Factor xia macrocycles with novel p1 groups

A compound of Formula (I):

• P-Ma (I)
• or a stereoisomer, an enantiomer, a diastereomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
• Ma is independently selected from Formulae (M1), (M2), (M3), and (M4):
• P is independently selected from Formulae (P1), (P2), (P3), (P4), (P5), (P6), (P7), (P8), P(9), P(10), P(11), P(12), P(13), and P(14):
• Cyc is C3-6 cycloalkyl;
• ring A is independently selected from
• Ring B is independently selected from aryl and 5- to 10-membered heterocyclyl;
• W1 is independently selected from (CR1R2)1-2, O, NH, and N(C1-4 alkyl);
• W2 is independently selected from —C(O)NH, —NHC(O)—, and —NHC(O)CH2—;
• X1 is independently selected from —CR23NH—, —NHC(═O)— and —C(═O)NH—;
• provided when W1 is O, NH, and N(C1-4 alkyl), X1 is not —NHC(═O)—;
• X2 is independently selected from N and CR4;
• X3 is independently selected from CR18 and N;
• X4 is independently selected from CR20, O, S, N, NH, and NC1-4alkyl;
• L1 is independently selected from CH2, O, NH, NC1-4alkyl, and S;
• L2 is independently selected from NH and NC1-4alkyl;
• R1 and R2 are independently selected from H, halogen, C1-4 alkyl substituted with 0-4 Re, ORb, and C3-5 cycloalkyl substituted with 1-4 R6;
• alternatively, two adjacent R1 groups form a bond;
• R3 is independently selected from H, NO2, ═O, halogen, C1-4 alkyl substituted with 1-5 R5, C2-4 alkenyl substituted with 1-5 R5, C2-4 alkynyl substituted with 1-5 R5, CN, —(CH2)n—ORb, —(CH2)n—NRaRa, —(CH2)n—C(═O)Rb, —(CH2)n—C(═O)ORb, —(CH2)n—NRaC(═O)ORb, —(CH2)n—NRaC(═O)Rb, —(CH2)n—NRaC(N—CN)NRaRa, —(CH2)n—NRaC(NH)NRaRa, —(CH2)n—N═CRbNRaRa, —(CH2)n—NRaC(═O)NRaRa, —(CH2)n—C(═O)NRaRa, —(CH2)n—NRaC(═S)NRaC(═O)Rb, —(CH2)n—S(═O)pRc, —(CH2)n—S(═O)pNRaRa, —(CH2)n—NRaS(═O)pNRaRa, —(CH2)n—NRaS(═O)pRc, —(CRdRd)n—C3-10 carbocyclyl substituted with 1-5 R5, and —(CRdRd)n-4- to 10-membered heterocyclyl substituted with 1-5 R5;
• optionally, two adjacent R3 groups on the carbocyclyl and heterocyclyl may form a ring substituted with 1-5 R5;
• R3a is independently selected from H and C1-4alkyl;
• R3b is independently selected from H, C1-4 alkyl substituted with 1-5 R5, C2-4 alkenyl substituted with 1-5 R5, C2-4 alkynyl substituted with 1-5 R5, —(CH2)n—CN, —(CH2)n—ORb, —(CH2)n—OC(═O)NRaRa, —(CH2)n—NRaRa, —(CH2)n—C(═O)Rb, —(CH2)n—C(═O)ORb, —(CH2)n—NRaC(═O)ORb, —(CH2)n—NRaC(═O)Rb, —(CH2)n—NRaC(N—CN)NRaRa, —(CH2)n—NRaC(NH)NRaRa, —(CH2)n—N═CRbNRaRa, —(CH2)n—NRaC(═O)NRaRa, —(CH2)n—C(═O)NRaRa, —(CH2)n—NRaC(═S)NRaC(═O)Rb, —(CH2)n—S(═O)pRc, —(CH2)n—S(═O)pNRaRa, —(CH2)n—NRaS(═O)pNRaRa, —(CH2)n—NRaS(═O)pRc, —(CRdRd)n—C3-10 carbocyclyl substituted with 1-5 R5, and —(CRdRd)n-4- to 10-membered heterocyclyl substituted with 1-5 R5;
• optionally, two adjacent R3 groups on the carbocyclyl and heterocyclyl may form a ring substituted with 1-5 R5;
• alternatively, R3a and R3b are taken together to form a C3-6 carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 heteroatoms selected from O, NR3c, S, wherein the carbocyclic or heterocyclic ring is substituted with R3d;
• alternatively, R3a and R10 are taken together to form a C3-6 carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, NR3cO, and S, wherein the carbocylic or heterocyclic ring is substituted with R3d;
• R3c is independently selected from H, C1-4 alkyl substituted with 1-5 R5, —(CH2)n—C(═O)Rb, —(CH2)n—C(═O)ORb, —(CH2)n—C(═O)NRaRa, —(CH2)n—NHC(═O)ORb, —(CH2)n—S(═O)pRc, —(CH2)n—S(═O)pNRaRa, —(CRdRd)n—C3-10 carbocyclyl substituted with 1-5 R5, and —(CRdRd)n-4- to 10-membered heterocyclyl substituted with 1-5 R5;
• R3d is independently selected from H, NO2, ═O, halogen, C1-4 alkyl substituted with 1-5 R5, C2-4 alkenyl substituted with 1-5 R5, C2-4 alkynyl substituted with 1-5 R5, CN, —(CH2)n—ORb, —(CH2)n—NRaRa, —(CH2)n—C(═O)Rb, —(CH2)n—C(═O)ORb, —(CH2)n—NRaC(═O)ORb, —(CH2)n—NRaC(═O)Rb, —(CH2)n—NRaC(N—CN)NRaRa, —(CH2)n—NRaC(NH)NRaRa, —(CH2)n—N═CRbNRaRa, —(CH2)n—NRaC(═O)NRaRa, —(CH2)n—C(═O)NRaRa, —(CH2)n—NRaC(═S)NRaC(═O)Rb, —(CH2)n—S(═O)pRc, —(CH2)n—S(═O)pNRaRa, —(CH2)n—NRaS(═O)pNRaRa, —(CH2)n—NRaS(═O)pRc, —(CRdRd)n—C3-10 carbocyclyl substituted with 1-5 R5, and —(CRdRd)n-4- to 10-membered heterocyclyl substituted with 1-5 R5;
