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Cyclic iminopyrimidine derivatives as kinase inhibitors

A technology of derivatives and solvates, applied in the field of cyclic iminopyrimidine derivatives as kinase inhibitors, can solve the problems of being unsuitable for brain tumors or cancer, low penetration into cell membranes, and into the brain

Pending Publication Date: 2020-06-05
ABM THERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, due to their structural features, many kinase inhibitors are substrates for active transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), and have extremely low penetration into cell membranes as well as into the brain the trend of
Therefore, they are not suitable for the treatment of brain tumors or cancers protected by the blood-brain barrier (BBB)

Method used

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  • Cyclic iminopyrimidine derivatives as kinase inhibitors
  • Cyclic iminopyrimidine derivatives as kinase inhibitors
  • Cyclic iminopyrimidine derivatives as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0259] Example 1: Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1- Sulfonamide (Compound 1)

[0260] plan 1

[0261]

[0262] Step 1: Synthesis of 6-methoxyquinazolin-4(3H)-one

[0263] A mixture of 2-amino-5-methoxybenzoic acid (10.0 g, 59.9 mmol), formamidine acetate (12.3 g, 119 mmol) in 80 mL of 2-methoxyethanol was heated at 125°C for 18 hours. After cooling to room temperature, the precipitate was collected by filtration, washed twice with 2-methoxyethanol, and dried in vacuo to provide 6-methoxyquinazolin-4(3H)-one (9.1 g, 87% yield Rate).

[0264] Step 2: Synthetic 4-chloro-6-methoxyquinazoline

[0265] 6-Methoxyquinazolin-4(3H)-one (3.0g, 17.0mmol) in POCl 3 (30 mL) and the solution was stirred overnight at 120°C. The mixture was then cooled to room temperature and evaporated. The residue was purified by silica gel column chromatography (PE / EtOAc from 10:1 to 5:1, v / v) to give 4-chloro-6-methoxyquinazoline (3.0 g, ...

Embodiment 2

[0276] Example 2: Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methyl Propane-1-sulfonamide (Compound 2)

[0277] Scenario 2

[0278]

[0279] Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methylpropane-1 -sulfonamide

[0280] 0°C, NaH (60% in mineral oil, 16.0 mg, 0.39 mmol) was slowly added to N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazole In a solution of olin-9-yl)oxy)phenyl)propane-1-sulfonamide (80mg, 0.20mmol) in DMF (10.0mL). The reaction mixture was washed with N 2 Degas and stir at room temperature for 60 minutes. Iodomethane (43 mg, 0.30 mmol) was then added, and the mixture was stirred at room temperature overnight under nitrogen. The resulting mixture was evaporated and the residue was purified by flash column chromatography (ACN / H 2 O), to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methyl Propane-1-sulfonamide (30 mg, 35% yield) as a white so...

Embodiment 3

[0281] Example 3: Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4-fluorophenyl) Propane-1-sulfonamide (Compound 3)

[0282] Option 3

[0283]

[0284] Step 1: Synthesis of 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-3,6-difluorobenzonitrile

[0285] 0 °C, NaH (60% in mineral oil, 111 mg, 2.78 mmol) was slowly added to 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (400 mg, 2.14 mmol) in DMF (20mL) solution. The reaction mixture was washed with N 2 Degas and stir at room temperature for 60 minutes. Then 2,3,6-trifluorobenzonitrile (37.0 mg, 2.35 mmol) was added, and the mixture was stirred at 80° C. for 1 hour. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM / MeOH from 100:1 to 30:1, v / v) to give 2-((2,3-dihydroimidazo[1,2- c] quinazolin-9-yl)oxy)-3,6-difluorobenzonitrile (200 mg, 29% yield).

[0286] Step 2: Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)...

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Abstract

Provided are cyclic iminopyridimdine compounds and their bicyclic derivatives, pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions, such as methods of treating a proliferation disorder, such as a cancer or a tumor, or in some embodiments disease or disorders related to the dysregulation of kinase such as, but not limited to B-Raf V600E kinase.

Description

[0001] cross reference [0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 561,142, filed September 20, 2017, the entire contents of which are incorporated herein by reference. technical field [0003] Provided herein are cyclic iminopyrimidine derivatives, pharmaceutical compositions comprising such compounds and methods of using such compounds or compositions, such as methods of treating proliferative diseases, cancer or tumors, or in some embodiments with kinase (eg, but not limited to, B-Raf V600E kinase) disorders or disorders associated with dysregulation. Background technique [0004] The present disclosure relates to the treatment of abnormal cell growth, such as cancer, and more particularly brain cancer. In addition, the present invention relates to methods of preparing such compounds. [0005] Kinases are enzymes that catalyze the transfer of a phosphate group from a high-energy, phosphate-donating molecule to a specific subs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61K31/517A61P35/00
CPCC07D487/14C07D487/04A61K31/519A61P35/00A61P25/28A61P35/04A61K45/06C07D471/14
Inventor 陈晨
Owner ABM THERAPEUTICS CORP