Alkylene phenylsulfonamide type selective ZAK inhibitor and application thereof

A technology of alkynephenylbenzenesulfonamide and benzenesulfonamide, applied in the field of alkynephenylbenzenesulfonamide selective ZAK inhibitors, can solve the problems of limited research and lack of ZAK selectivity

Active Publication Date: 2018-06-05
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds are all multi-targeted kinase inhibitors without exception, lacking selectivity for ZAK
At present, resear

Method used

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  • Alkylene phenylsulfonamide type selective ZAK inhibitor and application thereof
  • Alkylene phenylsulfonamide type selective ZAK inhibitor and application thereof
  • Alkylene phenylsulfonamide type selective ZAK inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1: 3-chloro-N-(2,4-difluoro-3-((3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzene base)-4-fluorobenzene (designated as CYD2823)

[0106]

[0107] Step a: Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (Compound 1)

[0108]

[0109] 5-Bromo-2-chloronicotinic acid methyl ester (50g, 200mmol) was dissolved in 500mL ethanol, 80% hydrazine hydrate (37.5g, 600mmol) was added with stirring, and heated to reflux for 12h. After cooling to room temperature and adding a large amount of ice water, a light yellow solid precipitated out. It was filtered under reduced pressure, and the filter cake was fully washed with water and dried in vacuo to obtain 36 g of a light yellow solid (Yield: 85%). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.41 (s, 1H), 11.04 (s, 1H), 8.47 (d, J=2.0Hz, 1H), 8.30 (d, J=2.0Hz, 1H). MS(ESI),m / z:214[M+H] + .

[0110] Step b: Preparation of 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (Compound 2)

[0111]

[...

Embodiment 2

[0138] Example 2: 3-chloro-N-(2,4-difluoro-3-((3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzene base)-2-fluorobenzene (named as CYD2826) preparation

[0139]

[0140] The synthesis method is as in Example 1.

[0141] 1 H NMR (400MHz, DMSO-d 6 )δ12.95(s,1H),10.84(s,1H),8.61(d,J=2.0Hz,1H),8.33(d,J=1.2Hz,1H),7.95(t,J=7.0Hz, 1H), 7.69 (t, J=6.8Hz, 1H), 7.41-7.31 (m, 2H), 7.25-7.21 (m, 1H), 4.02 (s, 3H).

[0142] 13 C NMR (150MHz, DMSO-d 6 )δ160.23(d, J=252.0Hz, 1C), 156.81(d, J=253.5Hz, 1C), 155.11, 153.77(d, J=255.0Hz, 1C), 152.20, 151.06, 136.16, 132.61, 129.86 (d,J=10.5Hz,1C),129.27(d,J=13.5Hz,1C),128.82,126.03(d,J=4.5Hz,1C),121.68(d,J=16.5Hz,1C),120.35 (d, J=12Hz, 1C), 112.26 (d, J=22.5Hz, 1C), 109.44, 103.20, 101.75 (t, J=19.5Hz, 1C), 97.74, 76.18, 55.99.

[0143] HRMS (ESI) calcd for C 21 h 12 CIF 3 N 4 o 3 S[M+H] + ,493.0344; found, 493.0348.

[0144] HPLC purity=99.32%, Rt 10.82min.

Embodiment 3

[0145] Example 3: N-(2,4-difluoro-3-((3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)phenyl)-2 -Preparation of toluenesulfonamide (designated as CYD2830)

[0146]

[0147] The synthesis method is as in Example 1.

[0148] 1 H NMR (400MHz, DMSO-d 6 )δ12.94(s,1H),10.37(s,1H),8.60(d,J=2.0Hz,1H),8.32(d,J=1.2Hz,1H),7.71(d,J=8Hz,1H ),7.55-7.52(m,1H),7.43(d,J=7.6Hz,1H),7.35-7.26(m,2H),7.19(t,J=8.8Hz,1H),4.02(s,3H) ,2.63(s,3H).

[0149] HRMS (ESI) calcd for C22 h 16 f 2 N 4 o 3 S[M+H] + ,455.0984; found, 455.0980.

[0150] HPLC purity=95.95%, Rt 14.10min.

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Abstract

The invention relates to application of an alkylene phenylsulfonamide compound with a structure of formula (I) (shown in the description) or pharmaceutically acceptable salt thereof or stereisomer thereof or a prodrug molecule thereof in preparation of a ZAK inhibitor. The alkylene phenylsulfonamide compound is capable of effectively and selectively inhibiting ZAK protein kinase and further regulating the activation of multiple routes such as downstream JNK/SAPK, p38 and ERK, can be used for preparing drugs for preventing and treating several ZAK kinase relevant diseases such as myocardial hypertrophy, myocardial fibrosis, stenocardia, coronary heart disease, cardiac failure and myocardial infarction and has the characteristics of relatively good pharmacokinetics, low toxicity and relatively high druggability.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to an alkynephenylbenzenesulfonamide selective ZAK inhibitor and its application. Background technique [0002] ZAK kinase (Leucine-zipper and sterile-αmotif kinase) belongs to the mixed lineage kinase (Mixed lineage kinase, MLK) family, is a new type of mitogen-activated protein kinase kinase kinase (Mitogen-activited protein kinase kinase kinase, MAP3K), Widely distributed in various tissues and organs of the human body, such as heart, skeletal muscle, placenta, pancreas, lung, liver, etc. ZAK kinase consists of 800 amino acids, and its structure includes kinase domain (KD), leucine zipper (Leucine-zipper, LZ) and sterile α motif (sterile-α motif, SAM). Overexpression of ZAK kinases in vivo is closely related to cardiac hypertrophy, myocardial fibrosis, inflammation and tumor formation. Biological studies have shown that ZAK is overexpressed in infarcted cardiomyocytes. Hi...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D231/56A61K31/437A61K31/444A61K31/416A61P9/10A61P9/04A61P9/00
CPCC07D231/56C07D471/04
Inventor 丁克陆小云常玉涂正超黄志扬张庆文罗金凤张章徐布
Owner JINAN UNIVERSITY
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