Focal adhesion kinase (FAK)-targeting compound and preparation method and application thereof

A technology of compound and precursor compound, applied in the field of compound, can solve the problem that tumor suppressor activity needs to be improved, and achieve the effect of good affinity, high selectivity and strong specificity

Active Publication Date: 2021-02-23
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, there are already some FAK small molecule inhibitors in clinical research at the general drug level, but the tumor suppressive activity of these existing FAK small molecule inhibitors needs to be improved

Method used

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  • Focal adhesion kinase (FAK)-targeting compound and preparation method and application thereof
  • Focal adhesion kinase (FAK)-targeting compound and preparation method and application thereof
  • Focal adhesion kinase (FAK)-targeting compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0074] The second aspect of the application provides the preparation method of the compound described in the first aspect of the application, which includes:

[0075] 1) make the compound of formula (II):

[0076]

[0077] With the compound of general formula (Ⅲ):

[0078] R'-NH 2 (Ⅲ),

[0079] In an organic solvent, at 90-110 ° C, the compound of general formula (IV) is synthesized by catalyzing p-toluenesulfonic acid:

[0080]

[0081] Wherein, R' is selected from

[0082] R' 1 from-NO 2 ,

[0083] 3) to Substitution compound -OH, obtain the compound of general formula (Ⅴ) or general formula (Ⅵ):

[0084]

[0085] 4) to Substitution compound -NO in 2 , obtain the compound of general formula (VII):

[0086]

[0087] Among them, R' 2 selected from -OH,

[0088] 5) -NO in the compound of general formula (Ⅳ)-(Ⅶ) 2 At least one of , -OH or -OTs is replaced by a fluorine-containing compound to obtain a compound of formula (I):

[0089] ...

preparation example 1

[0116] Preparation Example 1. Organic Synthesis of Compound 79 and Compound 80

[0117] The synthetic route is as follows:

[0118]

[0119] To 5-bromo-2,4-dichloropyrimidine (compound 60) (25.0 g, 111.1 mmol, 1 equiv) in THF (200 mL), add 2,4-dinitroaniline (compound 61) (24.4 g, 133.3mmol, 1.2equiv) in THF (200mL) and potassium carbonate (18.4g, 133.3mmol, 1.2equiv), heated to 70°C overnight. After the reaction, potassium carbonate was filtered out, and potassium carbonate was washed with ethyl acetate (50 mL*3 times). The organic phase was collected, the filtrate was concentrated by rotary evaporation, and separated on a medium-pressure preparative Flash silica gel column (petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to obtain compound 62 (21.9 g, yellow solid, yield 50.8%);

[0120] 1 H NMR (400MHz, CDCl 3 ,δppm): 11.33(s,1H), 9.32(d,J=9.2Hz,1H), 9.21(s,1H), 8.59(s,2H).

[0121] To a solution of compound 62 (20.0 g, 53.7 mmol, 1 equiv) in tetrahydrofuran (100 mL) and m...

preparation example 2

[0137] Preparation Example 2. Organic Synthesis of Compound 83 and Compound 84

[0138] The synthetic route is as follows:

[0139]

[0140] Compound 79 was obtained by referring to the method of Preparation Example 1;

[0141] To compound 79 (500 mg, 0.97 mmol, 1 equiv) in DMF (6 mL), add potassium carbonate (200 mg, 1.45 mmol, 1.5 equiv), add compound 81 (911 mg, 1.94 mmol, 2 equiv) in DMF (5 mL), The temperature was raised to 60°C for 3h. The reaction solution was concentrated by rotary evaporation, and separated on a medium-pressure Flash silica gel column (dichloromethane / methanol=20 / 1 to 5 / 1) to obtain compound 82 (505 mg, yellow solid, yield 64.1%);

[0142] 1 H NMR (600MHz, DMSO-d 6 ,δppm):10.02(s,1H),9.99(s,1H),9.43(s,1H),8.20(s,1H),8.16(s,1H),7.97(s,1H),7.76-7.73( m,3H),7.62(s,1H),7.49(d,J=8.2Hz,1H),7.39-7.38(m,3H),7.06(d,J=9.5Hz,1H),4.30(dd,J =2.0Hz, 10.6Hz, 1H), 4.16-4.11(m, 4H), 4.05-4.02(m, 1H), 2.32(s, 3H), 2.04(d, J=13.9Hz, 6H), 1.25(d ,J=13.4Hz,6H). ...

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Abstract

An embodiment of the invention provides an FAK-targeting compound as well as a preparation method and application of the compound. The compound has a structure as shown in a general formula (I) whichis described in the specification. The compound provided by the invention has high affinity with FAK, and can be used as a compound for targeting FAK. Furthermore, since the FAK-targeting compound provided by the invention has an inhibition effect on FAK, the FAK-targeting compound can be used for preparing tumor treatment medicines; Besides, after the FAK-targeting compound provided by the invention is subjected to radiochemical labeling, the FAK-targeting compound can be used as a tumor diagnosis imaging agent for preparing tumor diagnosis drugs. The FAK-targeting compound provided by the invention has the characteristics of good affinity, strong specificity and high selectivity, and has clinical application value.

Description

technical field [0001] The invention relates to the technical field of compounds, in particular to a compound targeting FAK and its preparation method and application. Background technique [0002] Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase, which is highly or overexpressed in most types of tumor cells, and plays an important role in the occurrence, development and metastasis of tumors. Links play a crucial role, especially in the process of tumor evolution to a malignant invasive phenotype. In theory, blocking the expression of FAK or inhibiting the function of FAK may achieve the purpose of inhibiting the invasion and metastasis of tumor cells. Therefore, FAK is a potential target for tumor diagnosis and treatment. [0003] It is necessary to develop radiopharmaceuticals with high tumor specificity and high sensitivity. Over the past three decades, a number of radiopharmaceuticals have been designed and developed to image and identify the unique bioch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D405/12C07D403/12C07D401/12A61P35/00A61K31/505A61K31/506
CPCC07D239/48C07D405/12C07D403/12C07D401/12A61P35/00C07B2200/05
Inventor 张华北齐月恒
Owner BEIJING NORMAL UNIVERSITY
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