FAK inhibitor and combined medicine thereof

A technology of solvates and compounds, applied in the field of medicinal chemistry

Active Publication Date: 2020-07-07
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The combined use of drugs is an effective way to improve the efficacy of drugs, and there is no report on the combined use of deuterated FAK inhibitors with other anti-cancer drugs or anti-cancer methods

Method used

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  • FAK inhibitor and combined medicine thereof
  • FAK inhibitor and combined medicine thereof
  • FAK inhibitor and combined medicine thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Embodiment 1, synthesis of N-trideuteromethyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (compound 25)

[0092]

[0093] The first step: synthesis of compound 25-2

[0094] 25-1 (200mg, 0.39mmol), DMAP (1.29g, 10.57mmol) was added to 10mL of dichloromethane, and then (Boc) 2 O (1.71 g, 7.83 mmol). The system was refluxed in an oil bath for 24h. The next day, cool to room temperature, add dichloromethane and 0.1N HCl solution, extract, leave to stand and separate layers, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation after suction filtration. The crude product, 25-2, was obtained as an off-white solid, 136 mg, yield: 42.8%. MS (M+1): 811.2.

[0095] The second step: synthesis of compound 25-3

[0096] Add 25-2 (136 mg, 0.17 mmol), deuterated methylamine hydrochloride (189 mg, 2.68 mmol) into 5 ...

Embodiment 2

[0101] Embodiment 2, synthesis of N-methyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (Compound 41)

[0102]

[0103] The first step: Synthesis of N-trideuteromethylmethanesulfonamide (compound 41-1)

[0104] Deuteromethylamine hydrochloride (7.75g, 109.99mmol) was placed in a 250mL single-neck round bottom flask, and dichloromethane (120mL) was added at the same time, and stirred at room temperature. Then the system was transferred to an ice-water bath for cooling and stirring. After 15 minutes, triethylamine (21.73 g, 214.75 mmol) and DMAP (128 mg, 1.05 mmol) were added in sequence. After completion, the system was kept in the ice-water bath for 10 minutes. Afterwards, methanesulfonyl chloride (12.0 g, 104.76 mmol) was added to the system. After completion, the ice bath was removed, and the system was stirred and reacted at room temperature overnight. The next day, when the TLC ...

Embodiment 3

[0118] Example 3, synthesis of N-trideuteromethyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (compound 44) ​​and its hydrochloride

[0119]

[0120] The first step: Synthesis of (4-(trideuteromethylcarbamoyl)phenyl) tert-butyl carbamate (compound 44-1)

[0121] N-Boc-4-aminobenzoic acid (6.0g, 25.29mmol) and EDCI (7.27g, 37.93mmol) were weighed and placed in a 250mL single-neck round bottom flask, and DMF (50mL) was added at the same time, and stirred at room temperature. Subsequently, triethylamine (6.40 g, 63.22 mmol) and deuterated methylamine hydrochloride (1.96 g, 27.82 mmol) were added to the system, and the system was stirred and reacted at room temperature overnight. On the next day, the plate was sampled, and TLC showed that the reaction had ended. Add ethyl acetate (50mL) and water (50mL) to the system and stir vigorously, then let stand to separate the layers, back-extr...

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PUM

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Abstract

The invention provides a deuterated compound shown as a formula (I) or an optical isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate thereof. Compared with a compound before deuteration, the deuterated compound disclosed by the invention shows better pharmacokinetics, higher highest blood concentration, higher exposure and longer half-life period, and has more excellent metabolic performance. Moreover, the deuterated compound provided by the invention can effectively inhibit the activity of FAK, and has a very good application prospect in preparation of an FAK inhibitor and / or a drug for treating cancers. Meanwhile, the deuterated compound and an anti-cancer drug (such as a PD-1 inhibitor) are combined for use, so that the synergistic effect can be achieved, the tumor inhibition effect is remarkably improved, and a better choice is provided for clinical treatment of cancers.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a FAK inhibitor and a combined drug thereof. Background technique [0002] Focal adhesion kinase (FAK), an intracellular non-receptor tyrosine kinase, was first discovered in transfected V-Src chicken embryo fibroblasts. FAK is highly expressed in most tissues, and its protein sequence has high homology in many species (mouse, toad, human, etc.). FAK is the intersection of multiple signal transduction pathways in the cell, and participates in multiple biological processes such as tumor formation, proliferation, metastasis, apoptosis, and cardiovascular diseases. It is one of the anti-tumor targets that has received widespread attention at present. [0003] In recent years, studies have found that FAK can be activated by a variety of factors, including integrins, G protein-coupled receptors, etc. At the same time, FAK regulates intracellular P53, PI3K-AKT-mTOR and o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D401/12C07D213/74C07D401/14C07D403/12C07D251/18C07D487/04C07D253/075C07D487/14A61K31/506A61K31/4439A61K31/5377A61K31/496A61K31/519A61K31/53A61P35/00A61P35/02
CPCC07D239/48C07D401/12C07D213/74C07D401/14C07D403/12C07D251/18C07D487/04C07D253/075C07D487/14A61P35/00A61P35/02A61K31/4439A61K31/506A61K31/496A61K31/5377C07D253/07C07D487/18A61K45/06A61K2300/00A61K31/53C07D513/18A61K39/3955C07B2200/05
Inventor 杜武李宇温坤李兴海陈元伟
Owner HINOVA PHARM INC
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