 additional heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rf;
R8a is H or C1-4 alkyl;
R9 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
wherein said alkyl and phenyl are optionally substituted with 0-2 Rf;
alternatively, R8 and R9, when attached to the same nitrogen, combine to form a 5- to 12-membered heterocycle 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;
R10 is, independently at each occurrence, H or C1-6 alkyl substituted with 0-3 R10a;
R10a is, independently at each occurrence, H, ═O, C1-4 alkyl, ORa, SRa, F, CF3, CN, NO2, —C(O)Ra, —C(O)ORa, —C(O)NR8R9, —NR8C(O)Rc, —S(O)pNR8R9, —NR8S(O)pRc, or —S(O)pRc;
R11 is H, C1-4 alkyl, or benzyl;
Ra is, independently at each occurrence, H, CF3, C1-6 alkyl, —(CH2)r—C3-7 cycloalkyl, —(CH2)r—C6-10 aryl, 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 cycloalkyl, aryl or heterocycle groups are optionally substituted with 0-2 Rf;
Rb is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-2 Rd, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p and substituted with 0-3 Rd;
Rc is, independently at each occurrence, CF3, C1-6 alkyl substituted with 0-2 Rf, C3-6 cycloalkyl substituted with 0-2 Rf, C6-10 aryl, 5- to 10-membered heteroaryl, (C6-10 aryl)-C1-4 alkyl, or (5- to 10-membered heteroaryl)-C1-4 alkyl, wherein said aryl is substituted with 0-3 Rf and said heteroaryl comprises:
carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p and substituted with 0-3 Rf;
Rd is, independently at each occurrence, H, ═O, ═NR8, ORa, F, Cl, Br, I, CN, NO2, —NR7R8, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR8C(O)Rc, —C(O)NR8R9, —SO2NR8R9, —NR8SO2NR8R9, —NR8SO2—C1-4 alkyl, —NR8SO2CF3, —NR8SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, or C2-6 alkynyl substituted with 0-2 Re;
Re is, independently at each occurrence, ═O, ORa, F, Cl, Br, I, CN, NO2, —NR7R8, —C(O)Ra, —C(O)ORa, —NR8C(O)Rc, —C(O)NR8R9, —SO2NR8R9, —NR8SO2NR8R9, —NR8SO2—C1-4 alkyl, —NR8SO2CF3, —NR8SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, or —(CF2)rCF3;
Rf is, independently at each occurrence, H, ═O, —(CH2)rORg, F, Cl, Br, I, CN, NO2, —NRgRg, —C(O)Rg, —C(O)ORg, —NRgC(O)Rg, —C(O)NRgRg, —SO2NRgRg, —NRgSO2NRgRg, —NRgSO2—C1-4 alkyl, —NRgSO2CF3, —NRgSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)n-phenyl, or —(CH2)n-5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
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;
and
r, at each occurrence, is selected from 0, 1, 2, 3, and 4.

56 more elements

Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIA inhibitors

Life of this patent

Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIA inhibitors

Life of this patent

Abstract

Claims15