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ROCK inhibitor as well as preparation method and application thereof

A technology of solvates and compounds, which is applied in the field of ROCK inhibitors and their preparation, achieves good application prospects, simple preparation methods, good safety and metabolic stability

Pending Publication Date: 2022-01-14
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are currently no marketed drugs that inhibit the ROCK pathway for the treatment of many conditions including fibrosis

Method used

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  • ROCK inhibitor as well as preparation method and application thereof
  • ROCK inhibitor as well as preparation method and application thereof
  • ROCK inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] Example 1, Compound 1 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-4,5,6,7- Preparation of tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (L001)

[0267]

[0268] 1.1 Preparation of compound 3-(3-nitropyridin-4-yl)-2-carbonyl propionate ethyl ester (L001-1)

[0269] Under nitrogen protection, 4-methyl-3-nitropyridine (10.0 g, 72.0 mmol) was dissolved in diethyl oxalate (50 mL), DBU (12.7 g, 83.0 mmol) was added to the reaction solution, and stirred overnight at room temperature. Add ice water (30.0g) to the reaction system to quench, adjust the pH to 4-5 with 1N dilute hydrochloric acid, filter, wash the filter cake with ethyl acetate (100ml*2), and obtain 18.0g red solid after oven drying. The crude product is cast directly to the next step. LC-MS[M+H] + :239.1.

[0270] 1.2 Preparation of compound 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (L001-2)

[0271] Hydrogen protection, 3-(3-nitropyridin-4-yl)-2-carbonylpropanoic...

Embodiment 2

[0286] Example 2, compound 7-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,2-a] Preparation of pyrazine-2-carboxylic acid (L002)

[0287]

[0288] 2.1 Preparation of compound imidazo[1,2-a]pyrazine-2-carboxylate ethyl ester (L002-1)

[0289] Pyrazin-2-amine (3.5 g, 36.82 mmol) and ethyl 3-bromo-2-carbonylpropionate (7.0 g, 44.18 mmol) were dissolved in ethylene glycol dimethyl ether (60 mL), and heated at 60° C. overnight. Cool to room temperature, collect the filter cake by filtration, add ethanol (40 mL), and heat at 80° C. for 3 hours. After concentration under reduced pressure, saturated sodium bicarbonate solution (30 mL) was added, extracted with ethyl acetate (30 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane:ethyl acetate=1:1) to obtain 1.15 g of a yellow oily product with a yield of 16.4...

Embodiment 3

[0296] Example 3, compound (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo Preparation of [1,5-a]pyrazin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (L003)

[0297]

[0298] 3.1 Preparation of compound 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (L003-1)

[0299] Add dimethyl 1H-pyrazole-3,5-dicarboxylate (5.00g, 27.10mmol) into anhydrous N,N-dimethylformamide (60mL), add potassium carbonate (5.61g, 40.60mmol) , ice-water bath, nitrogen protection, and then added tert-butyl (2-bromoethyl)carbamate (6.64g, 29.80mmol) to it, and stirred at room temperature for 3h. Add water (100 mL) to dilute, a large amount of solid precipitates out, filter with suction, and wash the filter cake with water (50 mL). The solid was collected and dried to obtain 8.70 g of crude product with a purity of 70% and a white solid with a yield of 68%. MS[M+H] + =350.2.

[0300] 3.2 Preparation of compound 1-(2-((tert-but...

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Abstract

The invention relates to the technical field of medicines, in particular to a ROCK inhibitor as shown in a formula (I) and a preparation method and application thereof. The compound provided by the invention has excellent ROCK inhibitory activity. In particular, the compound has better selective inhibition on ROCK2 kinase, and in addition, the compound has better safety and metabolic stability and high bioavailability. Finally, the compound provided by the invention is simple in preparation method and easy to purify, so that the compound has a good application prospect.

Description

[0001] The application requirements were submitted to the State Intellectual Property Office of China on July 14, 2020 and January 11, 2021, respectively. The patent application numbers are 202010676711.6 and 202110040185.9 respectively, and the title of the invention is "A ROCK inhibitor and its preparation method and use. priority of the two earlier applications. Both applications are hereby incorporated by reference in their entirety. technical field [0002] The invention relates to the technical field of medicines, in particular to a ROCK inhibitor and its preparation method and application. Background technique [0003] Idiopathic pulmonary fibrosis (Idiopathic interstitial pulmonary fibrosis, IPF) is a chronic, diffuse pulmonary interstitial disease of unknown cause characterized by common interstitial pneumonia. Manifestations of interstitial pneumonia. Because of its complex pathogenesis, the disease progresses irreversibly, and early diagnosis is difficult; after...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04C07D487/04C07D403/14C07D401/14C07D519/00A61P9/00A61P11/00A61P17/16A61P25/00A61P27/02A61P35/00A61P7/02A61P37/00A61P9/10A61P9/12A61P9/04A61P3/10A61P13/12A61P15/10A61P27/06A61P11/06A61P19/10A61P1/16A61P29/00A61P3/08C07D231/12C07D403/12
Inventor 李金平曾晶郭晓丹彭微娄军柳力陈晓亚张轶涵陈永凯王朝东吴伟袁意
Owner WUHAN LL SCI & TECH DEV
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