Imidazo-heterobicycles as factor Xa inhibitors

A compound of formula III:

• or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
• ring M is substituted with 0-2 R3 and is selected from the group:
• M3 is -A-B;
• G is a group of formula IIa or IIb:
• ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered non-aromatic ring consisting of carbon atoms, 0-1 double bonds, and from 0-2 N, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
• alternatively, ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered aromatic system consisting of carbon atoms and from 0-2 heteroatoms selected from the group consisting of N, O, and S, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 0-1 R;
• R is selected from F, Cl, Br, I, OH, 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), and CH2CH2N(C1-3 alkyl)2;
• alternatively, the bridging portion of ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with Ra and Rb;
• Ra is selected from F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, CN, C(═NR8)NR7R9, NHC(═NR8)NR7R9, NR8CH(═NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, SCH3, SCH2CH3, SCH(CH3)2, SCH2CH2CH3, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
• Rb is selected from H, F, Cl, Br, I, C1-4 alkyl, SR3, CO2R3, NO2, (CH2)tOR3, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
• alternatively, Ra and Rb combine to form methylenedioxy or ethylenedioxy;
• A is selected from:
• C3-10 carbocycle substituted with 0-2 R4, and
• 5-10 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
• B is selected from:
• H, Y, X-Y, C(═NR2)NR2R2a, and NR2C(═NR2)NR2R2a, provided that ring M and B are attached to different atoms on A;
• X is selected from C1-4 alkylene, —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:
• CH2NR2R2a;
• CH2CH2NR2R2a;
• C3-10 carbocycle substituted with 0-2 R4a, and,
• 5-10 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
• Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3c;
• R1a is selected from H, —(CH2)rR1b, —CH═CH—R1b, NCH2R1c, OCH2R1c, SCH2R1c, NH(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, S(CH2)2(cH2)tR1bS(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;
• 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 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 C3-6 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 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 carbocycle substituted with 0-2 R4b, a C3-6 carbocyclic-CH2-residue substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of:
• carbon atoms and 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, C3-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of:
• carbon atoms and 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 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of:
• carbon atoms and 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 containing 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 consisting of:
• 0-1 additional heteroatoms selected from the group consisting of N, O, and 5;
• R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
• R3a, at each occurrence, is selected from H, C1-4 alkyl, benzyl, 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, benzyl, and phenyl;
• R3d, at each occurrence, is selected from H, C1-4 alkyl, C1-4 alkyl-phenyl, and C(═O)R3c;
• R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(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, NCH2R1c, OCH2R1c, SCH2R1c, N(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, and S(CH2)2(CH2)tR1b;
• alternatively, one R4 is a 5-6 membered aromatic heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S;
• R4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, Cl, Br, F, I, C1-4 alkyl, s—CN, NO2, (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, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
• alternatively, one R4a is phenyl substituted with 0-1 R5 or a 5-6 membered aromatic heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
• R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, 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, and (CF2)rCF3;
• R5, at each occurrence, is selected from H, C1-6 alkyl, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —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)pC1-4 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, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6 aryloxy, C6 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 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
• 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;
• p, at each occurrence, is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;
• s, at each occurrence, is selected from 0, 1, and 2;
• and,
• t, at each occurrence, is selected from 0, 1, 2, and 3.