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KRAS-G12C inhibitor

A C1-C3, C3-C6 technology, applied in the field of new KRAS-G12C inhibitors, can solve the problem of no anti-RAS therapy

Inactive Publication Date: 2019-09-20
WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disappointingly, despite more than three decades of research efforts, there are still no clinically effective anti-RAS therapies, and targeting this gene with small molecules is challenging

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Example 1 (S)-4-(4-acryloylpiperazin-1-yl)-7-(5-methyl-1H-indazol-4-yl)-1-((1-methylpyrrolidine Synthesis of -2-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2(1H)-one (Compound 1)

[0147]

[0148] Compound 1 was prepared according to Method A as described below:

[0149] 4-(4-((Benzyloxy)carbonyl)piperazin-1-yl)-2-(methylmercapto)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- tert-butyl formate (1-1)

[0150] A1 (5.2g, 12.11mmol), DIPEA (3.2g, 24.22mmol), benzyl-1-piperazine carbonate (2.9g, 13.31mmol) and DMF (50mL) were added to a 250mL single-necked bottle, under the protection of Ar, Raise the temperature to 100°C for 1 hour reaction. TLC monitoring (PE / EA=10 / 1), the raw materials reacted completely, after cooling the reaction solution to room temperature, added water (100mL), extracted with EA (50mL*2), combined the organic phases, washed with saturated sodium chloride, organic The phase was concentrated and purified by column chromatography (PE / EA=1 / 0 to ...

Embodiment 2

[0168] Example 2 4-(4-acryloylpiperazin-1-yl)-6-cyclopropyl-8-methoxy-7-(5-methyl-1H-indazol-4-yl)-1- Synthesis of (((S)-1-methylpyrrolidin-2-yl)methyl)quinazolin-2(1H)-one (Compound 53)

[0169]

[0170] Compound 53 was prepared according to Method B as described below:

[0171] tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (53-1)

[0172] Add B1 (5g, 15.13mmol), DIPEA (4g, 30.3mmol), N-Boc-piperazine (2.96g, 15.89mmol) and DMF (100mL) into a 250mL single-necked bottle, under the protection of Ar, heat up to 80°C for reaction 2 Hour. TLC spot plate (PE / EA=5 / 1), the reaction of raw materials was complete, after cooling the reaction solution to room temperature, add water (100mL), extract with EA (100mL*2), combine the organic phases, wash with saturated sodium chloride, The organic phase was concentrated and purified by column chromatography (PE / EA=1:0 to 2 / 1) to give white solid 53-1 (5.23g, yield 72%), ESI-MS m / z: 479.1 / 481.1[M+ H...

Embodiment 3

[0188] Example 3 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-((( Synthesis of S)-1-methylpyrrolidin-2-yl)methyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 74)

[0189]

[0190] Compound 74 was prepared according to Method C as described below:

[0191] 2,6-Dichloro-5-fluoronicotinamide (74-1)

[0192] CDI (35.6g, 220mmol) was added in batches to a solution of C1 (42g, 200mmol) in THF (400mL), the mixture was stirred for 5min, protected by Ar, heated to 50°C, reacted for 1h, monitored by LC-MS, the raw material disappeared, and the reaction The solution was diluted with toluene (100 mL), concentrated to half of the original volume, the resulting mixture was cooled to 0 °C, and ammonium hydroxide (55 mL, 400 mmol) was added slowly. React at room temperature for 10 minutes, dilute with EA (200mL), and wash with water (100mL*3). Anhydrous Na for organic layer 2 SO 4 To dry, spin dry. PE / EA (10 / 1,200 mL) was beaten, filtered, the remai...

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Abstract

The invention provides a G12C mutant K-Ras protein irreversible inhibitor, the invention also discloses the G12C mutant K-Ras protein irreversible inhibitor and a preparation method and use thereof.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, and more specifically, relates to a novel KRAS-G12C inhibitor, a preparation method thereof, and a use method of the compound. Background technique [0002] RAS represent a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal development or physiological conditions, RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration and differentiation. RAS functions as a molecular switch, the on / off state of RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When RAS contains bound GDP, it is in a dormant or quiescent or off state, and is "inactive", in response to exposure to certain growth-promo...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00C07D403/14C07D405/14C07D413/14C07D401/14A61K31/519A61K31/5377A61K31/517A61P35/00A61P35/02
CPCC07D471/04C07D519/00C07D403/14C07D405/14C07D413/14C07D401/14A61P35/00A61P35/02
Inventor 樊后兴谢雨礼
Owner WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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