Certain chemical entities, compositions, and methods

Patent metadata

Field	Value
Publication number	US-2016304471-A1
Application number	US-201615044966-A
Country	US
Kind code	A1
Filing date	Feb 16, 2016
Priority date	Feb 17, 2015
Publication date	Oct 20, 2016
Grant date	—

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

First claim

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

is aryl or heteroaryl;

is selected from a group consisting of:

wherein; a is point of attachment for L and b is point of attachment for G;
X 3 is C—R 3 , or N; X 4 is C—R 4 , or N; X 5 is C—R 5 , or N; X 6 is C—R 19 , or N; X 7 is C—R 20 , or N; X 8 is C—R 21 , or
N; Y is O, S, or N—R 22 ;
L is —[(CR 30 R 31 ) x —O—(CR 32 R 33 )] z —, —[(CR 30 R 31 ) x ] z —, —[(CR 30 R 31 ) x —S—(CR 30 R 31 ) y ] z —, —[(CR 30 R 31 ) x —NR 29 —(CR 30 R 31 ) y ] z —, —[(CR 30 R 31 ) x —CO—(CR 30 R 31 ) y ] z —, —[(CR 30 R 31 ) x —SO 2 —(CR 30 R 31 ) y ] z —, —[(CR 30 R 31 ) x —CO 2 —(CR 30 R 31 ) y ] z —, or —[(CR 30 R 31 ) x —CONR 29 —(CR 30 R 31 ) y ] z —, or —[(CR 30 R 31 ) y ] z —;
each of R 3 , R 4 , R 5 , R 6 , R 14 , R 15 , R 16 , R 19 , R 20 , R 21 , R 30 , R 31 , R 32 , R 33 , and G is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo, 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;
R 17 , R 18 , R 22 and R 29 are independently hydrogen, sulfonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl;
or R 3 and R 4 , R 4 and R 5 , R 15 and R 16 , R 15 and R 17 , R 20 and R 21 , R 20 and R 22 , or R 21 and R 22 may optionally be joined together with any intervening atoms to form an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring;
each Z is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo, 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;
n is 0, 1, 2, 3, 4 or 5; and x, y, and z are independently 0, 1, 2, 3, or 4;
provided that when

G is

wherein

is aryl, heteroaryl, or heterocycloalkyl; m is 0, 1, 2, 3, 4, or 5 and each Q is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo, 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; and L is —NH—; then n is 1, 2, 3, 4, or 5, and at least one Z is E.

2 . (canceled)

3 . (canceled)

4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein G is halo, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

5 . (canceled)

6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein

is selected from the group consisting of: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, and thienyl.

7 - 9 . (canceled)

10 . The compound or pharmaceutically acceptable salt of claim 1 , wherein L is —O—, —CH 2 —, —NH—, —S—, —CO—, —CO 2 —, —CONH—, SO 2 —, or —SO 2 NH—.

11 . (canceled)

12 . (canceled)

13 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each Z is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aminocarbonyl, or E.

14 . (canceled)

15 . The compound or pharmaceutically acceptable salt of claim 13 , wherein n is 1, 2, 3, 4, or 5; and at least one Z is E.

16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein each E is independently an electrophilic group capable of forming a covalent bond with a cysteine residue of a protein.

17 . The compound or pharmaceutically acceptable salt of claim 16 , wherein each E is independently selected from a group consisting of

18 . (canceled)

19 . (canceled)

20 . The compound or pharmaceutically acceptable salt of claim 1 , wherein

X 10 is C—R 35 or N; and
R 34 , R 35 , R 36 , R 37 , and R 38 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 substitut

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• C07D473/30

  attached in position 6, e.g. hypoxanthine · CPC title

• C07D403/12

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

• C07D239/84 Primary

  Nitrogen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

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