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Preparation method and application of compound or its pharmaceutically acceptable salt or composition

A technology for compounds and medicinal salts, applied to the application field in the preparation of medicines, can solve the problems of no good treatment method, poor mutant effect, ineffective kinase activity and the like

Active Publication Date: 2019-08-06
SHENZHEN BO LI JIAN MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The T790M mutant abolishes the kinase activity of gefitinib and erlotinib
[0004] The second-generation non-reversible covalent bond EGFR inhibitor afatinib (afatinib) is more effective than gefitinib and erlotinib in the treatment of patients with EGFR (delE746-A750) and EGFR (L858R) positive non-small cell lung cancer. More potent, but less effective against drug-resistant T790M mutants due to more activity against wild-type EGFR than EGFR (delE746-A750 / T790M) and EGFR (L858R / T790M) drug-resistant mutants Higher, thus exhibiting dose-limiting toxicity (D'Arcangelo et al. Biologics: Target and Therapy, 2014, 8, 183-192)
The third-generation non-reversible covalent bond EGFR inhibitor osimertinib can effectively treat patients with EGFR (delE746-A750) and EGFR (L858R) positive non-small cell lung cancer, and can also effectively treat patients with EGFR (delE746-A750 / T790M) and EGFR (L858R / T790M) resistant mutants, but less effective against mutants that inhibit EGFR exon 20 insertions
[0005] EGFR exon 20 insertion mutant is an unusual EGFR mutation, which exists in a small number of non-small cell lung cancer patients, and currently there is no good treatment

Method used

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  • Preparation method and application of compound or its pharmaceutically acceptable salt or composition
  • Preparation method and application of compound or its pharmaceutically acceptable salt or composition
  • Preparation method and application of compound or its pharmaceutically acceptable salt or composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] (S)-N-(4amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazine[1,6-a]indole -8-yl)acrylamide

[0066] Step 1. tert-butyl 1H-pyrrol-1-ylcarbamate

[0067]

[0068]In a 2L three-neck flask, add tert-butyl carbazate (100 g, 0.76 mol), 2,5-dimethoxytetrahydrofuran (108 g, 0.83 mol) and dioxane (700 mL). Under stirring, dilute hydrochloric acid (2M, 10 mL) was slowly added to the above solution, and then heated to 100° C. for 48 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in EtOAc (500 mL). The ester phase is sequentially saturated with Na 2 CO 3 solution, washed with saturated NaCl aqueous solution, anhydrous Na 2 SO 4 Dry, filter and concentrate to give a yellow solid. The obtained solid was dispersed in EtOH (100 mL), filtered, and the filter residue was washed with a small amount of EtOH, and dried to obtain 80 g of the target product. Yield 58%. LCMS(ESI):m / z=183(M+H) + .

[0...

Embodiment 2

[0113] (R)-N-(4amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazine[1,6-a]indole -8-yl)acrylamide

[0114] Step 1. Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate

[0115]

[0116] Using N-Boc-L-serine methyl ester as a raw material, it is synthesized according to the method in Step 6 of Example 1. LCMS(ESI):m / z=352(M+Na) + .

[0117] Step 2. Methyl (S)-3-(4-aminopyrrole[1,2-f][1,2,4]triazin-7-yl)-2-(tert-butoxycarbonylamino)propionate

[0118]

[0119] According to the method of Step 7 of Example 1, it is synthesized from methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate. LCMS(ESI):m / z=336(M+H) + .

[0120] Step 3. Methyl(S)-3-(4-amino-5-iodopyrrole[1,2-f][1,2,4]triazin-7-yl)-2-(tert-butoxycarbonylamino ) propionate

[0121]

[0122] According to the method of step 8 of Example 1, from methyl (S)-3-(4-aminopyrrole[1,2-f][1,2,4]triazin-7-yl)-2-(tert-butoxy Carbonyl amino) propionate synthesized. LCMS(ESI):m / z=462(M+H) + .

[0123]...

Embodiment 3

[0145] (R)-N-(4-Amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopenta[4,5]pyrrole[2, 1-f][1,2,4]triazin-7-yl)acrylamide

[0146] Step 1. tert-butyl(R)-(4-amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopenta[4,5] Pyrrolo[2,1-f][1,2,4]triazin-7-yl)carbamate

[0147]

[0148] In a 50mL round bottom flask, under nitrogen protection, add tert-butyl (R)-(1-(4-amino-6-iodo-5-(quinolin-3-yl)pyrrole[1,2-f] [1,2,4]Triazin-7-yl)-but-3-en-2-yl)carbamate (1.0g, 1.8mmol), AcOK (353mg, 3.6mmol), pd(dppf)Cl 2 (131mg, 0.18mmol) and DMF (10mL), heated to 80°C for 1h. After the reaction was completed, water was added and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, anhydrous Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by silica gel column chromatography (CH 2 Cl 2 : MeOH (v / v)=40:1) to obtain 500 mg, yield 65%. LCMS(ESI):m / z=429(M+H) + .

[0149] Step 2. (R)-6-Methylene-5-(quinolin-3-yl)-7,8-dihydro...

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Abstract

The present invention relates to a tricyclic compound of formula (I) and a pharmaceutically acceptable salt thereof. The compound can be used for inhibiting mutants of epidermal growth factor receptor(EGFR) kinases, such as EGFR (delE746-A750), EGFR (L858R), EGFR (delE746-A750 / T790M), EGFR (L858R / T790M), EGFR exon 20insertion and other mutants, so the compound can be used to treat cancer caused by EGFR mutants, such as non-small cell lung cancer. The invention also relates to a medicinal composition containing the compound, a method for preparing the compound, and an application of the compound or the medicinal composition in the preparation of medicines for treating the cancers caused by EGFR mutants.

Description

technical field [0001] The present invention relates to a class of tricyclic compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds and applications of such compounds or compositions in the preparation of medicines. Background technique [0002] Epidermal growth factor receptor (EGFR, Erb-B1) is a receptor tyrosine protein kinase that regulates the proliferation, survival, and differentiation of normal and cancer cells. EGFR is overactivated or persistently activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer, etc. In non-small cell lung cancer (NSCLC) patients, EGFR is not only overexpressed, but also has kinase activity mutations in the tyrosine kinase domain of EGFR. The most common kinase active mutants are EGFR (delE746-A750) and EGFR (L858R). The first generation of EGFR small molecule inhibitors, gefitinib and erlotinib, have been approved for the treatment of patients with E...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/53A61P35/00
CPCC07D487/04A61K31/53A61P35/00C07D471/04
Inventor 黄立晔毛文金王志远刘运黄俊欧阳飞燕
Owner SHENZHEN BO LI JIAN MEDICINE CO LTD
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