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Heterocyclic compound as well as preparation method and medical application thereof

A technology of compound and heterocyclic group, applied in the field of heterocyclic compound, its preparation and its application in medicine, can solve problems such as difficulties

Inactive Publication Date: 2020-12-29
GUANGZHOU INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high sequence similarity of the active sites of the JAK kinase family, it is quite difficult to develop a selective JAK inhibitor

Method used

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  • Heterocyclic compound as well as preparation method and medical application thereof
  • Heterocyclic compound as well as preparation method and medical application thereof
  • Heterocyclic compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Cyclopropyl((3aR,6aS)-3a,6a-dimethyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)hexahydropyrrole And[3,4-c]pyrrol-2(1H)-yl)methanone

[0134]

[0135] first step

[0136] 3,7-Dimethylethylene-1,5-xylenesulfonyl-1,5-diazacyclooctane

[0137] p-Toluenesulfonamide (17.12g, 100mmol), anhydrous potassium carbonate (27.6g, 200mmol) and anhydrous acetonitrile (200mL) were mixed, then 3-chloro-2-chloromethyl-1- Propylene 1a (12.5 g, 100 mmol) in acetonitrile (20 mL). After the mixture was stirred under reflux for 18 hours, it was cooled to room temperature, and water (250 mL) was added, followed by stirring for 30 minutes. The precipitate was collected by filtration to obtain 20 g of crude product. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane=100 / 0 to 0 / 100) to obtain the target product (10.8 g, solid), yield: 48%.

[0138] MS m / z(ESI):447[M+1]

[0139] 1 H NMR (400MHz, CDCl 3 )δ7.70-7.64(m,4H),7.31(d,J...

Embodiment 2

[0165] 4-((4-((3aR,6aS)-5-(cyclopropylcarbonyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine- 2-yl)amino)benzoic acid

[0166]

[0167] first step

[0168] (3aR,6aS)-5-(2-((4-(tert-butoxycarbonyl)phenyl)amino)pyrimidin-4-yl)-3a,6a-dimethylhexahydropyrrolo[3,4 -c]pyrrole-2(1H)-tert-butyl carboxylate

[0169] To a 10-mL microwave reaction vial, add (3aR,6aS)-5-(2-chloropyrimidin-4-yl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-2- (1H)-tert-butylcarboxylate 1e (100mg, 0.283mmol), tert-butyl 4-aminobenzoate (55mg, 0.283mmol), p-toluenesulfonic acid (5mg, 0.0283mmol) and isopropanol (4mL ), then the mixture was stirred at 100 °C for 1 h in a microwave reactor. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1 to 1 / 2) to obtain the target product (3aR, 6aS)-5-(2-( (4-(tert-butoxycarbonyl)phenyl)amino)pyrimidin-4-yl)-3a,6a-d...

Embodiment 3

[0181] 4-((4-((3aR,6aS)-5-(cyclopropylcarbonyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine- 2-yl)amino)-N-ethylbenzamide

[0182]

[0183]4-((4-((3aR,6aS)-5-(cyclopropylcarbonyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine -2-yl)amino)benzoic acid 2 (56mg, 0.133mmol) was dissolved in dichloromethane (10mL), then diisopropylethylamine (59mg, 0.153mmol) and 2-(7-oxybenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58 mg, 0.153 mmol). After stirring at room temperature for 5 minutes, 3 drops of aqueous ethylamine (65%-70%wt) were added. The mixture was stirred at room temperature for 30 minutes, then the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to obtain the target product 4-((4-((3aR,6aS)-5-( Cyclopropylcarbonyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-yl)amino)-N-ethylbenzamide 3(3.3 mg, solid), yield: 6%.

...

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Abstract

The invention relates to a heterocyclic compound suitable for inhibiting or regulating Janus family kinase (JAK), in particular tyrosine kinase 2 (TYK2), a preparation method of the heterocyclic compound and application of the heterocyclic compound in medicine. Specifically, the present invention relates to a compound represented by a general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, and a method of using the compound or the pharmaceutically acceptable salt thereof to treat and / or prevent Janus kinase-mediated related diseases, especially autoimmune diseases, inflammatory diseases and cancers and a method for preparing the compound or pharmaceutically acceptable salt thereof. The invention also relates to application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the compound or the pharmaceutically acceptablesalt thereof in preparation of drugs for treating and / or preventing Janus kinase mediated related diseases, especially autoimmune diseases, inflammatory diseases and cancers. Each substituent of thegeneral formula (I) is as defined in the specification.

Description

technical field [0001] The present invention relates to a novel heterocyclic compound or a pharmaceutically acceptable salt thereof for regulating or inhibiting the activity of Janus kinase (JAK), especially tyrosine kinase 2 (TYK2), containing the compound or its pharmaceutically acceptable The pharmaceutical composition of the salt, the preparation method of the compound or its pharmaceutically acceptable salt and the pharmaceutical composition of the compound or its pharmaceutically acceptable salt or containing the compound or its pharmaceutically acceptable salt are used in the preparation Use in medicines for treating and / or preventing related diseases mediated by the kinase, especially autoimmune diseases, inflammatory diseases and cancers, and methods of use thereof. Background technique [0002] Janus kinase (JAK) is a non-receptor tyrosine protein kinase consisting of four family members, namely JAK1, JAK2, JAK3 and TYK2. JAK has 7 homologous domains (JAK Homology...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P37/02A61P29/00A61P35/00A61P17/00A61P3/10A61P27/02A61P37/08A61P11/06A61P37/06A61P11/00A61P25/00A61P19/02A61P7/06A61P1/04A61P15/00A61P7/04A61P21/04A61P1/16A61P13/12A61P19/08A61P17/14A61P1/00A61P15/14A61P35/02A61P17/06A61P17/04A61P27/04A61P27/14A61P25/28A61P25/16A61P21/00A61P25/14A61P9/10A61P9/00A61K31/506
CPCC07D487/04A61P37/02A61P29/00A61P35/00A61P17/00A61P3/10A61P27/02A61P37/08A61P11/06A61P37/06A61P11/00A61P25/00A61P19/02A61P7/06A61P1/04A61P15/00A61P7/04A61P21/04A61P1/16A61P13/12A61P19/08A61P17/14A61P1/00A61P15/14A61P35/02A61P17/06A61P17/04A61P27/04A61P27/14A61P25/28A61P25/16A61P21/00A61P25/14A61P9/10A61P9/00C07B2200/07A61P37/00A61K31/506
Inventor 不公告发明人
Owner GUANGZHOU INNOCARE PHARMA TECH CO LTD
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