Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors

A cycloalkyl, heterocycloalkyl technology, applied in the field of cyclobutyl-substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors

Inactive Publication Date: 2013-11-27
INCYTE HLDG & INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Thus, JAK inhibition may benefit cancer patients for reasons that extend beyond potential antitumor activity

Method used

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  • Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
  • Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
  • Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors

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Experimental program
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preparation example Construction

[0355] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. One skilled in the art can readily determine the need for protection and deprotection and the choice of suitable protecting groups. Protecting group chemistry can be found, eg, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is hereby incorporated by reference in its entirety.

[0356] The reaction can be monitored according to any suitable method known in the art. For example, methods such as NMR spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (for example, UV-visible spectrophotometry), mass spectrometry, or by spectroscopic means such as high performance liquid chromatography (HPLC) or thin layer chromatography (thin layer chromatography; TLC) to monitor product formation.

[0357] Useful intermediates 3-4 can be prepared following the procedur...

Embodiment 1a

[0472] Example 1a. 3-[(4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-fluorobenzonitrile

[0473]

[0474] Step 1. [2-Bromo-1-(bromomethyl)ethoxy](tert-butyl)diphenylsilane

[0475]

[0476] To a solution of 1,3-dibromo-2-propanol (20.00 g, 91.79 mmol) in dichloromethane (DCM) (100 mL) cooled to 0 °C was added 1H-imidazole (6.56 g, 96.4 mmol), Then tert-butylchlorodiphenylsilane (25.1 mL, 96.4 mmol) and 4-dimethylaminopyridine (1.12 g, 9.18 mmol) were added. The reaction was stirred while warming to room temperature overnight. The reaction mixture was diluted with ether, washed with water, and the aqueous layer was extracted once more with ether. The combined organic extracts were washed with water, then brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography (eluting with a gradient of 0% ethyl acetate / hexane to 15% ethyl acetate / hexane) gave the desired product (42 g, 100...

Embodiment 1b

[0506] Example 1b. 3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin 4-yl)-1H-pyrazole- 1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-fluorobenzonitrile

[0507]

[0508] Step 1. {trans-3-piperazin-1-yl-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

[0509]

[0510] To 4-{trans-3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazine-1-carboxylic acid tert-butyl ester (1.58 g, 2.66 mmol, peak 2 from step 8 of Example 1a) To a solution in 1,4-dioxane (100 mL) was added 4.0 M aqueous hydrogen chloride (20 mL) and stirred overnight for two nights. The reaction mixture was poured into saturated sodium bicarbonate in an amount sufficient to neutralize and render the reaction mixture basic. Subsequently, dioxane was removed from the mixture in vacuo. The product was extracted with three portions of ethyl acetate. The comb...

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Abstract

The present invention provides cyclobutyl substituted pyrrolopyrimidines and pyrrolopyridines of Formula I: wherein X, Y, Z, L, A, R5, n and m are defined above, as well as their compositions and methods of use, that modulate the activity of Janus kinases (JAKs) and are useful in the treatment of diseases related to the activity of JAKs including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Description

[0001] This application claims the benefit of priority to US Provisional Application No. 61 / 415,705, filed November 19, 2010, which is hereby incorporated by reference in its entirety. technical field [0002] The present invention provides cyclobutyl-substituted pyrrolopyrimidines and pyrrolopyridines that modulate the activity of Janus kinase (JAK) and are useful in the treatment of related Diseases of JAK activity include, for example, inflammatory disorders, autoimmune disorders, cancer, and others. Background of the invention [0003] Protein kinase (PK) regulates a variety of biological processes, including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration. Protein kinases also play specialized roles in many human diseases, including cancer. Cytokines (ie, low molecular weight polypeptides or glycoproteins) modulate many pathways involved in host inflammation in response to sepsis. Cytokines af...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/519
CPCC07D471/04C07D487/04A61P1/00A61P1/04A61P1/16A61P13/12A61P17/00A61P17/02A61P17/06A61P17/08A61P19/00A61P19/02A61P19/04A61P19/08A61P19/10A61P21/04A61P25/00A61P29/00A61P3/04A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P43/00A61P5/12A61P5/14A61P7/00A61P9/10A61P3/10A61K31/519A01N43/90C07D491/107A61P35/04A61P27/04
Inventor J·D·罗杰斯W·朱邵立新J·格伦S·谢巴德
Owner INCYTE HLDG & INCYTE
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