Glycinamides as factor Xa inhibitors

A compound of formula I:

• or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
• ring M, including P1, P2, M1, and M2, is
• ring M is substituted with 0–3 R1a;
• ring P, including P1, P2, and P3, is
• one of P4 and M4 is A-B and the other -G;
• G is a group of formula IIa:
• ring D, including the two atoms of Ring E to which it is attached, is a 5–6 membered ring consisting of:
• carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)p;
• ring D is substituted with 0–2 R and there are 0–3 ring double bonds;
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1–2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1–2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5–6 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5–6 membered heterocycle is substituted with 0–1 carbonyls and 1–2 R and has 0–3 ring double bonds;
• 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, ONHC(═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)tC(O)H, (CR8R9)tC(O)R2c, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, (CR8R9)tNR7C(O)R7, (CR8R9)tOR3, (CR8R9)tS(O)pNR7R8, (CR8R9)tNR7S(O)pR7, (CR8R9)tSR3, (CR8R9)tS(O)R3, (CR8R9)tS(O)2R3, and OCF3;
• alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
• A is phenyl substituted with 0–2 R4;
• B is selected from N(B1)C(O)C(R3R3g)OR3, N(B1)C(O)C(R3R3g)NB2B3, N(B1)C(O)C(R3R3g)C(R3R3g)NB2B3, N(B1)C(O)C(R3R3g)C(R3R3g)C(R3R3g)NB2B3, and N(B1)C(O)C(R3R3g)C(R3R3g)C(R3R3g)C(R3R3g)NB2B3;
• B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)0-2—C3-7 carbocycle substituted with 0–2 R4b, and —(CH2)0-2-5–6 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• B2 is selected from H, C1-6 alkyl substituted with 0–2 R4c, C(O)R2e, C(O)OR2d, C(O)NR2dR2d, C(O)NH(CH2)2NR2dR2d, SO2NR2dR2d, C(O)NHSO2—C1-4 alkyl, and S(O)pR5a;
• B3 is selected from H, C1-6 alkyl substituted with 0–1 R4c, —(CH2)0-1-3–8 membered carbocycle substituted with 0–2 R5, and a —(CH2)0-1-3–8 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R5;
• alternatively, NB2B3 is a 3–8 membered heterocycle consisting of:
• the shown N, carbon atoms, and 0–3 additional heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R5;
• R1a, at each occurrence, is selected from H, —(CR3R3a)r—R1b, —(CR3R3a)r—CR3R1bR1b, —(CR3R3a)r—O—(CR3R3a)r—R1b, —(CR3R3a)r—NR2—(CR3R3a)r—R1b, —(CR3R3a)r—S(O)p—(CR3R3a)r—R1b, —(CR3R3a)r—CO2—(CR3R3a)r—R1b, —(CR3R3a)r—C(O)NR2—(CR3R3a)r—R1b, —(CR3R3a)r—C(O)—(CR3R3a)r—R1b, —C2-6 alkenylene-R1b, —C2-6 alkynylene-R1b, and —(CR3R3a)r—C(═NR1b)NR3R1b, provided that R1a forms other than an N-halo, N—S, O—O, or N—CN bond;
• alternatively, when two R1a groups are attached to adjacent atoms or to the same carbon atom, 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, —NO2, —CHO, (CF2)rCF3, (CR3R3a)rOR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CH(CH2OR2)2, (CF2)rCO2R2a, S(O)pR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NR2R2a, NR2C(O)2R2a, OC(O)NR2R2a, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2, C(O)NR2SO2R2, C3-6 carbocycle substituted with 0–2 R4b, and 5–10 membered heterocycle substituted with 0–2 R4b and consisting of carbon atoms and from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond and provided that S(O)pR2 forms other than S(O)2H or S(O)H;
• R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, —(CH2)r—C3-10 carbocycle substituted with 0–2 R4b, and —(CH2)r-5–10 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, —(CH2)r—C3-10 carbocycle substituted with 0–2 R4b, and —(CH2)r-5–10 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and 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 S(O)p;
• R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl substituted with 0–2 R4b, —(CH2)r—C3-10 carbocycle substituted with 0–2 R4b, and —(CH2)r-5–10 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0–2 R4b, and —(CH2)r-5–10 membered heterocycle containing from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• R2d, at each occurrence, is selected from H, R4c, C1-6 alkyl substituted with 0–2 R4c, —(CR3R3a)r—C3-10 carbocycle substituted with 0–2 R4c, and —(CR3R3a)r-5–10 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4c, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
