Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade

A method of treating a thrombotic disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound having the following structure:

• or pharmaceutically acceptable salt thereof wherein
• A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl;
• W1 is —CH2—CH2—CH2—, —CH2—CH2—CR5R6—, —CH2—CR5R6—CH2—, —CH2—CH2—CR7R8—, —CH2—CR7R8—CH2—, —CH2—CR9—CH2—, or —CH2—CH2—CR9—, wherein W1 connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a five membered ring;
• R2 and R2′ are each independently hydrogen or alkyl;
• R3 and R4 are each independently H, (C1-C6)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO2alkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring;
• R5 is —OH, alkyl, halo(C1-C6)alkyl, —NR3R4, —OR2, halo, —CN, —CH2OR2, —CH2—NR3R4, aryl, monocyclic heteroaryl, alkylaryl, —CONR3R4, —COR2, or —CO2R2;
• R6 is H, alkyl, aralkyl, aryl, or monocyclic heteroaryl;
• R7 and R8 are each independently halo;
• R9 is ═O or ═NOR2;
• C is phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, —CO2R2, —COR2, —CONR2R2′, alkoxy, alkyl, —CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
• and
• B is heteroaryl,
• wherein Y1 is selected from CHRa, CHRa—CHRb, CHRa—CHRb—CHRc, CRa═CRb, NRc, wherein Ra—Rc are each independently H, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl, and
• is a bond;
• or B is
• wherein Y1 is selected from CHRa, CHRa—CHRb, CHRa—CHRb—CHRc, CRa═CRb, NRc, wherein Ra—Rc are each independently H, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl;
• or B is
• or B is
• wherein each
• is a bond and Y1, Y2, and Y3 are each independently selected from N or CRa;
• or B is
• wherein
• is a bond, Y2, is selected from NH or CHRa, and Y1 and Y3 are each independently selected from N or CRa;
• or B is
• wherein
• is a bond, Y2, is selected from N or CRa, and Y1 and Y3 are each independently selected from NH or CHRa;
• or B is
• wherein Y1, Y2, and Y3 are each independently selected from NH or CHRa;
• wherein said thrombic disorder is selected from arterial thrombosis, thrombophlebitis, pulmonary embolism, kidney embolism, cerebral embolism, first or recurrent myocardial infarction, cerebral infarction, arterial embolism, atherosclerosis, unstable angina, arterial fibrillation, stroke, or venous thrombosis including primary and secondary deep vein thrombosis.

A method of inhibiting Factor Xa in a mammal, comprising administering to a mammal in need of Factor Xa inhibition a therapeutically effective amount of a compound having the following structure:

• or pharmaceutically acceptable salts thereof wherein
• A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl;
• W1 is —CH2—CH2—CH2—, —CH2—CH2—CR5R6—, —CH2—CR5R6—CH2—, —CH2—CH2—CR7R8—, —CH2—CR7R8—CH2—, —CH2—CR9—CH2—, or —CH2—CH2—, —CR9—, wherein W1 connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a five membered ring;
• R2 and R2′ are each independently hydrogen or alkyl;
• R3 and R4 are each independently H, (C1-C6)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO2alkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring;
• R5 is —OH, alkyl, halo(C1-C6)alkyl, —NR3R4, —OR2, halo, —CN, —CH2OR2, —CH2—NR3R4, aryl, monocyclic heteroaryl, alkylaryl, —CONR3R4, —COR2, or —CO2R2;
• R6 is H, alkyl, aralkyl, aryl, or monocyclic heteroaryl;
• R7 and R8 are each independently halo;
• R9 is ═O or ═NOR2;
• C is phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, —CO2R2, —COR2, —CONR2R2′ alkoxy, alkyl, —CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
• and
• B is heteroaryl,
• wherein Y1 is selected from CHRa, CHRa—CHRb, CHRa—CHRb—CHRc, CRa═CRb, NRc, wherein Ra—Rc are each independently H, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl, and
• is a bond;
• or B is
• wherein Y1 is selected from CHRa, CHRa—CHRb, CHRa—CHRb—CHRc, CRa═CRb, NRc, wherein Ra—Rc are each independently H, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl;
• or B is
• or B is
• wherein each
• is a bond and Y1, Y2, and Y3 are each independently selected from N or CRa;
• or B is
• wherein
• is a bond, Y2, is selected from NH or CHRa, and Y1 and Y3 are each independently selected from N or CRa;
• or B is
• wherein
• is a bond, Y2, is selected from N or CRa, and Y1 and Y3 are each independently selected from NH or CHRa;
• or B is
• wherein Y1, Y2, and Y3 are each independently selected from NH or CHRa.