Bicyclic pyrimidinones as coagulation cascade inhibitors

A compound of Formula (I):

• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
• A1 is —CH2;
• wherein A1 is optionally substituted with 0–2 R14;
• X is —C(O)NH—(CR16R16)n—R8, —S(O)2NH—(CR16R16)n—R8, —CR15R15—NHC(═O)—(CR16R16)n—R8, —CR15R15—NHS(═O)2—(CR16R16)n—R8, or —CR16R16—NH—R8;
• n is 0, 1, or 2;
• R1 is H, C1–C6 alkyl substituted with 0–3 R2b, C2–C6 alkenyl substituted with 0–3 R2b, C2–C6 alkynyl substituted with 0–3 R2b, C3–C10 carbocycle substituted with 0–3 R2c, aryl substituted with 0–3 R2c, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R2c;
• R2 is H, —C(═O)R2a, —C(═O)OR2a, —C(═O)NR2aR2a, —S(═O)R2a, —S(═O)2R2a, —S(═O)2NR2aR2a, C1–C6 alkyl substituted with 0–3 R2b, C2–C6 alkenyl substituted with 0–3 R2b, C2–C6 alkynyl substituted with 0–3 R2b, C3–C10 carbocycle substituted with 0–3 R2c, aryl substituted with 0–3 R2c, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R2c;
• each R2a is, independently at each occurrence, H, C1–C6 alkyl substituted with 0–3 R2b, C2–C6 alkenyl substituted with 0–3 R2b, C2–C6 alkynyl substituted with 0–3 R2b, C3–C10 carbocycle substituted with 0–3 R2c, aryl substituted with 0–3 R2c, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R2c;
• provided when R2 is —S(═O)R2a or —S(═O)2R2a, then R2a is not H;
• each R2b is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21R21, —OR21a, —SR21a, C(═O)R21a, —S(═O)R21a, C1–C4 haloalkyl, C1–C4 haloalkoxy, C3–C10 carbocycle substituted with 0–3 R2c, aryl substituted with 0–3 R2c, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R2c;
• each R2c is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21R21, —OR21a, —SR21a, —C(═O)R21a, —S(═O)R21a, C1–C4 haloalkyl, C1–C4 haloalkoxy, C1–C4 alkyl substituted with 0–3 R2d, C2–C4 alkenyl substituted with 0–3 R2d, C2–C4 alkynyl substituted with 0–3 R2d, C3–C6 carbocycle substituted with 0–3 R2d, (C3–C6 carbocycle)C1–C4 alkyl- substituted with 0–3 R2d, (aryl)C1–C4 alkyl- substituted with 0–5 R2d, or 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–4 R2d;
• each R2d is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21R21, —OR21a, —SR21a, —C(═O)R21a, —S(═O)R21a, C1–C4 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, or C1–C4 haloalkoxy;
• R3 is H, F, Cl, Br, I, C1–C6 alkyl substituted with 0–3 R3a, C2–C6 alkenyl substituted with 0–3 R3a, C2–C6 alkynyl substituted with 0–3 R3a, C3–C10 carbocycle substituted with 0–3 R3b, aryl substituted with 0–3 R3b, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R3b;
• each R3a is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21R21, —OR21a, —SR21a, —C(═O)R21a, —S(═O)R21a, C1–C4 haloalkyl, C1–C4 haloalkoxy, C3–C10 carbocycle substituted with 0–3 R3b, aryl substituted with 0–3 R3b, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R3b;
• each R3b is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21R21, —OR21a, —SR21a, —C(═O)R21a, —S(═O)R21a, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C4 haloalkyl, C1–C4 haloalkoxy, C3–C10 carbocycle substituted with 0–3 R3c, aryl substituted with 0–3 R3c, or 5–10 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R3c;
• each R3c is, independently at each occurrence, H, F, Cl, Br, I, NO2, CN, —NCS, —CF3, —OCF3, —CH3, —OCH3, ═O, OH, CO2H, NH2, NH(CH3), N(CH3)2, CO2R21, —C(═O)NR21R21, —NHC(═O)R21, —NR21R21, —NHSO2R21, —SO2R21, —SO2NR21 R21, —OR21a, —SR21a, —C(═O)R21a, —S(═O)R21a, C1–C4 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, or C1–C4 haloalkoxy;
