FIVE-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS

摘要

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.

主权项

1. A compound of Formula (V):or its stereoisomers, tautomers, a pharmaceutically acceptable salts, or solvates thereof, wherein:
A is 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 when A is a heterocycle containing one or more nitrogen atoms, A is not attached to L via any of the nitrogen atoms on the A ring; X1, X2, and X3 are independently CR3, CR4, CR4R5, O, S(O)p, N, NR3, NR6, or C(O); provided that no S—S, S—O, or O—O bond is present in the ring; provided thatis other than Z is —C(R11)(R12)—, —C(R11)(R12)—(CH2)—, —NR13—, or —NR13CH2—; L is —C(O)NR10—, —NR10C(O)—, —CH2C(O)NR10—, —CH2NR10C(O)—, —C(O)NR10CH2—, —NR10C(O)CH2—, —S(O)2NR10—, —NR10S(O)2—, —CH2S(O)2NR10—, —CH2NR10S(O)2—, —S(O)2NR10CH2—, —NR10S(O)2CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2NR7—, —NR7CH2—, —CH2CH2NR7—, —NR7CH2CH2, —CH2NR7CH2—, —CH2O—, —OCH2—, —CH2S(O)p—, —S(O)pCH2—, —CH2CH2O—, —OCH2CH2—, —CH2OCH2—, —CH2CH2S(O)p—, —S(O)pCH2CH2—, —CH2S(O)pCH2—, —CH2C(O), —CH2C(O)CH2—, —CH2CH2C(O)—, —C(O)CH2CH2—, or —C(O)CH2—; R1 is, independently at each occurrence, —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —C(═NH)NH2, —C(O)NR8R9, —S(O)pNR8R9, —(CH2)rNR7R8, —(CH2)rNR7C(O)ORa, —CH2NH2, —CH2NH(C1-3 alkyl), —CH2N(C1-3 alkyl)2, —CH2CH2NH2, —CH2CH2NH(C1-3 alkyl), —CH2CH2N(C1-3 alkyl)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; alternately, when R1 and R2 groups are substituted on adjacent ring atoms, they can be taken together with the ring 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, wherein said carbocycle or heterocycle is substituted with 0-2 R2b; R3 is, independently at each occurrence, —(CH2)rC(O)NR8R9, —(CH2)rC(O)NR8(CH2)sCO2R3b, —(CH2)rCO2R3b, —(CH2)r—C3-10 carbocycle substituted with 0-3 R3a and 0-1 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 R3a 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)—C1-4 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; alternately, when two R3a groups are located 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)rC3-10 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, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF3, CF3, ORa, SRa, CN, NO2, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR8R9, —NR7C(O)Rb, —S(O)pNR8R9, —NR8S(O)pRc, —S(O)Rc, —S(O)2Rc, C1-6 alkyl substituted with 0-2 R4a, C2-6 alkenyl substituted with 0-2 R4a, C2-6 alkynyl substituted with 0-2 R4a, —(CH2)r—C3-10 carbocycle substituted with 0-3 R4b, 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 R4b; R4a is, independently at each occurrence, H, F, ═O, C1-6 alkyl, ORa, SRa, CF3, CN, NO2, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR8R9, —NR7C(O)Rb, —S(O)pNR8R9, —NR8S(O)2Rc, —S(O)Rc, or —S(O)2Rc; R4b is, independently at each occurrence, H, ═O, ═NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, CF3, —SO2Rc, —NR7R8, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR8R9, —NR7C(O)Rb, —S(O)pNR8R9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, or C1-4 haloalkoxy-; alternately, R3 and R4 groups when located on adjacent atoms, can be taken together 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; R5 is, independently at each occurrence, H, F, OCF3, CF3, ORa, SRa, CN, NO2, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)pNR8R9, —NR8S(O)2Rc, —S(O)Rc, —S(O)2Rc, C1-6 alkyl substituted with 0-2 R5a, C2-6 alkenyl substituted with 0-2 R5a, C2-6 alkynyl substituted with 0-2 R5a, —(CH2)r—C3-10 carbocycle substituted with 0-3 R5b, or —(CH2)r-5-10 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 R5b; R5a is, independently at each occurrence, H, ═O, ORa, SRa, F, Cl, Br, I, CF3, OCF3, CN, NO2, —NR7R8, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)2NR8R9, —NR8S(O)2Rc, —S(O)Rc, or —S(O)2Rc; R5b is, independently at each