Inhibitors of factor Xa

A compound according to the formula:

• wherein:
• A is selected from the group consisting of:
• (a) C1-C6-alkyl;
• (b) C3-C8-cycloalkyl;
• —N(—R2,—R3—C(═N—R2)—, (—R2, —R3)N—C(═N—R2)—(—R2, —R3)N—C(═N—R2)—N(—R—)—
• (d) phenyl, which is independently substituted with 0-2 R1 substituents;
• (e) naphthyl, which is independently substituted with 0-2 R1 substituents;
• and
• (f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from the group consisting of N, O and S, and wherein the ring system may be substituted with 0-2 R1 substituents;
• R1 is selected from the group consisting of:
• Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, R2—C(═N—R3)—, (—R2, —R3)N—C(═N—R2)—, —(CH2)mNR2R3, —C(═O)—N(—R2, —R3), —SO2N(—R2, —R3), —SO2R2, —CF3, —OR2, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, —CN C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and —NO2;
• R2 and R3 are independently selected from the group consisting of:
• H, —OR2, —N(—R2, —R3), —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl, —C0-4alkylphenyl and —C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
• or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system,
• wherein the heterocyclic ring system may have from 5 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, C1-C4—alkyl, —CN—C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl and —NO2;
• m is an integer of 0-2;
• Q is a member selected from the group consisting of:
• a direct link, —CH2—, —C(═O)—, —N(R4)—, —N(R4)CH2—, —C═N(R4)—, —C(═O)—N(R4)—, —N(R4)—C(═O)—, —SO2—, —O—, —SO2—N(R4)— and —N(R4)—SO2—;
• R4 is selected from the group consisting of:
• H, —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl, —C0-4alkylphenyl and —C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
• D is a phenyl, which is independently substituted with 0-2 R1a substituents;
• R1a is selected from the group consisting of:
• Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, (CH2)mNR2aR3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
• R2a and R3a are independently selected from the group consisting of:
• H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
• M is a member selected from the group consisting of:
• —C(—R17,—R18)—C(═O)—, —C(—R17,—R17a)—C(—R18,—R18a)—, —C(—R17)═C(—R18)—, —C(═O)—C(═O)—and —C(═C(R17b, —R17c))—C(═O)—, wherein the first named atom of the chain is directly attached to D, and wherein D, M and the N atom attached to the last chain atom of M collectively form a bicyclic ring structure;
• R17, R17a, R18 and R18a are each independently selected from the group consisting of:
• hydrogen, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2 , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, —CN, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and —NO2;
• R17b and R17c are each independently a member selected from the group consisting of:
• hydrogen, —halo, hydroxy, —C1-4alkyl, C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkyl—C3-8cycloalkyl, —CN, —NO2, —(CH2)mNR2R3, —SO2NR2R3, —SO2R2, —CF3, —OR2, phenyl, and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the cycloalkyl, the phenyl ring, or the aromatic heterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, —CN, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and —NO2;
• E is a member selected from the group consisting of:
• a direct link, —C(═O)—, —C(═O)—N(R5)—, —C(—R5a,—R6a)— and —C(—R5b,—R6b)—C(—R5c,—R6c)—;
• wherein R5, R5a, R6a, R5b, R6b, R5c and R6c are independently selected from the group consisting of:
• p2 H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheteroaryl, C1-4alkylCOOH and C1-4alkylCOOC1-4alkyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —OH, —O—C1-4alkyl, —SH, —S—C1-4alkyl, —CN and —NO2;
• G is selected from the group consisting of:
• a direct link, —C(R7,R8)—, —C(R7a,R8a)—C(R7b,R8b)— and —C(R7c)═C(R8c)—;
• wherein R7, R8, R7a, R8a, R7b, R8b, R7c and R8 c are independently a member selected from the group consisting of:
