JPWO2020092139A5

JPWO2020092139A5 -

Info

Publication number: JPWO2020092139A5
Application number: JP2021547662A
Authority: JP
Publication date: 2022-10-20

Claims

A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein R ¹ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and R ² is hydrogen,

and
here,
p is an integer ranging from 1 to 6; and R ³ is optionally substituted alkyl (eg optionally substituted aralkyl or optionally substituted heteroaralkyl), substituted optionally alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R ⁶ is hydrogen, optionally substituted alkyl (e.g., optionally substituted aralkyl or optionally substituted heteroaralkyl), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
with the proviso that R ¹ and R ² are not both hydrogen;
Said compound, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is optionally substituted C _1-6 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is unsubstituted C _1-6 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

^R2 is

and R ³ is optionally substituted C _1-12 alkyl, such as unsubstituted, or hydroxyl, carboxyl, halogen (eg, F), alkyl (eg, C _1-6 alkyl), heteroalkyl (eg C _1-6 heteroalkyl), alkoxy (eg C _1-6 alkoxyl), aryl (eg phenyl), heteroaryl (eg 5- or 6-membered heteroaryl), acyl, sulfonyl, substituted with 1, 2, or 3 substituents each independently selected from sulfhydryl, alkylsulfanyl, cycloalkyl, heterocyclyl, amino, alkylamino, dialkylamino, cyano, ester groups, and trifluoromethyl The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is

R ³ is C _1-4 alkyl (eg methyl) optionally substituted with an optionally substituted heterocyclyl group, for example R ² is

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, which is

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted straight or branched chain C _1-12 alkyl (eg n-hexyl).

8. The claim 7, wherein R ³ is unsubstituted straight or branched C _1-6 alkyl, such as ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl. compound, or a pharmaceutically acceptable salt thereof.

^R2 is

where n is an integer ranging from 1 to 6 and R ⁴ is hydrogen, optionally substituted alkyl (eg, optionally substituted aralkyl or heteroaralkyl), substituted optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl , a compound of claim 5, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

R ⁴ is hydrogen, C _1-12 alkyl (eg, C _1-6 alkyl, such as ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl), phenyl, or benzyl , a compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof.

^R2 is

and where
R ⁵ is hydrogen, optionally substituted alkyl (e.g., optionally substituted aralkyl or heteroaralkyl), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, which is cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen, C _1-12 alkyl (eg C _1-6 alkyl), phenyl, or benzyl.

^R2 is

and p is 1, 2, or 3, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen or C _1-12 alkyl (eg, C _1-6 alkyl).

^R2 is

The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is

^R2 is

A compound selected from Compound Nos. 1-19, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, formulated for oral administration such as tablets, capsules, powders, granules, liquids (eg, oral solutions, suspensions, emulsions, etc.), or syrups.

A pharmaceutical composition for treating venous thrombotic disease and/or arterial thrombotic disease in a subject , comprising a therapeutically effective amount of one or more compounds or pharmaceuticals according to any one of claims 1 to 18 said pharmaceutical composition, comprising a legally acceptable salt thereof .

said thrombotic disease is deep leg vein thrombosis, reocclusion after bypass surgery or angioplasty (PT(C)A), occlusion in peripheral artery disease, pulmonary embolism, disseminated intravascular coagulation, coronary artery thrombosis 22. The pharmaceutical composition of claim 21 selected from , stroke, and shunt or stent occlusion.

19. A pharmaceutical composition for reducing the risk of stroke and systemic embolism in a subject with non-valvular atrial fibrillation, in a therapeutically effective amount of any one of claims 1-18. Said pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof.

A pharmaceutical composition for treating deep vein thrombosis and/or pulmonary embolism in a subject in need thereof, comprising a therapeutically effective amount of one or more of any one of claims 1-18. Said pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for reducing the risk of recurrent deep vein thrombosis and/or pulmonary embolism in a subject in need thereof, according to any one of claims 1 to 18, in a therapeutically effective amount. or a pharmaceutically acceptable salt thereof .

A pharmaceutical composition for the prophylactic treatment of deep vein thrombosis and/or pulmonary embolism in a subject in need thereof, in a therapeutically effective amount of one or more of any one of claims 1-18 or a pharmaceutically acceptable salt thereof .

27. The pharmaceutical composition of claim 26, wherein the subject has undergone hip replacement surgery.

A pharmaceutical composition for treating atherosclerosis, coronary artery disease, cerebral arteriopathy, and/or peripheral arteriopathy in a subject in need thereof, in a therapeutically effective amount of any of claims 1-18 Said pharmaceutical composition comprising one or more compounds according to Clause 1 or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition according to any one of claims 1 to 18 in a therapeutically effective amount for providing antithrombotic support, for example in thrombolytic therapy with rt-PA or streptokinase, in a subject in need thereof or a pharmaceutically acceptable salt thereof .

19. A pharmaceutical composition for preventing long-term restenosis after PT(C)A in a subject in need thereof, comprising a therapeutically effective amount of one or more of any one of claims 1-18. Said pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for preventing clot-dependent tumor metastasis, growth, and/or fibrin-dependent inflammatory processes in a subject in need thereof, in a therapeutically effective amount, claims 1-18 or a pharmaceutically acceptable salt thereof .

The pharmaceutical composition according to any one of claims 21-31, which is administered orally .