Factor IXa inhibitors

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof;

wherein: m is an integer of 1 to 2; n is an integer of 1 to 2; o is an integer of 0 or 1; p is an integer of 0 to 5; q is an integer of 0 to 4; r is an integer of 0 to 4; s is an integer of 0 to 4; X is a nitrogen atom or CH; Y is an oxygen atom, a sulfur atom or NH (when o=0), a nitrogen atom or CH (when o=1);

Z 1 , Z 2 , Z 3 , Z 4 are each independently a nitrogen atom or CH;

each R 1 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, a C 3-12 cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 2-7 alkanoyl group or a group of —NR A R B ;

R A and R B are each independently a hydrogen atom, a C 1-6 alkyl group or a C 2-7 alkanoyl group;

each R 2 is independently a hydroxyl group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 6-14 aryl group, a heteroaryl group or oxo;

each R 3 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 3-12 cycloalkyl group, a C 1-6 alkoxy group or a halogenated C 1-6 alkoxy group;

each R 4 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a C 3-12 cycloalkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyanated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, a C 2-7 alkanoyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfonyl group, a group of —NR A R B or oxo;

a dotted line in a substructure of a bicycle represented by Formula (II):

represents a single bond when o is 0 or a double bond when o is 1;

is heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein o is 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein o is 0.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is an integer of 0 to 2, q is an integer of 0 to 2, r is an integer of 0 to 2 and s is 0 or 1.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the substructure of Formula (V):

in Formula (I) is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the substructure of Formula (II):

in Formula (I) is:

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein a substructure of Formula (II):

in Formula (I) is:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group or a halogenated C 1-6 alkyl group.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 2 is a hydroxyl group, a C 1-6 alkyl group or a C 6-14 aryl group.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 3 is a halogen atom or a C 1-6 alkyl group.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 4 is a cyano group, a C 1-6 alkyl group, a C 3-12 cycloalkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group or oxo.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:

N-(1-(3-Aminobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Aminobenzo[d]isoxazol-7-yl)-3-methylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Aminobenzo[d]isoxazol-7-yl)-3-phenylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Aminobenzo[d]isothiazol-7-yl)pyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Aminoisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Amino-5-methylbenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2,6-dichloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

N-((3R*,4S*)-1-(3-Aminobenzo[d]isoxazol-7-yl)-3,4-dimethylpyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-((3S*,4S*)-1-(3-Aminobenzo[d]isoxazol-7-yl)-4-hydroxypyrrolidin-3-yl)-2,6-dichloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloro-5-methylbenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-fluorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4,5-dichlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4H-1,2,4-triazol-4-yl)benzamide;

N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)-3-methylpyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-5-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(pyrimidin-5-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(2-methoxypyrimidin-5-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(2-cyanopyrimidin-5-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(2-hydroxyethyl)-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(5-(hydroxymethyl)pyridin-3-yl)benzamide;

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4-(2-hydroxyethyl)-1H-pyrazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4-(2-hydroxyethyl)-1H-imidazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-4-(1H-benzo[d]imidazol-1-yl)-2-chlorobenzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(pyridazin-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(5-(2-hydroxyethyl)pyridin-3-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1H-imidazo[4,5-b]pyridin-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(pyrazin-2-yl)benzamide;

(R)—N-(1-(3-Amino-5-cyanobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(6-oxo-1-(2,2,2-trifluoroethyl)-1, 6-dihydropyridin-3-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-4-(4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1-(difluoromethyl)-6-oxo-1, 6-dihydropyridin-3-yl)benzamide;

(R)-4-([1,2,4]Triazolo[4,3-a]pyridin-6-yl)-N-(1-(3-amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chlorobenzamide;

(R)—N-(1-(3-Amino-5-(difluoromethyl)isoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzamide;

(R)—N-(1-(3-Amino-5-cyanoisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-5-methylisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(5-oxo-1, 5-dihydro-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(1-(2-hydroxyethyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(9H-purin-9-yl)benzamide;

(R)—N-(1-(3-Amino-5-methylisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2,6-dichloro-4-(1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(5-oxo-1-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-2-chloro-4-(7H-purin-7-yl)benzamide;

(R)—N-(1-(3-Amino-4-chloroisoxazolo[5,4-c]pyridin-7-yl)pyrrolidin-3-yl)-3-chloro-5-(3-methyl-1H-1,2,4-triazol-1-yl)picolinamide or

(R)—N-(1-(3-Amino-4-chlorobenzo[d]isoxazol-7-yl)pyrrolidin-3-yl)-2-chloro-4-(2-(hydroxymethyl)pyridin-4-yl)benzamide.

15. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

16. A method of treating a thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, thromboembolic disorders in the chambers of the heart, unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , further comprising administering to said patient at least one anticoagulant agent selected from the group consisting of a thrombin inhibitor, a thrombin receptor (PAR-1) antagonist, a factor VIIa inhibitor, factor VIIIa inhibitor, a factor IXa inhibitor different from the compound of claims 1 - 5 , 6 - 15 and 16 , a factor Xa inhibitor, a factor XIa inhibitor, TAFI or a fibrinogen inhibitor.

18. A pharmaceutical composition comprising:

a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent which is: (a) an anticoagulant, (b) an anti-thrombin agent, (c) an anti-platelet agent, (d) a fibrinolytic, (e) a hypolipidemic agent, (f) an antihypertensive agent, and (g) an anti-ischemic agent.

19. A pharmaceutical composition comprising:

a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent which is (a-1) warfarin, (a-2) heparin, (a-3) aprotinin, (a-4) synthetic pentasaccharide, (a-5) direct acting thrombin inhibitors, (a-6) a factor VIIa inhibitor, (a-7) a factor VIIIa inhibitor, (a-8) a second factor IXa inhibitor, (a-9) a factor Xa inhibitor, (a-10) a factor XIa inhibitor, (a-11) a thrombin inhibitor, (a-12) a TAFI, (a-13) a fibrinogen inhibitor, (b-1) a boroarginine derivative, (b-2) a boropeptide, (b-3) heparin, (b-4) hirudin, (b-5) argatroban, (c-1) a NSAID, (c-2) a IIb/IIIa antagonist, (c-3) a thromboxane-A2-receptor antagonist, (c-4) a thromboxane-A2-synthetase inhibitor, (c-5) a PDE-III inhibitor, (c-6) a PDE V inhibitor, (c-7) a ADP receptor antagonist, (c-8) an antagonist of the purinergic receptor P2Y1, (c-9) an antagonist of the purinergic receptor P2Y12, (d-1) tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, (d-2) anistreplase, (d-3) urokinase, (d-4) streptokinase, (d-5) tenecteplase (TNK), (d-6) lanoteplase (nPA), (d-7) a factor VIIa inhibitor, (d-8) a PAI-I inhibitor, (d-9) an alpha-2-antiplasmin inhibitor, (d-10) an anisoylated plasminogen streptokinase activator complex, (e-1) a HMG-CoA reductase inhibitor, (e-2) a squalene synthetase inhibitor, (e-3) a fibrate, (e-4) a bile acid sequestrant, (e-5) an ACAT inhibitor, (e-6) a MTP inhibitor, (e-7) a lipooxygenase inhibitor, (e-8) a cholesterol absorption inhibitor, (e-9) a cholesterol ester transfer protein inhibitor, (f-1) an alpha adrenergic blocker, (f-2) a beta adrenergic blocker, (f-3) a calcium channel blocker, (f-4) a diuretics, (f-5) a renin inhibitor, (f-6) an angiotensin-converting enzyme inhibitor, (f-7) an angiotensin-II-receptor antagonist, (f-8) an ET receptor antagonist, (f-9) a Dual ET/All antagonist, (f-10) a neutral endopeptidase inhibitors, (f-11) a vasopepsidase inhibitor, (g-1) a Class I agent, (g-2) a Class II agent, (g-3) a Class III agent, a (g-4) Class IV agent, (g-5) a K+ cannel opener, (g-6) an IKur inhibitor or (g-7) a cardiac glycoside.

20. A compound of the Formula (VII):

or a pharmaceutically acceptable salt thereof; wherein:

m is an integer of 1 or 2; n is an integer of 1 or 2; o is an integer of 0 or 1; p is an integer of 0 to 5; q is an integer of 0 to 4; X is a nitrogen atom or CH; Y is an oxygen atom, a sulfur atom or NH (when o=0), Y is a nitrogen atom or CH (when o=1);

each R 1 is independently a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 3-12 cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 2-7 alkanoyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfonyl group or a group of —NR A R B ;

R A and R B are each independently a hydrogen atom, a C 1-6 alkyl group or a C 2-7 alkanoyl group;

each R 2 is independently a hydroxyl group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 6-14 aryl group, a heteroaryl group or oxo;

a dotted line in a substructure of a bicycle represented by Formula (II):

represents a single bond when o=0 or a double bond when o=1.