Heteroaryl- phenyl heterobicyclic factor Xa inhibitors

A compound of formula Ia, Ib, or Ic:

• 162
• or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
• ring D1 is selected from pyridine, pyrazine, pyridazine, and pyrimidine and is substituted with 1 Ra and 0-1 Rb;
• ring D2 is a 5-membered heteroaromatic ring system comprising E, carbon atoms, and 0-3 N atoms, wherein E is selected from O, S, and N—Rc and ring D2 is substituted with 1 Ra and 0-1 Rb;
• ring D3 is a 5-membered heteroaromatic ring system comprising carbon atoms and from 0-3 additional N atoms and ring D3 is substituted with 1 Ra and 0-1 Rb;
• R is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, CN, C(═NR8)NR7R9,
• NHC(═NR8)NR7R9, NR8CH (═NR7), NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1 3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)2, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, and OCF3;
• Ra is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, CN, C(═NR8)NR7R9, NHC(═NR8)NR7R9, NR8CH (═NR7), NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH (C1-3 alkyl), CH2CH2N (C1-3 alkyl)2, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, and OCF3;
• Rb is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, CN, C(—NR8)NR7R9, NHC(═NR8)NR7R9, NR8CH(═NR7), NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)2, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, and OCF3;
• Rc is selected from H, C1-4 alkyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl) 2,CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)2, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, and OCF3;
• G is absent or is selected from CH2, C(O), O, NR3, s(O)p, CH2CH2, C(O)CH2, CH2C(O), OCH2, CH2O, NR3CH2, CH2NR3, s(O)pCH2, CH2S(O)p, CH2CH2CH2, C(O)CH2CH2, CH2C(O)CH2, CH2CH2C(O), OCH2CH2, CH2OCH2, CH2CH2O, NR3CH2CH2, CH2NR3CH2, CH2CH2NR3, S(O)pCH2CH2, CH2S(O)pCH2, and CH2CH2S(O)p;
• G1 is absent or is selected from (CR3R3a)1-5, (CR3R3a)0-2CR3═CR3(CR3R3a)0-2, (CR3R3a)0-2C═C(CR3R3a)0-2, (CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uC(O)O(CR3R3a)w, (CR3R3a)uOC(O)(CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CR3R3a)uNR3(CR3R3a)w, (CR3R3a)uC(O)NR3(CR3R3a)w, (CR3R3a)uNR3C(O)(CR3R3a)w, (CR3R3a)uOC(O)NR (CR3R3a)w, (CR3R3a)uNR C(O)O(CR3R3a)w, (CR3 R3a)uNR3C(O)NR3(CR3R3a)w, (CR3R3a)NR3C(S)NR3(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w, (CR3R3a)S(O)2(CR3R3a)w, (CR3R3a)S(O)NR3(CR3R3a)w, (CR3R3a)uNR3S(O)2(CR3R3a)w, (CR3R3a)uS(O)2NR3(CR3R3a)w, and (CR3R3a)uNR3S(O)2NR3(CR3R3a)w, wherein u+w total 0, 1, 2, 3, or 4, provided that G1 does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
• G2 is phenyl, naphthyl, or a 5-10 membered heteroaryl consisting of carbon atoms and from 1-3 heteroatoms selected from N, O, and S;
• Q is a group of formula II:
• 163
• one of P4 and M3 is -Z-A-B and the other is attached to G1;
• ring M, including M1 and M2, is a 6 or 7 membered carbocycle or 6 or 7 membered heterocycle, consisting of:
• carbon atoms and 1-3 heteroatoms selected from O, S(O)p, N, and NZ2
• ring M is substituted with 0-2 R1a and 0-2 carbonyl groups, and, comprises:
• 0-2 additional double bonds;
• ring P, including P1, P2, P3, and P4 is selected from group:
• 164
• “a” is absent or is a bond
• provided that when Q is a dihydroimidazolo[4,5-c]-pyridin-4-one then:
• (i) G1 is present and is other than alkylene;
• (ii) Z is present and is other than alkylene;
• (iii) Ring D1-G is present, D1-G is other than benzyloxy;
• (iv) Ring D3 is present;
• or
• (v) Ring D2 is present and is other than 5-methyl-1,2,4-oxadiazole or 5-oxo-1,2,4-oxadiazole;
• Z is selected from a bond, (CR2R2a)1-4—, (CR2R2a)qO(CR2R2a)q1, (CR2R2a)qNR3(CR2R2a)q1, (CR2R2a)qC(O) (CR2R2a)q1, (CR2R2a)qC(O) O(CR2R2a)q1, (CR2R2a)qOC(O) (CR2R2a)q1, (CR2R2a)qC(O)NR3(CR2R2a)q1, (CR2R2a)qNR3C(O) (CR2R2a)q1, (CR2R2a)qOC(O)O(CR2R2a)q1, (CR2R2a)qOC(O)NR3(CR2R2a)q1, (CR2R2a)qNR3C(O)O(CR2R2a)q1, (CR2R2a)qNR3C(O) NR3 (CR2R2a)q1, (CR2R2a)qS(CR2R2a)q1, (CR2R2a)qS(O) (CR2R2a)q1, (CR2R2a)qS(O) 2 (CR2R2a)q1, (CR2R2a)qSO2NR3 (CR2R2a)q1, (CR2R2a)qNR3SO2(CR2R2a)q1, and (CR2R2a)qNR3SO2NR3(CR2R2a)q1, wherein q+q1 total 0, 1, or 2, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
• Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3C;
• R1a is selected from H, —(CH2)r—R1b, —CH═CH—R1b, NCH2R1c, OCH2R1c, SCH2R1c, NH(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, S(CH2)2(CH2)tR1b, S(O)p(CH2)rR1d, O(CH2)rR1d, NR3(CH2)rR1d, OC(O)NR3 (CH2)rR1d, NR3C(O)NR3 (CH2)rR1d, NR3C(O) O(CH2)rR1d, and NR3C(O) (CH2)rR1d, provided that R1a forms other than an N-halo, N—N, N—S, N—O, or N—CN bond;
• alternatively, when two R1a's are attached to adjacent atoms, together with the atoms to which they are attached they form a 5-7 membered ring consisting of:
• carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, this ring being substituted with 0-2 R4b and comprising:
• 0-3 double bonds;