• R3e is independently selected from H and C1-4alkyl;
• alternatively, R3b and R3e are taken together to form a heterocyclic ring compring carbon atoms and 1-3 heteroatoms selected from O, NR3c, S, wherein the heterocyclic ring is substituted with R3d;
• R4 is independently selected from H, halogen, CN, C1-6 alkyl substituted with 1-5 R9, and C3-6 cycloalkyl substituted with 1-5 R9;
• R5, at each occurrence, is independently selected from H, D, —(CH2)n—ORb, ═O, —(CH2)nNH2, —(CH2)nCN, halogen, C1-6 alkyl, —(CH2)n—C(═O)ORb, —(CH2)n—ORb, —(CH2)n—C3-10 carbocyclyl substituted with 0-5 Re, —(CH2)n-4- to 10-membered heterocyclyl substituted with 0-5 Re, and —O-4- to 10-membered heterocyclyl substituted with 0-5 Re;
• R6 is independently selected from H, OH, ═O, —(CH2)nNH2, —(CH2)nCN, halogen, C1-6 alkyl, —(CH2)n—C(═O)OH, —(CH2)n—C(═O)OC1-4 alkyl, —(CH2)n—OC 1-4 alkyl, —(CH2)n—C3-10 carbocycle substituted with 0-5 Re, —(CH2)n-4- to 10-membered heterocycle substituted with 0-5 Re, and —(CH2)n-4- to 10-membered heterocycle substituted with 0-5 Re;
• R7 is —(CH2)nNH2;
• R8 is independently selected from H, OH, F, Cl, Br, C1-4 alkyl, C1-4 alkoxy, CF3, CN, C3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle;
• R9, at each occurrence, is independently selected from H, halogen and OH;
• R10 is independently selected from H, C1-4alkyl, and aryl;
• R1 is independently selected from H, halogen, CN, OCH3, OCF3, CH3, C(═O)CH3, CHF2, CF3, CCH3F2, OCHF2, aryl, C3-6 cycloalkyl, and 4-6 membered heterocycle, wherein said aryl, cycloalkyl and heterocycle is optionally substituted with R24;
• R12 is independently selected from H and halogen;
• R13 is independently selected from H, F, Cl, methyl, ethyl, isopropyl, and OCH3;
• R14 is independently selected from H, F, and Cl;
• R15 is independently selected from pyrazolyl, aminopyrazolyl, pyrrolidinyl, triazolonyl, aminothiadiazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and 2-pyridonyl;
• R16 is independently selected from H, CN, ORb, halogen, NRaRa, and C1-3 alkyl substituted with 0-5 Re;
• R17 is independently selected from H, methyl and halogen;
• R18 is independently selected from H, methyl and halogen;
• R19 is independently selected from C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, and C3-6 cycloalkyl;
• R20 is independently selected from H, halogen, CN, and C1-4 alkyl;
• R21 is independently selected from C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, and C3-6 cycloalkyl;
• R22 is independently selected from C1-4 alkyl and NRaRa;
• R23 is independently selected from H, C1-4 alkyl substituted with 0-3 Re, CO2H, —(CH2)nCO2(C1-4 alkyl), —(CH2)nCO2NH2, —CONH(C1-4 alkoxy), —CO2(CH2)2O(C1-4 alkyl), —CO2(CH2)2N(C1-4 alkyl)2, —CONH(CH2)2O(C1-4 alkyl), —CONH(CH2)2N(C1-4 alkyl)2, —CON(C1-4 alkyl)(CH2)2O(C1-4 alkyl), —CON(C1-4 alkyl)(CH2)2N(C1-4 alkyl)2, —CONHBn, —CONH(OBn), and —(CO)0-1(CH2)0-3—C3-6 carbocycle;
• R24, at each occurrence, is independently selected from H, halogen, CN, NO2, ═O, C(═O)NRaRa, C(═O)ORb, Si(C1-4 alkyl)3, —(CH2)n—ORb, —(CH2)n—NRaRa, C(═NOH)NH2, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, aryl substituted with 0-5 Re, —(CH2)n—C3-6 cycloalkyl substituted with 0-5 Re, —(CH2)n—O-4- to 10-membered heterocyclyl substituted with 0-5 Re;
• Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re;
• or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
• Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re;
• Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3-6carbocyclyl, and heterocyclyl;
• Rd, at each occurrence, is independently selected from H and C1-4alkyl substituted with 0-5 Re;
• Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, ═O, C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, —(CH2)n—C3-6 cycloalkyl, —(CH2)n-aryl, —(CH2)n-heterocyclyl, CO2H, —(CH2)nORf, SRf, and —(CH2)nNRfRf;
• Rf, at each occurrence, is independently selected from H, C1-5 alkyl optionally substituted with F, Cl, Br, C3-6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1-4alkyl;
• n, at each occurrence, is an integer independently selected from 0, 1, 2, and 4;
• and
• p, at each occurrence, is an integer independently selected from 0, 1, and 2.