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Heterobicyclic inhibitors of mat2a and methods of use for treating cancer

A heterocycloalkyl and carbocyclyl technology, applied in the field of heterobicyclic inhibitors of MAT2A and in the treatment of cancer, can solve problems such as gene inactivation

Active Publication Date: 2020-11-13
LES LAB SERVIER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deletion usually inactivates more than one gene

Method used

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  • Heterobicyclic inhibitors of mat2a and methods of use for treating cancer
  • Heterobicyclic inhibitors of mat2a and methods of use for treating cancer
  • Heterobicyclic inhibitors of mat2a and methods of use for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0085] According to various embodiments, the compound of formula (I) has a structure according to formula (IA):

[0086]

[0087] Alternatively, the compound of formula (I) has a structure according to formula (IB):

[0088]

[0089] The present disclosure also provides compounds according to formula II and pharmaceutically acceptable salts thereof:

[0090]

[0091] In Formula II, L is O, S, NR, or a bond; and R is H or C 1 -C 6 -alkyl.

[0092] R 1 Selected from: C 1 -C 6 -Alkyl, C 2 -C 6 -Alkenyl, C 3 -C 6 -carbocyclyl, -(C 1 -C 6 -Alkyl)(C 3 -C 6 -carbocyclyl) and -(C 1 -C 6 -Alkyl)(C 3 -C 6 -cycloalkenyl), wherein R 1 Any alkyl in is linear or branched, and R 1 Optionally substituted with 1-6 halo.

[0093] Alternatively, in some embodiments, when L is NR, then R and R 1 Combination with L represents optionally one or more R A Substituted 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from: N, O and S)...

Embodiment

[0186] The present invention will be more fully understood by reference to the following examples. However, the examples provided herein are illustrative and should not be construed as limiting the scope of the present disclosure.

[0187] List of abbreviations and terms:

[0188] anhy. anhydrous

[0189] aq. Water-based

[0190] min minutes

[0191] mL milliliter

[0192] mmol millimole

[0193] mole mole

[0194] MS mass spectrometry

[0195] NMR nuclear magnetic resonance

[0196] TLC thin layer chromatography

[0197] HPLC high performance liquid chromatography

[0198] RT(r.t.) room temperature

[0199] -spectrum

[0200] Hz hertz

[0201] δ chemical shift

[0202] J coupling constant

[0203] s unimodal

[0204] d doublet

[0205] t triplet

[0206] q quartet

[0207] m multiplet

[0208] br broad peak

[0209] qd quadruple doublet

[0210] dquin double quintet

[0211] dd double doublet

[0212] dt double triplet

[0213] Solvents and reagents: ...

preparation Embodiment 101

[0259]

[0260]Step A: 1-tert-butyl 3-ethyl 3-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)pyrrolidine-1,3-dicarboxylate

[0261]

[0262] To a solution of 1-tert-butyl 3-ethyl pyrrolidine-1,3-dicarboxylate (4.8 g, 19.8 mmol, 1.5 equiv) in THF (30 mL) over a period of 1 h at -78 °C via an addition funnel LiHMDS (1M in THF, 26.4 mL, 26.4 mmol, 2.0 equiv) was added to LiHMDS. The mixture was stirred at -78°C for 4 hours. Then a solution of 4-chloro-5-(dimethoxymethyl)-2-(methylthio)pyrimidine (3.1 g, 13.2 mmol, 1.0 equiv) in THF (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for an additional 3 hours. Then the reaction mixture was washed with NH 4 Quenched with Cl(sat. aq.) (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined and washed with Na 2 SO 4 Dry, filter, concentrate and the resulting residue is purified by flash column chromatography on silica gel (PE / EtOAc=20 / 1 to 4 / 1) to give 3-(5-(dimetho...

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PUM

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Abstract

The present disclosure provides for compounds according to Formula I or Formula II and their pharmaceutically acceptable salts, stereoisomers, and / or tautomers thereof. Also provided are pharmaceutical compositions and the compounds of formulae I and II for use in methods of treating cancers via inhibition of MAT2B, including some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted.

Description

Background technique [0001] Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthase) catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP Cellular enzyme; this catalysis is considered the rate-limiting step of the methionine cycle. SAM is a propylamino donor in polyamine biosynthesis, and is a major methyl donor for DNA methylation, and it is involved in gene transcription and cell proliferation as well as the production of secondary metabolites. [0002] Two genes (designated MAT1A and MAT2A) encode two distinct catalytic MAT isoforms, respectively. The third gene, MAT2B, encodes the MAT2A regulatory subunit. MAT1A is specifically expressed in the adult liver, while MAT2A is widely distributed. Because MAT isoforms differ in catalytic kinetics and regulatory properties, cells expressing MAT1A have much higher levels of SAM than cells expressing MAT2A. Hypomethylation of the MAT2A promoter and histone acetylation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/20A61K31/4375A61K31/498A61K31/4985A61K31/502A61K31/519A61P35/00
CPCC07D471/20A61P35/00A61K31/527C07D471/04A61K31/519C07D519/00C07D471/10
Inventor Z.D.康泰蒂斯李明宗刘朋M.梅戴罗斯S.K.雷兹尼克隋治华J.M.特拉文斯J.波波维奇-穆勒周树宝马光宁
Owner LES LAB SERVIER
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