# US 7,407,974 B2 · Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade

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- Number: US 7,407,974 B2
- Document ID: US7407974B2
- Status: Granted
- Kind: B2
- Application number: 11/108,582
- Filed: 2005-04-18
- Published: 2005-11-10
- Granted: 2008-08-05
- Earliest claimed: 2001-11-29
- Assignees: Pfizer Inc.
- Inventors: Christopher Franklin Bigge; Agustin Casimiro-Garcia; Danette Andrea Dudley; Jeremy John Edmunds; Kevin James Filipski; Jeffrey Thomas Kohrt; Chad Alan Van Huis
- Web page: https://patentgrep.com/patent/US7407974B2

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/20: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 207/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 207/24: Oxygen or sulfur atoms
- C07D 207/26: 2-Pyrrolidones
- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 211/76: attached in position 2 or 6
- C07D 213/64: attached in position 2 or 6
- C07D 231/06: having one double bond between ring members or between a ring member and a non-ring member
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 237/14: Oxygen atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of Formula (I): wherein A, B, C, G, and W1 have any of the values defined in the specification, and pharmaceutically acceptable salt thereof, that are useful to treat thrombotic disorders. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula I, processes for preparing compounds of Formula I, and intermediates useful for preparing compounds of Formula I.

## Claims

### Claim 1

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 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} or a pharmaceutically acceptable salt thereof.

### Claim 2

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 4-(2,4-Difluoro-phenyl)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide] or a pharmaceutically acceptable salt thereof.

### Claim 3

A method of treating a thrombotic disorder 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 in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of 4-(2,4-Difluoro-phenyl)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide] or a pharmaceutically acceptable salt thereof.

### Claim 4

A method of treating a thrombotic disorder 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 in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} or a pharmaceutically acceptable salt thereof.

### Claim 5

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.

### Claim 6

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.