Certain chemical entities, compositions, and methods

Patent metadata

Field	Value
Publication number	US-10947201-B2
Application number	US-201615044966-A
Country	US
Kind code	B2
Filing date	Feb 16, 2016
Priority date	Feb 17, 2015
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

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

First claim

What is claimed is:

1. A compound having the following formula:

or a pharmaceutically acceptable salt thereof, wherein:
X 10 is C—R 35 ;

is aryl or heteroaryl;
each of R 3 , R 4 , R 5 and R 6 is independently hydrogen, cyano, fluoro, or chloro;
R34, R35, R36, R37, and R38 are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkyl, optionally substituted amino, or E;
each Q is independently hydrogen, cyano, or halo;
wherein E is

and
m is 0, 1, or 2;
wherein at least one of R 34 , R 35 , R 36 , R 37 , and R 38 is E;
wherein:
each substituted alkoxy is —O-(substituted alkyl);
each substituted amino is —NHR d or —NR d R e ; wherein each R d is independently unsubstituted or substituted alkyl, or unsubstituted or substituted heterocycloalkyl; and each R e is independently unsubstituted or substituted alkyl, or unsubstituted or substituted heterocycloalkyl; and
each substituted alkyl and substituted heterocycloalkyl is substituted with one or more groups independently selected from —R a , —OR b , —NH 2 —NHR d , —NR d R e , and halo; each R a is independently unsubstituted or substituted C 1 -C 6 alkyl; each R b is independently hydrogen or unsubstituted or substituted C 1 -C 6 alkyl; each R d is independently unsubstituted or substituted alkyl; and each R e is independently unsubstituted or substituted alkyl;
wherein when any R a , R b , R d , or R e group is substituted, the R a , R b , R d , or R e group is substituted with one or more substituents independently selected from a group D consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, halo, —OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), and —NH(C 1 -C 4 alkyl).

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

is aryl.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 35 or R 37 is E.

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 36 is

wherein R 28 is hydrogen or alkyl.

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

is phenyl or pyridinyl.

6. The compound or pharmaceutically acceptable salt of claim 1 , having the following Formula:

wherein
R 34 , R 36 , R 37 , and R 38 are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkyl, or optionally substituted amino.

7. The compound or pharmaceutically acceptable salt of claim 6 , wherein R 3 , R 4 , R 6 and R 5 are each hydrogen.

8. The compound of claim 1 , selected from the group consisting of:
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide,
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide,
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylazetidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylazetidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylazetidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(methyl(1-methylazetidin-3-yl)amino)phenyl)acrylamide,
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide,
N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(2-(3-(dimethylamino)azetidin-1-yl)-5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-2-(3-(dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-2-(3-(dimethylamino)azetidin-1-yl)-4-methoxyphenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide,
N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(2-(3-(dimethylamino)azetidin-1-yl)-5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxyphenyl)acrylamide,
N-(5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide,
N-(5-((8-(5-fluoropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide,
N-(5-((8-(3-chlorophenyl)quinazolin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide,
N-(5-((8-(5-chloropyridin-3-yl)quinazolin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide,
N-(2-(2-(dimethylamino)ethoxy)-5-((8-(3-fluorophenyl)quinazolin-2-yl)amino)-4-methoxyphenyl)acryla

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• C07D239/84 Primary

  Nitrogen atoms · CPC title

• C07D401/12

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

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D473/30

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