Benzamides and related inhibitors of factor Xa

A compound of the following formula:

• A—Q—D—E—G—J—X
• wherein:
• A is N(R1,R2)—C(═NR3)—, wherein;
• R1, R2 and R3 are independently selected from the group consisting of:
• H, —OR5, —N(—R5, —R6), —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
• R1 and R2, 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 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from 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, —C3-8-cycloalkyl, —C0-4alkylC3-8cycloalkyl and —NO2;
• R5 and R6 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;
• or
• R5 and R6 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from 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, —C3-8-cycloalkyl, —C0-4alkylC3-8cycloalkyl and —NO2;
• Q is a direct link;
• D is phenylene, wherein Q and E are attached to D to form a 1,4-disubstituted phenylene ring, and wherein D is further substituted with 0-2 R1a substituents, wherein
• R1a is selected from:
• halo, —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-8cycloalkyl, —C0-4alkylC3-8cycloalkyl, —CN, —NO2, —(CH2)nNR2aR3a, —(CH2)nCO2R2a, —(CH2)nCONR2aR3a, —SO2NR2aR3a, —SO2R2a, —CF3, —OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from 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, —C2-6alknyl, —C3-8-cycloalkyl, —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;
• n is an integer of 0-2;
• E is —C(═O)—N(—R8)—, wherein
• R8 is a member selected from the group consisting of:
• H;
• —C1-4-alkyl;
• —C0-4-alkylaryl;
• —C0-4-alkyl-heteroaryl;
• —C1-4-alkyl-C(═O)—OH, —C1-4-alkyl-C(═O)—O—C1-4-alkyl, and —C1-4-alkyl-C(═O)—N(R2b, —R3b);
• R2b and R3b are each a member independently selected from the group consisting of:
• H, —C1-4alkyl, —C0-4-alkyl-aryl;
• —C0-4-alkyl-heterocyclic group, and R2b and R3b together with the N atom to which they are attached can form a 5-8 membered heterocyclic ring containing1-4 heteroatoms selected from N, O and S, wherein the heterocyclic ring may be substituted with 0-2 R1c groups;
• R1c is a member selected from the group consisting of:
• Halo;
• —C1-4-alkyl;
• —CN, —NO2;
• —C(═O)—N(—R2c, —R3c);
• —C(═O)—OR2c;
• —(CH2)q—N(—R2c, —R3c);
• —SO2—N(—R2c, —R3c);
• —SO2R2c;
• —CF3 and —(CH2)q—OR2c;
• R2c and R3c are each independently a member selected from the group consisting of:
• H;
• —C1-4-alkyl and —C1-4-alkyl-aryl;
• q is an integer of 0-2;
• G is phenylene group, wherein E and J are attached to G to form a 1,2-disubstituted phenylene group;
• and wherein G is further substituted with 0-4 R1d groups, wherein;
• R1d is a member selected from the group consisting of:
• H, halo;
• C1-6alkyl, carbocylic aryl, —CN;
• —NO2;
• —(CH2)0-6—NR2dR3d;
• —SO2NR2dR3d;
• —SO2R2d;
• —CF3;
• —(CH2)0-6—OR2d;
• —O—(CH2)1-6OR2d;
• —O—(CH2)1-6—C(═O)—O—R2d;
• —O—(CH2)1-6—C(═O)—N(R2d,R3d);
• —N(R5a)—(CH2)1-6—OR2d;
• —N(R5a)—(CH2)1-6—N(R2d,R3d);
• —C(═O)—N(R2d,R3d);
• —N(R5a)—(CH2)1-6—C(═O)—N(R2d,R3d);
• —N(—(CH2)1-6—OR2d)2;
