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Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (CDK7)

A technology of solvates and uses, applied in the fields of compounds of elements of group 5/15 of the periodic table, organic chemical methods, chemical instruments and methods, etc., can solve problems such as few commercial applications

Pending Publication Date: 2021-08-06
SYROS PHARMACEUTICALIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, developing molecular diagnostics is challenging and has few commercial applications

Method used

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  • Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (CDK7)
  • Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (CDK7)
  • Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (CDK7)

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0099] In case of doubt, a compound of formula (I), (Ia) or any specified form of its species may be contained in a pharmaceutical composition for use and administered according to the invention (for example, in an effective amount (for example, a therapeutically effective quantity)). The pharmaceutical compositions used in the methods of the present invention can be prepared by relevant methods known in the field of pharmacology. Generally, such preparation method comprises the following steps: the compound described herein, including the compound of formula (I), (Ia), its species or its specified form (for example, its pharmaceutically acceptable salt, solvate, stereo isomers, tautomers, or isotopic forms thereof) are combined with a carrier and / or one or more other active ingredients (for example, a second agent as described herein) and / or auxiliary ingredients, and then, If necessary and / or desired, molding and / or packaging of the product are carried out in desired single...

Embodiment 1

[0112] Example 1: Benzyl (2R,5R)-5-amino-2-methyl-piperidine-1-carboxylate and (2S,5S)-5-amino-2-methyl-piperidine-1-carboxylate Synthesis of esters

[0113] Step 1: Benzyl 5-(tert-butoxycarbonylamino)-2-methyl-piperidine-1-carboxylate

[0114]

[0115] At 0°C, we prepared a solution containing commercially available racemic trans-N-(6-methyl-3-piperidinyl)carbamate tert-butyl ester (5 g, 23.33 mmol, 1 eq.) and NaHCO 3 (13.72g, 163.32mmol, 7eq) in tetrahydrofuran (THF; 50mL) and H 2 To a solution in O (50 mL) was added CbzCl (5.97 g, 35.00 mmol, 4.98 mL, 1.5 equiv) dropwise. The mixture was stirred at 15 °C for 2 hours, then poured into water (50 mL) and extracted with ethyl acetate (EtOAc; 50 mL x 3). The combined organic layers were washed with brine (50mL×3), washed with Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure, and the residue was subjected to medium pressure liquid chromatography (MPLC; SiO 2 , PE:EtOAc=5:1 to 1:1) to afford...

Embodiment 2

[0119] Example 2: 7-Dimethylphosphoryl-3-[2-[[(3S,6S)-6-methyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidine-4 Synthesis of -yl]-1H-indole-6-carbonitrile (compound 100)

[0120] Step 1: (2S,5S)-5-[[4-(7-Chloro-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino ]-2-Methyl-piperidine-1-carboxylic acid benzyl ester

[0121]

[0122] We added 7-chloro-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carbonitrile (0.81 g, 2.27 mmol, 1 equivalent), (2S ,5S)-5-Amino-2-methyl-piperidine-1-carboxylic acid benzyl ester (732.20 mg, 2.95 mmol, 1.3 equiv) and N,N-diisopropylethylamine (DIEA or DIPEA; 879.41 mg, 6.80 mmol, 1.19 mL, 3 eq) in N-methyl-2-pyrrolidone (NMP; 8 mL) was stirred at 140 °C for 1 h. The reaction mixture was treated with H 2 Diluted with O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100mL x 2), washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to give a r...

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Abstract

The present invention relates to methods of identifying patients suffering from various types of cancer who are more likely to respond to treatment with a CDK7 inhibitor conforming to structural Formula (I), (la), a species thereof, or a specified form thereof (as described herein), either when administered or used alone or in combination with a second therapeutic agent (e.g., another anti-cancer therapy). Patients are identified based on one or more features (e.g., gene copy number or expression level) of certain biomarkers (e.g., RB1 or another member of the E2F pathway). In addition, the present invention relates to methods of treating an identified patient with a compound conforming to structural Formula (I), (la), a species thereof, or a specified form thereof, either alone or in combination with a second therapeutic agent. In another aspect, the present invention features kits including instructions for treating a patient identified as described herein.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application 62 / 754,398, filed November 1, 2018; U.S. Provisional Application 62 / 877,189, filed July 22, 2019; U.S. Provisional Application 62 / 915,983, filed October 16, 2019; and 2019 Filing Date Benefit of U.S. Provisional Application 62 / 927,469, filed October 29. The contents of each of these prior applications are hereby incorporated by reference in their entirety. Background technique [0003] The long-term evolution of healthcare has reached a point where the promise of biomarker analysis is beginning to be realized. When physicians can group patients—even those with many similar physiological characteristics and exhibit common symptoms of a given disease—into more specific groups, they can better tailor treatments and optimize outcomes for each patient. However, developing molecular diagnostics is challenging and has few commercial applications. Contents of the invention...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404A61K31/506A61K31/66C07D209/30C07D247/02C07D403/04
CPCA61P35/00A61K31/519C07F9/65583A61K31/506A61K31/7068A61K31/555A61K31/4439A61K9/0019A61K31/565A61K31/675A61K45/06A61K2300/00A61K9/0053A61K9/20A61K9/48A61K47/26A61K47/36A61K47/38C07B2200/05
Inventor J.G.霍奇森L.H.约翰尼森
Owner SYROS PHARMACEUTICALIS INC
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