Claims for Patent: 10,759,793

Summary for Patent: 10,759,793

Title:	2-(pyrazolopyridin-3-yl)pyrimidine derivatives as JAK inhibitors
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).
Inventor(s):	Esteve Trias; Cristina (Barcelona, ES), Taltavull Moll; Joan (Barcelona, ES), Gonzalez Rodriguez; Jacob (Barcelona, ES), Vidal Juan; Bernat (Barcelona, ES)
Assignee:	Almirall, S.A. (Barcelona, ES)
Application Number:	15/735,235
Patent Claims:	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: ##STR00008## wherein: X is a --NR.sup.3-- group; R.sup.1 and R.sup.2 are independently chosen from a hydrogen atom, a halogen atom, a linear or branched C.sub.1-4 alkyl group, a linear or branched C.sub.1-4 alkoxy group, and a --CN group; R.sup.3 is chosen from a hydrogen atom, a linear or branched C.sub.1-4 alkyl group, a --(CH.sub.2).sub.1-3NR'R'' group, and a --(CH.sub.2).sub.1-3-pyrrolidine group; G.sup.1 is a --O--R.sup.6 group; Q is chosen from Qa, Qb, or Qc: ##STR00009## wherein: R.sup.4 is chosen from a --CO(CH.sub.2).sub.1-2--OH group and a --CO(CH.sub.2).sub.1-2--CN group, R.sup.5 is chosen from a --(CH.sub.2).sub.m--CN group and a --(CH.sub.2).sub.m--OH group; G.sup.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.sub.1-4 alkyl group, a hydroxyl group, and a --CN group, R.sup.6 is chosen from a linear or branched (C.sub.1-6 alkoxy)-(C.sub.1-6 alkyl) group and a linear or branched C.sub.1-6 alkyl group, wherein the linear or branched C.sub.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.sup.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.sup.2 is chosen from a hydrogen atom and a fluorine atom. 4. The compound according to claim 1, wherein R.sup.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.sup.1 is chosen from a hydrogen atom, a fluorine atom, a chlorine atom, and a methyl group; R.sup.2 is chosen from a hydrogen atom and a fluorine atom; X is a --NR.sup.3-- group; R.sup.3 is a hydrogen atom; Q is Qa; R.sup.4 is chosen from a --CO(CH.sub.2).sub.1-2--OH group and a --CO(CH.sub.2).sub.1-2--CN group; G.sup.1 is a --O--R.sup.6 group; R.sup.6 is chosen from a linear or branched (C.sub.1-6 alkoxy)-(C.sub.1-6 alkyl) group and a linear or branched C.sub.1-6 alkyl group, wherein the linear or branched C.sub.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.sup.3-- group; R.sup.1 and R.sup.2 are independently chosen from a hydrogen atom, a fluorine atom, and a methyl group; R.sup.3 is chosen from a hydrogen atom and a methyl group; G.sup.1 is a --O--R.sup.6 group; R.sup.4 is chosen from a --CO(CH.sub.2)--OH group, a --CO(CH.sub.2)--CN group; R.sup.5 is a --CH.sub.2--CN group; G.sup.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.sup.6 is chosen from a --(CH.sub.2).sub.2OCH.sub.3 group, a --(CH.sub.2).sub.2OCH.sub.2CH.sub.3 group, a --CH(CH.sub.3)CH.sub.2OCH.sub.3 group, a methyl group, an ethyl group, a butyl group, a --CH.sub.2CF.sub.3 group, a --CH.sub.2CHF.sub.2 group, a CH(CH.sub.3).sub.2 group, a --(CH.sub.2).sub.2-3OH group, a --CH(CH.sub.3)--CH.sub.2OH group, and a --CH.sub.2CH(OH)CH.sub.2OH 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]py- ridin-3-ylpyrimidin-4-yl)amino]cyclohexyl}acetonitrile; {Trans-4-[(6-{[(2R)-2,3-dihydroxypropyl]oxy}-5-fluoro-2-pyrazolo[1,5-a]py- ridin-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-ylpy- rimidin-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-ylpy- rimidin-4-yl)oxy]propane-1,2-diol; 3-((3R)-3-{[5-fluoro-6-(2-hydroxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyr- imidin-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-ylpyr- imidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol; 2-((3R)-3-{[5-Fluor-6-(2-methoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyri- midin-4-yl]amino}piperidin-1-yl)-2-oxoethanol; 2-((3R)-3-{[5-Fluor-6-(2-hydoxyethoxy)-2-pyrazolo[1,5-a]pyridin-3-ylpyrim- idin-4-yl]amino}pieridin-1-yl)-2-oxoethanol; 3-[(5-Fluoro-6-{[(3R)-1-glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1,5-a]p- yridin-3-ylpyrimidin-4-yl)oxy]propan-1-ol; 2-((3R)-3-{[5-Fluoro-6-methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-y- l)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-trifluoroetho- xy)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-yl- pyrimidin-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]p- yridin-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-ylpyri- midin-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-y- l)amino]piperidin-1-yl}-2-oxoethanol; 2-{(3R)-3-[(6-Methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]p- iperidin-1-yl)-2-oxoethanol; 3-((3R)-3-[(6-Methoxy-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]p- iperidin-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-y- l]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-pyrazol- o[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-ylpyri- midin-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-ylpyr- imidin-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-ylpyr- imidin-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.

Details for Patent 10,759,793

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924	10,759,793	2036-06-10