Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10112926-B2
Application number	US-201415303879-A
Country	US
Kind code	B2
Filing date	Apr 24, 2014
Priority date	Apr 24, 2014
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
E is selected from N and CR E ;
R 1 , R 2 and R E are independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl and C 3-7 cycloalkyl;
R 3 is selected from
(i) C 1-4 alkyl which is unsubstituted or substituted with 1 or more substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl, oxo, CN, —(C 0-3 alkyl)-NR 3a R 3b , C 3-7 cycloalkyl and C 3-7 heterocyclyl, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(ii) C 1-4 alkoxy which is unsubstituted or substituted with 1 or more substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl, oxo, CN, —(C 0-3 alkyl)-NR 3a R 3b , C 3-7 cycloalkyl and C 3-7 heterocyclyl, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(iii) —C 3-7 cycloalkyl or —O—C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(iv) —(C 0-3 alkyl)-C 3-7 cycloalkyl or —O—(C 0-3 alkyl)-C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is spiro fused to a second C 3-7 cycloalkyl or C 3-7 heterocyclyl by one single carbon atom, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(v) —(C 0-3 alkyl)-C 3-7 heterocyclyl or —O—(C 0-3 alkyl)-C 3-7 heterocyclyl, and wherein said C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(vi) —(C 0-3 alkyl)-C 3-7 heterocyclyl or —O—(C 0-3 alkyl)-C 3-7 heterocyclyl, and wherein said C 3-7 heterocyclyl is spiro fused to a second C 3-7 heterocyclyl or a C 3-7 cycloalkyl by one single carbon atom, and wherein the C 3-7 heterocyclyl or C 3-7 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(vii) pyridyl wherein the pyridyl is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl and —(C 0-3 alkyl)-NR 3a R 3b ; and

(viii) H;
R 4 is selected from H and C 1-4 alkyl; or
R 3 and R 4 together with the nitrogen atom to which they are attached form a C 3-7 heterocyclyl, which C 3-7 heterocyclyl is optionally spiro fused to a second C 3-7 heterocyclyl or a C 3-7 cycloalkyl by one single carbon atom, and which C 3-7 heterocyclyl and C 3-7 cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
R 3a and R 3b are independently selected from H, C 1-4 alkyl and C 1-4 haloalkyl;
Y is selected from the group consisting of
oxazol-5-yl,
thiazol-5-yl,
thiazol-4-yl,
isothiazol-5-yl,
pyrazol-4-yl,
pyrazol-1-yl,
pyrid-4-yl,
1,2,4-triazol-1-yl,
1,2,3-triazol-4-yl,
1,2,4-oxadiazol-5-yl,
1,3,4-oxadiazol-2-yl,
isoxazol-5-yl,
isoxazol-4-yl, and
pyrrol-3-yl,

each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, —(C═O)—C 3-7 heterocyclyl, —(C 0-3 alkyl)-NR′R″ and —(C═O)—NR′R″; and
R′ and R″ are independently selected from H and C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
E is selected from N and CR E ;
R 1 , R 2 and R E are independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl and C 3-7 cycloalkyl;
R 3 is selected from
(i) C 1-4 alkyl which is unsubstituted or substituted with 1 or more substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl, oxo, CN, —(C 0-3 alkyl)-NR 3a R 3b , C 3-7 cycloalkyl and C 3-7 heterocyclyl, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(ii) C 1-4 alkoxy which is unsubstituted or substituted with 1 or more substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl, oxo, CN, —(C 0-3 alkyl)-NR 3a R 3b , C 3-7 cycloalkyl and C 3-7 heterocyclyl, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(iii) —C 3-7 cycloalkyl or —O—C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(iv) —(C 0-3 alkyl)-C 3-7 cycloalkyl or —O—(C 0-3 alkyl)-C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is spiro fused to a second C 3-7 cycloalkyl or C 3-7 heterocyclyl by one single carbon atom, and wherein the C 3-7 cycloalkyl or C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(v) —(C 0-3 alkyl)-C 3-7 heterocyclyl or —O—(C 0-3 alkyl)-C 3-7 heterocyclyl, and wherein said C 3-7 heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(vi) —(C 0-3 alkyl)-C 3-7 heterocyclyl or —O—(C 0-3 alkyl)-C 3-7 heterocyclyl, and wherein said C 3-7 heterocyclyl is spiro fused to a second C 3-7 heterocyclyl or a C 3-7 cycloalkyl by one single carbon atom, and wherein the C 3-7 heterocyclyl or C 3-7 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, oxo and —(C 0-3 alkyl)-NR 3a R 3b ;
(vii) pyridyl wherein the pyridyl is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, hydroxy, C 1-4 hydroxyalkyl, halogen, C 1-4 haloalkyl and —(C 0-3 alkyl)-NR 3a R 3b ; a

Assignees

• Bellenie Benjamin Richard
• Bloomfield Graham Charles
• Bruce Ian
• Culshaw Andrew James
• Hall Edward Charles
• Hollingworth Gregory John
• Neef James
• Spendiff Matthew
• Watson Simon James
• Novartis Ag

Inventors

• Bellenie Benjamin Richard
• Bloomfield Graham Charles
• Bruce Ian
• Culshaw Andrew James
• Hall Edward Charles
• Hollingworth Gregory John
• Neef James
• Spendiff Matthew
• Watson Simon James

Classifications

• A61P37/06

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title