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Tertiary cyclic amine Alk kinase inhibitors for the treatment of cancer

A compound, C1-C6 technology, applied in the field of cyclic amine compounds and their preparation, can solve the problems of cell proliferation, uncontrolled cell cycle, etc.

Active Publication Date: 2018-11-20
ZHEJIANG DTRM BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Uncontrolled activation of this ALK kinase and the resulting downstream signaling lead to uncontrolled cell proliferation, survival, and cell cycle

Method used

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  • Tertiary cyclic amine Alk kinase inhibitors for the treatment of cancer
  • Tertiary cyclic amine Alk kinase inhibitors for the treatment of cancer
  • Tertiary cyclic amine Alk kinase inhibitors for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101]

[0102] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetic acid

[0103] Step A:

[0104]

[0105] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetic acid methyl ester

[0106] Steps:

[0107] The compound methyl 2-chloroacetic acid (11 mg, 0.12 mmol, 1.2 equivalents), potassium carbonate (0.5 mmol, 5 equivalents) and sodium iodide (2 mg) were added to the compound 3-[1-(2 , 6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridin-2-amine (45 mg, 0.1 mmol, 1 equivalent) in 2 ml of ethanol solution, heated to reflux for 2 hours and then quenched with water, then added the water layer and dichloromethane, layered, the water layer was extracted three times with dichloromethane, after the organic phases were combined, dried After spin-drying, the product was directly used in the next step (40 mg, yield 77%).

[0108] Step B:

[0109]...

Embodiment 2

[0117]

[0118] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetamide

[0119] Steps:

[0120]2-Chloroacetamide (132 mg, 1.44 mmol, 1.2 equivalents), potassium carbonate (4.8 mmol, 4 equivalents) and sodium iodide (12 mg) were added to compound 3-[1-(2,6- Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-pyridyl)pyrazol-4-yl]piperidinyl-2-amine (0.54 mg, 1.2 mmol, 1 equivalent ) in 15 ml of ethanol solution, heated to reflux for 2 hours and then quenched with water, then added the water layer and dichloromethane, layered, the water layer was extracted three times with dichloromethane, after the organic phases were combined, dried and spin-dried, The crude product was purified by chromatography (instrument: SHIMADZU LC-8A, chromatographic column: synergi-10μm, 250×50mmI.D. mobile phase: A is water (containing 1‰TFA, v / v) and B is acetonitrile, concentration gradient: B30-80%. Flow rate: 80mL / min). Using the HPLC purified solut...

Embodiment 3

[0124]

[0125] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1

[0126] -piperidinyl]-N-methyl-acetamide

[0127] Steps:

[0128] The compound 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Methyl]-1-piperidinyl]acetate (0.8 g, 1.53 mmol, 1.0 equiv) was dissolved in a solution of methylamine in THF. Then spin dry the solvent after reacting in a microwave at 80 degrees for a total run time of 45. The target compound was purified by HPLC (instrument: SHIMADZU LC-8A, chromatographic column: synergi-10μm, 250×50mmI.D. mobile phase: A for water (Add1‰TFA, v / v) and B for CAN, concentration gradient: B30-80%. Flow rate: 80mL / min). Use the HPLC purified solution to adjust the pH value to 7-8 with sodium bicarbonate, extract the aqueous layer three times with dichloromethane, combine the organic layers, backwash with saturated saline, and dry Spin-dry to obtain the target compound (582.4 mg).

[0129] S...

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Abstract

The present invention provides certain novel substituted cyclic amine compounds or salts. Such compounds or salts are inhibitors of anaplastic lymphoma kinase (ALK). The invention also relates to pharmaceutical preparations containing these compounds as active ingredients. The present invention also includes the use of these compounds and their preparations to treat and inhibit non-small cell lung cancer (NSCLC), neuroblastoma, and anaplastic large cell lymphoma (ALCL), liver cancer and other diseases caused by increased levels of ALK activity. method of causing disease.

Description

[0001] technical field of invention [0002] The invention relates to a series of new substituted cyclic amine compounds and their preparation method, a pharmaceutical composition containing them as active ingredients and their application in treating tumors and other diseases. Background technique [0003] Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor family. In humans, it is a kinase encoded by the ALK gene. As a receptor tyrosine kinase, it consists of an extracellular domain, a transmembrane region and an intracellular tyrosine kinase domain. ALK plays an important role in the development of the brain and central nervous system. However, the function of ALK in adults is unknown. [0004] In humans, abnormal ALK signaling is associated with the pathogenesis of various cancers. These aberrant ALK signaling activities result from ALK gene rearrangements (including translocations, amplifications, and mutations) and ALK kinase overexpression. Abnorma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D413/14A61K31/5377A61K31/4545A61P35/00
CPCC07D401/14C07D413/14A61P35/00
Inventor 何伟
Owner ZHEJIANG DTRM BIOPHARMA
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