Pyrrolopyrimidine compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10179133-B2
Application number	US-201715790700-A
Country	US
Kind code	B2
Filing date	Oct 23, 2017
Priority date	Oct 3, 2011
Publication date	Jan 15, 2019
Grant date	Jan 15, 2019

Abstract

Compounds of Formula I:

wherein: one of X and X′ is N and the other of X and X′ is C, are described, along with compositions containing the same and methods of use thereof in the treatment of cancer.

First claim

That which is claimed is:

1. A pharmaceutical composition comprising an effective amount of a compound of Formula I having the following structure:

wherein:
one of X and X′ is N and the other of X and X′ is C;
one of the dashed lines in Formula I is a single bond and the other of the dashed lines in Formula I is a double bond;
R 1 is aryl; wherein the aryl is unsubstituted or substituted from 1 to 3 times with one or a combination of 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, aryl amino, arylalkylamino, heterocycloamino , heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano, where m=0, 1 , 2 or 3, and wherein the alkyl or heterocycloalkyl-S(O) m can be substituted from 1 to 3 times with one or a combination of halo, alkyl, haloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein the substituted heterocycloalkyl can be substituted from 1 to 3 times with one or a combination of halo, alkyl, or haloalky; or
R 1 is heteroaryl, wherein the heteroaryl is unsubstituted or substituted from 1 to 3 times with one or a combination of 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, and wherein the alkyl or heterocycloalkyl-S(O) m can be substituted from 1 to 3 times with one or a combination of halo, alkyl, haloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein the substituted heterocycloalkyl can be substituted from 1 to 3 times with one or a combination of halo, alkyl, or haloalkyl;
R 2 is —R 5 R 6 , where R 5 is a covalent bond or C1 to C3 alkyl and R 6 is cycloalkyl, and 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; cycloalkylalkyl, heterocycloalkylalkyl, heteroaryalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
or R 2 and R 3 together form a linking group;
R 4 is H, loweralkyl, halo, or loweralkoxy; and
R 5 is H, loweralkyl, halo, or loweralkoxy;

or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable vehicle.

2. The pharmaceutical composition of claim 1 , wherein the compound of Formula I has the following structure:

3. The pharmaceutical composition of claim 1 , wherein the compound of Formula I has the following structure:

4. The pharmaceutical composition 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 pharmaceutical composition of claim 1 , wherein R 1 is phenyl, wherein the phenyl is substituted from 1 to 3 times with one or a combination of halo or heterocycloalkyl-S(O) 2 , wherein the heterocycloalkyl-S(O) 2 can be substituted from 1 to 3 times with one or a combination of halo, alkyl, or haloalkyl.

6. The pharmaceutical composition of claim 1 , wherein R 1 is phenyl, wherein the phenyl is substituted once with halo, alkyl, cycloalkyl, heterocycloalkyl, sulfonamide, or heterocycloalkyl-S(O) 2 , and wherein the alkyl or heterocycloalkyl-S(O) 2 can be substituted once with halo, alkyl, haloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein the substituted heterocycloalkyl can be substituted once with alkyl.

7. The pharmaceutical composition of claim 3 , wherein R 1 is phenyl, wherein the phenyl is substituted from 1 to 3 times with one or a combination of halo or heterocycloalkyl-S(O) 2 , wherein the heterocycloalkyl-S(O) 2 can be substituted from 1 to 3 times with one or a combination of halo, alkyl, or haloalkyl.

8. The pharmaceutical composition of claim 3 , wherein R 1 is phenyl, wherein the phenyl is substituted once with halo, alkyl, cycloalkyl, heterocycloalkyl, sulfonamide, or heterocycloalkyl-S(O) 2 , and wherein the alkyl or heterocycloalkyl-S(O) 2 can be substituted once with halo, alkyl, haloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein the substituted heterocycloalkyl can be substituted once with alkyl.

9. The pharmaceutical composition of claim 1 , wherein the cycloalkyl of R 6 is substituted once with amino or hydroxyl.

10. The pharmaceutical composition of claim 9 , wherein the cycloalkyl is substituted once with hydroxyl.

11. The pharmaceutical composition of claim 1 , wherein R 5 is a covalent bond.

12. The pharmaceutical composition of claim 11 , wherein R 7 is H.

13. The pharmaceutical composition of claim 1 , wherein R 8 is cycloalkylalkyl.

14. The pharmaceutical composition of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 14 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 14 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

18. A method of treating a cancer comprising administering to a subject in need the

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Wang Xiaodong
• Liu Jing
• Zhang Weihe
• Frye Stephen
• Kireev Dmitri

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D487/18

  Bridged systems · CPC title

• A61K31/5377

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