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Fused imidazo-piperidine JAK inhibitor compound

A technology of compound and pharmaceutical composition, which is applied in the field of preparing the compound and can solve the problem that the disease is not controlled by conventional therapy

Active Publication Date: 2019-12-13
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although most patients can achieve control of asthma symptoms with inhaled corticosteroids, which can be combined with leukotriene modifiers and / or long-acting beta agonists, a proportion of patients with severe asthma still have disease not controlled by conventional therapy

Method used

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  • Fused imidazo-piperidine JAK inhibitor compound
  • Fused imidazo-piperidine JAK inhibitor compound
  • Fused imidazo-piperidine JAK inhibitor compound

Examples

Experimental program
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example

[0187] The following synthetic and biological examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. In the examples below, the following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their generally accepted meanings.

[0188] CAN = acetonitrile

[0189] DCC = Dicyclohexylcarbodiimide

[0190] DIPEA=N,N-Diisopropylethylamine

[0191] DMAc = dimethylacetamide

[0192] DMF=N,N-Dimethylformamide

[0193] DMSO = dimethyl sulfoxide

[0194] EtOAc = ethyl acetate

[0195] HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea salt of hexafluorophosphate

[0196] LDA = lithium diisopropylamide

[0197] Min=minute

[0198] MTBE = methyl tert-butyl ether

[0199] NBS = N-bromosuccinimide

[0200] NMP = N-methyl-2-pyrrolidone

[0201] RT = room temperature

[0202] THF = Tetrahydrofuran

[0203] Bis(pinacolyl)diboron=4,4,5,5,4',4',5',...

example 1

[0256] Example 1: 1-(2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7- Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-morpholinoethan-1-one (1)

[0257]

[0258] 5-Ethyl-2-fluoro-4-(4-fluoro-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- Base)-1H-indazol-6-yl)phenol (6) 2HCl (100g, 214mmol), 2,5-dioxopyrrolidinyl-1-2-morpholinoacetic acid ester (7') (67.2g, 278 mmol) and DIPEA (69 g, 534 mmol) in DMF (600 mL) for 12 h and filtered. By reverse phase chromatography (Agela FLEXATM FS-1L instrument; 2kg Agela C18 DAC column; 200g sample is dissolved in DMF (900mL); Flow rate 300mL / min; Solvent A water, solvent B ACN; Gradient (B%, time (mins): 0 / 15, 0-40 / 45, 40 / 50) Purification of the solution afforded the title compound (50.0 g, 44.8% yield) as a light yellow solid. (m / z): [M+H ] + C 27 h 28 f 2 N 6 o 3 Calculated value: 523.22; Experimental value: 523.0. 1 H NMR (400MHz,MeOD)δ7.22(s,1H),6.80-6.96(m,3H),4.68-4.78(m,2H),3.96(s,2H),3.65-3.95(m...

example 2

[0259] Example 2: Crystalline 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6,7 -Tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-morpholinoethan-1-one (1) Form 1

[0260] To a 250 mL flask was added 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-3-yl)-1,4,6, 7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-2-morpholinoethan-1-one (1), the product of Example 1 (5 g) and ethanol (50 mL), And the reaction mixture was stirred at 50-80 °C for 10 minutes, and then ACN (75 mL) was added slowly at 50-80 °C, followed by the seed crystals of Example 3. The reaction mixture was stirred at 20-25°C for 18 hours. The resulting solid was collected by filtration and dried under vacuum at 50 °C for 18 hours to afford the title compound Form 1 (3.6 g, 72% yield)

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Abstract

The invention provides a compound of formula 1 formula 1 or a pharmaceutically-acceptable salt thereof that is useful as a JAK inhibitor. The invention also provides crystalline forms of the compound,pharmaceutical compositions comprising the compound, methods of using the compound to treat diseases amenable to a JAK inhibitor, and processes and intermediates useful for preparing the compound.

Description

technical field [0001] The invention relates to a JAK kinase inhibitor compound suitable for treating various diseases, especially eye, skin and respiratory diseases. The invention also relates to crystalline forms of said compounds, pharmaceutical compositions comprising such compounds, methods of using such compounds in the treatment of diseases amenable to treatment with JAK inhibitors and processes and intermediates suitable for the preparation of said compounds. Background technique [0002] Cytokines are intercellular signaling molecules that include chemokines, interferons, interleukins, lymphoid mediators, and tumor necrosis factor. Cytokines are critical for normal cell growth and immune regulation and also drive immune-mediated diseases and contribute to malignant cell growth. Higher levels of many cytokines have been implicated in a number of diseases or conditions, specifically those pathologies characterized by inflammation. A variety of cytokines involved in ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P11/00A61P17/00A61P27/02
CPCA61K9/0019A61K9/0048A61K9/10A61K31/5377A61P11/00A61P11/06A61P11/08A61P17/00A61P17/04A61P27/02A61P29/00C07D471/04
Inventor P·R·法特里姜岚R·M·麦金内尔V·R·萨兰迪张浩M·达布罗斯J·恩泽雷姆N·本杰明M·A·克莱因舍尔克G·D·克拉泰尔
Owner THERAVANCE BIOPHARMA R&D IP LLC
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