Phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11021467-B2
Application number	US-201514735244-A
Country	US
Kind code	B2
Filing date	Jun 10, 2015
Priority date	Jun 13, 2014
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

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

or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein n, W, A′, B′, 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 (IVa):

wherein:
n is 0, 1, 2, 3, or 4;
m is 0;
A is a single bond or C(O);
B is C 1-6 alkyl or C 3-8 cycloalkyl wherein each of the alkyl and cycloalkyl is optionally substituted with hydroxyl or C 1-6 alkoxy;
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 1-6 alkylsulfonyl, optionally substituted C 3-8 aryl, optionally substituted C 3-8 heteroaryl, optionally substituted C 3-8 cycloalkyl, and optionally substituted C 2-8 heterocycloalkyl;
R 2 is cyano, optionally substituted C 3-8 heterocycloalkyl, optionally substituted C 3-8 heteroaryl, —NR 2x R 2x , —NR 2y C(O)R 2x , —C(O)NR 2x R 2y , —OR 2y , or —SO 2 R 2z ,
where R 2x is independently hydrogen, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-8 heterocycloalkyl, or C 4-8 heteroaryl;
wherein R 2y is independently selected from hydrogen and C 1-6 alkyl; and
wherein R 2z is C 1-6 alkyl;

R 3 is hydrogen, optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, or C 6-10 aryl;
R 4 is a six- to twelve-membered bicyclic heteroaryl having at least one aromatic group and at least two heteroatoms selected from N and S, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, optionally substituted haloalkyl, optionally substituted C 1-6 alkyl, and —NH 2 ; and
R 5 is hydrogen or optionally substituted C 1-6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof.

2. The compound of claim 1 , wherein:
n is 0, 1, 2 or 3;
m is 0;
A is a single bond or C(O);
B is C 1-6 alkyl or C 3-8 cycloalkyl—wherein each of the alkyl and cycloalkyl is optionally substituted with hydroxyl or C 1-6 alkoxy;
each R 1 is independently selected from halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 alkylsulfonyl;
R 2 is cyano, morpholinyl, —NR 2x R 2x , —NR 2y C(O)R 2x , —C(O)NR 2x R 2y , —OR 2y , —SO 2 R 2z , pyrrolidinyl, piperidinyl, optionally substituted piperazinyl, pyrazolyl, or triazolyl,
where R 2x is independently hydrogen, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-8 heterocycloalkyl, or C 4-8 heteroaryl;
wherein R 2y is independently selected from hydrogen and C 1-6 alkyl; and
wherein R 2z is C 1-6 alkyl;

R 3 is hydrogen, optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, or C 6-10 aryl;
R 4 is a six- to twelve-membered bicyclic heteroaryl having at least one aromatic group and at least two heteroatoms selected from N and S, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, optionally substituted haloalkyl, optionally substituted C 1-6 alkyl, and —NH 2 ; and
R 5 is hydrogen or optionally substituted C 1-6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof.

3. A compound selected from the group consisting of:
(S)-3-(3-amino-3-methylbutyl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-5-chloro-3-(3-morpholinopropyl)quinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-5-chloro-2-(cyclopropyl(imidazo[2,1-f][1,2,4]triazin-4-ylamino)methyl)quinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-2-(((5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)(cyclopropyl)methyl)-5-chloroquinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-5-chloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)quinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-5-chloro-2-(((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)(cyclopropyl)methyl)quinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)quinazolin-4(3H)-one;
(S)-3-(3-aminopropyl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one; and
(S)-3-((1H-pyrazol-3-yl)methyl)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein B is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with methoxy, ethoxy, or hydroxyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein each R 1 is independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, and fluoroethyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein each R 2 is selected from cyano, morpholinyl, —NH 2 , —NHR 2x , —NR 2x R 2x , —NHC(O)R 2y , —NR 2y C(O)R 2x , —C(O)NHR 2y , —C(O)NR 2x R 2y , —OH, —OR 2y , and —SO 2 R 2z ; wherein each R 2x is independently methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, phenyl, phenylmethyl, phenylethyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclohexyl, or oxetanyl, each of R 2x is optionally substituted with one, two, or three members selected from fluoro, chloro, bromo, and iodo; wherein each R 2y is independently hydrogen, methyl, ethyl, propyl, or butyl; and wherein each R 2z is independently methyl, ethyl, propyl, or butyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, and phenyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein R 5 is hydrogen, methyl, ethyl, or propyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein R 4 is bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms, and at least one additional heteroatom selected from N, O, and S; wherein R 4 is optionally substituted with two or three members independently selected from bromo, chloro, fluoro, cyano, methyl, ethyl, propyl, and —NH 2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is an atropisomer.

11. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, and at least one pharmaceutically acceptable vehicle.

12. A method of treating a disease or condition in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, or a mixture thereof, wherein the disease or condition is selected from cancer, hematologic malignancies, leukemias, lymphomas, myeloproliferative disorders, myelodysplastic syndromes, plasma cell neoplasms, solid tumor, inflammation, fibrosis, autoimmune disorders, alle

Assignees

• Gilead Sciences Inc

Inventors

• Cai Shaopei
• Du Zhimin
• Kim Musong
• Loyer-Drew Jennifer A
• Naduthambi Devan
• Patel Leena
• Phillips Barton W
• Phillips Gary
• Stevens Kirk L
• Treiberg Jennifer Anne
• Van Veldhuizen Joshua
• Watkins William J
• Yeung Suet Chung

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D473/34

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title