Tricyclic compound and pharmaceutical compositions thereof and application thereof

A technology for compounds and medicinal salts, applied to the application field in the preparation of medicines, can solve problems such as dose limitation, toxicity, ineffective kinase activity and the like

Inactive Publication Date: 2015-03-25
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] Second-generation nonreversible covalently bonded EGFR inhibitors such as afatinib inhibited the T790M mutant but exhibited dose-limiting toxicity due to the simultaneous inhibition of wild-type EGFR (D'Arcangelo et al .Biologics: Target and Therapy, 2014, 8, 183-192)

Method used

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  • Tricyclic compound and pharmaceutical compositions thereof and application thereof
  • Tricyclic compound and pharmaceutical compositions thereof and application thereof
  • Tricyclic compound and pharmaceutical compositions thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] (R)-N-(1-(1-acryloylazepan-3-yl)-6-isopropyl-1,6-dihydroimidazo[4,5-e]indazol-2- base)-2-methylisonicotinamide

[0107]

[0108] Step 1. 4-Chloro-1-isopropyl-5-nitro-1H-indazole

[0109]

[0110] In a 250mL round bottom flask, add 10g (63.3mmol) of 2-chloro-6-fluorobenzaldehyde and 100mL of concentrated sulfuric acid, and place in an ice-salt bath to cool. With stirring, 8.1 mL of 70% concentrated nitric acid was slowly added dropwise, and the reaction temperature was maintained for 1 hour. The reaction mixture was poured into 300 mL ice water, filtered, and the filter residue was washed with ice water, then dissolved in EtOAc. The ester phase was saturated with Na 2 CO 3 solution, washed with water, anhydrous Na 2 SO 4 After drying, filtering and concentrating to remove the solvent, 10 g of 2-chloro-6-fluoro-3-nitrobenzaldehyde was obtained, with a yield of 77%, as a yellow solid.

[0111] In a 100mL round bottom flask, add 10g (49.3mmol) of 2-chloro-6-fluor...

Embodiment 2

[0133] (R)-N-(1-(1-acryloylazepan-3-yl)-6-isopropyl-1,6-dihydroimidazo[4,5-e]indazol-2- base) isonicotinamide

[0134]

[0135] This example is synthesized according to the synthesis method of Example 1.

[0136] 1 H NMR (400MHz, CDCl 3 ): δ12.90(s,1H),8.77(m,2H),8.41(s,1H),8.08(m,2H),7.43-7.34(m,2H),6.67(dd,J=10.4,16.7 Hz, 1H), 6.49&6.46(d&d, J=16.1Hz, 1H), 5.78&5.66(d&d, J=10.3Hz, 1H), 5.1-4.7(m, 1.5H), 4.7-4.2(m ,1.5H),4.2-3.9(m,1H),3.8-3.3(m,2H),3.0-2.2(m,1H),2.2-1.8(m,4H),1.65(d,J=7.0Hz, 6H),1.6-1.5(m,1H).

[0137] LCMS(ESI):m / z=472(M+H) + .

Embodiment 3

[0139](R)-N-(1-(1-acryloylazepan-3-yl)-6-(2-hydroxy-2-methylpropyl)-1,6-dihydroimidazol[4, 5-e]indazol-2-yl)-2-methylisonicotinamide

[0140]

[0141] Step 1, 1-hydrazino-2-methylpropan-2-ol

[0142]

[0143] Hydrazine hydrate 40g (800mmol, 40mL) was dissolved in 50mL of methanol and placed in a 250mL round-bottomed flask, under stirring at room temperature, slowly dripped into a methanol solution of 2,2-dimethyloxirane (8.1g, 115mmol) ( 10 mL), stirred at room temperature for 1 hour, and LC-MS showed that the reaction was complete. Hydrazine hydrate and methanol were removed by concentration under reduced pressure, and the obtained product (11.1 g) was directly used in the next reaction. LCMS(ESI):m / z=105(M+H) + .

[0144] Step 2, 1-(4-chloro-5-nitro-1H-indazol-1-yl)-2-methylpropan-2-ol

[0145]

[0146] Synthesized from 2-chloro-6-fluoro-3-nitrobenzaldehyde and 1-hydrazino-2-methylpropan-2-ol according to step 1 of Example 1. LCMS(ESI):m / z=270(M+H) + .

[01...

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PUM

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Abstract

The invention relates to a tricyclic compound of the formula (I) and the formula (II) and pharmaceutical acceptable salts of the tricyclic compound. The compounds of the kind can be applied to inhibit mutants, such as EGFR (L858R), EGFR (delE746-A750) and EGFR (T790M), of EGFR kinase, and can also be used for treating cancer, such as the non-small cell lung cancer, caused by the mutants of the EGFR. The invention further relates to pharmaceutical compositions containing the compounds of the kind, methods for preparing the compounds of the kind and application of the compounds of the kind or the pharmaceutical compositions for preparing medicines for treating the cancers caused by the mutants of the EGFR.

Description

technical field [0001] The present invention relates to a class of tricyclic compounds and their pharmaceutically acceptable salts or prodrug molecules, pharmaceutical compositions containing such compounds and applications of these compounds or compositions in preparing 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 activating mutations in the tyrosine kinase domain of EGFR. The most common activating mutants are L858R and delE746-A750. The first generation of small molecule inhibitors of EGFR, gefitinib and erlotinib, have been approved for the treatment of patients with advance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/55A61P35/00A61P35/02
CPCC07D487/04
Inventor 黄立晔刘运李涛黄俊朱星星
Owner SHENZHEN BO LI JIAN MEDICINE CO LTD
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