Substitutive phenyl pyrimidine derivative as JAK kinase inhibitor or medicinal salt, preparation method and application thereof

A phenylpyrimidine-like and kinase inhibitor technology, applied in the field of kinase inhibitors, can solve problems such as the inability to regulate gene expression in the nucleus

Active Publication Date: 2019-10-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] How to inhibit the combination of ATP and the ATP binding site on JAK, block the hydrolysis of ATP, interfere with the phosphorylation of JAKs, thereby preventing the activation of JAKs, cutting off the signal transmission to STATs, resulting in the inability to regulate the expression of genes in the nucleus, thus preventing Breaking the JAK-STAT signaling pathway is the focus of research

Method used

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  • Substitutive phenyl pyrimidine derivative as JAK kinase inhibitor or medicinal salt, preparation method and application thereof
  • Substitutive phenyl pyrimidine derivative as JAK kinase inhibitor or medicinal salt, preparation method and application thereof
  • Substitutive phenyl pyrimidine derivative as JAK kinase inhibitor or medicinal salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] N-(3-(6-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide

[0113]

[0114] A) 4-Chloro-6-(3-nitrophenyl)pyrimidine

[0115] To 3-bromonitrobenzene (1 g) and 50 mL of anhydrous 1,4-dioxane at room temperature, were added bis-pinacol borate (1.34 g) and KOAc (1.48 g) over catalyst Pd ( PPh 3 ) 4 (3%) and react at 100° C. for 12 h under anaerobic conditions. Cool to room temperature, add 4,6-dichloropyrimidine (1.07g) to the mixed solution, 2M K 2 CO 3 Aqueous solution and Pd(PPh 3 ) 4 (3%) The temperature was raised to 100° C. to ensure anaerobic conditions to continue the reaction for 12 hours. Cool to room temperature, filter with celite, dry under reduced pressure, and purify by silica gel column chromatography to obtain the title compound (0.93 g).

[0116] 1 H NMR (300MHz, CDCl 3 ( t, J=8.0Hz, 1H).

[0117] B) 6-(3-nitrobenzene)-N 4 -(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-4-aminopyrimidine

[0118] Add 1-(2-methoxyethyl)-1H-p...

Embodiment 2 to 23

[0128] In Examples 2 to 23, the same method as in Example 1 was used.

[0129] Wherein embodiment 3, 5, 7, 9, 15, 16, 19 and 20 in step A) 3-bromonitrobenzene (1g) is correspondingly replaced with 4-bromonitrobenzene (1g) and other conditions remain unchanged.

[0130] According to the structural formula of the embodiment, the step B) corresponds to different aminoalkylated substituents, specifically the Z substituent (described above).

[0131] Among them, in Examples 13-23, corresponding to step D), dropwise addition of 1 mL of acryloyl chloride diluted in dry DCM at 0°C was replaced by dropwise addition of 1 mL of crotonyl chloride diluted in dry DCM at 0°C, and other conditions remained unchanged.

[0132] The above molar equivalent ratio is the same as the corresponding reaction equivalent of Example 1.

[0133] The following title compounds can then be obtained, see Table 2. MS in this table means the measured value.

[0134] Table 2 Structure and NMR data of some com...

Embodiment 24

[0143] 2-cyano-N-(3-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide

[0144]

[0145] Experimental steps A), B), and C) utilize the same method as in Example 1 to obtain 6-(3-aminobenzene)-N 4 -(1-Methyl-1H-pyrazol-4-yl)-4-aminopyrimidine.

[0146] E) 2-cyano-N-(3-(6-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide

[0147] 6-(3-Aminobenzene)-N 4 -(1-Methyl-1H-pyrazol-4-yl)-4-aminopyrimidine (0.12g,), cyanoacetic acid (0.04g), DIEA (0.13g) and 15mL dry THF, HATU was added under stirring at 0°C (0.37g) was stirred and reacted for 30min, then turned to room temperature and stirred for reaction. After the reaction was completed, 20 mL of ethyl acetate was added, and 10% citric acid aqueous solution was added to saturate NaHCO 3 The aqueous solution was washed twice, the organic phase was mixed, and the title compound was obtained by separation and purification by silica gel column chromatography.

[0148] 1 H NMR (300MHz, DMSO) δ8.66(s...

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Abstract

The invention discloses a substitutive phenyl pyrimidine derivative as shown in a formula (I) as a JAK kinase inhibitor or medicinal salt, a preparation method and application thereof. The compound has excellent JAK inhibiting action and is used for preparing a drug for preventing, treating or improving autoimmune disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus and the like. The high activity JAK-3 inhibiting action IC50 shown by the compound can reach 1.7 n. The substitutive phenyl pyrimidine derivative is simple in synthetic route and high in implementation.

Description

technical field [0001] The present invention relates to kinase inhibitors, preparation methods and applications, in particular to substituted phenylpyrimidine derivatives as JAK kinase inhibitors or pharmaceutically acceptable salts thereof, preparation methods and applications. Background technique [0002] There are four subtypes of JAK kinase (janus kinase): JAK-1, JAK-2, JAK-3 and TYK-2, which interact with downstream effectors, signal transducers and activators of transcription proteins (STATs) ) forms an important cytokine signaling pathway—JAK-STAT pathway (Science, 1994, 264: 1415-1421). The discovery of this pathway has greatly improved researchers' understanding of gene regulation. Studies have found that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors, and participate in cell proliferation, differentiation, apoptosis, angiogenesis and immune regulation. Process (World J Gastroenterol, 2007, 13:6478-6491). JAK kinases medi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D239/42A61K31/506A61K31/5377A61P37/00A61P9/10A61P37/02A61P17/06A61P19/02A61P1/00A61P27/02A61P43/00
CPCC07D403/12C07D239/42A61P37/00A61P9/10A61P37/02A61P17/06A61P19/02A61P1/00A61P27/02A61P43/00
Inventor 张大永张天泰舒蕾
Owner CHINA PHARM UNIV
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