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Cycloalkyl and heterocycloalkyl inhibitors as well as preparation method and application thereof

A technology of heterocycloalkyl and cycloalkyl is applied in the field of cycloalkyl and heterocycloalkyl inhibitors and their preparation, and can solve the problems of no drug approval and marketing.

Pending Publication Date: 2021-04-23
SUZHOU ZELGEN BIOPHARML +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is still no KRAS-targeted G12C Mutated drug approved

Method used

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  • Cycloalkyl and heterocycloalkyl inhibitors as well as preparation method and application thereof
  • Cycloalkyl and heterocycloalkyl inhibitors as well as preparation method and application thereof
  • Cycloalkyl and heterocycloalkyl inhibitors as well as preparation method and application thereof

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Experimental program
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Effect test

preparation example Construction

[0221]The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.

[0222] The present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .

[0223] Compared with the prior art, the present invention has the following main advantages:

[0224] (1) The compound is to KRAS G12C Has a good selective inhibitory effect;

[0225] (2) The compound has better pharmacodynamics, pharmacokinetic prop...

Embodiment 1

[0386] Example 1 2-(1-acryloyl-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methyl Preparation of (1-naphthalen-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0387]

[0388] The first step: 2-(cyanomethyl)-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8 Preparation of tert-butyl -methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0389] 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyridin[3 ,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (72mg, 0.128mmol) was added to the reaction flask, followed by the addition of toluene (0.8mL), (S)-2-(cyclobutyl (methyl)amino)-3-methoxypropyl-1-ol (45mg, 0.256mmol) and sodium tert-butoxide (37mg, 0.384mmol). The reaction solution was stirred under ice-water bath for 0.5 h, then water (50 mL) was added, and then extracted with ethyl acetate (3 x 30 mL). All organic p...

Embodiment 2

[0398] Example 2 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy) -5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0399]

[0400] LCMS:m / z 600(M+H) + . 1 HNMR (400MHz, CDCl 3 )δ7.76(m,1H),7.62(m,1H),7.52(m,1H),7.44(m,1H),7.33(m,1H),7.23(m,1H),6.58(m,1H ),6.41(d,J=16.8Hz,1H),5.84(d,J=10.4Hz,1H),5.08(brs,0.5H),4.61(brs,0.5H),4.41(m,1H),4.05 (m,6H),3.56(m,1H),3.42(m,1H),3.14(m,4H),2.40(m,11H),0.72(m,2H),0.54(m,2H).

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Abstract

The invention relates to cycloalkyl and heterocycloalkyl inhibitors as well as a preparation method and application thereof. Specifically, the compounds disclosed by the invention have a structure as shown in a formula (I). The invention also discloses a preparation method of the compounds and application of the compounds as KRASG12C inhibitors. The compounds have a good selective inhibition effect on KRASG12C, and have better pharmacodynamic and pharmacokinetic properties and lower toxic and side effects.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a cycloalkyl and heterocycloalkyl inhibitor, a preparation method and application thereof. Background technique [0002] Lung cancer is one of the important causes of human cancer death. According to cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was about 20.9 billion US dollars, of which the US market accounted for half, followed by Japan, Germany and China. Judging from the existing trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018; 553(7689):446-454). [0003] At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs and tumor im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61P35/00A61P35/02A61K31/519A61K31/5377
CPCC07D471/04C07D519/00A61P35/00A61P35/02A61K31/519A61K31/5377Y02P20/55
Inventor 吕彬华崔大为刘连军韩涛王润卿倪沛钟盛泽林
Owner SUZHOU ZELGEN BIOPHARML
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