• R4 is H, halo, —CF3, —OCF3, OH, CN, NO2, —OR22, —SR22, —NR22R23, —C(═O)R22, —C(═O)NR22R23, —NR24C(═O)R22, —NR24C(═O)NR22R23, —NR24C(═O)NR24C(═O)R22, —C(═O)OR22, —OC(═O)R22, —OC(═O)OR22, —NR24C(═O)OR22, —OC(═O)NR22R23, —S(═O)R22, —S(═O)2R22, —S(═O)NR22R23, —S(═O)2NR22R23, —NR24S(═O)2NR22R23, —NR24S(═O)R22, —NR24S(═O)2R22, C1–C4 haloalkyl, C1–C8 alkoxy, (C1–C4 haloalkyl)oxy, C1–C8 alkyl substituted with 0–3 R4a, C2–C8 alkenyl substituted with 0–3 R4a, C2–C8 alkynyl substituted with 0–3 R4a, C3–C10 carbocycle substituted with 0–3 R26, aryl substituted with 0–5 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• each R4a is, independently at each occurrence, H, halo, —CF3, —OCF3, OH, CN, NO2, —OR22, —SR22, —NR22R23, —C(═O)R22, —C(═O)NR22R23, —NR24C(═O)R22, —NR24C(═O)NR22R23, —NR24C(═O)NR24C(═O)R22, —C(═O)OR22, —OC(═O)R22, —OC(═O)OR22, —NR24C(═O)OR22, —OC(═O)NR22R23, —S(═O)R22, —S(═O)2R22, —S(═O)NR22R23, —S(═O)2NR22R23, —NR24S(═O)2NR22R23, —NR24S(═O)R22, —NR24S(═O)2R22, C1–C4 haloalkyl, C1–C8 alkoxy, C1–C4 haloalkyl)oxy, C3–C10 carbocycle substituted with 0–3 R26, aryl substituted with 0–5 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• R5 is H, halo, C1-4 haloalkyl, C1–C8 alkyl substituted with 0–3 R4a, C2–C8 alkenyl substituted with 0–3 R4a, C2–C8 alkynyl substituted with 0–3 R4a, C3–C10 carbocycle substituted with 0–3 R26, aryl substituted with 0–5 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• alternatively, R4 and R5 may be joined together with the carbon atom to which they are attached to form:
• C3–C10 carbocycle substituted with 0–3 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• R6 is H, C1–C4 alkyl, C2–C4 alkenyl, aryl(C1–C3 alkyl)-, or C1–C4 alkoxyalkyl;
• R8 is phenyl substituted with one R8a and 0–2 R8b, 5–6 membered heteroaryl group comprising carbon atoms and 1, 2, or 3 heteroatoms selected from N, O, S, SO, and SO2, wherein said 5–6 membered heteroaryl is substituted with one R8a and 0–2 R8b, 9–10 membered bicyclic carbocycle, wherein said 9–10 membered bicyclic carbocycle contains at least one aromatic ring, and is substituted with one R8a and 0–2 R8b, or 9–10 membered bicyclic heterocycle comprising carbon atoms and 1, 2, or 3 heteroatoms selected from N, O, S, SO, and SO2, wherein said 9–10 membered bicyclic heterocycle contains at least one aromatic ring, and substituted with one R8a and 0–2 R8b;
• each R8a is, independently at each occurrence, C1–C6 alkyl, F, Cl, Br, I, OH, —CF3, —OCF3, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, CN, NO2, NH2, NH(C1–C3 alkyl), N(C1–C3 alkyl)2, —C(═NH)NH2, —C(═O)NH2, —CH2NH2, —CH2NH(C1–C3 alkyl), —CH2N(C1–C3 alkyl)2, —CH2CH2NH2, —CH2CH2NH(C1–C3 alkyl), —CH2CH2N(C1-3 alkyl)2, —(CR18R19)tC(═NR18)NR17R19, —(CR18R19)tC(═NR17)NR18R19, —(CR18R19)tNHC(═NR18)NR17R19, —(CR18R19)tNHC(═NR17)NR18R19, —(CR18R19)tNR17C(═NR18)NR18R19, —(CR18R19)tNR18CH(═NR17), —(CR18R19)tNR17CH(═NR18), —(CR18R19)tC(═O)H, —(CR18R19)tC(═O)R20, —(CR18R19)tNR18R19, —(CR18R19)tC(═O)NR18R19, —(CR18R19)tNR19C(═O)R20, —(CR18R19)tOR20, —(CR18R19)tS(═O)NR18R19, —(CR18R19)tS(═O)2NR18R19, —(CR18R19)tNR19S(═O)R20, —(CR18R19)tNR19S(═O)2R20, —(CR18R19)tSR20, —(CR18R19)tS(═O)R20, or —(CR18R19)tS(═O)2R20;
• provided that the moiety S(═O)R20 forms other than S(═O)H, and the moiety S(═O)2R20 forms other than S(═O)2H;
• each R8b is, independently at each occurrence, H, halogen, C1–C4 alkyl, C1–C4 alkoxy, OH, —CF3, —OCF3, CN, NO2, —C(═O)NH2, NH2, NH(C1–C3 alkyl), or —N(C1–C3 alkyl)2;
• each R14 is, independently at each occurrence, H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, OH, C1–C6 alkoxy, NH2, NH(C1–C3 alkyl), N(C1–C3 alkyl)2, C2–C6 alkoxyalkyl-, C2–C6 alkylaminoalkyl-, or C3–C6 dialkylaminoalkyl-;
• each R15 is, independently at each occurrence, H, F, methyl, ethyl, or propyl;
• alternatively, —CR15R15— forms a gem disubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group;