• R2e, at each occurrence, is selected from H, R4c, C1-6 alkyl substituted with 0–2 R4c, —(CR3R3a)r—C3-10 carbocycle substituted with 0–2 R4c, and —(CR3R3a)r-5–6 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4c, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
• R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• R3a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of:
• carbon atoms, the nitrogen atom to which R3 and R3a are attached, and 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
• R3b, at each occurrence, is selected from CF3, C1-4 alkoxy substituted with 0–2 R4b, C1-6 alkyl substituted with 0–2 R4b, —(CH2)r—C3-10 carbocycle substituted with 0–2 R4b, and —(CH2)r-5–10 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C1-4 alkyl-phenyl, and C(═O)R3c;
• R3g, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)r-3–6 membered carbocycle, and —(CH2)r-5–6 membered heterocycle consisting of:
• carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p;
• alternatively, when R3 and R3g are attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;
• R4, at each occurrence, is selected from H, ═O, (CR3R3a)rOR2, F, Cl, Br, I, C1-4 alkyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rC(═NR2)NR2R2a, (CR3R3a)rC(═NS(O)2R5a)NR2R2a, (CR3R3a)rNHC(═NR2)NR2R2a, (CR3R3a)rC(O)NHC(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rNR2SO2—C1-4 alkyl, (CR3R3a)rNR2SO2R5a, (CR3R3a)rS(O)pR5a, (CR3R3a)r(CF2)rCF3, NHCH2R1b, OCH2R1b, SCH2R1b, N(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, and S(CH2)2(CH2)tR1b;
• R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, (CH2)rNR3C(O)R3a, (CH2)r—C(O)NR3R3a, (CH2)rNR3C(O)NR3R3a, (CH2)r—C(═NR3)NR3R3a, (CH2)rNR3C(═NR3)NR3R3a, (CH2)rSO2NR3R3a, (CH2)rNR3SO2NR3R3a, (CH2)rNR3SO2—C1-4 alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (CH2)rS(O)p-phenyl, and (CH2)r(CF2)rCF3;
• R4c, at each occurrence, is selected from ═O, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a)rCF3, C1-4 alkyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rN(→O)R2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rN═CHOR3, (CR3R3a)rC(O)NH(CR3R3a)2NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rC(═NR2)NR2R2a, (CR3R3a)rNHC(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rC(O)NHSO2—C1-4 alkyl, (CR3R3a)rNR2SO2R5a, (CR3R3a)rS(O)pR5a, (CF2)rCF3, (CR3R3a)rC3-10 carbocycle substituted with 0–2 R4b, and (CR3R3a)r5–10 membered heterocycle consisting of carbon atoms and from 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 R4b;
• 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, (CH2)rNR3C(O)R3a, (CH2)rC(O)NR3R3a, (CH2)rNR3C(O)NR3R3a, (CH2)rCH(═NOR3d), (CH2)rC(═NR3)NR3R3a, (CH2)rNR3C(═NR3)NR3R3a, (CH2)rSO2NR3R3a, (CH2)rNR3SO2NR3R3a, (CH2)rNR3SO2—C1-4 alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (CH2)rS(O)p-phenyl, (CF2)rCF3, phenyl substituted with 0–2 R6, naphthyl substituted with 0–2 R6, and benzyl substituted with 0–2 R6;
• R5a, at each occurrence, is selected from C1-6 alkyl, (CH2)rOR3, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, (CH2)rNR3C(O)R3a, (CH2)rC(O)NR3R3a, (CF2)rCF3, phenyl substituted with 0–2 R6, naphthyl substituted with 0–2 R6, and benzyl substituted with 0–2 R6, provided that R5a does not form a S—N or S(O)p—C(O) bond;
• 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 alkyl-C(O)—, C1-6 alkyl-O—, (CH2)n-phenyl, C1-4 alkyl-OC(O)—, C6-10 aryl-O—, C6-10 aryl-OC(O)—, C6-10 aryl-CH2—C(O)—, C1-4 alkyl-C(O)O—C1-4 alkyl-OC(O)—, C6-10 aryl-C(O)O—C1-4 alkyl-OC(O)—, C1-6 alkyl-NH2—C(O)—, phenyl-NH2—C(O)—, and phenyl C1-4 alkyl-C(O)—;
• 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 5–10 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;
• 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;
• t, at each occurrence, is selected from 0, 1, 2, and 3.