• —N(R5a)—(CH2)1-6—OR2d;
• —N(R5a)—C(═O)—R2d;
• —N(R5a)—SO2—R2d;
• —(CH2)0-6—C(═O)—O—R2d;
• —(CH2)0-6—C(═O)—N(R2d,R3d);
• —(CH2)0-6—C(═NR2d)—N(R3d,R4d);
• —(CH2)0-6—N(R5a)C(═NR2d)—N(R3d,R4d);
• a —(CH2)0-6—N(R3d)C5-6 membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, and a —(CH2)0-6-5-6 membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
• R5a, R2d, R3d and R4d are each independently a member selected from the group consisting of:
• H, C1-6-alkyl and C1-6-alkylaryl, —CN;
• —NO2;
• carbocylic aryl, —CN;
• —NO2;
• or
• R2d and R3d taken together with the N atoms they are independently attached form a 5-7 membered saturated, partially unsaturated or aromatic heterocyclic ring;
• or
• R3d and R4d taken together with the N atom to which they are attached form a 5-8 membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
• J is —C(═O)—N(—R9)—, wherein
• R9 is a member selected from the group consisting of:
• H;
• —C1-4-alkyl;
• —C0-4-alkyl-carbocyclic aryl;
• —(CH2)0-4-5-6 membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
• —(CH2)1-6—C(═O)—O—C1-4-alkyl;
• and —(CH2)1-6—C(═O)—N(R6a,R6b);
• R6a and R6b are each a member independently selected from the group consisting of:
• H and —C1-6-alkyl;
• X is a phenyl substituted with 0-3 R1e groups, wherein
• R1e is a member independently selected from the group consisting of:
• Halo;
• CF3;
• —C1-4-alkyl;
• carbocyclic aryl;
• —C0-2-alkyl-CN;
• —O—R2e;
• —C0-2-alkyl-C(═O)—O—R2e;
• —C0-2-alkyl-C(═O)—N(R2e,R3e);
• —C0-2-alkyl-NO2;
• —C0-2-alkyl-N(R2e,R3e;
• —C0-2-alkyl-SO2-N(R2e,R3e);
• —C0-2-alkyl-SO2—R2e;
• trihaloalkyl;
• —O—C0-2-alkyl-O—R2e;
• —C0-2-alkyl-O—R2e;
• —O—C1-4-alkyl-C(═O)—N(R2e,R3e);
• —O—C1-4-alkyl-C(═O)—O—R2e;
• —C0-2-alkyl-N(R2e)—C(═O)—R3e;
• —C0-2-alkyl-N(—R2e)—SO2—R3e;
• —CH2—N(R2e)—C(═O)—R3e;
• —CH2—N(R2e)—SO2—R3e;
• —(CH2)0-6—NR2eR3e;
• —C(═O)—N(R2e,R3e);
• —N(—(CH2)1-6—OR2e)z;
• —N(R10)—(CH2)1-6—OR2e;
• —N(R10)—C(═O)—R2e;
• —N(R10)—SO2—R2e;
• —C(═N(R10))—N(R2e,R3a);
• and a —(CH2)0-6-5-6 membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
• R10, R2e and R3e are each independently a member selected from the group consisting of:
• H;
• —C1-4-alkyl;
• —C0-2-alkyl-O—R1g;
• —C0-2-alkyl-N(—R1g, —R2g);
• —C1-4-alkyl-carbocyclic aryl;
• —C1-4-alkyl-heterocyclic;
• and R10 and R2e, or R2e and R3e together with the N atom to which they are attached can form 5-8 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S which can be substituted with 0-2 R1g groups;
• R1g and R2g are independently a member selected from the group of:
• H;
• halo;
• —C1-4-alkyl, a carbocyclic aryl group;
• a saturated, partially unsaturated or aromatic heterocyclic group;
• —CN;
• —C(═O)—N(R3g)R4g;
• —C(═O)—OR3g;
• —NO2;
• —(CH2)p—NR3gR4g;
• —SO2NR3gR4g;
• —SO2R3g;
• —CF3;
• and —(CH2)pOR3g;
• p is an integer of 0-2;
• R3g and R4g are each independently selected from the group consisting of:
• H;
• C1-4-alkyl and —C0-4-alkyl-carbocyclic aryl;
• and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.