PI3K protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11352359-B2
Application number	US-201414902536-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Jul 2, 2013
Publication date	Jun 7, 2022
Grant date	Jun 7, 2022

Abstract

The present disclosure provides novel compounds useful as PI3K protein kinase modulators, in particular as PI3K delta (δ) and/or gamma (γ) protein kinase modulators. The present disclosure also provides methods for preparing PI3K protein kinase modulators, pharmaceutical compositions containing them, and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

First claim

What is claimed is:

1. A compound selected from:
3-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-fluoro-2-phenylisoquinolin-1(2H)-one;
2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one;
2-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one;
3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-fluoro-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-fluoro-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-fluoro-2-phenylisoquinolin-1(2H)-one;
2-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(+)-2-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(−)-2-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2 , further comprising one or more additional therapeutic agents selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and mixtures thereof.

4. A method of inhibiting a catalytic activity of a PI3 kinase present in a cell, comprising contacting the cell with an effective amount of a compound of claim 1 .

5. The method of claim 4 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, or cardiac disease.

6. A compound selected from:
3-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
3-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenylquinazolin-4(3H)-one;
(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenylquinazolin-4(3H)-one;
(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenylquinazolin-4(3H)-one;
3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
N-(5-(4-amino-1-(1-(1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
(+)-N-(5-(4-amino-1-(1-(1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
(−)-N-(5-(4-amino-1-(1-(1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
2-(1-(4-amino-3-(4-methoxy-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenylquinazolin-4(3H)-one;
3-(1-(4-amino-3-(3-amino-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-phenylisoquinolin-1(2H)-one;
N-(5-(4-amino-1-(1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
3-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
3-(1-(4-amino-3-(4-methoxy-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
3-(1-(4-amino-3-(3-amino-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
N-(5-(4-amino-1-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
(+)-N-(5-(4-amino-1-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
(−)-N-(5-(4-amino-1-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide;
3-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+)-3-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;
(+3-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one;

and pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 , further comprising one or more additional therapeutic agents selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and mixtures thereof.

9. A method of inhibiting a catalytic activity of a PI3 kinase present in a cell, comprising contacting the cell with an effective amount of a compound of claim 6 .

10. The method of claim 9 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, or cardiac disease.

11. A compound selected from:
2-{1-[4-Amino-3-(3-fluoro-4-isopropoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]-propyl}-3-phenyl-3H-quinazolin-4-one;
and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , further comprising one or more additional therapeutic agents selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and mixtures thereof.

14. A method of inhibiting a catalytic activity of a PI3 kinase pres

Assignees

• Rhizen Pharmaceuticals Sa
• Rhizen Pharmaceuticals Ag

Inventors

• Bhavar Prashant Kashinath
• Vakkalanka Swaroop Kumar Venkata Satya
• Babu Govindarajulu

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/10

  for osteoporosis · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title