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Substituted aromatic fused ring derivative, and composition and application thereof

A compound and hydrate technology, applied in the field of medicine, can solve problems such as genome instability

Pending Publication Date: 2020-08-25
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mutations render c-KIT function independent of activation by SCF, leading to high cell division rates and possible genomic instability

Method used

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  • Substituted aromatic fused ring derivative, and composition and application thereof
  • Substituted aromatic fused ring derivative, and composition and application thereof
  • Substituted aromatic fused ring derivative, and composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0282] Example 1 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazole Preparation of [1,2-b]pyridazin-3-yl)phenyl)urea (Compound T-1)

[0283]

[0284] Adopt the following synthetic route:

[0285]

[0286] Step 1: Synthesis of the compound 7-chloroimidazo[1,2-b]pyridazine

[0287] Add 5-chloropyridazin-3-amine (0.84 g, 6.5 mmol) and 40% aqueous solution of chloroacetaldehyde (2.55 g, 19.5 mmol) into 15 mL of isopropanol, and heat to reflux for 3 hours. Remove the solvent by rotary evaporation, dilute with 30 mL of water, extract with ethyl acetate (20 mL*3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate through a silica gel column to obtain 0.79 g of a light yellow solid , yield 80%. ESI-MS:154[M + +1].

[0288] Step 2: Synthesis of compound 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine

[0289] 7-chloroimidazo[1,2-b]pyridazine (0.79g, 5.2mmol), 1-...

Embodiment 2

[0296] Example 2 2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)phenyl)-N- Preparation of (5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (compound T-2)

[0297]

[0298] Adopt the following synthetic route:

[0299]

[0300] Step 1: Compound 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5- Synthesis of (1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

[0301] 4-(carboxymethyl)phenylboronic acid pinacol ester (0.94g, 3.6mmol), 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3 - Amine (0.7g, 3.6mmol) and triethylamine (0.73g, 7.2mmol) were dissolved in 20mL of dichloromethane, HATU (2.05g, 5.4mmol) was added under ice-cooling, and reacted overnight at room temperature. The reaction solution was diluted with 20 mL of dichloromethane, washed with water, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to o...

Embodiment 3

[0304] Example 3 2-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl)pyridine-3- Preparation of -N-(5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (compound T-3)

[0305]

[0306] Adopt the following synthetic route:

[0307]

[0308] Step 1: Synthesis of the compound 7-chloroimidazo[1,2-c]pyrimidine

[0309] Add 4-amino-6-chloropyrimidine (0.84g, 6.5mmol) and 40% aqueous solution of chloroacetaldehyde (2.55g, 19.5mmol) into 15mL of isopropanol, and heat to reflux for 3 hours. Remove the solvent by rotary evaporation, dilute with 30 mL of water, extract with ethyl acetate (20 mL*3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate through a silica gel column to obtain 0.79 g of a light yellow solid , yield 80%. ESI-MS:154[M + +1].

[0310] Step 2: Synthesis of the compound 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

[0311] 7-chloroimidazo[1,2-c]pyrim...

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Abstract

The invention provides a substituted aromatic fused ring derivative, a composition containing the derivative and application of the derivative. The substituted aromatic fused ring derivative is a compound as shown in a formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the compound. The compound and the composition inthe invention are useful in the treatment of various protein tyrosine kinase mediated diseases or illnesses.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to substituted aromatic condensed ring derivatives with inhibitory effect on protein tyrosine kinases, pharmaceutical compositions containing them, and their preparation methods and uses. Background technique [0002] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific serine, threonine or tyrosine in cellular proteins. Post-translational modifications of these substrate proteins function as molecular switches that play key roles in various biological processes such as control of cell growth, metabolism, tumor microenvironment (eg VEGFR), differentiation and apoptosis. Aberrant, excessive or more generally inappropriate PK activity has been observed in several disease states, including malignant proliferative disorders such as mutations of function in medullary thyroid carcinoma (MTC) and other human malignancies, acute myeloid leukemia ITD ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04A61P35/00A61P35/02
CPCC07D487/04C07D471/04A61P35/00A61P35/02
Inventor 王义汉邢青峰艾义新
Owner SHENZHEN TARGETRX INC