Disubstituted pyrazolines and triazolines as factor Xa inhibitors

A compound of formula I:

• or a steroisomer or pharmaceutically acceptable salt thereof, wherein;
• M1 is CR1c;
• M2 is CR1aR1a;
• D is selected from C(═NR8)NR7R9, NHC(═NR8)NR7R9, NR8CH(═NR7), C(O)NR7R8, and CR8R9NR7R8;
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R;
• alternatively, D—E—G together represent pyridyl substituted with 1 R;
• R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
• G is selected from NHCH2, OCH2, and SCH2, provided that when s is 0, then G is absent;
• Z is selected from a C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with group A;
• R1a and R1b are, at each occurrence, independently selected from H, —(CH2)r—R1′, NCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′;
• R1c is selected from H, —(CH2)q—R1′, C1-3 alkyl, C(O)R2c, (CF2)rCO2R2c, C(O)NR2R2a, C3-6 carbocyclic residue substituted 0-2 R4, and 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted 0-2 R4;
• R1′ is selected from H, C1-3 alkyl, halo, (CF2)rCF3, OR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted 0-2 R4, and 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted 0-2 R4;
• R1″ is selected from H, C(O)R2b, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
• R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted 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, C3-6 carbocyclic residue substituted 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 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 0-2 R4b;
• alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted 0-2 R4b which comprises 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;
• A is selected from:
• C3-10 carbocyclic residue substituted 0-2 R4, and
• 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted 0-2 R4;
• B is selected from:
• X—Y, NR2R2a, C(═NR2)NR2R2a, NR2C(═NR2)NR2R2a,
• C3-10 carbocyclic residue substituted with 0-2 R4a, and
• 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted 0-2 R4a;
• X is selected from C1-4 alkylene, —CR2(CR2R2b)(CH2)t—, —C(O)—, —C(═NR)—, —CR2(NR1″R2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —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:
• (CH2)rNR2R2a, provided that X—Y do not form a N—N, O—N, or S—N bond,
• C3-10 carbocyclic residue substituted 0-2 R4a, and
• 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted 0-2 R4a;
• R4, at each occurrence, is selected from ═O, (CH2)rOR2, halo, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2-C1-4 NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′,
• alternatively, one R4 is a 5-6 membered aromatic heterocycle comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S;
• R4a, at each occurrence, is selected from ═O, (CH2)rOR2, halo, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2-C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
• alternatively, one R4a is a 5-6 membered aromatic heterocycle comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-R5;
• R4b, at each occurrence, is selected from ═O, (CH2)rOR3, halo, C1-4 alkyl, —CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(═NR3)NR3R3a, NH3C(═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 CF3, C1-6 alkyl, phenyl substituted 0-2 R6, and benzyl substituted 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, CH(═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, C6-10 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 combine to form a 5 or 6 membered saturated, ring which comprises 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;
• m, at each occurrence, is selected from 0, 1, and 2;
• p, at each occurrence, is selected from 0, 1, and 2;
• q, at each occurrence is selected from 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 and 1
• provided that when a heterocyclic group is present it is other than a morpholine, pyrazine, primidine, pyridazine, piperidine, pyridine or tetrazole.