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A kind of fused pyrimidine compound and the composition comprising the compound and its application

A technology for synthesizing pyrimidines and compounds is applied in the field of fused pyrimidine compounds and compositions containing the compounds, and can solve the problems of primary drug resistance or secondary drug resistance and the like

Active Publication Date: 2021-01-05
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although EGFR inhibitors such as gefitinib and erlotinib have achieved remarkable curative effects on EGFR-mutant advanced non-small cell lung cancer (NSCLC), it was later found that existing EGFR-TKIs would cause primary tumors in the treatment of NSCLC. Therefore, the treatment of advanced NSCLC is facing new challenges, and we need to carry out new explorations and find new countermeasures

Method used

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  • A kind of fused pyrimidine compound and the composition comprising the compound and its application
  • A kind of fused pyrimidine compound and the composition comprising the compound and its application
  • A kind of fused pyrimidine compound and the composition comprising the compound and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] The following synthetic route is used to prepare intermediate A-1: ​​N-(3-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, comprising the following steps:

[0139]

[0140] step one:

[0141] Under nitrogen protection, 2,4-dichlorothieno[3,2-d]pyrimidine (410mg, 2mmol), DMF (10mL), Cs 2 CO 3 (0.98g, 3mmol) and tert-butyl (3-hydroxyphenyl)carbamate (419mg, 2mmol) were successively added into a 50mL single-necked flask, stirred at room temperature for 2 hours, added 50mL of water, extracted with ethyl acetate, The organic phase was collected and purified by column chromatography to obtain a white solid product tert-butyl 3-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamate (700mg, yield 92.6%) . 1 H NMR (300MHz, CDCl 3 )(δ / ppm) 8.01(d, J=5.4Hz.1H), 7.55(br s, 1H), 7.50(d, J=5.4Hz, 1H), 7.35(t, J=8.1Hz, 1H), 7.15-7.11(m, 1H), 6.97-6.94(m, 1H), 6.73(br, 1H), 1.51(s, 9H); LC-MS(APCI): m / z=377(M+1) + .

[0142] Step two:

[0143] Under nitrogen prote...

Embodiment 2

[0145] The following synthetic route is used to prepare intermediate B-1: N-(3-(2-chlorothieno[3,2-d]pyrimidin-4-ylamino)phenyl)acrylamide, comprising the following steps:

[0146]

[0147] step one:

[0148] Under nitrogen protection, 2,4-dichlorothieno[3,2-d]pyrimidine (410mg, 2mmol), n-butanol (n-BuOH, 10mL), N,N-diisopropylethylamine, (DIPEA, 390mg, 3mmol) and tert-butyl 3-aminophenylcarbamate (417mg, 2mmol) were added to a 50mL single-necked flask, stirred at room temperature for 16 hours, cooled to room temperature, and filtered to obtain a white solid Product (430 mg, yield 57%). 1 H NMR (300MHz, acetone-d6) (δ, ppm) 9.31 (br, 1H), 8.59 (br, 1H), 8.18-8.15 (m, 1H), 7.93-7.91 (m, 1H), 7.63-7.58 ( m, 1H), 7.38-7.32(m, 3H), 1.50(s, 9H); LC-MS(APCI): m / z=376.1(M+1) + .

[0149] Step two:

[0150] Under nitrogen, a solution of tert-butyl 3-(2-chlorothieno[3,2-d]pyrimidin-4-ylamino)phenylcarbamate (520 mg, 1.38 mmol) in dichloromethane (10 mL) was cooled To 0°C, trif...

Embodiment 3

[0153] The following synthetic route was used to prepare N-(3-(2-(2-d3-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidine -4-base oxy group) phenyl) acrylamide (formula (4)), comprises the following steps:

[0154]

[0155] step one:

[0156] Under nitrogen protection, 5-fluoro-2-nitrophenol (1.89g, 12mmol), acetonitrile (20mL), Cs 2 CO 3 (7.8g, 24mmol) and d3-methyl p-toluenesulfonate (CD 3 OTs, 3.42g, 18mmol) was added to a single-necked flask, refluxed for 3 hours, cooled to room temperature, added 50mL of water, extracted with dichloromethane, collected the organic phase, spin-dried and passed through the column to obtain the white solid product 4-fluoro-2-d3 - Methoxynitrobenzene (1.41 g, yield 67.3%). LC-MS(APCI): m / z=175.1(M+1) + .

[0157] Step two:

[0158] Under nitrogen protection, 4-fluoro-2-d3-methoxynitrobenzene (1.4g, 8mmol), DMF (15mL), K 2 CO 3 (2.2g, 16mmol) and N-methylpiperazine (1.2g, 12mmol) were added to a single-necked fla...

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Abstract

The present invention discloses a fused pyrimidine compound as shown in formula (I), and preparation and use of same. In particular, the present invention discloses a fused pyrimidine compound as shown in formula (I), or a crystal form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotopic variant, a hydrate or solvate thereof, and a pharmaceutical composition comprising same and use of same. The fused pyrimidine compound and the composition comprising the compound disclosed in the present invention exhibit an excellent inhibitory effect against protein kinases, and have improved pharmacokinetic parameter characteristics, which allow increased drug concentration of the compounds in an animal body and enhance drug efficacy and safety.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a condensed pyrimidine compound, a composition containing the compound and an application thereof. Background technique [0002] Protein tyrosine kinases play important roles in cellular regulation and their aberrant expression or mutations have been observed in cancer cells or autoimmune diseases. Protein tyrosine kinases are enzymes that catalyze the transport of phosphate groups from ATP to tyrosine located on protein substrates. Many growth factor receptor proteins function as tyrosine kinases to transmit cellular signals. Interactions between growth factors and their receptors normally control cell growth, but aberrant signaling caused by mutation or overexpression of any of the receptors often induces a variety of cancers or autoimmune diseases (such as rheumatoid arthritis inflammation). [0003] EGFR tyrosine kinase inhibitor (EGFR-TKI) is a molecularly ta...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61P35/00
CPCA61K31/519C07D495/04
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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