Heterocyclic benzene sulfonamide compound and application thereof

A technology of cyclobenzenesulfonamide and benzenesulfonamide, which is applied in the field of chemical medicine and can solve the problems of lack of ZAK selectivity and limited research

Active Publication Date: 2020-07-10
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, research on ZAK kinase inhibitors is still very limited, and selective small molecule inhibitors against ZAK have not been reported yet.

Method used

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  • Heterocyclic benzene sulfonamide compound and application thereof
  • Heterocyclic benzene sulfonamide compound and application thereof
  • Heterocyclic benzene sulfonamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1: 3-chloro-N-(2,4-difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H -1,2,3-Triazolepiperazin-1-yl)phenyl)benzenesulfonamide

[0098]

[0099] Step a: Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (Compound 1)

[0100]

[0101] 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] + .

[0102] Step b: Preparation of 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (Compound 2)

[0103]

[...

Embodiment 2

[0126] Example 2: N-(2,4-difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-1,2 , 3-triazol-1-yl) phenyl) benzenesulfonamide (designated as YJZ3039) preparation

[0127]

[0128] The synthesis method is as in Example 1 (Yield: 90%).

[0129] 1 H NMR (400MHz, DMSO-d6) δ12.76(d, J=3.1Hz, 1H), 10.60(d, J=3.1Hz, 1H), 9.08(d, J=3.1Hz, 1H), 9.06(t ,J=2.5Hz,1H),8.56(d,J=2.4Hz,1H),7.82–7.75(m,2H),7.68(dd,J=6.6,2.4Hz,1H),7.65–7.58(m, 2H), 7.49(dd, J=7.7, 4.5Hz, 2H), 4.05(d, J=3.0Hz, 3H).

[0130] HPLC analysis:MeOH-H 2 O(80:20), 4.12min, 96.7%purity.

[0131] HRMS (ESI) for C 21 h 15 f 2 N 7 o 3 S[M+H]+, calcd: 484.0998; found, 484.0993.

Embodiment 3

[0132] Example 3: 3-bromo-N-(2,4-difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H Preparation of -1,2,3-triazole piperazin-1-yl)phenyl)benzenesulfonamide (named YJZ3007)

[0133]

[0134] The synthesis method is as in Example 1 (Yield: 90%).

[0135] 1 H NMR (400MHz, DMSO-d6) δ12.77(s, 1H), 10.74(s, 1H), 9.10(s, 1H), 9.07(d, J=2.1 Hz, 1H), 8.56(d, J= 2.1Hz, 1H), 7.96–7.90(m, 2H), 7.76(dt, J=7.9, 1.4Hz, 1H), 7.58(t, J=7.9 Hz, 1H), 7.51(d, J=7.6Hz, 2H), 4.05(s, 3H).

[0136] HPLC analysis:MeOH-H 2 O(85:15), 3.28min, 96.1%purity.

[0137] HRMS (ESI) for C 21 h 14 BrF 2 N 7 o 3 S[M+H]+, calcd: 562.0103; found, 562.0102.

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Abstract

The invention relates to a heterocyclic benzene sulfonamide compound with a structure as shown in a formula (I) which is described in the specification and an application of the heterocyclic benzene sulfonamide compound in preparation of a ZAK inhibitor. The heterocyclic benzene sulfonamide compound can be used for effectively and highly selectively inhibiting ZAK protein kinase and further regulating the activation of downstream JNK/SAPK, p38, ERK and other pathways. The compound can be used for preparing medicines for preventing and treating various diseases related to ZAK kinase, such as myocardial hypertrophy, myocardial fibrosis, angina pectoris, coronary heart disease, heart failure, myocardial infarction and inflammation, and has the characteristics of better pharmacokinetics, low toxicity and higher druggability.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a heterocyclic benzenesulfonamide compound 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. High expression o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/4545A61K31/541A61K31/496A61P9/10A61P9/00A61P9/04
CPCA61P9/00A61P9/04A61P9/10C07D471/04
Inventor 陆小云丁克阳建章黄志扬徐布涂正超
Owner JINAN UNIVERSITY
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