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tam family kinases/and csf1r kinase inhibitors and uses thereof

A technology of selection and pharmacy, applied in the field of medicine, can solve the problems such as the listing of inhibitors, and achieve the effect of improving compliance, reducing the burden of taking medicine, and tumor immune effect and anti-tumor effect.

Active Publication Date: 2022-04-19
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, CSF1R inhibitors are mostly used in combination with PD-1 in clinical practice, and there are no inhibitors targeting TAM / and CSF1R on the market

Method used

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  • tam family kinases/and csf1r kinase inhibitors and uses thereof
  • tam family kinases/and csf1r kinase inhibitors and uses thereof
  • tam family kinases/and csf1r kinase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0373] Example 1: Synthesis of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid

[0374]

[0375] step

[0376]

[0377] Step 1: Synthesis of 2-(p-tolyl)acetyl chloride

[0378]

[0379]Under nitrogen protection, 2-(p-tolyl)acetic acid (25g, 0.17mol, 1.0eq) was added to dichloromethane (250mL), and oxalyl chloride (42.25g, 0.34mol, 2.0eq) was added dropwise at room temperature, and then Add DMF (0.25mL), and reflux reaction for 1h after dropping. Concentrate to remove the solvent, add dichloromethane (100 mL) to redissolve, and concentrate again (repeated twice). The obtained crude product is directly used in the next reaction without purification. Step 2: Synthesis of 2,2-dimethyl-5-(2-(p-tolyl)acetyl)-1,3-dioxane-4,6-dione

[0380]

[0381] Add 2,2-dimethyl-1,3-dioxane-4,6-dione (36g, 0.25mol, 1.05eq), pyridine (31g, 0.39mol, 2.3eq) into dichloromethane (350mL ), add the acid chloride prepared in the step dropwise a...

Embodiment 2

[0396] Example 2 N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro-2H-pyridine Synthesis of pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide (compound 1)

[0397]

[0398] step:

[0399]

[0400] Step 1: Synthesis of 4-((6-bromopyridin-3-yl)oxy)-6,7-dimethoxyquinoline

[0401]

[0402] 6-bromopyridin-3-ol (1.74g, 10.0mmol, 1.0eq), 4-chloro-6,7-dimethoxybenzopyridine (2.24g, 10.0mmol, 1.0eq) and 4-dimethyl Aminopyridine (3.67g, 30.0mmol, 3.0eq) was dissolved in toluene (50mL), heated to 100°C for 16 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1~20:1) to obtain a white solid 4-((6-bromopyridin-3-yl)oxy base)-6,7-dimethoxyquinoline (1.70g, yield: 47%)

[0403] Step 2: Synthesis of 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-amine

[0404]

[0405] 4-((6-bromopyridin-3-yl)oxy)-6,7-dimethox...

Embodiment 3

[0411] Example 3: Synthesis of intermediate 4-oxo-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid ethyl ester hydrochloride

[0412]

[0413] Step 1: Synthesis of 2-(p-tolyl)acetyl chloride

[0414]

[0415] Dissolve 2-(p-tolyl)acetic acid (9.0g, 60mmol, 1.0eq) in DCM (90mL), add oxalyl chloride (15.2g, 120mmol, 2.0eq) dropwise at room temperature, after the addition is complete, add DMF dropwise (0.1 mL), heated to reflux for 2 hours. After cooling to room temperature, the reaction solution was concentrated to obtain the product (10 g crude product), which was directly used in the next reaction.

[0416] Step 2: Synthesis of ethyl 2-diazo-3-oxo-4-(p-tolyl)butyrate

[0417]

[0418] The intermediate 2-(p-tolyl)acetyl chloride (10g crude product, 60mmol, 1.0eq) was added into a three-necked flask, cooled to 0°C, and ethyl diazoacetate (13.7g, 120mmol, 2.0eq) was slowly added dropwise. After the dropwise addition was completed, return to room temperature and stir t...

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Abstract

The present invention provides a novel inhibitor compound represented by general formula (I), which has good kinase inhibitory activity. The compounds of the present invention can be used to prevent and / or treat diseases mediated by abnormal expression of TAM family kinase receptors and / or their ligands. In addition, the compound of the present invention can also target CSF1R kinase, and can be used to prevent and / or treat diseases mediated by abnormal expression of TAM family kinase receptors / and CSF1R kinase receptors and / or their ligands.

Description

technical field [0001] The present invention belongs to the field of medicine, in particular to TAM family kinases / and CSF1R kinase inhibitor compounds represented by general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers and their containing Pharmaceutical compositions, pharmaceutical preparations and their uses. The compound of the present invention can selectively inhibit tyrosine kinase TAM family / and CSF1R kinase, and can be used for the treatment of diseases mediated by abnormal expression of TAM family kinase / CSF1R kinase receptor and / or its ligand. Background technique [0002] The TAM family includes three members, Axl, Mer, and Tyro-3, and this family includes an extracellular domain, a transmembrane domain and a conserved intracellular kinase domain. The ectodomain consists of two immunoglobulin-like domains linked by two type III fibronectin repeat units. The conserved amino acid sequence KW(I / L)A(I / L)ES of the intracellular ki...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D409/14C07D491/056A61K31/4709A61K31/501A61K31/506A61K31/513A61K31/444A61P35/00A61P15/00A61P17/06A61P27/02A61P13/12A61P19/02A61P29/00A61P19/10
CPCC07D405/14C07D409/14C07D491/056A61P35/00A61P15/00A61P17/06A61P27/02A61P13/12A61P19/02A61P29/00A61P19/10A61K31/4709A61K31/501A61K31/506A61K45/06
Inventor 吴永谦李琳万中晖
Owner TRANSTHERA SCIENCES (NANJING) INC