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Compound used as RET kinase inhibitor and application thereof

A compound and solvate technology, applied in the field of regulating RET kinase activity or treating RET-related diseases, can solve the problems of VEGFR inhibition toxicity and low targeting

Active Publication Date: 2021-11-26
TYK MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current treatment plan for RET gene alteration mainly uses multi-kinase inhibitors, such as cabozantinib and vandetanib. Due to the low targeting, severe toxicity related to VEGFR inhibition usually occurs due to off-target

Method used

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  • Compound used as RET kinase inhibitor and application thereof
  • Compound used as RET kinase inhibitor and application thereof
  • Compound used as RET kinase inhibitor and application thereof

Examples

Experimental program
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preparation example Construction

[0404] The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula I' or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.

[0405] The present invention also provides a method of treatment, which comprises the steps of: administering the compound of formula I' described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to a subject in need of treatment, or Administering the pharmaceutical composition of the present invention for inhibiting RET.

[0406] The present invention has the following main advantages:

[0407] (1) The compound of the present invention has excellent inhibitory ability to RET kinase, especially WT-RET, RET-V804L and RET-V804M;

[0408] (2) The compound of the prese...

Embodiment 1

[0414] The synthetic compound of the present invention:

[0415]

[0416] The experimental process is as follows:

[0417] 1. Synthesis of intermediate C1-7

[0418] The synthetic route is as follows:

[0419]

[0420] 1. Synthesis of C1-9

[0421] C1-8 (6.98g, 34.9mmol), 4-fluoro-1H-pyrazole (3.3g, 35mmol), potassium carbonate (11.1g, 73.6mmol) and DMF (30mL) were added to a 100mL single-necked bottle, at 100°C Reacted for 15 hours, cooled to room temperature, poured into water, filtered and dried to obtain 5.93g of compound C1-9. NMR analysis data of compound C1-9: 1 H NMR (400MHz, CDCl 3 ): δ8.96-8.95(d, J=1.8Hz, 1H), 8.47-8.45(dd, 1H), 8.37-8.34(dd, 1H), 8.05-8.03(dd, 1H), 7.66-7.65(d , J=3.96,1H), 2.65(s,3H).

[0422] 2. Synthesis of C1-10

[0423] Add C1-9 (4.2g, 0.02mol), R-tert-butylsulfinamide (2.48g, 0.02mol), tetraethyl titanate (9.34g, 0.041mol) and THF (50mL) into a 100mL three-necked flask , reacted at 75°C for 15h, cooled to room temperature, pour...

Embodiment 2

[0475] The synthetic compound of the present invention:

[0476]

[0477] The synthetic route and experimental process are as follows:

[0478]

[0479] 1. Synthesis of C2-2

[0480] Compound C2-1 (1.0g, 5.32mmol) was dissolved in dichloromethane (30mL), then DIPEA (2.06g, 15.96mmol) was added, cooled to 0°C in an ice-water bath, and SEM-Cl (2.22g, 13.30 mmol), keep stirring at the temperature for 1.5h, dilute with water, and extract with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.19 g of compound C2-2. 1 H NMR (400MHz, CDCl 3 )δ8.23(s,1H),5.82(s,2H),3.72-3.68(t,2H),0.99-0.95(t,2H),0.00(s,9H).

[0481] 2. Synthesis of C2-3

[0482] Compound C2-2 (1.09g, 3.43mmol) was dissolved in anhydrous THF (50mL), then potassium tert-butoxide (0.38g, 3.43mmol) and p-methoxybenzyl alcohol ( 0.45g, 3.26mmol) of anhydrous THF (20mL) solution, aft...

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Abstract

The invention belongs to the technical field of medicine, and particularly discloses a compound shown in a formula I' or pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and all symbols are defined in the claims. The compound provided by the invention can be used as a medicine for regulating RET kinase activity or treating RET related diseases, and has better pharmacokinetic properties.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to compounds used as RET kinase inhibitors and their application in regulating RET kinase activity or treating RET-related diseases. Background technique [0002] The RET (Rearranged during transfection) gene is located on chromosome 10, and the RET protein encoded by it is a receptor tyrosine kinase (RTK) present on the cell membrane, and its variant types mainly include interactions with KIF5B, Fusion mutations in genes such as TRIM33, CCDC6, and NCOA4, and point mutations in the M918T allele. Common RET mutations in people mainly occur in various cancer types such as thyroid cancer and non-small cell lung cancer. The incidence of RET gene fusion in NSCLC patients is about 1% to 2%, and the incidence in papillary thyroid carcinoma (accounting for about 85% of all thyroid cancers) is 10% to 20%. RET fusion is more common in young patients More common, especially in young non-smo...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14C07D471/04C07D498/04C07D513/04C07D491/048C07D491/056C07D487/04C07D473/34A61P35/00A61K31/444A61K31/497A61K31/4545A61K31/519A61K31/517A61K31/4985A61K31/501A61K31/5383A61K31/5025A61K31/52A61K31/522
CPCC07D401/14C07D413/14C07D471/04C07D498/04C07D513/04C07D491/048C07D491/056C07D487/04C07D473/34A61P35/00C07B59/002C07F7/1804C07B2200/05A61K31/519
Inventor 李钧郑茂林牛成山梁阿朋吴豫生
Owner TYK MEDICINES INC
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