Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10004732-B2
Application number	US-201415303868-A
Country	US
Kind code	B2
Filing date	Apr 24, 2014
Priority date	Apr 24, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 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)

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 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 ; and
(vii) 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; and
Y is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein
R 3 is selected from

or R 3 and R 4 together with the nitrogen atom to which they are attached form a ring selected from

or a pharmaceutically acceptable salt thereof.

3. A compound of formula (I)

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;
Y is selected from the group consisting of

R 4 is H and R 3 is selected from the group consisting of

or R 3 and R 4 together with the nitrogen atom to which they are attached form a C 3-7 heterocyclyl selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 selected from
3-[5-amino-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrazin-2-yl]-N-(4-hydroxy-cyclohexyl)-4-methyl-benzenesulfonamide;
3-[5-amino-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrazin-2-yl]-N-(4-hydroxy-cyclohexyl)-4-methyl-benzenesulfonamide;
3-[5-amino-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrazin-2-yl]-N-(3-hydroxy-3-methyl-butyl)-4-methyl-benzenesulfonamide;
3-[5-amino-6-(3-methyl-isoxazol-5-yl)-pyrazin-2-yl]-N-(4-hydroxy-cyclohexyl)-4-methyl-benzenesulfonamide;
3-[5-amino-6-(1-methyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-4-methyl-N-(3-methyl-oxetan-3-ylmethyl)-benzenesulfonamide;
3-(5-amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide;
3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide;
3-[5-amino-6-(2-methyl-thiazol-5-yl)-pyrazin-2-yl]-N-(3-hydroxy-2,2-dimethyl-propyl)-4-methyl-benzenesulfonamide;
3-[5-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-N-(6-hydroxy-spiro[3.3]hept-2-yl)-4-methyl-benzenesulfonamide;
3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-N-(3-hydroxypropyl)-4-methylbenzenesulfonamide;
3-(5-amino-6-(pyridin-4-yl)pyrazin-2-yl)-N-(4-hydroxycyclohexyl)-4-methylbenzenesulfonamide;
3-(5-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazin-2-yl)-N-(3-hydroxy-3-methylbutyl)-4-methylbenzenesulfonamide;
3-[5-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-N-(3-hydroxy-3-methyl-butyl)-4-methyl-benzenesulfonamide;
3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-N-(4-hydroxycyclohexyl)-4-methylbenzenesulfonamide;
3-(5-amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-N-(4-hydroxycyclohexyl)-4-methylbenzenesulfonamide;
3-[5-amino-6-(1,3-dimethyl-1H-pyrazol-4

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• 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