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

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

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

13. A combination product comprising (i) at least one 2-(pyrazolopyridin-3-yl)pyrimidine derivative according to claim 1 , and (ii) at least one additional active ingredient chosen from:

a) Corticoids and glucocorticoids;

b) Dihydrofolate reductase inhibitors;

c) Dihydroorotate dehydrogenase (DHODH) inhibitors;

d) Purine antagonists;

e) Antimalarials;

f) Calcineurin inhibitors;

g) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors;

h) Fumaric acid esters;

i) Vitamine D3 derivatives;

j) Retinoids;

k) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies;

l) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors;

m) Anti-Interleukin 6 Receptor (IL-6R) antibody;

n) Anti-Interleukin 12 Receptor (IL-12R)/Interleukin 23 Receptor (IL-23R) antibody;

o) Anti-Interleukin 17 Receptor (IL-17R) antibody;

p) Anti-CD20 (B lymphocyte protein) antibody;

q) Anti-Interleukin 5 (IL-5) antibody;

r) Anti-Interleukin 5 Receptor (IL-5R) antibody;

s) Anti-Interleukin 13 (IL-13) antibody;

t) Anti-Interleukin 4 Receptor (IL-4R)/Interleukin 13 Receptor (IL-13R) antibody;

u) Anti-Interleukin 17 (IL-17) antibody;

v) Anti-Interleukin 1 Receptor (IL-1R) antibody;

w) Anti-Inmunoglobuline E (IgE) antibody;

x) Anti-B-cell activating factor (BAFF);

y) Anti-CD19 (B lymphocyte protein) monoclonal antibody;

z) Kappa opioid agonists;

aa) Neurokinin receptor 1 antagonists;

bb) Dihydropteroate synthase inhibitors;

cc) Histamine 1 (H1) receptor antagonists;

dd) Cysteinyl leukotriene (CysLT) receptor antagonists;

ee) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors; and

ff) Topical anti-septics.