• R1b is selected from H, C1-3 alkyl, F, Cl, Br, I, —CN, —CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2a, S(O)pR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocycle substituted with 0-2 R4a, and 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p substituted with 0-2 R4a, provided that R1b forms other than an N-halo, N—N, N—S, N—O, or N—CN bond;
• R1c is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
• R1d is selected from C3-13 carbocycle substituted with 0-2 R4a, and 5-13 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p substituted with 0-2 R4a, provided that R1d forms other than an N—N, N—S, or N—O bond;
• R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
• R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
• R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
• R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
• alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
• R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
• R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
• R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
• R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
• R3d, at each occurrence, is selected from H, C1-4 alkyl, C1-4 alkyl-phenyl, and C(═O)R3c;
• A is selected from:
• C3-10 carbocyclic residue substituted with 0-2 R4, and
• 5-12 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
• is selected from:
• H, Y, and X-Y, provided that Z and B are attached to different atoms on A;
• X is selected from —(CR2R2a)1-4—, —CR2(CR2R2b) (CH2)t—, —C(O)—, —C(═NR1c)—, —CR2 (NR1cR2)—CR2 (OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, CR2R2aC(O), —S—, —S(O)—, —S(O)2—, —SCR2R2a—, —S(O)CR2R2a—, —S(O)2CR2R2a—, —CR2R2aS—, —CR2R2aS(O)—, —CR2R2aS(O)2—, —S(O)2NR2—, —NR2S(O)2—, NR2S(O)2CR2R2a—, —CR2R2aS(O )2NR2—, —NR2S(O)2NR2—, —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)O—, —OC(O)NR2—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—;
• Y is selected from:
• C3-10 carbocyclic residue substituted with 0-2 R4a, and
• 5-12 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
• R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR2R2a, (CH2)rN (→O) R2R2a, (CH2)rC(O)R2C, (CH2)rNR2C(O)R2b, (CH2)rC(O)NR2R2a, (CH2)rNR2C(O)NR2R2a, (CH2)rC(═NR2)NR2R2a, (CH2)rC(═NS(O)2R5)NR2R2a, (CH2)rNHC(═NR2)NR2R2a, (CH2)rC(O)NHC(═NR2)NR2R2a, (CH2)rSO2NR2R2a, (CH2)rNR2 O2NR2R2a, (CH2)rNR2SO2—C1-4 alkyl, (CH2)rNR2SO2R5, (CH2)r—NR2SO2R5a, (CH2)rS(O)pR5, (CH2)r—S(O)pR5a, (CF2)rCF3, (CH2)r—CF3, (CR4CR4d) (CR3eR3e)r—NR4eR4f, (CR4cR4d) (CR3eR3e)rOR4e, (CR4cR4d) (CR3eR3e)r—SR4e, (CR4cR4d) (CR3eR3e)rN (O) R4eR4f, (CH2)rNCH2R1c, CH2)rOCH2R1c, (CH2)rSCH2R1c, (CH2)rN(CH2)2(CH2)tR1b, (CH2)rO(CH2)2(CH2)tR1b, (CH2)rS(CH2)2(CH2)tR1b, (CH2)r5-6 membered carbocycle substituted with 0-1 R5, and CH2)r5-6 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p substituted with 0-1 R5;
• R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, CH2)rCN, (CH2)rNO2, (CH2)rNR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, C(═NS(O)2R5)NR2R2a, NHC(═NR2)NR2R2a, C(O)NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, (CH2)rCF3, NCH2R1c, OCH2R1c, SCH2R1c, N(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, S(CH2)2(CH2)tR1b, 5-6 membered carbocycle substituted with 0-1 R5, and 5-6 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p substituted with 0-1 R5;
• R4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CF2)rCF3, (CH2)r—CF3, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, C1-4 alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR2R2a, (CH2)rC(O) R2C, NR2C(O) R2b, C(O) NR2R2a, (CH2)rN═CHOR3, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, C(O)NHSO2—C1-4 alkyl, S(O)pR5, 5-6 membered carbocycle substituted with 0-1 R5, and 5-6 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p substituted with 0-1 R5;
• R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, CH2)r—F, (CH2)r—Cl, (CH2)r—Br, (CH2)r—I, C1-4 alkyl, CH2)r—CN, (CH2)r—NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p-C1-4 alkyl, S(O)p-phenyl, (CH2)rCF3, and (CF2)rCF3;
• R5, at each occurrence, is selected from H, C1-6 alkyl, ═O, CH2)rOR3, F, Cl, Br, I, —CN, NO2, (CH2)rNR3R3a, CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(═NOR3d), C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3—, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
• R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O )R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
• R7, at each occurrence, is selected from H, OH, C1-4 alkoxycarbonyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
• R8, at each occurrence, is selected from H, C1-6 alkyl, and (CH2) n-phenyl;
• alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5-6 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
• R9, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
• n, at each occurrence, is selected from 0, 1, 2, and 3;
• m, at each occurrence, is selected from 0, 1, and 2;
• p, at each occurrence, is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, and 3;
• s, at each occurrence, is selected from 0, 1, and 2;
• and,
• t, at each occurrence, is selected from 0, 1, 2, and 3.