Phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10479770-B2
Application number	US-201715711875-A
Country	US
Kind code	B2
Filing date	Sep 21, 2017
Priority date	Sep 23, 2016
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

Abstract

The present application provides the compounds of formula I

or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein t, R 1 , R 2 , R 3 , R 4 , and R 6 are as described herein.

First claim

What is claimed:

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

wherein: R 1 is selected from:

n is 1, 2, 3 or 4;
s is 1, 2 or 3;
t is 1 or 2;
each X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 is independently selected from C and N;
R 2 is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 2 is optionally substituted with one to four R 101 ;

R 3 is selected from halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 3 is optionally substituted with one to four R 102 ;

R 4 is selected from 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 4 is optionally substituted with one to four R 103 ;

each R 5 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 5 is optionally substituted with one to four R 104 ;

each R 6 is independently hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
each R 7 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 7 is optionally substituted with one to four R 100 ;

each R a and R b is independently selected from hydrogen, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
wherein each C 1-6 alkyl, C 2-6 alkynyl of R a and R b , C 2-6 alkynyl, is optionally substituted with one to four R 200 ;

each R 100 , R 101 , R 102 , R 103 and R 104 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R c , —C(O)OR c , —C(O)NR c R d , —N(R c )C(O)R d , —N(R c )C(O)NR c R d , —N(R c )C(O)NR c R d , —OC(O)NR c R d , —NR c S(O) 2 NR c R d , —NR c S(O) 2 R c , —OC(O)NR c R d , —NR c S(O) 2 NR c R d , —NR c S(O) 2 R c , —S(O)NR c R d , —S(O) 2 NR c R d , —S(O)R c , —S(O) 2 R g , —NR c R d , —OR c , —SR d , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R 100 , R 101 , R 102 , R 103 and R 104 is optionally substituted with one to four R 201 , and
each R c and R d is independently selected from hydrogen, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

each R 200 and R 201 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R e , —C(O)OR e , —C(O)NR e R f , —N(R e )C(O)R f , —S(O)NR e R f , —S(O) 2 NR e R f , NR e R f , —OR e , —SR e , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl,
each R e and R f is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; and

each R g is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl of R g is optionally substituted with one to four R 200 ,

or a pharmaceutically acceptable salt, double bond isomer, racemate, stereoisomer, enantiomer, diastereomer, or atropisomer thereof.

2. The compound of claim 1 having the structure of formula IA:

wherein t, R 1 , R 2 , R 4 , and R 6 are as defined in claim 1 ;
represents a single or double bond;
X 12 is N or C;
each X 8 , X 9 , X 10 and X 11 is independently selected from S, O, CR 10 and NR 11 ;
wherein each R 10 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R c , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S,
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 201 ;

wherein each R 11 is independently selected from absent, hydrogen, halo, cyano,

Assignees

• Gilead Sciences Inc

Inventors

• Chandrasekhar Jayaraman
• Naduthambi Devan
• Patel Leena
• Perreault Stephane
• Phillips Gary
• Sedillo Kassandra F
• Till Nicholas Alexander
• Treiberg Jennifer Anne
• Watkins William J
• Codelli Julian A
• Van Veldhuizen Joshua J

Classifications

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D235/08 Primary

  Radicals containing only hydrogen and carbon atoms · CPC title