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EGFR tyrosine kinase inhibitor and application thereof

An amino, selected technology, applied in the field of chemical medicine, can solve the problems of dose-dependent toxicity, no further confirmation of clinical effect, poor effect of drug-resistant T790M mutant, and achieves good prognosis effect, improved curative effect, and good inhibition. effect of effect

Pending Publication Date: 2021-10-12
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second-generation irreversible covalent inhibitors, such as afatinib (Afatinib), are more effective in treating EGFR (delE746-A750) and EGFR (L858R), but are not effective against drug-resistant T790M mutants. It is more active against wild-type EGFR than inhibiting EGFR (delE746-A750 / T790M) and EGFR (L858R / T790M) drug-resistant mutants, thus showing dose-dependent toxicity (Biologics, 2014, 8:183-192) , the effective treatment window cannot be obtained
Severely limit the increase of clinical dose and clinical efficacy
In addition, there are compounds CLN-081 and DZ9008 that have just entered the clinic recently. Although the in vitro activity shows that the toxicity to the wild type is reduced, their clinical effects have not been further confirmed.
In summary, compounds with higher activity and lower toxicity remain to be developed

Method used

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  • EGFR tyrosine kinase inhibitor and application thereof
  • EGFR tyrosine kinase inhibitor and application thereof
  • EGFR tyrosine kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-fluorophenyl)amino)-5-(4- Methoxyphenyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0047]

[0048] step one:

[0049]

[0050] Compound 1.1 (15.000g, 54.57mmol, 1eq.) was dissolved in DMSO (100mL), and compound 1.2 (6.67g, 60.03mmol, 1.1eq.) was added, K 2 CO 3 (15.08g, 109.14mmol, 2eq.), heated to 80°C, and reacted for 15 hours. Pour the system into water (200 mL), let stand for 30 min, filter, and dry the filter cake to obtain a brown solid (7.350 g, yield 38.53%).

[0051] Step two:

[0052]

[0053] Compound 1.3 (2.500g, 7.15mmol, 1eq.) was dissolved in dioxane (100mL), compound 1.4 (1.30g, 8.58mmol, 1.2eq.), Pd(dppf)Cl 2 (523.35mg, 715.25umol, 0.1eq.), K 3 PO 4 (1.52g, 7.15mmol, 1eq.), H 2 O (10mL), replaced by nitrogen three times, protected by nitrogen, heated to 60°C, reacted for 1.5 hours, poured the system into water (150mL), extracted with EtOAC (300mL), separated the li...

Embodiment 2

[0066] Example 2 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-(4-fluorophenyl)-4-(p-tolylamino) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0067]

[0068] Using a method similar to Example 1, replace compound 1.2 in step 1 with p-toluidine, and compound 1.4 in step 2 with (4-fluorophenyl)boronic acid to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) (ppm): 10.13 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.47- 7.50(m,2H),7.42-7.45(d,2H),7.28-7.32(t,2H),6.94-6.98(m,3H),6.40-6.44(m,1H),6.18-6.22(dd,1H ),5.73-5.76(dd,1H),3.80(s,3H),2.85-2.88(t,2H),2.71(s,3H),2.23-2.31(t,2H),2.18-2.22(m,9H ). LC-MS(m / z):569.69[M+H] + .

Embodiment 3

[0069] Example 3 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-(4-fluorophenyl)-4-((2-methyl Pyrimidin-5-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0070]

[0071] Using the method similar to Example 1, the compound 1.2 in step 1 was replaced by 2-methylpyrimidin-5-amine, and the compound 1.4 in step 2 was replaced by (4-fluorophenyl)boronic acid to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) (ppm): 10.08 (brs, 1H), 8.84 (s, 2H), 8.55 (brs, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.93 ( s,1H),7.50-7.54(m,2H),7.29-7.34(t,2H),6.97(s,1H),6.34(s,1H),6.14-6.18(d,1H),5.70-5.73( m, 1H), 3.79(s, 3H), 2.91-2.93(m, 2H), 2.71(s, 3H), 2.28-2.50(m, 9H). LC-MS(m / z):571.66[M+H] + .

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Abstract

The invention provides a compound as shown in formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, and an application of the compound in preparation of a medicine for preventing or treating related diseases caused by EGFR mutation.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to an EGFR tyrosine kinase inhibitor and its application. Background technique [0002] Lung cancer is one of the most common malignant tumors in the world. Lung cancer is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma and large cell carcinoma. Compared with SCLC, NSCLC cancer cells grow and divide more slowly, and spread and metastasize relatively later. NSCLC accounts for about 80% of all lung cancers, and the prognosis is poor, and about 75% of the patients are already in the middle and advanced stages when they are discovered. The overexpression and mutation of epidermal growth factor receptor (EGFR) has been clearly confirmed to lead to uncontrolled cell growth, which is related to the progress of most cancer diseases, especially NSCLC (Oncotarget.20...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D239/47C07D401/04A61K31/505A61K31/506A61P35/00A61P35/02
CPCC07D239/48C07D239/47C07D401/04A61P35/00A61P35/02A61K31/505A61K31/506A61K31/675C07D401/14C07D403/04C07D403/12C07D405/04C07F9/53
Inventor 胡佳琪陈弘道郑杨
Owner PHARMABLOCK SCIENCES (NANJING) INC
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