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Fused ring compounds

a technology of ring compounds and ring compounds, applied in the field of ring compounds, can solve the problems of tumor shrinkage, poor prognosis of ras mutation in cancer,

Active Publication Date: 2021-07-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively inhibit mutant Ras protein activity, offering a therapeutic approach to treat cancer by targeting the underlying cause of uncontrolled cell growth associated with these mutations.

Problems solved by technology

Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer.
Mutations of Ras in cancer are associated with poor prognosis.
Inactivation of oncogenic Ras in mice results in tumor shrinkage.

Method used

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  • Fused ring compounds
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Examples

Experimental program
Comparison scheme
Effect test

embodiment 1

[0398]A compound of Formula (I):

[0399]or a pharmaceutically acceptable salt thereof;[0400]wherein,[0401]R1 is an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a K-Ras G12C mutant protein;[0402]R2 is selected from the group consisting of H, OH, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, cyclopropyl, and —NHR, wherein R is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, C1-6 hydroxyalkanoyl, C1-6 cyanoalkyl, C1-6 alkylamino, —(C1-6 alkylenyl)NH(CH3)—(C1-6 alkylenyl)N(CH3)2, and —(C1-3 alkylenyl)(3-7 membered-heterocyclyl);[0403]R3 and R4 are each independently selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, and cyclopropyl;[0404]R5 is selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, ...

embodiment 2

[0417]The compound of Embodiment 1 having a Formula (II):

[0418]or a pharmaceutically acceptable salt thereof;[0419]wherein,[0420]R2 is selected from the group consisting of H, OH, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, cyclopropyl, and —NHR, wherein R is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, C1-6 hydroxyalkanoyl, C1-6 cyanoalkyl, C1-6 alkylamino, —(C1-6 alkylenyl)NH(CH3)—(C1-6 alkylenyl)N(CH3)2, and —(C1-3 alkylenyl)(3-7 membered-heterocyclyl);[0421]R3 and R4 are each independently selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, and cyclopropyl;[0422]R5 is selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, and C3-7 cycloalkyl,[0423]wherein at least one of R2, R3, R4, and R5 is other than H; or[0424]R2 and R3, R3 and R4, ...

embodiment 3

[0439]The compound of Embodiment 1 having a Formula (III):[0440]or a pharmaceutically acceptable salt thereof;

[0441]wherein,[0442]R2 is selected from the group consisting of H, OH, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, cyclopropyl, and —NHR, wherein R is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, C1-6 hydroxyalkanoyl, C1-6 cyanoalkyl, C1-6 alkylamino, —(C1-6 alkylenyl)NH(CH3)—(C1-6 alkylenyl)N(CH3)2, and —(C1-3 alkylenyl)(3-7 membered-heterocyclyl);[0443]R3 and R4 are each independently selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, and cyclopropyl;[0444]R5 is selected from the group consisting of H, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylamino, and C3-7 cycloalkyl,[0445]wherein at least one of R2, R3, R4, and R5 is other than H; or[0446]R2 and R3, R3 and R4,...

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Abstract

This invention pertains to fused ring compounds of Formula (I), as further detailed herein, which are used for the inhibition of Ras proteins, as well as compositions comprising these compounds and methods of treatment by their administration.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to International Application Serial Number PCT / CN2018 / 114788, filed on Nov. 9, 2018, which is herein incorporated by reference in its entirety.FIELD OF THE DISCLOSURE[0002]This invention pertains to fused ring compounds of Formula (I), as further detailed herein, which are used for the inhibition of Ras proteins, such as K-Ras, H-Ras, and N-Ras, as well as compositions comprising these compounds and methods of treatment by their administration.BACKGROUND OF THE DISCLOSURE[0003]Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch for central growth signaling pathways. In response to extracellular signals, Ras is converted from a GDP-bound (RasGDP) to a GTP-bound (RasGDP) state, as catalyzed by guanine nucleotide exchange factors (GEFs), notably the SOS1 protein. Active RasGDP mediates its diverse growth-stimulating functions through its direct interactions with effectors includ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/14C07D405/14A61P35/00A61K9/00
CPCC07D401/14C07D405/14A61K9/0019A61K9/0053A61P35/00C07B2200/07C07D401/04C07D471/04A61P35/02A61P35/04A61K31/517
Inventor MALHOTRA, SUSHANTXIN, JIANFENGDO, STEVENTERRETT, JACK
Owner F HOFFMANN LA ROCHE & CO AG
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