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Fused imidazo-piperidine jak inhibitors

A compound, -OH technology, applied in the field of treating respiratory diseases and preparing such compounds, can solve problems such as poor results and unapproved treatments

Active Publication Date: 2019-10-25
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Similar to CLAD, pulmonary GVHD is a chronic progressive disease with dismal outcomes and no currently approved treatments

Method used

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  • Fused imidazo-piperidine jak inhibitors
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  • Fused imidazo-piperidine jak inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0216] 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.

[0217] ACN = acetonitrile

[0218] DCM = dichloromethane

[0219] DIPEA=N,N-Diisopropylethylamine

[0220] DMF=N,N-Dimethylformamide

[0221] EtOAc = ethyl acetate

[0222] h = hour

[0223] HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate

[0224] IPA = isopropyl alcohol

[0225] IPAc = isopropyl acetate

[0226] MeOH = Methanol

[0227] min=minute

[0228] Pd(PPh 3 ) 4 =Tetrakis(triphenylphosphine)palladium(0)

[0229] RT = room temperature

[0230] TFA = trifluoroacetic acid

[0231] THF = Tetrahydrofuran

[0232] Bis(pinacol radical) diboron = 4,4,5,5,4',4',5',5'-octamethyl-[2,2'...

example 1

[0299] Example 1: ((S)-2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6 ,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)((1S,4S)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane Alk-2-yl)methanone

[0300]

[0301] To (S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7- Tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (30mg, 0.052mmol), (1S,4S)-5-methyl-2,5-diazabicyclo[2.2. 1] To a solution of heptane dihydrobromide (42.7mg, 0.156mmol) and DIPEA (0.064ml, 0.364mmol) in DMF (1.5ml) was added HATU (29.6mg, 0.078mmol) and the reaction was stirred at room temperature The mixture was left overnight. Hydrazine (5 equiv) was added, the reaction mixture was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound (27 mg, 66% yield). C 31 h 36 FN 7 o 2 (m / z):[M+H] + Calculated value 558.29 experimental value 558.3. 1 H NMR (400MHz, methanol-d 4 )δ8.17(dt,1H),7.59-7.50(m,1H),7.32(dd,1H),6.95...

example 3

[0302] Example 3: ((S)-3-(dimethylamino)pyrrolidin-1-yl)((S)-5-ethyl-2-(6-(2-ethyl-5-fluoro-4- Hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone

[0303]

[0304] To (S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5 isopropyl-4,5,6,7- Tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (179mg, 0.310mmol), (S)-N,N-dimethylpyrrolidin-3-amine (0.079mL, 0.620 mmol) and DIPEA (0.162 mL 0.930 mmol) in DMF (4 mL) was added HATU (177 mg, 0.465 mmol) and the reaction mixture was stirred at room temperature overnight. Hydrazine (5 equiv) was added, the reaction mixture was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound (107 mg, 44% yield). C 31 h 38 FN 7 o 2 (m / z):[M+H] + The calculated value is 560.31 and the experimental value is 560.2. 1 H NMR (400MHz, methanol-d 4 )δ8.21(d,1H),7.50(s,1H),7.26(d,1H),6.94(d,1H),6.90(d,1H),4.83-4.66(m,1H),4.48-4.25 (m,2H),4.23-4.12(m,1...

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Abstract

The invention provides compounds of formula (I): (I) where the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are useful as JAK kinase inhibitors. Theinvention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat respiratory diseases, and processes and intermediates useful for preparing suchcompounds.

Description

technical field [0001] The present invention is directed to compounds useful as JAK kinase inhibitors. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat respiratory diseases, and methods and intermediates suitable for the preparation of such compounds. Background technique [0002] Asthma is a chronic disease of the airways for which there is no prevention or cure. The disease is characterized by airway inflammation, fibrosis, hyperresponsiveness, and remodeling, all of which contribute to airflow limitation. An estimated 300 million people worldwide suffer from asthma, and it is estimated that by 2025, the number of people living with asthma will grow by more than 100 million. In the United States, approximately 6% to 8% of the population suffers from asthma, making it one of the most common chronic diseases in the country. Although most patients can achieve control of asthma symptoms with in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P11/00A61K31/437
CPCA61P11/00A61P11/06C07D471/04C07D519/00A61K31/437
Inventor P·R·法特里G·E·L·勃兰特C·史密斯S·D·E·沙利文L·J·范奥登M·A·克莱因舍尔克G·D·克拉泰尔
Owner THERAVANCE BIOPHARMA R&D IP LLC