Oxepinopyrazole derivatives as inhibitors of P13-kinase activity

Patent metadata

Field	Value
Publication number	US-11555040-B2
Application number	US-201816604605-A
Country	US
Kind code	B2
Filing date	Apr 16, 2018
Priority date	Apr 18, 2017
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

The invention is directed to compounds of formula (I), and salts thereof. The compounds are inhibitors of kinase activity, in particular PI3-kinase activity.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
R 1 is 5- or 6-membered heteroaryl wherein the heteroaryl contains from one to three heteroatoms independently selected from oxygen and nitrogen and is substituted by one or two substituents independently selected from halo, cyano, C 1-6 alkoxy, —NHSO 2 C 1-6 alkyl, —XR 3 and C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted by halo;
R 2 is —OR 4 , —CONHR 5 , or 5- or 6-membered heteroaryl wherein the heteroaryl contains from one to three heteroatoms independently selected from oxygen and nitrogen and is substituted by one or two substituents independently selected from halo, cyano, C 1-6 alkoxy, —NHSO 2 C 1-6 alkyl, —CONR 6 R 7 , —YR 8 and C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted by one or two substituents independently selected from hydroxy and —NR 9 R 10 ;
R 3 is 5- or 6-membered heterocyclyl wherein the heterocyclyl contains one or two heteroatoms independently selected from oxygen and nitrogen and is optionally substituted by from one to three substituents independently selected from C 1-6 alkyl;
R 4 is C 1-6 alkyl optionally substituted by C 3-6 cycloalkyl or 5- or 6-membered heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen wherein the C 3-6 cycloalkyl is optionally substituted by —NHCO 2 C 1-6 alkyl and the heterocyclyl is optionally substituted by from one to three substituents independently selected from halo, —COC 1-6 alkyl, —CO 2 C 1-6 alkyl and C 1-6 alkyl optionally substituted by —OR 11 ;
R 5 is hydrogen or C 1-6 alkyl optionally substituted by 6-membered heterocyclyl wherein the heterocyclyl contains an oxygen atom or a nitrogen atom and is optionally substituted by C 1-6 alkyl;
R 6 and R 7 , together with the nitrogen atom to which they are attached, are linked to form a 5- or 6-membered heterocyclyl wherein the heterocyclyl optionally contains an oxygen atom or a further nitrogen atom and is optionally substituted by C 1-6 alkyl;
R 8 is 5- to 9-membered heterocyclyl wherein the heterocyclyl contains one or two heteroatoms independently selected from oxygen and nitrogen and is substituted by from one to three substituents independently selected from oxo, hydroxy, halo, —COC 1-6 alkyl and C 1-6 alkyl optionally substituted by —OR 12 ;
R 9 , R 10 , R 11 and R 12 are each independently hydrogen or C 1-6 alkyl;
X and Y are each independently —CH 2 — or —CH(CH 3 )—;
or a salt thereof.

2. A compound according to claim 1 , or a salt thereof wherein R 1 is 5- or 6-membered heteroaryl wherein the heteroaryl contains one or two nitrogen atoms and is substituted by one or two substituents independently selected from halo, C 1-6 alkoxy, —XR 3 and C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted by halo.

3. A compound according to claim 1 , or a salt thereof, wherein R 2 is 5- or 6-membered heteroaryl wherein the heteroaryl contains one or two nitrogen atoms and is substituted by one or two substituents independently selected from halo, C 1-6 alkoxy, —YR 8 and C 1-6 alkyl.

4. A compound according to claim 1 , or a salt thereof, wherein R 3 is 6-membered heterocyclyl wherein the heterocyclyl contains one or two nitrogen atoms and is optionally substituted by from one to three substituents independently selected from C 1-6 alkyl.

5. A compound according to claim 1 , or a salt thereof, wherein R 8 is 5- or 6-membered heterocyclyl wherein the heterocyclyl contains one or two heteroatoms independently selected from oxygen and nitrogen and is substituted by from one to three substituents independently selected from oxo, hydroxy, halo, —COC 1-6 alkyl and C 1-6 alkyl optionally substituted by —OR 2 .

6. A compound which is:
1-(1-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-3-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
3-(1-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
N-(2-methoxy-5-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-1-yl)pyridin-3-yl)methanesulfonamide;
1-(6-methoxy-5-methylpyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
N-(2-methoxy-5-(1-(1-methyl-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)pyridin-3-yl)methanesulfonamide;
1-(2-methoxypyrimidin-5-yl)-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
3-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
3-(1-((1-isopropylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(6-methoxy-5-methylpyridin-3-yl)-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(5-fluoro-6-methoxypyridin-3-yl)-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(5-fluoro-6-methoxypyridin-3-yl)-3-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
N-(2-methoxy-5-(3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-1-yl)pyridin-3-yl)methanesulfonamide;
2-methoxy-5-(3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-1-yl)nicotinonitrile;
5-(3-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-1-yl)-2-methoxynicotinonitrile;
1-(5-(fluoromethyl)-6-methoxypyridin-3-yl)-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(5-(fluoromethyl)-6-methoxypyridin-3-yl)-3-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
N-(5-(3-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-1-yl)-2-methoxypyridin-3-yl)methanesulfonamide;
3-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide;
1-(6-methoxy-5-methylpyridin-3-yl)-N-((1-methylpiperidin-3-yl)methyl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide;
1-(3-((4-(1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-2-methylpropan-2-ol;
(R)-1-(3-((4-(1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-2-methylpropan-2-ol;
(S)-1-(3-((4-(1-(6-methoxy-5-methylpyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-2-methylpropan-2-ol;
3-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
1-(6-methoxy-5-methylpyridin-3-yl)-3-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
(R)-1-(6-methoxy-5-methylpyridin-3-yl)-3-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
(S)-1-(6-methoxy-5-methylpyridin-3-yl)-3-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
3-(6-methoxy-5-methylpyridin-3-yl)-1-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole;
2-(4-((4-(1-(6-m

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Baxter Andrew
• Bertrand Sophie Marie
• Campbell Matthew
• Down Kenneth David
• Haffner Curt Dale
• Hamblin Julie Nicole
• Henley Zoe Alicia
• Miller William Henry
• Talbot Eric Philippe Andre
• Taylor Jonathan Andrew

Classifications

• C07D491/044 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title