Pyrazolopyrimidine compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9290499-B2
Application number	US-201113641729-A
Country	US
Kind code	B2
Filing date	May 12, 2011
Priority date	May 19, 2010
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

Compound of Formula (I): are described, along with pharmaceutically acceptable salts thereof, compositions containing the same, and methods of use thereof in the treatment of cancer.

First claim

That which is claimed is:

1. A compound of Formula I:

wherein:
R 1 is aryl, wherein the aryl is unsubstituted or substituted from 1 to 3 times with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or 3;
or R 1 is heteroaryl, wherein the heteroaryl is unsubstituted or substituted from 1 to 3 times with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or 3;
R 2 is —R 5 R 6 , where R 5 is a covalent bond or C1 to C3 alkyl and R 6 is cycloalkyl, wherein R 6 is optionally substituted from one to two times with independently selected polar groups;
R 3 is —NR 7 R 8 , where R 7 and R 8 are each independently selected from H, alkyl, arylalkyl, and alkoxyalkyl; wherein the alkyl, arylalkyl, or alkoxyalkyl is unsubstituted or substituted from 1 to 3 times with alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl; and
R 4 is H, loweralkyl, halo, or loweralkoxy;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 5 is C1 to C3 alkyl.

3. The compound of claim 2 , wherein R 5 is —CH 2 —.

4. The compound of claim 1 , wherein R 1 is phenyl, or pyridyl, which phenyl or pyridyl is unsubstituted or substituted from 1 to 3 times with halo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

5. The compound of claim 1 , wherein R 8 is C1-C8 alkyl or C1-C8 arylalkyl; wherein the alkyl or arylalkyl is unsubstituted or substituted from 1 to 3 times with alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl.

6. The compound of claim 1 , wherein R 6 is cyclohexyl.

7. The compound of claim 1 , wherein R 6 is substituted once with hydroxyl.

8. The compound of claim 1 , wherein R 7 is H.

9. The compound of claim 1 , wherein R 8 is loweralkyl.

10. The compound of claim 1 , wherein R 4 is H.

11. The compound of claim 1 , wherein said compound has the structure:

or a pharmaceutically acceptable salt thereof.

12. A composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

13. A compound of Formula I:

wherein:
R 1 is phenyl, which phenyl is unsubstituted or substituted from 1 to 3 times with halo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl,
R 2 is —R 5 R 6 , where R 5 is a covalent bond or C1 to C3 alkyl and R 6 is cycloalkyl, wherein R 6 is optionally substituted from one to two times with independently selected polar groups;
R 3 is —NR 7 R 8 , where R 7 and R 8 are each independently selected from H, alkyl, arylalkyl, and alkoxyalkyl; wherein the alkyl, arylalkyl, or alkoxyalkyl is unsubstituted or substituted from 1 to 3 times with alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl; and
R 4 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein R 6 is cyclohexyl substituted once with hydroxyl.

15. The compound of claim 13 , wherein R 7 is H.

16. The compound of claim 14 , wherein R 8 is loweralkyl.

17. The compound of claim 15 , wherein R 4 is H.

18. The compound of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

20. A compound of Formula I,

wherein:
R 1 is aryl or heteroaryl; wherein the aryl or heteroaryl is unsubstituted or substituted from 1 to 3 times with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or 3;
R 2 is —R 5 R 6 , where R 5 is a covalent bond or C1 to C3 alkyl and R 6 is cycloalkyl, wherein R 6 is optionally substituted from one to two times with independently selected polar groups;
R 3 is —NR 7 R 8 , where R 7 is selected from H, alkyl, arylalkyl, and alkoxyalkyl; and R 8 is

C3-C8 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted from 1 to 3 times with alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl; and
R 4 is H, loweralkyl, halo, or loweralkoxy;

or a pharmaceutically acceptable salt thereof.

21. A composition comprising a compound of claim 13 in a pharmaceutically acceptable carrier.

22. A composition comprising a compound of claim 20 in a pharmaceutically acceptable carrier.

Assignees

• Wang Xiaodong
• Liu Jing
• Yang Chao
• Zhaug Weihe
• Frye Stephen
• Kireev Dmitri
• Univ North Carolina

Inventors

• Wang Xiaodong
• Liu Jing
• Yang Chao
• Zhaug Weihe
• Frye Stephen
• Kireev Dmitri

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/519 Primary

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

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title