Compounds and compositions for modulating EGFR mutant kinase activities

A technology of compounds and medicinal salts, applied in the field of compounds and compositions for regulating the kinase activity of EGFR mutants, capable of solving problems such as precise effects, small pleiotropic defects, etc.

Active Publication Date: 2017-05-31
YUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since it is predominantly expressed in hematopoietic cells, highly selective JAK3 inhibitors should have precise effects against immune cells and minimal pleiotropic defects

Method used

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  • Compounds and compositions for modulating EGFR mutant kinase activities
  • Compounds and compositions for modulating EGFR mutant kinase activities
  • Compounds and compositions for modulating EGFR mutant kinase activities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0607] Compound 1: N-(3-(4-(4-(azetidin-1-ylmethyl)-3-methyl-1H-pyrazol-1-yl)pyrimidine-2- (amino)-4-methoxyphenyl)acrylamide

[0608]

[0609] step 1:

[0610] To a solution of Intermediate 1 (35.0 mg, 0.10 mmol), diisopropylethylamine (DIPEA, 50 μL, 0.30 mmol) in dimethylacetamide (DMAA, 2 mL) was added 18.5 mg of the azacycline at room temperature Butane hydrochloride (0.20 mmol). After stirring for 20 minutes, 62.8 mg of sodium triacetoxyborohydride (NaBH(OAc) 3 , 0.30 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the mixture was purified by column chromatography (0 to 10% MeOH in DCM) to afford 4-(4-(azetidin-1-ylmethyl)-3-methyl as a red solid -1H-pyrazol-1-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine (32.0 mg, 82%); MS (ESI) m / z 396.2 [M +H] + .

[0611] Step 2:

[0612] To a solution of the above nitro compound (56.0 mg, 0.14 mmol) in 3 mL of a mixture of ethanol and water (5...

Embodiment 2

[0616] Compound 2: N-(3-(4-(4-((3-hydroxyazetidin-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl) Pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide

[0617] The title compound was prepared as described in Example 1 using Intermediate 1 and azetidin-3-ol hydrochloride; MS (ESI) m / z 436.2 [M+H] + .

Embodiment 3

[0619] Compound 3: N-(3-(4-(4-(azetidin-1-ylmethyl)-3-methyl-1H-pyrazol-1-yl)pyrimidine-2- Amino)phenyl)acrylamide

[0620] The title compound was prepared as described in Example 1 using Intermediate 2 and azetidine hydrochloride; MS (ESI) m / z 390.2 [M+H] + .

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PUM

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Abstract

The present invention provides a new group of protein kinase inhibitors, aminopyrimidine derivatives, and pharmaceutically acceptable salts thereof that are useful for treating cell proliferative disease and disorder such as cancer and immune disease. The present invention provides methods for synthesizing and administering the protein kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefore. The invention also provides useful intermediates generated during the syntheses of the aminopyrimidine derivatives.

Description

technical field [0001] The present invention relates to novel compounds exhibiting inhibitory activity against certain mutant forms of EGFR and pharmaceutically acceptable compositions thereof. Background technique [0002] Protein kinases catalyze the transfer of terminal phosphates from ATP or GTP to the hydroxyl groups of tyrosine, serine and / or threonine residues in proteins. Protein kinases are classified into families according to the substrates they phosphorylate, eg protein tyrosine kinases (PTK) and protein serine / threonine kinases. Phosphorylation by protein kinases results in functional changes in target proteins (substrates) by altering enzyme activity, cellular localization, or association with other proteins. Protein kinases play key roles in a variety of cellular processes: cell proliferation, cell survival, metabolism, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and immune responses. [0003] Dysregulation of protein kinases has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D405/14C07D413/14C07D401/14C07D409/14C07D403/04A61K31/506A61K31/5377A61K31/167A61K31/4155A61P35/00A61P37/02A61P31/00A61P9/00A61P25/00
CPCC07D401/14C07D403/04C07D403/14C07D405/14C07D409/14C07D413/14A61P11/00A61P25/00A61P31/00A61P35/00A61P37/00A61P37/02A61P43/00A61P9/00A61K31/506
Inventor 徐炳铁帕雷什·德维达·萨尔冈卡李载揆高锺声宋虎骏李仁溶李载相丁东植金重虎金世源
Owner YUHAN
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