Tyrosine kinase inhibitor and preparation method and use thereof

A technology of tyrosine kinase and inhibitor, applied in the field of tyrosine kinase inhibitor and its preparation

Active Publication Date: 2017-05-31
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, there is still no better small-molecule inhibitor for the above-mentioned tyrosine kinases, and research and development workers are still required to make unremitting efforts

Method used

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  • Tyrosine kinase inhibitor and preparation method and use thereof
  • Tyrosine kinase inhibitor and preparation method and use thereof
  • Tyrosine kinase inhibitor and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Compound 8a, methyl 4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)-2-thiazolyl)amino)-2-methyl-4-pyrimidinyl) - Preparation of 1-piperazine carboxylate.

[0105] (1) Compound I-7 was synthesized according to the above route.

[0106] Wherein compound I-3, I-4, I-5, I-6 are known compounds, and synthetic method is operated according to existing literature (F.Fernández et al., Synthesis 2001, No.2,239-242; Bang-Chi Chen . et al ARKIVOC 2010(vi), 32-38).

[0107] The characterization data of compound 1-3 are: 1 H NMR (400MHz, CDCl 3 )δppm7.60(d, J=12.10Hz, 1H), 5.32(d, J=12.10Hz, 1H), 3.88(q, J=7.10Hz, 2H), 1.20(t, J=7.10Hz, 3H) .

[0108] The characterization data of compound I-4 are: 1 H NMR (400Hz, DMSO-d 6 )δppm9.28(s,1H),7.45(d,J=12.4Hz,1H),7.27-7.37(d,J=7.5Hz,1H),7.10-7.27(m,J=7.5Hz,2H), 5.58(d, J=12.4Hz, 1H), 3.94(q, J=7Hz, 2H), 2.15(s, 3H), 1.26(t, J=7Hz, 3H).

[0109] The characterization data of compound I-5 are: 1 H NMR (400Hz, DMSO-d 6)δppm 9.63 (s, 1...

Embodiment 2

[0119] Compound 8b, ethyl 4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)-2-thiazolyl)amino)-2-methyl-4-pyrimidinyl) - Preparation of 1-piperazine carboxylate.

[0120] The preparation method is the same as in Example 1, using compound I-7 to react with ethyl chloroformate. A yellow solid 8b was obtained in 76% yield.

[0121] The characterization data of the compound 8b are: 1 H NMR (400MHz, DMSO-d 6 )δ10.03(s, 1H), 8.31(s, 1H), 7.39(d, J=6.8Hz, 1H), 7.26(d, J=9.3Hz, 2H), 6.21(s, 1H), 4.07( dd,J=13.6,6.6Hz,2H),3.49(s,8H),2.48(s,3H),2.24(s,3H),1.20(t,J=6.9Hz,3H); 13 C NMR (125MHz, DMSO-d 6 )δ163.64,162.51,161.29,160.25,159.57,156.99,156.49,154.70,138.80,133.40,132.44,129.07,128.27,127.04,83.69,61.02,44.02,42.15,24.14,18.32,14.59.ESI-MS m / z: 516.2(M+H) + ,514.1(M-H) - .

[0122] The structural formula of the compound 8b is:

[0123]

Embodiment 3

[0125] Compound 8c, isopropyl 4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)-2-thiazolyl)amino)-2-methyl-4-pyrimidinyl )-1-piperazine carboxylate preparation.

[0126] The preparation method is the same as in Example 1, using compound I-7 and isopropyl chloroformate. 8c was obtained as a yellow solid in 93% yield.

[0127] The characterization data of the compound 8c are: 1 H NMR (400MHz, DMSO-d 6 )δ9.99(s,1H),8.28(s,1H),7.40(d,J=6.6Hz,1H),7.27(d,J=9.6Hz,2H),6.18(s,1H),4.94- 4.66(m,1H),3.59(s,4H),3.48(s,4H),2.47(s,3H),2.24(s,3H),1.21(d,J=5.7Hz,6H); 13 C NMR (125MHz, DMSO-d 6 )δ163.61,160.32,159.32,158.19,156.49,154.26,138.74,137.83,134.37,133.37,132.38,128.99,128.18,126.97,83.45,68.23,43.95,42.52,24.15,21.95,18.27.ESI-MSm / z:530.2 (M+H) + ,528.2(M-H) - .

[0128] The structural formula of the compound 8c is:

[0129]

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Abstract

The invention relates to a tyrosine kinase inhibitor and a preparation method and use thereof, and belongs to the technical field of pharmaceutical chemistry. The tyrosine kinase inhibitor having the structural features shown in the general formula I, or its pharmaceutically acceptable salts or stereoisomers can effectively inhibit tyrosine kinase activity, and can inhibit kinases such as DDR1, DDR2, Abl, Src, Btk and Kit. Compared with a positive contrast dasatinib, the tyrosine kinase inhibitor has higher half inhibitory concentration or the same half inhibitory concentration, and especially, aiming at DDR1, DDR2, Src, Btk and Kit, the compound 8j has lower K562 cell half inhibitory concentration. The tyrosine kinase inhibitor has good enzyme inhibitory activity and cell activity and has a large application prospect.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a tyrosine kinase inhibitor and its preparation method and application. Background technique [0002] Protein kinases make up one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins. In particular, tyrosine kinases phosphorylate the phenolic moieties of proteins at tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration and differentiation. Aberrant kinase activity has been demonstrated in many human diseases, including cancer, autoimmune disorders, and inflammatory diseases, among others. Since protein kinases are among the key regulators of cellular signaling, they are targets for small molecule kinase inhibitors to modulate cellular function, and thus good targets for drug design. [0003] Chronic myelogenous leukemia (CML) is a malignant tumor ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14C07K5/062A61P35/00
CPCA61K38/00C07D417/12C07D417/14C07K5/06026C12N9/12
Inventor 张健存刘露陈超南段安娜涂正超姚国强
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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