Substituted quinazolines for inhibiting kinase activity

Patent metadata

Field	Value
Publication number	US-9550770-B2
Application number	US-201414466896-A
Country	US
Kind code	B2
Filing date	Aug 22, 2014
Priority date	Aug 23, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions containing the same, and methods of use thereof are described. Specifically quinazoline derivatives of Formula Ia:

and their uses in modulating kinase activities are disclosed.

First claim

What is claimed is:

1. A compound having the structure of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein
X 1 is C—R 2 , or N;
X 2 is C—R 11 , or N;
X 3 is C—R 12 ;
X 4 is C—R 13 ;
X 5 is C—R 14 ;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; and
R 8 , R 9 , and R 10 are independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or E;

wherein E is an electrophilic group capable of forming a covalent bond with a nucleophile; and
wherein at least one of R 8 , R 9 , and R 10 is E.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen, cyano, halo, hydroxy, —CONH 2 , optionally substituted alkoxy, or optionally substituted cycloalkyloxy.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 , R 3 , and R 4 are independently hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, or optionally substituted aminocarbonyl.

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 2 and R 4 are hydrogen, and R 3 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azetidinyl, or optionally substituted amino.

5. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 2 and R 3 are hydrogen, and R 4 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azetidinyl, or optionally substituted amino.

6. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 6 is hydrogen or optionally substituted amino.

8. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 7 and R 11 are independently hydrogen, cyano, optionally substituted lower alkyl, halo, or methoxy.

9. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 8 , R 9 , and R 10 are independently hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or E; wherein E is an electrophilic group capable of forming a covalent bond with a nucleophile.

10. The compound or pharmaceutically acceptable salt of claim 9 , wherein at least one of R 8 , R 9 , and R 10 is halo or optionally substituted amino.

11. The compound or pharmaceutically acceptable salt of claim 9 , wherein at least one of R 8 , R 9 , and R 10 is E; and wherein E is selected from

12. The compound or pharmaceutically acceptable salt of claim 11 , wherein E is

13. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 12 is hydrogen, halo, cyano, —CONH 2 , —NHCOCH 3 , or optionally substituted lower alkyl.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 13 and R 14 are independently hydrogen, cyano, optionally substituted lower alkyl, halo, or methoxy.

15. The compound or pharmaceutically acceptable salt of claim 1 , wherein:
X 1 is C—R 2 and X 2 is C—R 11 ;
X 1 is N and X 2 is C—R 11 ; or
X 1 is C—R 2 and X 2 is N.

16. The compound or pharmaceutically acceptable salt of claim 1 , having the Formula Ib′:

wherein:
X 1 is N or C—R 2 ;
each R 1 , R 2 , R 4 , and R 5 is independently H or halo;
R 3 is optionally substituted heterocycloalkyl; and
E is an electrophilic group capable of forming a covalent bond with a nucleophile.

17. The compound or pharmaceutically acceptable salt of claim 16 , wherein R 1 is hydrogen.

18. The compound or pharmaceutically acceptable salt of claim 16 , wherein X 1 is C—R 2 and R 2 is hydrogen or halo.

19. The compound or pharmaceutically acceptable salt of claim 16 , wherein X 1 is C—R 2 , and R 1 and R 2 are fluoro.

20. The compound or pharmaceutically acceptable salt of claim 16 , wherein R 3 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, or optionally substituted azetidinyl.

21. The compound or pharmaceutically acceptable salt of claim 16 , wherein:
R 3 is piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl, optionally substituted with —R a , —OR b , optionally substituted amino, —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , —NR c SO 2 R a , halo, cyano, azido, nitro, oxo, optionally substituted acyl, —COR b , optionally substituted alkoxycarbonyl, —CO 2 R b , aminocarbonyl, —CONR b R c , —OCOR b , —OCO 2 R a , —OCONR b R c , —OP(O)(OR b )OR c , sulfanyl, SR b , sulfinyl, —SOR a , sulfonyl, —SO 2 R a , or —SO 2 NR b R c ,
where R a is optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
R b is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title