Compound serving as protein kinase inhibitor and application of compound

A compound and mixture technology, applied in the field of medicine, can solve problems such as unmet clinical needs and drug resistance

Active Publication Date: 2021-04-06
CHENGDU HYPERWAY PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some cancer patients will develop drug resistance to the first-generation BTK inhibitors, resulting in new unmet clinical needs

Method used

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  • Compound serving as protein kinase inhibitor and application of compound
  • Compound serving as protein kinase inhibitor and application of compound
  • Compound serving as protein kinase inhibitor and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179]

[0180] Step 1: Synthesis of compounds 1-3

[0181] Compound 1-1 (11.232g, 72.2mmol), potassium carbonate (14.967g, 108.3mmol), 1-2 (8.154g, 86.6mmol), DMF (60mL) were added to the reaction flask, stirred at room temperature overnight, and TLC showed The response is complete. The reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 16.5 g of product 1-3, yield: 99%. The product was used directly in the next step without purification.

[0182] Step 2: Synthesis of compounds 1-4

[0183] Compound 1-3 (16.5g, 72mmol), KOH aqueous solution (220mL, 5M), and ethanol (45mL) were added to the reaction flask, and the temperature was raised to 100°C for overnight reaction. TLC showed that the raw materials were completely reacted. Cool the reaction system to 0°C, add concentrated hydro...

Embodiment 2

[0201]

[0202] Step 1: Synthesis of compound 2-2

[0203] Compound 2-1 (200mg, 1.31mmol) and THF (6mL) were added to the reaction flask, Lithium aluminum hydride (100mg, 2.63mmol) was added in batches to the reaction solution, and the reaction solution was stirred at room temperature overnight, and TLC showed that the reaction was complete . The reaction solution was cooled in an ice-water bath, and 200 mg of water was slowly added dropwise to quench the reaction. The resulting suspension was suction-filtered, the filter cake was washed with THF, and the filtrate was concentrated under reduced pressure to obtain 120 mg of product 2-2, yield: 74%. The product was used directly in the next step without purification.

[0204] Step 2: Synthesis of Compound 2

[0205] Compound 1-7 (50mg, 0.13mmol), 2-2 (32mg, 0.26mmol), TsOH (25mg, 0.13mmol) and n-butanol (2ml) were added to the reaction flask, and the reaction solution was reacted at 120°C for 2 hours. TLC showed the react...

Embodiment 3

[0209]

[0210] Compound 1 (60mg, 0.126mmol), potassium carbonate (53mg, 0.381mmol), absolute ethanol (1mL) and bromoethanol (16mg, 0.126mmol) were added to the reaction flask, the reaction mixture was heated to reflux and stirred for 1 hour, TLC Shows complete reaction. The reaction system was cooled to room temperature and directly concentrated to dryness under reduced pressure. Purified by preparative silica gel plate (DCM / MeOH=10 / 1) to obtain 10 mg of product 3, yield: 16%.

[0211] LC / MS: m / z=518.2[M+H]+.

[0212] 1H NMR(400MHz,d6-DMSO)δ1.33-1.38(2H,m),1.46-1.53(2H,m),1.61-1.70(2H,m),1.92-1.99(2H,m),3.54-3.67 (3H,m),3.78-3.82(2H,m),3.88-3.93(1H,m),4.15-4.16(1H,m),4.53(1H,t,J=5.7Hz),7.03(1H,dd ,J=8.5,2.5Hz),7.19-7.26(4H,m),7.47-7.51(2H,m),7.59-7.64(2H,m),8.25(1H,s),8.80-8.83(1H,m ),12.67(1H,brs).

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PUM

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Abstract

The invention discloses a compound used as a protein kinase inhibitor and application of the compound, the compound has an obvious inhibition effect on protein kinase activity, can be used as a BTK inhibitor for preparing medicines for treating BTK-mediated diseases such as malignant tumors, autoimmune diseases and the like, and has wide application prospect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a compound as a protein kinase inhibitor and its application. Background technique [0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor protein tyrosine kinases, mainly expressed in a variety of hematopoietic cell lines. The Tec family is the second largest family after the Src family among human non-receptor kinases, and its main members include BTK, BMX (etk), ITK, TEC and TXK (RLK). BTK was identified as a defective protein in human X-linked agammaglobulinemia (X-linked agammaglobulinemia, XLA) in 1993. BTK is a key regulator of the B cell receptor (BCR) signal transduction pathway, which plays an important role in the activation, proliferation, differentiation and survival of B cells, and is closely related to a variety of B cell tumors and autoimmune diseases. [0003] The BTK structure contains five main structural domains, namely the PH ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D519/00C07F9/6561A61P29/00A61P19/02A61P37/06A61P17/00A61P11/06A61P1/00A61P1/04A61P35/00A61P35/02A61P17/06A61K31/519A61K31/675A61K31/437
CPCC07D487/04C07D471/04C07D519/00C07F9/6561A61P29/00A61P19/02A61P37/06A61P17/00A61P11/06A61P1/00A61P1/04A61P35/00A61P35/02A61P17/06C07B2200/07
Inventor 刘冠锋岳春超李筛李英富原晨光
Owner CHENGDU HYPERWAY PHARM CO LTD
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