Phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10092563-B2
Application number	US-201514735254-A
Country	US
Kind code	B2
Filing date	Jun 10, 2015
Priority date	Jun 13, 2014
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

The present application provides the compounds of formula (J),

or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein W, B, n, m, A′, R 1 , R 2 , and R 3 are described herein. The compounds are inhibitors to the activities of phosphatidylinositol 3-kinase (PI3K) and are useful for treating conditions mediated by one or more PI3K isoforms. The present application further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts, isomers, tautomer, or mixture thereof, and methods of using these compounds and compositions for treating conditions mediated by one or more PI3K isoforms.

First claim

What is claimed:

1. A compound having the structure of formula (I):

wherein
n is 0, 1, 2, or 3;
m is 0;
A is a single bond;
B is piperazinyl optionally substituted with halo, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 heterocycloalkyl, C 1-6 haloalkyl, or optionally substituted C 3-8 cycloalkyl;
each R 1 is independently selected from halo, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted sulfonyl, optionally substituted C 3-8 aryl, optionally substituted C 3-8 heteroaryl, optionally substituted C 3-8 cycloalkyl, and optionally substituted C 3-8 heterocycloalkyl;
each R 2 is independently halo, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, or —NH 2 ;
R 3 is hydrogen, optionally substituted C 1-6 alkyl or C 3-8 cycloalkyl;
R 4 is a six- to twelve-membered heteroaryl having at least one aromatic group and at least two heteroatoms, wherein said heteroatom is N, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, and —NH 2 ; and
R 5 is hydrogen,
or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

2. The compound of claim 1 , wherein
n is 1 or 2;
m is 0;
B is piperazinyl optionally substituted with one or two members independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 heterocycloalkyl, and C 3-8 cycloalkyl, wherein C 3-8 heterocycloalkyl is optionally substituted with C 1-6 alkyl;
each R 1 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 2 is independently selected from halo, —NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 3 is hydrogen or C 1-6 alkyl;
R 4 is a six- to twelve-membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano and —NH 2 ; and
R 5 is hydrogen,
or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein each R 1 is selected from chloro, bromo, fluoro, methyl, ethyl, and propyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, and cyclobutyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein R 4 is a pyrimidinyl or pyrazinyl; wherein the pyrimidinyl or pyrazinyl is optionally substituted with two or three members independently selected from bromo, chloro, fluoro, cyano and —NH 2 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein R 4 is selected from purinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopydmidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one, two, or three members independently selected from bromo, chloro, fluoro, cyano and —NH 2 .

7. A compound selected from the group consisting of:
(S)-2,4-diamino-6-(((5-chloro-3-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(4-methylpiperazin-1-yl)quinazolin-4(3H)-one;
(S)-4-amino-6-((1-(5-chloro-3-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2-amino-4-((1-(5-chloro-8-fluoro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile;
(S)-3-amino-6-chloro-N-(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide;
(S)-3,5-diamino-6-chloro-N-(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide;
(S)-5-chloro-2-(1-(furo[3,2-d]pyrimidin-4-ylamino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(1-((5-chlorothieno[2,3-d]piperidin-4-yl)amino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2-amino-N-(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(S)-2-(1-((6-amino-5-chloropyrimidin-4-yl)amino)ethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(5,8-di fluoro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-5,8-difluoro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2-(cyclopropyl(imidazo[2,1-f][1,2,4]triazin-4-ylamino)methyl)-5,8-difluoro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)propyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(cyclopropyl(imidazo[2,1-f][1,2,4]triazin-4-ylamino)methyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2-amino-4-((1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-methylpyrimidine-5-carbonitrile;
(S)-2-amino-4-(((5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile;
(S)-5-chloro-2-(cyclopropyl(imidazo[2,1-f][1,2,4]triazin-4-ylamino)methyl)-8-fluoro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-(((5-chloro-8-fluoro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-5,8-dichloro-3-(piperazin-1-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-5-chloro-8-fluoro-3-(piperazin-1-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5,8-dichloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-amino-N-(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide;
(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-amino-N-(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)-5,6-dimethylpyrazine-2-carboxamide;
(S)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(1-((5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-3-(piperazin-1-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)-5-chloro-3-(piperazin-1-yl)-2-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-4-ami

Assignees

• Gilead Sciences Inc

Inventors

• Cai Shaopei
• Du Zhimin
• Kaplan Joshua
• Loyer-Drew Jennifer A
• Naduthambi Devan
• Phillips Barton W
• Phillips Gary
• Van Veldhuizen Joshua
• Watkins William J
• Yeung Suet Chung

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title