• hydrogen, halogen, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl —C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, —OR9, —N(R9R10), —C0-4alkylCOOR9, —C0-4alkylC(═O)NR9R10, —C0-4alkylC(═O)OR9, —C0-4alkylC(═O)NR9—CH2—CH2—O—R10, —C0-4alkylC(═O)NR9(—CH2—CH2—O—R10—)2, —N(R9)COR10, —N(R9)C(═O)R10,—N(R9)SO2R10, a naturally occurring or synthetic amino acid side chain, and C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC1-4alkyl, CH2COOC1-4alkylphenyl and CH2COOC1-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the CO0-4alkylheterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
• wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl—C3-8cycloalkyl, —CN and —NO2;
• R9 and R10 are independently selected from the group consisting of:
• H, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C3-8cycloalkyl, and C1-4alkyl—O—C1-4alkyl, C1-4alkyl—COOH wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl—C3-8cycloalkyl, —CN and —NO2, and wherein R9 and R10 taken together can form a 5-8 membered heterocylic ring;
• J is a member selected from the group consisting of:
• a direct link, —O—, —O—C(—R11, —R11a)—, —S—, —S(═O)—, —S(═O)2—, —S—C(—R11, —R11a)—, —S(═O)—C(—R11, —R11a)—, —S(═O)2—(—R11, —R11a)—, —C(═O)—, —C(═O)—N(R11b)—, —N(R11b)—C(═O)—, —N(R11b)—, —N(R11b)—C(—R11, —R11a)— O and a monocyclic aromatic or non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atoms of the ring system are selected from the group consisting of N, O and S, and wherein the ring system may be substituted with 0-2 R11 substituents;
• R11, R11a, R11b, and R11 are a member independently selected from the group consisting of:
• hydrogen, halo, —CF3, —CN, —NR9R10, —SO2Me, —NO2, —OH, —O—C1-4alkyl, —O—C2-6alkenyl, —O—C—2-6alkynyl, —O—C3-8cycloalkyl, —O—C1-4alkyl, —O—C1-4alkyl, —O—C1-4alkyl—COOH, —O—C1-4alkyl-phenyl, —COOH, —C(═O)—O—C1-4alkyl, —C(═O)—O—C2-6alkenyl, —C(═O)—O—C2-6alkynyl, —C(═O)—O—C3-8cycloalkyl, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl—C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylC(═O)NR9R10, C0-4alkylC(═O)OR9, C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC1-4alkyl, CH2COOC1-4alkylphenyl and CH2COOC1-4alkylnaphthyl;
• wherein from 1-4 hydrogen atoms on the C0-4alkylheterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-phenyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
• wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl—C3-8cycloalkyl, —CN and —NO2;
• Y is a member selected from the group consisting of:
• (a) phenyl, which is independently substituted with 0-2 R1b substituents;
• (b) naphthyl, which is independently substituted with 0-2 R1b substituents;
• and
• (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from the group consisting of N, O and S, and wherein the ring system may be substituted with 0-2 R1b substituents;
• R1b is a member selected from the group consisting of:
• halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, —NO2, NR2bR3b, SO2NR2bR3b, SO2R2b, CF3, OR2b, O—CH2—CH2—OR2b, O—CH2—COOR2b, N(R2b)—CH2—CH2—OR2b, N(—CH2—CH2—OR2b)2, N(R2b)—C(═O)R3b, N(R2b)—SO2—R3b, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkyl-phenyl, —CN and —NO2;
• R2b and R3b are independently selected from the group consisting of:
• H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN and —NO2;
• L is selected from the group consisting of:
• H, —CN, C(═O)NR12R13, —(CH2)nNR12R13, C(═NR12) NR12R13, OR12, —NR12C(═NR12)NR12R13, and NR12C(═NR12)—R13;
• n is an integer from 0 to 8;
• R12 and R13 are independently selected from the group consisting of:
• <hydrogen, —OR14, —NR14R15, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, COOC1-4alkyl, COO—C0-4alkylphenyl and COO—C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, —OH, —O—C1-4alkyl, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
• R14 and R15 are independently selected from the group consisting of:
• H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, —CN, and —NO2;
• and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.