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Inhibitors of cyclin dependnt kinase 7 (CDK7)

A C0-C6, C1-C6 technology, applied in the field of cyclin-dependent kinase 7 (CDK7) inhibitors, can solve problems that hinder the discovery of CDK7 selective inhibitors

Pending Publication Date: 2019-07-19
SYROS PHARMACEUTICALIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, inhibition of human CDK7 kinase activity may result in antiproliferative activity
[0005] High sequence and structural similarity in the kinase domains of CDK family members hampers the discovery of CDK7-selective inhibitors

Method used

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  • Inhibitors of cyclin dependnt kinase 7 (CDK7)
  • Inhibitors of cyclin dependnt kinase 7 (CDK7)
  • Inhibitors of cyclin dependnt kinase 7 (CDK7)

Examples

Experimental program
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preparation example Construction

[0178] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such a preparation method comprises the following steps: combining a compound of formula (I) (ie, the "active ingredient") with a carrier and / or one or more other auxiliary agents, and then, if necessary and / or desired , forming and / or packaging the product into desired single- or multi-dose units.

[0179] The pharmaceutical compositions may be prepared, packaged and / or sold in bulk as a single unit dose and / or multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined quantity of active ingredient. The amount of said active ingredient is usually equal to the dose of active ingredient to be administered to the subject and / or a simple fraction of that dose, for example, one-half or one-third of that dose.

[0180]The relative amounts of the active ingredients, pharmace...

Embodiment 1

[0223] Example 1 Synthesis of (S)-5-chloro-4-(5,6-difluoro-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine.

[0224] Step 1: 3-(2,5-Dichloropyrimidin-4-yl)-5,6-difluoro-1H-indole

[0225]

[0226] To a solution of 2,4,5-trichloropyrimidine (700 μL, 6.11 mmol) in dichloroethane (40 mL) was added aluminum chloride (940 mg, 7.05 mmol). The resulting suspension was stirred at 80°C for 30 minutes. The reaction mixture was then cooled to room temperature and 5,6-difluoroindole (1.00 g, 6.54 mmol) was added, and the resulting solution was stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature and crushed ice (15 mL) was added. The resulting slurry was stirred vigorously for 30 min, then further diluted with EtOAc (200 mL) and water (60 mL). The mixture was warmed to dissolve the suspended solids, the layers were separated and the aqueous layer was extracted with warm EtOAc (150 mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter...

Embodiment 2

[0233] Example 2 Synthesis of (S)-N-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)quinuclidin-3-amine (compound 131).

[0234]

[0235] (S)-N-(5-Chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)quinuclidin-3-amine (50mg, 0.101 mmol) and NaOH 5M (1 mL, 5.00 mmol) in dioxane (1.0 mL) was heated at 70 °C for 6 h. The cooled mixture was then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (C18, H 2 O / ACN+0.1%HCO 2 H, 0 to 100% gradient), then the title compound (24 mg, 0.067 mmol, 67% yield) was obtained as a white solid after lyophilization.

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Abstract

The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benignneoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition ofthe invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and / or inhibit transcription in the subject.

Description

[0001] priority claim [0002] This application claims priority to US Provisional Application No. 62 / 361,852, filed July 13, 2016, which is hereby incorporated by reference in its entirety. Background technique [0003] Members of the cyclin-dependent kinase (CDK) family play key regulatory roles in proliferation. CDK7 is unique among mammalian CDKs with integrated kinase activity and regulates cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to function as a CDK1 / 2-activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 by CDK7 is fully catalytic Required for CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAP II, an essential step for the initiation of gene transcription. Together, the two functions of CDK7 (ie, CAK and CTD...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00A61K31/506
CPCC07D401/14A61P29/00A61P31/00A61P35/00A61P35/02A61P37/06C07D413/14C07D417/14C07D471/04A61K31/506A61K31/541C07D471/08C07F9/65583
Inventor J.J.马里内奥R.扎勒S.西布拉特D.K.温特A.卡布罗S.罗伊D.施密特C.丘亚基G.马洛西克H.皮拉斯K.M.惠特莫尔K-L.伦德B.辛科K.斯普罗特
Owner SYROS PHARMACEUTICALIS INC
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