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Gcn2 inhibitors and uses thereof

a technology of gcn2 and inhibitors, applied in the field of gcn2 inhibitors, can solve the problems of reducing the translation of most and reducing the global utilization of amino acids

Pending Publication Date: 2022-10-27
VERTEX PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent compound described in the patent can be used in combination with other antiproliferative compounds for the treatment of cancer. These other compounds can include aromatase inhibitors, antiestrogens, topoisomerase inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-angiogenic compounds, gonadorelin agonists, anti-androgens, methionine aminopeptidase inhibitors, matrix metalloproteinase inhibitors, bisphosphonates, biological response modifiers, antiproliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematologic malignancies, compounds which target, decrease or inhibit the activity of Flt-3, Hsp90 inhibitors, and inhibitors of Rho-kinase. This combination of compounds is particularly useful for treating hormone receptor positive tumors, such as breast tumors.

Problems solved by technology

Phosphorylation of eIF2α results in initiation of protein translation, which causes a reduction in the translation of most mRNAs leading to reduced global utilization of amino acids.

Method used

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  • Gcn2 inhibitors and uses thereof
  • Gcn2 inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

S)-1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide, II-36

[1456]

[1457]3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (511.5 mg, 1.82 mmol), N-[[(3S,5S)-4,4-difluoro-5-methyl-3-piperidyl]methyl]methane sulfonamide (400 mg, 1.65 mmol) and DIPEA (426.8 mg, 575.2 μL, 3.30 mmol) were combined in NMP (5 mL) and stirred at 80° C. for 16 hours. The mixture was filtered through a Whatman filter, washing with DMSO (8 mL) and the resulting solution was purified by reverse phase chromatography (C18, MeCN / water / 0.05% TFA as eluent). The clean fractions were then passed through bicarbonate resin cartridges, combined and the resulting solution lyophilised, to give N-[[(3S,5S)-1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide as an off-white solid (428 mg, 53%).

[1458]The following compounds were prepared using a methodo...

example 2

2,4-Triazol-4-yl)methyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine, II-29

[1823]

[1824]A mixture of 2-(1,2,4-triazol-4-ylmethyl)morpholine (trifluoroacetate salt) (15 mg, 0.053 mmol), 6-(difluoromethyl)-3-(6-fluoropyrimidin-4-yl)imidazo[1,2-b]pyridazine (14.1 mg, 0.053 mmol) and K2CO3 (40 mg, 0.289 mmol) in NMP (1 mL) was stirred at 90° C. in a sealed tube for 24 hours. The crude mixture was purified by reverse phase chromatography (C18, MeCN / water / 0.05% TFA as eluent). The pure fractions were combined and lyophilised to yield 2-((4H-1,2,4-triazol-4-yl)methyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine as a pale yellow solid (10 mg, 45%).

[1825]The following compounds were prepared using a methodology similar to the one described in Example 2:[1826](S)—N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methyl-6-oxopiperazin-2-yl)methyl)methanesulfonamide II-7;[1827]N-((1-(6-(6-(Difluorometh...

example 3

(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide, II-59

[1845]

[1846]To 6-(difluoromethyl)-3-iodo-imidazo[1,2-b]pyridazine (65 mg, 0.22 mmol) in dry 1,4-dioxane (4 mL) was added tributyl(tributylstannyl)stannane (255.6 mg, 0.44 mmol), LiCl (46.72 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.7 mg, 0.011 mmol). The mixture was heated at 105° C. under nitrogen for 15 hours. N-[[1-(6-Bromopyrimidin-4-yl)-3-piperidyl]methyl]methanesulfonamide (38 mg, 0.11 mmol) and Pd(PPh3)2Cl2 (15.5 mg, 0.022 mmol) were added sequentially and the mixture was stirred at 140° C. in a sealed tube for 4 hours. Another portion of N-[[1-(6-bromopyrimidin-4-yl)-3-piperidyl]methyl]methanesulfonamide (76 mg, 0.22 mmol) was added and the mixture was stirred at 140° C. for a further 4 hours. The mixture was purified by reverse phase chromatography (C18, MeCN / Water 0.05% TFA as eluent) to afford N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazi...

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 623,299, filed Jan. 29, 2018, the content of which is incorporated herein in its entirety by reference.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to compounds and methods useful for inhibiting General amino acid Control Non-derepressible 2 kinase (“GCN2”). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION[0003]GCN2 (General amino acid Control Non-derepressible 2) is a ubiquitously expressed protein kinase involved in cellular responses to amino acid deficiency across eukaryotes (Castilho et al., 2014). Cellular deficiency in one or more amino acids causes the accumulation of uncharged cognate transfer RNAs (tRNAs), which are bound directly by GCN2, ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00C07D513/04C07D519/00
CPCC07D487/04C07D519/00C07D513/04A61P35/00A61K31/5377A61P29/00A61K31/5025A61P9/00A61P37/00A61K31/4545A61P3/00A61K31/506A61P25/28A61P19/02A61P9/10A61P3/10
Inventor BAYLY, ANDREWBLEICH, MATTHEWCHARRIER, JEAN-DAMIENDODD, JAMESDURRANT, STEVENENO, MEREDITH SUZANNEETXEBARRIA I JARDI, GORKAEVERITT, SIMONFRAYSSE, DAMIENKELLY, SHAZIAKNEGTEL, RONALDMOCHALKIN, IGORMORTIMORE, MICHAELNORTH, KIRIPORICHIS, FILIPPOSPULLIN, ROBERTRUTHERFORD, ALISTAIRSTORCK, PIERRE-HENRITWIN, HEATHER CLARE
Owner VERTEX PHARMA INC
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