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Substituted heteroaryl compound and composition and application thereof

A technology for compounds and heterocyclic groups, which can be used in drug combinations, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as high infection sensitivity and tumor surveillance defects.

Active Publication Date: 2018-09-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

TYK2-deficient mice grow and reproduce but exhibit multiple immunodeficiencies, primarily hypersensitivity to infection and deficits in tumor surveillance

Method used

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  • Substituted heteroaryl compound and composition and application thereof
  • Substituted heteroaryl compound and composition and application thereof
  • Substituted heteroaryl compound and composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0480] Example 1 4-(3-Azaspiro[5.5]undecan-9-ylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H- Pyrrolo[2,3-b]pyridine-5-carboxamide

[0481]

[0482] Step 1) 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

[0483] To a suspension of sodium hydride (60% [w / w] mass fraction, suspended in mineral oil, 2.68 g, 67.0 mmol) in tetrahydrofuran (60 mL) at 0 °C, 4-chloro-1H-pyrrole was added dropwise A solution of iso[2,3-b]pyridine (8.24 g, 54.0 mmol) in tetrahydrofuran (80 mL). After the resulting reaction mixture was stirred at room temperature for 30 minutes, tris(isopropyl)chlorosilane (12.73 g, 66.0 mmol) was added to the above system. The reaction system was stirred at room temperature for 5 hours, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (100% PE) to give the title compound as a colorless oil (16.68 g, yield 100%).

[0484] MS(ESI,pos.ion)m / z:309.0[M+H] + ;

[0485] 1 H NMR (400MHz, CDCl ...

Embodiment 2

[0515] Example 2 4-((3-Acetyl-3-azaspiro[5.5]undecan-9-yl)amino)-2-(1-methyl-1H-pyridine oxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0516]

[0517] 4-(3-Azaspiro[5.5]undecan-9-ylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b ] Pyridine-5-carboxamide (110.1 mg, 0.27 mmol) and triethylamine (76.4 mg, 0.76 mmol) were suspended in dichloromethane (8 mL), and acetic anhydride (34.6 mg, 0.34 mmol) was added to the suspension. ) in dichloromethane (2 mL). The reaction system was stirred at room temperature for 20 minutes, then water (50 mL) was added to quench the reaction and extracted with dichloromethane (150 mL x 6). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH / DCM (v / v)=1 / 5) to obtain the title compound as an off-white solid (64.0 mg, yield 52.7%).

[0518] MS(ESI,p...

Embodiment 3

[0520] Example 3 4-((3-(2-cyanoacetyl)-3-azaspiro[5.5]undecan-9-yl)amino)-2-(1-methyl) yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0521]

[0522] To 4-(3-azaspiro[5.5]undecan-9-ylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b ] Pyridine-5-carboxamide (0.55 g, 1.30 mmol) and 2-cyanoacetic acid (171.0 mg, 2.01 mmol) in dichloromethane (40 mL) and DMF (10 mL) was added HATU (758.4 mg) , 2.00 mmol) and triethylamine (0.35 g, 3.50 mmol). The reaction system was stirred at room temperature for 10 minutes, then water (50 mL) was added to quench the reaction, and it was extracted with dichloromethane (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH / DCM (v / v)=1 / 5) to obtain the title compound as an off-white solid (54.4 mg, yield 8.5%).

[0523] MS(ESI,pos...

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Abstract

The invention provides a substituted heteroaryl compound and a pharmaceutical composition and application thereof. The compound is a compound as shown in formula (I) or the stereisomer, tautomer, nitric oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I). The pharmaceutical composition containing the compound can regulate the activity ofprotein kinase and especially the activity of Aurora kinase and JAK kinase and is used for preventing, treating and relieving diseases or disorder mediated by protein kinase and especially JAK kinase.

Description

Field of Invention [0001] The present invention belongs to the field of medicine, and specifically relates to a new class of substituted heteroaryl compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds, as well as the use of the compounds and their pharmaceutical compositions in the preparation of methods for treating mammals. Use in the medicament of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer or other diseases. More specifically, the compounds described herein can modulate the JAK kinase family (including JAK1, JAK2, JAK3, and TYK2), FLT3 kinase (also known as FLK-2), and Aurora kinases (including Aurora-A, Aurora-B, and Aurora) -C) activity, thereby regulating signal transduction inside and outside the cell. Background of the Invention [0002] The protein kinase family comprises a large class of structurally related enzymes that control variou...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04A61K31/437A61K31/5025A61K45/06A61P35/00A61P37/00A61P29/00A61P37/06A61P35/02A61P11/00A61P11/06A61P17/06A61P37/02A61P17/00A61P3/10A61P19/02
CPCA61K45/06C07D471/04C07D487/04
Inventor 习宁李晓波李敏雄张涛胡海洋吴彦君
Owner SUNSHINE LAKE PHARM CO LTD
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