2-(pyrazolopyridin-3-yl)pyrimidine derivatives as JAK inhibitors

Patent metadata

Field	Value
Publication number	US-10759793-B2
Application number	US-201615735235-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 11, 2015
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

New 2-(pyrazolopyridin-3-yl)pyrimidine derivatives are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy as inhibitors of Janus Kinases (JAK).

First claim

The invention claimed is:

1. A 2-(pyrazolopyridin-3-yl)pyrimidine derivative, wherein the 2-(pyrazolopyridin-3-yl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, or deuterated derivative thereof:

wherein:
X is a —NR 3 — group;
R 1 and R 2 are independently chosen from a hydrogen atom, a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 alkoxy group, and a —CN group;
R 3 is chosen from a hydrogen atom, a linear or branched C 1-4 alkyl group, a —(CH 2 ) 1-3 NR′R″ group, and a —(CH 2 ) 1-3 -pyrrolidine group;
G 1 is a —O—R 6 group;
Q is chosen from Qa, Qb, or Qc:

wherein:
R 4 is chosen from a —CO(CH 2 ) 1-2 —OH group and a —CO(CH 2 ) 1-2 —CN group,
R 5 is chosen from a —(CH 2 ) m —CN group and a —(CH 2 ) m —OH group;
G 2 is chosen from a phenyl group, a pyrimidine group, and a pyridine group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a linear or branched C 1-4 alkyl group, a hydroxyl group, and a —CN group,
R 6 is chosen from a linear or branched (C 1-6 alkoxy)-(C 1-6 alkyl) group and a linear or branched C 1-6 alkyl group, wherein the linear or branched C 1-6 alkyl group is unsubstituted or substituted with one or more substituents chosen from a halogen atom and a hydroxyl group, and
m is independently 0, 1, 2, or 3.

2. The compound according to claim 1 , wherein R 1 is chosen from a hydrogen atom, a fluorine atom, a chlorine atom, and a methyl group.

3. The compound according to claim 1 , wherein R 2 is chosen from a hydrogen atom and a fluorine atom.

4. The compound according to claim 1 , wherein R 3 is a hydrogen atom.

5. The compound according to claim 1 , wherein Q is Qa.

6. The compound according to claim 1 , wherein:
R 1 is chosen from a hydrogen atom, a fluorine atom, a chlorine atom, and a methyl group;
R 2 is chosen from a hydrogen atom and a fluorine atom;
X is a —NR 3 — group;
R 3 is a hydrogen atom;
Q is Qa;
R 4 is chosen from a —CO(CH 2 ) 1-2 —OH group and a —CO(CH 2 ) 1-2 —CN group;
G 1 is a —O—R 6 group;
R 6 is chosen from a linear or branched (C 1-6 alkoxy)-(C 1-6 alkyl) group and a linear or branched C 1-6 alkyl group, wherein the linear or branched C 1-6 alkyl group is unsubstituted or substituted with one or more substituents chosen from a halogen atom and a hydroxyl group.

7. The compound according to claim 1 , wherein:
X is a —NR 3 — group;
R 1 and R 2 are independently chosen from a hydrogen atom, a fluorine atom, and a methyl group;
R 3 is chosen from a hydrogen atom and a methyl group;
G 1 is a —O—R 6 group;
R 4 is chosen from a —CO(CH 2 )—OH group, a —CO(CH 2 )—CN group;
R 5 is a —CH 2 —CN group;
G 2 is chosen from a pyrimidine group and a pyridine group, wherein the pyrimidine and pyridine groups are unsubstituted or substituted by a fluorine atom; and
R 6 is chosen from a —(CH 2 ) 2 OCH 3 group, a —(CH 2 ) 2 OCH 2 CH 3 group, a —CH(CH 3 )CH 2 OCH 3 group, a methyl group, an ethyl group, a butyl group, a —CH 2 CF 3 group, a —CH 2 CHF 2 group, a CH(CH 3 ) 2 group, a —(CH 2 ) 2-3 OH group, a —CH(CH 3 )—CH 2 OH group, and a —CH 2 CH(OH)CH 2 OH group.

8. The compound according to claim 1 , wherein the compound is chosen from:
(Trans-4-{[5-fluoro-6-(2-hydroxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}cyclohexyl)acetonitrile;
{Trans-4-[(6-{[(2S)-2,3-dihydroxypropyl]oxy}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]cyclohexyl}acetonitrile;
{Trans-4-[(6-{[(2R)-2,3-dihydroxypropyl]oxy}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]cyclohexyl}acetonitrile;
2-[(5-Fluoro-6-{[(1 S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]etanol;
(2S)-3-[(5-fluoro-6-{[(1 S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propane-1,2-diol;
3-((3R)-3-{[5-fluoro-6-(2-hydroxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile;
3-{(3R)-3-[(6-butoxy-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile;
2-((3R)-3-{[6-(2-Methoxyethoxy)-5-methyl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
2-((3R)-3-{[5-Fluor-6-(2-methoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
2-((3R)-3-{[5-Fluor-6-(2-hydoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}pieridin-1-yl)-2-oxoethanol;
3-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propan-1-ol;
2-((3R)-3-{[5-Fluoro-6-methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol;
2-{(3R)-3-[(6-Ethoxy-5-fluoro-2-pyrazoa[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol;
2-((3R)-3-{[5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
2-((3R)-3-{[6-(2,2-Difluoroethoxy)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
2-{(3R)-3-[(5-Fluoro-6-isopropoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol;
2-[(3R)-3-({5-Fluoro-6-[(1 S)-2-methoxy-1-methylethoxy]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-2-oxoethanol;
(2S)-2-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propan-1-ol;
2-[(3R)-3-({5-Fluoro-6-[(1R)-2-methoxy-1-methylethoxy]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-2-oxoethanol;
(2R)-2-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propan-1-ol;
2-((3R)-3-{[6-(2-Ethoxyethoxy)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
(2S)-1-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]oxy}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propan-2-ol;
2-{(3R)-3-[(6-Methoxy-5-methyl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol;
2-{(3R)-3-[(6-Methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl)-2-oxoethanol;
3-((3R)-3-[(6-Methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile;
2-((3R)-3-{[6-(2-Methoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol;
3-((3R)-3-{[6-(2-Methoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile;
3-((3R)-3-([6-(2-Hydroxyethoxy)-2-pyrazolo[1,5a]pyridin-3-ylpyrimidin-4-yl]amino)piperidin-1-yl)-3-oxopropanenitrile;
a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.

9. A 2-(pyrazolopyridin-3-yl)pyrimidine derivative according to claim 1 which is 3-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)oxy]propan-1-ol, or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.

10. A 2-(pyrazolopyridin-3-yl)pyrimidine derivative according to claim 1 which is 2-{(3R)-3-[(5-Fluoro-6-methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol, or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.

11. A 2-(pyrazolopyridin-3-y

Assignees

• Almirall Sa

Inventors

• Esteve Trias Cristina
• Taltavull Moll Joan
• Gonzalez Rodriguez Jacob
• Vidal Juan Bernat

Classifications

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• A61P11/00

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• A61P19/02

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• A61P3/10

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