• each R16 is, independently at each occurrence, H, methyl, ethyl, propyl, butyl, phenyl, or benzyl;
• each R17 is, independently at each occurrence, H, OH, C1–C6 alkyl, —OR17a, —C(═O)OR17a, —OC(═O)R17a, —OC(═O)OR17a, —C(═O)R17a, —CH2OC(═O)R17a, —C(═O)SR17a, —C(═S)OR17a, —C(═S)SR17a, phenyl, phenyl-(C1–C3 alkyl)-, C1–C4 alkyl-C(═O)O—(C1–C4 alkyl)-OC(═O)—, aryl-C(═O)O—(C1–C4 alkyl)-OC(═O)—, C1–C6 alkyl-NH2—C(═O)—, or phenyl-NH2—C(═O)—;
• each R17a is, independently at each occurrence, C1–C6 alkyl substituted with 0–3 R17b, C2–C6 alkenyl substituted with 0–3 R17b, C3–C6 alkynyl substituted with 0–3 R17b, C3–C8 carbocycle substituted with 0–3 R17b, C3–C8 carbocycle(C1–C3 alkyl)- substituted with 0–3 R17b, aryl substituted with 0–3 R17b, aryl(C1–C3 alkyl)- substituted with 0–3 R17b, 5–6 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R17b;
• or 5–6 membered heterocycle-(C1–C3 alkyl)- group consisting of carbon atoms and 1–4 heteroatoms selected from the group:
• O, S, and N, and substituted with 0–3 R17b;
• each R17b is, independently at each occurrence, H, halogen, —CF3, —OCF3, C1–C6 alkyl, OH, C1–C6 alkoxy, CN, NO2, NH2, N(CH3)2, CO2H, —C(═O)O(C1–C6 alkyl), or —OC(═O)aryl;
• each R18 is, independently at each occurrence, H or C1–C4 alkyl;
• alternatively, R17 and R18 combine to form —C(═O)OC(═O)—, —C(═O)O—, —C(═O)S—, or —C(═S)O—;
• each R19 is, independently at each occurrence, H or C1–C4 alkyl;
• alternatively, R18 and R19, when attached to the same nitrogen, combine to form a 5–10 membered heterocycle consisting of one nitrogen atom, carbon atoms and 0–2 additional heteroatoms selected from the group consisting of N, O, and S;
• each R20 is, independently at each occurrence, H or C1–C6 alkyl;
• each R21 is, independently at each occurrence, H, C1–C4 alkyl, aryl, or aryl(C1–C3 alkyl)-;
• each R21a is, independently at each occurrence, H, C1–C4 alkyl, aryl, aryl(C1–C3 alkyl)-, or C1–C4 haloalkyl;
• each R22 is, independently at each occurrence, H, C1–C8 alkyl substituted with 0–3 R25, C2–C8 alkenyl substituted with 0–3 R25, C2–C8 alkynyl substituted with 0–3 R25, C3–C10 carbocycle substituted with 0–3 R26, aryl substituted with 0–5 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• provided when R4 or R4a are —OC(═O)OR22, —S(═O)R22, —S(═O)2R22, —NR24S(═O)R22, or —NR24S(═O)2R22, then R22 is not H;
• each R23 is, independently at each occurrence, H, C1–C4 alkyl, C2–C4 alkenyl, or C2–C4 alkynyl;
• alternatively, R22 and R23, when attached to the same nitrogen, combine to form a 5–6 membered heterocycle consisting of one nitrogen atom, carbon atoms and 0–1 additional heteroatoms selected from the group consisting of —N(R24)—, O, and S;
• each R24 is, independently at each occurrence, H or C1–C4 alkyl;
• each R25 is, independently at each occurrence, H, halo, —CF3, —OCF3, OH, CN, NO2, C1–C4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy, C3–C10 carbocycle substituted with 0–3 R26, aryl substituted with 0–5 R26, or 5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0–3 R27;
• each R26 is, independently at each occurrence, H, OH, halo, CN, NO2, —CF3, —SO2R28, NR29R30, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, C1–C4 haloalkyl, C1–C4 haloalkyl-oxy-, C1–C4 alkyloxy-, C1–C4 alkylthio-, C1–C4 alkyl-C(═O)—, or C1–C4 alkyl-C(═O)NH—;
• each R27 is, independently at each occurrence, H, OH, halo, —CF3, —SO2R28, NR29R30, or C1–C4 alkyl;
• each R28 is, independently at each occurrence, C1–C4 alkyl, phenyl, or benzyl;
• each R29 is, independently at each occurrence, H, —SO2R28, —C(═O)R28, C1–C4 alkyl, phenyl, or benzyl;
• each R30 is, independently at each occurrence, H or C1–C4 alkyl;
• and
• t, at each occurrence, is selected from 0, 1, 2, and 3.