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Isothiazole heterocyclic compound, and preparation method, pharmaceutical composition and application thereof

A technology of isothiazoles and compounds, applied in the field of medicinal chemistry, can solve the problems of being unable to take orally, only injecting or dripping, unstable in the body, etc., and achieve the effect of inhibiting growth and high inhibitory activity

Pending Publication Date: 2022-05-17
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, monoclonal antibody therapy has its own defects: it is easily decomposed by protease, so it is unstable in the body and cannot be taken orally; it is easy to produce immune cross-reaction; the product quality is not easy to control, and the production technology requirements are high; High cost; inconvenient to use, only injection or drip

Method used

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  • Isothiazole heterocyclic compound, and preparation method, pharmaceutical composition and application thereof
  • Isothiazole heterocyclic compound, and preparation method, pharmaceutical composition and application thereof
  • Isothiazole heterocyclic compound, and preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0502] Example 1: 1-(3-(2-chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyrazine-6-ylidene Methyl)pyrrolidin-3-ol

[0503]

[0504] 3-Hydroxy-5-methylpyrazine-2-carboxamide:

[0505] In the 100mL reaction flask, add methylglyoxal (40% aqueous solution, 21.6ml, 120mmol) and NaHSO 3 (15.6g, 150mmol), start stirring, and then slowly add dropwise NaOH aqueous solution (500mg, 12.5mmol, 39ml water) to the solution, react at 80°C after the dropwise addition, and slowly add 2-aminopropyl Diamide (11.7g, 100mmol), continue to react at 80°C for 3h, stop heating, add NaA after cooling to room temperature C (20.5 g, 250 mmol) and H 2 o 2 (16.4ml), stirred overnight at room temperature. The reaction solution was suction filtered to obtain 9.7 g of pink solid. Yield: 63.4%. 1 H NMR (400MHz, DMSO-d 6 )δ13.40(s,1H),8.64(s,2H),7.39(s,1H),2.21(s,3H).

[0506] 3-Chloro-5-methylpyrazine-2-carbonitrile:

[0507] Add 3-hydroxyl-5-methylpyrazine-2-carboxamide (9.7 g, 63.4 mm...

Embodiment 2

[0518] Example 2: 1-(3-(2-chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyridine-6-methylene base) pyrrolidin-3-ol

[0519]

[0520] 2-cyano-3-nitro-5-methylpyridine:

[0521] Add 2-bromo-3-nitro-5-methylpyridine (1g, 4.61mmol) and CuCN (454mg, 5.07mmol) into a three-necked flask, replace with argon, add 5ml of DMF into the syringe, and react at 70°C for 4h. Cool down to room temperature, add EA / H 2 O (40ml / 20ml), filter with diatomaceous earth, separate liquid, wash the organic phase once with 20ml water, wash once with 20ml ammonium chloride / ammonia water, extract the aqueous phase twice with 20ml EA, combine the organic phases, and wash once with 20ml saturated brine twice, and dried over anhydrous sodium sulfate. It was evaporated to dryness under reduced pressure, and prepared under medium pressure (PE:EA 4:1-2:1) to obtain 347 mg of yellow-white solid. Yield: 46.14%. HRMS(ESI)m / z:164.04453[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=1.8,0.7Hz,1H...

Embodiment 3

[0535] Example 3: (S)-1-(3-(2-chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyrazine -6-methylene)pyrrolidin-3-ol

[0536]

[0537] Using (S)-3-hydroxypyrrolidine instead of racemic 3-hydroxypyrrolidine, the operation is the same as in Example 1 to obtain (S)-1-(3-(2-chloro-3-(1,4-benzobis Oxan-6-yl)anilino)isothiazolo[4,5-b]pyrazin-6-methylene)pyrrolidin-3-ol yellow solid. HRMS(ESI)m / z:496.11857[M+H] + .

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses an isothiazole heterocyclic compound, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention relates to an isothiazole heterocyclic compound as shown in a general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof and a preparation method thereof, a composition containing one or more of the compounds, and application of the compounds in treatment of diseases related to PD-1 / PD-L1 signal pathways, such as cancers, infectious diseases and autoimmune diseases.

Description

[0001] field of invention [0002] The invention belongs to the field of medicinal chemistry, and discloses a class of isothiazolo heterocyclic compounds, a preparation method, a pharmaceutical composition and application thereof. Specifically, it relates to isothiazolo heterocyclic compounds represented by general formula I, pharmaceutically acceptable salts thereof, stereoisomers and preparation methods thereof, compositions containing one or more of these compounds, and such compounds Use in the treatment of diseases related to the PD-1 / PD-L1 signaling pathway, such as cancer, infectious diseases, and autoimmune diseases. [0003] Background of the invention [0004] With the in-depth study of tumor immunity, it has been found that the tumor microenvironment can protect tumor cells from being recognized and killed by the body's immune system, and the immune escape of tumor cells plays a very important role in the occurrence and development of tumors. In 2013, Science magazi...

Claims

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Application Information

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IPC IPC(8): C07D513/04C07D519/00A61P35/00A61P35/02A61P37/02A61P31/00A61P5/16A61P5/14A61P3/10A61P1/04A61P21/04A61P1/00A61P11/00A61P1/16A61P25/00A61P29/00A61P19/02A61P17/00A61P7/06A61P31/04A61P31/12A61K31/437A61K31/4985
CPCC07D513/04C07D519/00A61P35/00A61P35/02A61P37/02A61P31/00A61P5/16A61P5/14A61P3/10A61P1/04A61P21/04A61P1/00A61P11/00A61P1/16A61P25/00A61P29/00A61P19/02A61P17/00A61P7/06A61P31/04A61P31/12
Inventor 冯志强黄旭鹏陈浩
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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