Phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10214519-B2
Application number	US-201715711957-A
Country	US
Kind code	B2
Filing date	Sep 21, 2017
Priority date	Sep 23, 2016
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present application provides the compounds of formula I or IA

or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof,
wherein s, t, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described herein.

First claim

What is claimed:

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

wherein n is 1, 2, 3 or 4;
m is 1, 2, 3 or 4;
s is 1 or 2;
t is 1 or 2;
each R 1 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 a , —S(O) 2 R a , —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 100 ;

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 a , —S(O) 2 R a , —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 101 ;

R 3 is selected from 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 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 102 ;

R 4 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, acyl, C 3-8 cycloalkyl and C 1-6 alkyl sulfonyl;
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 , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R a , —S(O) 2 R a , —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 103 ;

each R 6 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 a , —S(O) 2 R a , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
each R a and R b is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, is optionally substituted with one to four R 200 ;

each R 100 , R 101 , R 102 , and R 103 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —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 a , —S(O) 2 R a , —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 and 4-10 membered heterocyclyl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, is optionally substituted with one to four R 201 ; and,

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

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

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

wherein is a single or double bond;
X 1 is N or C;
each X 2 , X 3 , X 4 and X 5 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 a , —S(O) 2 R a , —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 104 ;

wherein each R 11 is independently selected from absent, 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 a , —S(O) 2 R a , —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;
alternatively, one R 10 and one R 11 group, together with the atoms to which they are attached form a five, six or seven membered fused or bridged ring;
each R 104 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —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 a , —S(O) 2 R a , —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 and 4-10 membered heterocyclyl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, is optionally substituted with one to four R 201 ; and

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

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

3. The compound of claim 1 , wherein R 3 is selected from:

wherein t is 1 or 2;
wherein each R 13 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 a , —S(O) 2 R a , —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 sele

Assignees

• Gilead Sciences Inc

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title