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RAS inhibitors

A pharmaceutical, optional technology, applied in the field of RAS inhibitors, which can solve problems such as unapproved drugs

Pending Publication Date: 2022-07-22
REVOLUTION MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Despite extensive drug discovery efforts targeting Ras over the past few decades, no drugs that directly target Ras have been approved

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[1073] [1] A compound or a pharmaceutically acceptable salt thereof having the structure of formula I:

[1074]

[1075] where dashed lines represent zero, one, two, three or four non-adjacent double bonds;

[1076] A is -N(H or CH 3 )C(O)-(CH 2 )-, where the amino nitrogen is bound to -CH(R 10 )- carbon atom; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 10-membered heteroarylene;

[1077] B does not exist and is -CH(R 9 )-, >C=CR 9 R 9' or >CR 9 R 9' , where the carbon is bound to -N(R 11 ) carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroarylene;

[1078] G is optionally substituted C 1 -C 4 Alkylene; optionally substituted C 1 -C 4 Alkenylene; optionally su...

Embodiment

[1488] The present disclosure will be further illustrated by the following examples and synthetic examples, which should not be construed to limit the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to thereby limit the scope of the present disclosure. It should also be understood that various other embodiments, modifications and equivalents thereof, which may occur to those skilled in the art, may also be resorted to without departing from the spirit of the present disclosure or the scope of the appended claims.

[1489] chemical synthesis

[1490] Definitions used in the following examples and elsewhere herein are as follows:

[1491] CH 2 Cl 2 , DCM methylene chloride, dichloromethane

[1492] CH 3 CN, MeCN Acetonitrile

[1493] CuI copper(I) iodide

[1494] DIPEA Diisopropylethylamine

[1495] DMF N,N-Dimethylformamide...

Embodiment A75

[1590] Example A75. Synthesis of (2S)-N-[(8S,14S,20M)-22-ethyl-4-hydroxy-21-{2-[(1S)-1-methoxyethyl]pyridine-3 -yl}-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ] Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]-3-methyl-2-{N-methyl- Two atropisomers of 1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]carboxamido}butanamide.

[1591]

[1592] Step 1. At 0°C, to ((6 3 S,4S)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Hexahydro-1 1 H-8-oxa-1(5,3)-indoleza-6(1,3)-pyridazine-2(1,3)-benzcycloundecan-4-yl)carbamic acid tert. To a stirred mixture of butyl ester (18.0 g, 20.1 mmol) in THF (180 mL) was added 1 M TBAF in THF (24.1 mL, 24.1 mmol). The mixture was stirred at 0 °C for 1 hour, then diluted with brine (1.5 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (2 x 500 mL), washed with anhy...

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Abstract

The present disclosure provides macrocyclic compounds capable of inhibiting Ras proteins, as well as pharmaceutical compositions and protein complexes thereof, and their use in the treatment of cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims US Application No. 62 / 930,355, filed November 4, 2019; US Application No. 62 / 951,652, filed December 20, 2019; US Application No. 63 / 000,357, filed March 26, 2020 ; US Application No. 63 / 011,636, filed April 17, 2020; and US Application No. 63 / 043,588, filed June 24, 2020, all of which are hereby incorporated by reference in their entirety. Background technique [0003] The vast majority of small-molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the protein's activity. For example, cholesterol-lowering drugs called statins bind to the enzyme active site of HMG-CoA reductase, preventing the enzyme from engaging its substrate. The fact that many such drug / target interaction pairs are known may mislead some to believe that small molecule modulators of most, if not all, proteins can be discovered, providing a reasonable amount of time, effort and r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K5/02A61K31/504A61K38/12
CPCA61P35/00C07D245/04C07D498/18A61K31/504A61K31/5377A61K31/5386A61K31/55C07D513/22C07D498/22
Inventor E·S·科尔屯J·克雷格A·L·吉尔J·阿根G·L·伯内特J·皮岑A·巴克尔J·E·克诺克斯Y·刘
Owner REVOLUTION MEDICINES INC
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