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Novel KRAS G12C protein inhibitor as well as preparation method and application thereof

A solvate and independent technology, applied in the field of medicinal chemistry, can solve the problems of high hepatic first-pass effect, excessive dosage, and rapid metabolism

Pending Publication Date: 2021-03-23
INNOVENT BIOLOGICS (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although some candidate compounds targeting the KRAS G12C target have entered the clinical research stage, the early candidate compounds generally have some problems that restrict their druggability, such as low activity, excessive clinical dosage, fast metabolism, and high hepatic first pass effect

Method used

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  • Novel KRAS G12C protein inhibitor as well as preparation method and application thereof
  • Novel KRAS G12C protein inhibitor as well as preparation method and application thereof
  • Novel KRAS G12C protein inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0387] The present invention provides the preparation method of above-mentioned formula I compound, it comprises the following steps:

[0388] 1) Compound I-1 reacts with Compound I-a to obtain Compound I-2;

[0389]

[0390] 2) Compound I-2 undergoes an oxidation reaction to introduce -L-R 1 The reaction and the deprotection reaction of removing PG' to obtain compound I-3;

[0391]

[0392] 3) react compound I-3 and compound I-b to obtain compound I-4;

[0393]

[0394] 4) compound I-4 undergoes a deprotection reaction to remove PG to obtain compound I-5;

[0395]

[0396] 5) Compound I-5 is reacted with compound I-c to obtain a compound of formula I;

[0397]

[0398] Wherein: Y is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy; Z is hydroxyl, bromine or chlorine; PG and PG' represent protecting groups; A, L.X 0 、X 1 、X 2 、X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5' , R 6 , m and n are as defined ...

Embodiment 1

[0448] Example 1: 8-Benzyl-2-(methylthio)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yltrifluoro Synthesis of mesylate (Intermediate A).

[0449]

[0450] Step 1: At room temperature, mix benzylamine (Intermediate 1) (50g, 0.47mol) and triethylamine (70.7g, 0.70mol) in acetonitrile (500mL), and add 2-bromoacetic acid dropwise to it under stirring Ethyl ester (78.5g, 0.47mol) in acetonitrile solution (100mL), dripped over about 4h. Filter and wash the filter cake with acetonitrile. The filtrate and acetonitrile washings were combined and concentrated under reduced pressure to obtain the crude N-benzylglycine ethyl ester (Intermediate 2) (76 g, 84% yield), which was directly used in subsequent reactions without purification.

[0451] LC-MS: 194[M+1] + .

[0452]

[0453] Step 2: Mix N-benzylglycine ethyl ester (intermediate 2) (23g, 0.12mol) and triethylamine (14.4g, 0.14mol) in acetonitrile (250mL), and add 5-bromo Ethyl n-valerate (25 g, 0.12 mol). The reaction ...

Embodiment 2

[0465] Example 2: 8-Benzyl-2-(methylthio)-6,7,8,9-tetrahydropyrimidine[4,5-f][1,4]oxazepane-4- Synthesis of triflate (Intermediate B).

[0466]

[0467] Using a synthetic route similar to that of Example 1, 8-benzyl- 2-(Methylthio)-6,7,8,9-tetrahydropyrimidine[4,5-f][1,4]oxazepan-4-yl trifluoromethanesulfonate (intermediate Body B).

[0468] LC-MS: 436[M+1] + .

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a novel KRAS G12C protein inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound with a structure as shown in a formula I, and the compound can be used as an efficient KRAS G12C protein inhibitor and has various pharmacological activities of resisting tumors, proliferative diseases, inflammation, autoimmune diseases and the like.

Description

[0001] References to related applications [0002] The present invention claims the priority of the invention patent application filed in China on September 23, 2019, entitled "Novel KRASG12C Protein Inhibitor and Its Preparation Method and Use", and the application number is 201910899784.9, which is incorporated by reference in its entirety The content is incorporated into this article. technical field [0003] The invention belongs to the field of medicinal chemistry, and relates to a novel KRAS G12C protein inhibitor, its preparation method, a pharmaceutical composition containing it, and its medical application, especially in the preparation for preventing and / or treating at least part of the KRASG12C protein inhibitor Use in medicines for mediated diseases. Background technique [0004] RAS represent a group of closely related monomeric globular proteins of 189 amino acids (21 kDa molecular weight) that associate with the plasma membrane and bind GDP or GTP. RAS funct...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D498/04A61K31/55A61K31/551A61K31/553A61P35/00
CPCC07D487/04C07D498/04A61P35/00
Inventor 张龙宋国伟杨智亮
Owner INNOVENT BIOLOGICS (SUZHOU) CO LTD
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