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Pyrimidine compounds as jak kinase inhibitors

A compound, methoxypyrimidine technology, applied in the field of pyrimidine compounds, can solve problems such as adverse systemic immunosuppressive effects

Inactive Publication Date: 2018-12-21
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, systemic exposure to JAK inhibitors may have adverse systemic immunosuppressive effects due to the modulatory effects of the JAK / STAT pathway on the immune system

Method used

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  • Pyrimidine compounds as jak kinase inhibitors
  • Pyrimidine compounds as jak kinase inhibitors
  • Pyrimidine compounds as jak kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0249] 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.

[0250] ACN = acetonitrile

[0251] CPME = cyclopentyl methyl ether

[0252] d = days

[0253] DIPEA=N,N-Diisopropylethylamine

[0254] DMF=N,N-Dimethylformamide

[0255] DMSO = dimethyl sulfoxide

[0256] EtOAc = ethyl acetate

[0257] EtOH = ethanol

[0258] h = hour

[0259] HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

[0260] IPA = isopropyl alcohol

[0261] MeOH = Methanol

[0262] min=minute

[0263] NMP = N-methylpyrrolidone

[0264] RT = room temperature

[0265] TEA = Triethylamine

[0266] THF = Tetrahydrofuran

[0267] TFA = trifluoroacetic acid

[0268] Xantphos...

example 1

[0346] Example 1: 1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine- 2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetidine-3-carbonitrile

[0347]

[0348]To (3-((2-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino)-6-methoxypyrimidin-4-yl )amino)-1H-pyrazol-5-yl)methanol (15mg, 0.042mmol) in DMF (4.0mL) were added successively DIPEA (0.022ml, 0.125mmol) and 3-cyano-1-aza Cyclobutanesulfonyl chloride (7.54 mg, 0.042 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the crude residue was purified by reverse phase HPLC to afford the TFA salt of the title compound (3.2 mg). C 21 h 29 N 9 o 4 S(m / z):[M+H] + The calculated value is 504.21 and the experimental value is 504.1.

example 2

[0349] Example 2: 1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine- 2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetidine-3-carbonitrile

[0350]

[0351] (3-((2-(((1R,3s,5S)-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)-6-methoxy To a solution of pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol HCl (150 mg, 0.402 mmol) and DIPEA (0.351 mL, 2.008 mmol) in DMF (3 mL) was added 3-cyano - 1-azetidinesulfonyl chloride (72.5 mg, 0.402 mmol) and the reaction mixture was stirred at 0°C for 10 min and then at room temperature for 15 h. The reaction mixture was concentrated in vacuo to give a red liquid, which was purified by preparative HPLC to afford the TFA salt of the title compound (72.4 mg, 0.115 mmol, 28.5% yield) as a white solid. C 22 h 31 N 9 o 4 S(m / z):[M+H] + The calculated value is 518.22 and the experimental value is 518.

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Abstract

The invention provides compounds of formula (I): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of JAK kinases. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat gastrointestinal and other inflammatory diseases, and processes and intermediates usefulfor preparing such compounds.

Description

technical field [0001] The present invention relates to pyrimidine compounds useful as JAK kinase inhibitors. The invention also relates to pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of inflammatory diseases and processes and intermediates useful for the preparation of said compounds. Background technique [0002] Ulcerative colitis is a chronic inflammatory disease of the colon. The disease is characterized by inflammation and ulceration of the mucosal layers of the rectum and large intestine. Common symptoms include diarrhea, bloody stools, and abdominal pain. The clinical course is intermittent, characterized by alternating periods of exacerbation and remission. The incidence appears to be greater in developed countries than in developing countries. Ulcerative colitis affects an estimated 1.2 million people in major industrialized countries and is expected to increase with population growth. Patients with u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/14C07D451/04A61K31/506
CPCA61K31/519C07D211/00C07D211/06C07D451/04C07D451/14C07D487/04A61P1/00A61P1/04A61P17/00A61P17/06A61P29/00A61P43/00C07B2200/13
Inventor 瑞安·赫德森J·科扎克梅莉萨·弗勒里保罗·R·法特里安妮-玛丽·博索莱伊D·D·波德什托黄小军
Owner THERAVANCE BIOPHARMA R&D IP LLC