Selective dual inhibitors of PI3 delta and gamma protein kinases
The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.
1. A compound selected from (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , wherein the compound is substantially free of (R)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound has an enantiomeric excess greater than about 95%.
4. (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide.
5. The compound of claim 4 , wherein the compound is substantially free of (R)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide.
6. The compound of claim 4 , wherein the compound has an enantiomeric excess greater than about 95%.
7. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier.
8. A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of claim 1 .
9. A method of treating rheumatoid arthritis, psoriasis, lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of claim 1 .
10. A process for the preparation of compound of formula (A1)
comprising the steps of:
(a) reacting (R)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one
with 3-(4-methoxy-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
under Mitsunobu conditions using triphenylphosphine and diisopropylazodicarboxylate to give (S)-2-(1-(4-amino-3-(4-methoxy-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (Intermediate 3)
(b) reducing intermediate 3 to give (S)-2-(1-(4-amino-3-(3-amino-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (Intermediate 4)
and
(c) reacting Intermediate 4 with methanesulphonyl chloride to give a compound of the formula (A1).