Polycyclic compound for inhibiting RNA helicase DHX33

A compound, CH3 technology, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve the problem that mutants lacking helicase activity do not have the function of DHX33 protein, cannot replace the function, and are rare in small molecule inhibitors And other issues

Active Publication Date: 2021-04-16
成都开悦生命科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The helicase activity-deficient mutant of DHX33 does not have the function of DHX33 protein and cannot replace the function of wild-type DHX33 gene
At present, there are few small molecule inhibitors targeting DHX33, so there is an urgent need to develop a class of DHX33 inhibitors with high activity and good druggability

Method used

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  • Polycyclic compound for inhibiting RNA helicase DHX33
  • Polycyclic compound for inhibiting RNA helicase DHX33
  • Polycyclic compound for inhibiting RNA helicase DHX33

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Example 1: Compound (E)-2-(3-(2-cyano-2-(3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-dimethyl Synthesis of 1H-pyrrol-1-yl)-4,5-dimethylfuran-3-carbonitrile (AB24249)

[0140] (1) Synthesis of compound 3 (2-(3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile)

[0141]

[0142] Compound 1 (3,4-diaminopyridine) (400 mg, 3.67 mmol, 1.0 eq) and compound 2 (ethyl cyanoacetate) (1.24 g, 11.01 mmol, 3.0 eq) were dissolved in dimethylformamide (6 mL ), stirred at 180°C for 5 hours. After the reaction was cooled, the solvent was removed. The residue was purified by flash column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain brown solid powder compound 3 (2-(3H-imidazo[4,5-c]pyridin-2-yl) Acetonitrile) (180 mg, yield: 31.0%). MS(ESI)m / z:159[M+H] + . TLC: DCM / MeOH (10:1); R f (Compound 1) = 0.1; R f (compound 3) = 0.3.

[0143] (2) Compound AB24249 ((E)-2-(3-(2-cyano-2-(3H-imidazo[4,5-c]pyridin-2-yl)vinyl)-2,5-di Synthesis of methyl-1H-pyrrol-1-yl)-4,5-dimethylf...

Embodiment 2

[0146] Example 2: Compound (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)- Synthesis of 2,5-Dimethyl-1H-pyrrol-1-yl)-4,5-Dimethylfuran-3-carbonitrile (AB24254)

[0147] (1) Synthesis of compound 6 (6-methoxypyridine-3,4-diamine)

[0148]

[0149] Compound 5 (2-methoxy-5-nitropyridin-4-amine) (3.0 g, 17.74 mmol, 1.0 eq) was dissolved in methanol (30 mL), and a carbon-supported palladium catalyst (300 mg, 0.1 wt %) was added . The mixture was stirred at room temperature under hydrogen for 16 hours. The solid was filtered, and then the filtrate was concentrated to obtain a brown solid compound 6 (6-methoxypyridine-3,4-diamine) (2.6 g, yield: 100%). MS(ESI)m / z:140[M+H] + . TLC: DCM:MeOH (10:1); Rf (compound 5) = 0.7; Rf (compound 6) = 0.5.

[0150] (2) Synthesis of compound 7 (2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)acetonitrile)

[0151]

[0152] Compound 6 (6-methoxypyridine-3,4-diamine) (1.5g, 10.2mmol, 1.0eq) and compound 2 (ethyl cyanoacet...

Embodiment 3

[0156] Example 3: Compound (E)-2-(3-(2-cyano-2-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)vinyl)- Synthesis of 2,5-Dimethyl-1H-pyrrol-1-yl)-5-methylthiophene-3-carbonitrile (AB24288)

[0157] AB24288 was synthesized in the same manner as in Example 2 (yield: 13.6%), 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.16(s,1H),7.31(s,1H),6.96(s,1H),6.89(s,1H),3.89(s, 3H), 2.51(s,3H), 2.30(s,3H), 2.08(s,3H).

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Abstract

The invention relates to a polycyclic compound for inhibiting RNA helicase DHX33. In particular, the invention relates to a compound shown as a formula I or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the compound, a preparation method of the compound, and medical application of the compound to prevention and/or treatment of DHX33 related diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a small molecule inhibitor of DHX33, a pharmaceutical composition containing it, a preparation method thereof, and a medical application for preventing and / or treating DHX33-related diseases. Background technique [0002] DHX33 belongs to the DEAD / H box-containing RNA helicase protein family. Among them, DEAD / H stands for the abbreviation of amino acid Asp-Glu-Ala-Asp / His. This sequence, together with other conservative amino acid sequences, appears in the protein sequence of RNA helicase family members and is highly involved in nucleic acid substrates. Binding and ATP hydrolysis. Although these family members share these same sequences, each RNA helicase has its own specific specificity and unique biological function. The molecular weight of human DHX33 protein is 72kDa, and it has the function of unwinding nucleic acid. It uses the bioenergy released by ATP hydrolysis to driv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D471/14A61K31/4375A61K31/437A61K31/444A61P35/00
Inventor 张严冬李相鲁
Owner 成都开悦生命科技有限公司
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