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Novel benzo-heterocyclic bipyrimidine inhibitor having CDK or HDAC inhibitory activity

A technology of CH2 and heteroaromatic rings, applied in the field of novel heterocyclic derivatives and their pharmaceutical compositions, which can solve the problems of increasing the attractive force between DNA and histones, enhancing deacetylation, and unfavorable tumor suppressor gene expression

Inactive Publication Date: 2018-12-04
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In tumor cells, the overexpression of HDAC leads to the enhancement of deacetylation, which restores the positive charge of histones, thereby increasing the gravitational force between DNA and histones, making the relaxed nucleosomes very compact, which is not conducive to some tumors repress gene expression

Method used

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  • Novel benzo-heterocyclic bipyrimidine inhibitor having CDK or HDAC inhibitory activity
  • Novel benzo-heterocyclic bipyrimidine inhibitor having CDK or HDAC inhibitory activity
  • Novel benzo-heterocyclic bipyrimidine inhibitor having CDK or HDAC inhibitory activity

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preparation example Construction

[0020] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0021] The invention also relates to novel intermediates and / or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.

[0022] Both intermediates and final products can be worked up and / or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0023] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0024] The following examples are only used to illustrate the present invention and do not limit the present invention in any way.

Embodiment 1

[0025] Example 1 N-1-(4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)phenyl)-N-8-hydroxyaminooxyoctanoic acid amide

[0026]

[0027] Add 8-((4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) Pyrimidin-2-yl)amino)phenyl)amino)-8-oxooctanoic acid methyl ester (400 mg, 0.71 mmol), hydroxylamine aqueous solution (50%, 4 mL), methanol 20 mL, heated at reflux at 80°C, reacted overnight . After the reaction, the solvent was removed, and the residue was purified by column chromatography to obtain 305 mg, yield = 76%. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.35 (s, 1H), 9.80 (s, 1H),9.70 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 7.67 (dd, J = 19.3, 10.3 Hz, 3H), 7.55 (d, J = 8.5 Hz, 2H), 4.91 – 4.76 (m, 1H), 2.64(s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 1.95 (t, J = 7.3 Hz, 2H), 1.66 – 1.45 (m,12H), 1.28 (d, J = 7.4 Hz, 2H).

Embodiment 2

[0028] Example 2 N-1-(4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)phenyl)-N-7-hydroxyaminooxyheptanoic acid amide

[0029]

[0030] Add 8-((4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) Pyrimidin-2-yl)amino)phenyl)amino)-7-oxoheptanoic acid methyl ester (200 mg, 0.36 mmoL), hydroxylamine aqueous solution (50%, 2 mL), methanol 10 mL, heated at reflux at 80°C, reacted overnight. After the reaction, the solvent was removed, and the residue was purified by column chromatography to obtain 140 mg, yield = 70%. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.35 (s, 1H), 9.80 (s,1H), 9.70 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 7.67(dd, J = 19.3, 10.3 Hz, 3H), 7.55 (d, J = 8.5 Hz, 2H), 4.92 – 4.78 (m, 1H),2.64 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 1.95 (t, J = 7.3 Hz, 2H), 1.67 – 1.46(m, 10H), 1.31-1.23 (m, 2H).

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Abstract

The invention discloses a novel benzo-heterocyclic bipyrimidine inhibitor having CDK or HDAC inhibitory activity. The inhibitor relates to a novel heterocyclic derivative shown in a formula (I) and asalt thereof, including a medicinal salt, wherein R<1>, R<2>, R<3>, R<4> and R<5> and X, Z and L are defined in the description. The compound is a CDK or HDAC inhibitor, and can be used for treating diseases and disorders mediated by CDK or HDAC, such as cancer, including mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell esophageal cancer, breast cancer, etc. Apharmaceutical composition containing the compound is also related. To treat related disorders by using the compound or the pharmaceutical composition containing the compound is also related. The structure of the novel heterocyclic derivative is shown in the formula (I).

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives and their pharmaceutical compositions, especially novel heterocyclic derivatives and their pharmaceutical compositions as CDK or HDAC inhibitors. The invention also relates to the use of these compounds and compositions in the treatment of hyperproliferative disorders such as cancer. Background technique [0002] The life of a cell begins with the cell cycle, and the normal operation of the cell cycle depends on fine regulatory mechanisms. Cyclin-dependent kinases (CDKs) have been found to be central to cell cycle regulation. The CDKs family is mainly divided into two categories: CDK1-4, 6 control the cell cycle, and combine with the corresponding cell cycle proteins to regulate the cell to enter the G1 phase, thereby affecting the synthesis of cellular DNA; CDK5, 7-9 control cell transcription, research findings, cancer, etc. The occurrence and development of diseases are related to the...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/14A61K31/506A61P35/00
CPCC07D401/14C07D403/04
Inventor 向荣范艳黄志李永涛王鑫刘艳华
Owner NANKAI UNIV
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