Selective factor xa inhibitors

A compound having the formula:

• 46
• wherein:
• R1 is H, C1-6alkyl or C1-3alkylaryl;
• R2 is H, C1-6alkyl, C3-6cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl or aryl and R3 is H, C1-6alkyl, or R2 and R3 are taken together to form a carbocyclic ring;
• R13 and R14 are independently selected from the group consisting of H, halogen, C1-3alkyl, C1-3alkylaryl, aryl, C1-3alkyl-C3-8cycloalkyl, C1-3alkylheterocyclic and —CF3;
• C1-3alkyl, C1-3alkylaryl, aryl, C1-3alkyl-C3-8cycloalkyl and C1-3alkylheterocyclic can be optionally substituted by amino, guanidino, amidino or N-hydroxyamidino groups;
• X is N or CR17, where R17 is independently selected from the group consisting of H, halogen, C1-3alkyl, C1-3alkylaryl, aryl, C1-3alkyl-C3-8cycloalkyl, C1-3alkylheterocyclic and —CF3, where C1-3alkyl, C1-3alkylaryl, aryl, C1-3alkyl-C3-8cycloalkyl and C1-3alkylheterocyclic can optionally be substituted by one or more amino, guanidino, amidino or N-hydroxyamidino groups;
• m is an integer from 0-3;
• n is an integer from 0-6;
• p is an integer from 0-4;
• s is an integer from 0-2;
• A is selected from the group consisting of:
• a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
• R4;
• —NR4R5;
• 47
• where R4, R5, R19 and R20 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
• R21 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R19 or R20 to form a 5-6 membered ring;
• and R22 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R20 to form a 5-6 membered ring;
• W is a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
• D is a direct link, —CO—, —SO2—, —CH2—, -0—CO—, —NR18SO2— or —NR18—CO—, where R18 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
• K is selected from the group consisting of a direct link, C3-8cycloalkyl, aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
• E is selected from the group consisting of R26, —NR26R27, 48
• where R26, R27, R28 and R29 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
• R30 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R28 or R29 to form a 5-6 membered ring;
• and R31 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R29 to form a 5-6 membered ring;
• with the proviso that when E is R26, then K must contain at least one N atom;
• Y is selected from the group consisting of H, 49
• where R15 and R16 are independently selected from the group consisting of H, C1-3alkyl and aryl;
• and G is —COOR23, —CONR23R24, —CF3, —CF2CF3 or a group having the formula:
• 50
• where:
• R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
• J is —S—, —SO—, —SO2—, —O— or —NR6—, where R6 is H, C1-6alkyl or benzyl;
• and
• L is selected from the group consisting of:
• 51
• a C6-10 heterocyclic ring system substituted by R9 and R10 and containing 1-4 heteroatoms selected from N, S and O;
• where r is an integer from 0-2;
• R7 and R8 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR11, —CONR11R12, —CN and —CF3;
• R9 and R10 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR11R12, —NR11COR12, —O—R11, —O—COR11, —COOR11, —CONR11R12, —CN, —CF3, —SO2NR11R12 and C1-6alkyl-O—R11;
• and R11 and R12 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
• U is —O—, —S—, —N— or —N(H)—;
• and
• V is —O—, —S—, —N— or —N(H)—;
• with the proviso that at least one of U or V is —N— or —N(H)—;
• and all optical isomers thereof.