occurrence, H, ═O, ═NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, CF3, —SO2Rc, —NR7R8, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR7R8, —C(O)NR8R9, —NR7C(O)Rb, —S(O)2NR8R9, —S(O)2Rc, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, or C1-4 haloalkoxy-; R6 is, independently at each occurrence, H, C1-6 alkyl, C1-4 haloalkyl, —CH2ORa, —C(O)Rc, —C(O)2Rc, —S(O)2Rc, or —(CH2)r-phenyl substituted with 0-3 Rd; 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)n-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; R10 is, independently at each occurrence, H, C1-6 alkyl substituted with 0-3 R10a, C2-6 alkenyl substituted with 0-3 R10a, C2-6 alkynyl substituted with 0-3 R10a, —(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; R10a is, independently at each occurrence, H, ═O, C1-4 alkyl, ORa, SRa, F, CF3, CN, NO2, —C(O)ORa, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)pNR8R9, —NR8SO2Rc—, —S(O)Rc or —S(O)2Rc; R11 is C1-4 haloalkyl, —(CH2)rC(O)NR8R9, C1-6 alkyl substituted with 0-3 R11a, C2-6 alkenyl substituted with 0-3 R11a, C2-6 alkynyl substituted with 0-3 R11a, —(CR14R15)r—C3-10 carbocycle substituted with 0-3 R11b, or —(CR14R15)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 R11b; R11a is, independently at each occurrence, H, ═O, C1-4 alkyl, ORa, CF3, SRa, F, CN, NO2, NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —S(O)pNR8R9, —NR8S(O)pRc, —C(O)Ra, —C(O)ORa, —S(O)pRc, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy-, —(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, and substituted with 0-3 Rd; R11b is, independently at each occurrence, H, ═O, ═NR8, ORa, F, Cl, Br, CN, NO2, CF3, OCF3, OCHF2, —C(O)Ra, —C(O)ORa, —SORc, —SO2Rc, —NR7R8, —C(O)NR7R8, —NR7C(O)Rb, —NR8C(O)2Rc, —S(O)pNR8R9, —NR8S(O)pRc, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy-, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rd, or —(CH2)r-5-10 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; alternately, when two R11b 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 heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p and substituted with 0-2 Rg; R12 is, independently at each occurrence, H, F, or C1-4 alkyl; R13 is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n-phenyl, —(CH2)n-(5-10 membered heteroaryl), —C(O)Rc, —C(O)ORc, —CONR8Rc, —OCONR8Rc, —S(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 the said alkyl, phenyl, heteroaryl, aryl are optionally substituted with 0-2 Rf; R14 and R15 are, independently at each occurrence, H, F, or C1-4 alkyl; alternately, R14 combines with R15 to form ═O; 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 and heteroaryl 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 0-3 Rd, or —(CH2)r-5-10 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; 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 and heteroaryl groups are optionally 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)Ra, —C(O)NR7R8, —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, —NR8R9, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —NR8C(O)Ra, —C(O)NR7R8, —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)r—ORg, F, Cl, Br, I, CN, NO2, —NR9aR9a, —C(O)Rg, —C(O)ORg, —NR9aC(O)Rg, —C(O)NR9aR9a, —SO2NR9aR9a, —NR9aSO2NR9aR9a, —NR9aSO2—C1-4 alkyl, —NR9aSO2CF3, —NR9aSO2-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, 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; provided that: (a) when group i. and when L is —NHC(O)—, R14 does not combine with R15 to form ═O; ii. and when L is —C(O)NH— and A is phenyl, R1 is not —NHC(O)H; (b) when group i. and when L is —NHC(O)— and R3 combines with R4 to form a phenyl ring fused with the thiazole, the phenyl ring is substituted with at least one R3a; ii. and when L is —C(O)NH— and A is phenyl, R1 is not —NHC(O)H; and (c) A is not a substituted or unsubstituted oxazolinone, thiophene, oxadiazole, or furan.