Substituted quinazolines for inhibiting kinase activity

Patent metadata

Field	Value
Publication number	US-2020306259-A1
Application number	US-202016843610-A
Country	US
Kind code	A1
Filing date	Apr 8, 2020
Priority date	Aug 23, 2013
Publication date	Oct 1, 2020
Grant date	—

Abstract

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

First claim

1 .- 97 . (canceled)

98 . A process for preparing a compound having the structure of Formula Ib″:

comprising
(i) contacting a compound having the structure of Formula A:

with a compound having a structure of Formula B:

in the presence of a base and a palladium catalyst under reaction conditions that provide a compound having the structure of Formula C:

and
contacting a compound having the structure of Formula C with acryloyl chloride to provide the compound having the structure of 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;
each R 6 , R 12 , R 13 , and R 4 is independently H; and
R′ are each independently OH or both R′ taken together with the oxygen atoms to which they are attached to form a 5-membered optionally substituted boronic ester.

99 . The process of claim 98 , wherein the base is Na 2 CO 3 , K 2 CO 3 , or Cs 2 CO 3 .

100 . The process of claim 99 , wherein the base is Na 2 CO.

101 . The process of claim 98 , wherein the reaction is conducted at a temperature ranging from about 25° C. to about 180° C.

102 . The process of claim 98 , wherein the reaction is conducted in a solvent comprising 1,4 dioxane, water, tetrahydrofuran, or combinations thereof.

103 . The process of claim 102 , wherein the reaction is conducted in a solvent comprising 1,4 dioxane, water, or a combination thereof.

104 . The process of claim 98 , wherein the palladium catalyst comprises [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ).

105 . The process of claim 98 , wherein the compound having the structure of Formula A is prepared from contacting a compound having the structure of Formula D:

with a compound having the structure of Formula E:

in the presence of a base or an acid.

106 . The process of claim 105 , wherein the base is Cs 2 CO 3 , NaH, KH, t-BuOK, LiH, or CaH 2 .

107 . The process of claim 105 , wherein the acid is trifluoroacetic acid.

108 . The process of claim 105 , wherein the process is conducted at a temperature ranging from about 25° C. to about 240° C.

109 . The process of claim 105 , wherein the process is conducted in a solvent comprising dimethylformamide, dimethylsulfoxide, dimethylacetamide, or N-methyl piperidone.

110 . The process of claim 105 , wherein the process is conducted in a solvent comprising n-butanol.

111 . The process of claim 98 , wherein the compound having the structure of Formula Ib″ is selected from the group consisting of:
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, and
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

112 . A process for preparing a compound having the structure of Formula Ib″:

comprising
(i) contacting a compound having the structure of Formula F:

with hydrogen in the presence of a palladium catalyst under conditions that provide a compound having the structure of Formula G:

(ii) contacting the compound having the structure of Formula G with a compound having the structure of Formula H:

in the presence of an acid under conditions that provide a compound having the structure of 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
each R 6 , R 12 , R 13 , and R 14 is independently H.

113 . The process of claim 112 , wherein the palladium catalyst comprises palladium on carbon.

114 . The process of claim 112 , wherein the conditions used in step (i) include use of a solvent comprising methanol and room or ambient temperature.

115 . The process of claim 112 , wherein the acid used in step (ii) is trifluoroacetic acid.

116 . The process of claim 112 , wherein the conditions used in step (ii) include use of a solvent comprising n-butanol, and a temperature ranging from about 80° C. to about 90° C.

117 . The process of claim 112 , wherein the compound having the structure of Formula Ib″ is selected from the group consisting of
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
methyl 4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate,
N-(3-(2-((4-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-N-methylpiperazine-1-carboxamide,
N-(3-(2-((4-4-propionylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide,
methyl 4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpiperazine-2-carboxylate,
N-(3-(2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)quinazolin-8-y

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• A61K31/517 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D401/12

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

• C07D239/84 Primary

  Nitrogen atoms · CPC title

• C07C57/145

  Maleic acid · CPC title