Pyrrolopyrimidine compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9795606-B2
Application number	US-201615014573-A
Country	US
Kind code	B2
Filing date	Feb 3, 2016
Priority date	Oct 3, 2011
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

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 method of treating a cancer in a subject comprising administering 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, acyloxy, 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, heterocycloalkyl, aryl, heteroaryl or alkyl, 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, wherein the treatment of said cancer is mediated by Mer receptor tyrosine kinase activity.

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

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

4. The method 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 method 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 method 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 method 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 method 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 method of claim 1 , wherein the cancer is selected from the group consisting of myeloid leukemia, lymphoblastic leukemia, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancer.

10. The method of claim 1 , wherein the cancer is selected from the group consisting of melanoma, breast, lung, colon, and brain cancer.

11. The method of claim 1 , wherein the cycloalkyl of R6 is substituted once with amino or hydroxyl.

12. The method of claim 11 , wherein the cycloalkyl is substituted once with hydroxyl.

13. The method of claim 12 , wherein R 5 is a covalent bond.

14. The method of claim 13 , wherein R 7 is H.

15. The method of claim 14 , wherein R 8 is cycloalkylalkyl.

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

or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , wherein said compound has the structure:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 16 , wherein said compound has the structure:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 16 , wherein said compound has the structure:

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519 Primary

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