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Vinylheterocycles as RHO-associated coiled-coil kinase (ROCK) inhibitors

A heterocyclic group and group technology, applied in the field of vinyl heterocyclic rings as RHO-related coiled-coil kinase (ROCK) inhibitors, can solve the problem that the use has not yet been approved in the United States

Pending Publication Date: 2020-07-10
ЭНДЖИОН БАЙОМЕДИКА КОРП
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For hyperacute indications such as cerebral vasospasm, taking Fasudil (en.wikipedia.org / wiki / Fasudil) probably poses no significant risk, although its use is not yet approved in the US

Method used

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  • Vinylheterocycles as RHO-associated coiled-coil kinase (ROCK) inhibitors
  • Vinylheterocycles as RHO-associated coiled-coil kinase (ROCK) inhibitors
  • Vinylheterocycles as RHO-associated coiled-coil kinase (ROCK) inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0288] Example 1. (E)-5-methoxy-2-(4-(2-(pyridin-4-yl)vinyl)-[2,4'-bipyrimidinyl]-2'-yl)isoindyl Indoline (Ex.1).

[0289]

[0290] Step 1: 2-(5-Methoxyisoindolin-2-yl)pyrimidine-4-carbonitrile (1-3): To 2-chloropyrimidine (1-1, 1.5g, 10.8mmol) and 5 - A stirred mixture of methoxyisoindoline hydrochloride (1-2, 2.0 g, 10.8 mmol) in aqueous acetonitrile (40 mL) was added dropwise with N,N-diisopropylethylamine (4.14 mL, 23.76 mmol). The reaction mixture was stirred at 80°C for 3 hours. The resulting solution was concentrated under vacuum then triturated with water and filtered. The filter cake was thoroughly washed with water and dried under vacuum to obtain brown product 1-3 (2.45 g, yield: 90%). MS (ESI + ):m / z:253.1(M+H) + .

[0291] Step 2: 2-(5-methoxyisoindoline-2-yl) pyrimidine-4-formimidate (carbimidate) methyl ester (1-4): at 0 ° C, to 1-3 (1.2 g, 4.8 mmol) in anhydrous dichloromethane (25 mL) was added acetyl chloride (3.4 mL, 47.6 mmol) followed by anhydro...

Embodiment 2

[0295] Example 2. (E)-2-(4-(2-(1H-pyrazol-3-yl)vinyl)-[2,4'-bipyrimidinyl]-2'-yl)-5-methoxy Isoindoline (Ex.2).

[0296]

[0297] Step 1: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (2-3):

[0298] To a stirred solution of pyrazolecarbaldehyde (2-1,300 mg, 3.1 mmol) in tetrahydrofuran was added 3,4-dihydro-2H-pyran (2-2,867 mg, 10.3 mmol) followed by a catalytic amount of trifluoroacetic acid. The resulting solution was refluxed for 4 hours, then cooled to room temperature. The reaction was quenched by adding a trace of sodium hydride. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography to afford 2-3 (520 mg, 92%). MS (ESI + ):m / z:181.1(M+H) + .

[0299] Step 2: (E)-5-Methoxy-2-(4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)ethenyl) -[2,4'-bipyrimidine]-2'-yl)isoindoline (2-4):

[0300] To a stirred solution of 1-7 (50 mg, 0.15 mmol) and tetrabutylammonium bromide (TBAB, 40 mg, 0.12 mmol) in 3 mL of ...

Embodiment 3

[0303] Example 3. (E)-4-(2-(2'-(5-methoxyisoindolin-2-yl)-[2,4'-bipyrimidin]-4-yl)ethenyl) Quinoline (Ex.3)

[0304]

[0305] -Preparation by following the same procedure as described in step 5 of Example 1. A yellow solid was obtained in 56% yield. 1 H-NMR (300MHz, CDCl 3 ): δ (ppm): 9.03 (d, J = 5.1Hz, 1H), 8.99 (d, J = 4.3Hz, 1H), 8.84 (d, J = 15.9Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.32(d, J=8.1Hz, 1H), 8.22(d, J=8.1Hz, 1H), 7.75(m, 4H), 7.48(d, J=5.1Hz, 1H), 7.41( d, J=15.6Hz, 1H), 7.26(s, 1H), 6.90(s, 1H), 6.87(d, J=2.4Hz, 1H), 5.06(br, 4H), 3.85(s, 3H). MS (ESI + ): m / z: 459.3 (M+H) + .

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Abstract

The present invention provides compounds having formula (I), and pharmaceutically acceptable salts thereof, wherein Cy1, Cy2, Cy3, R, R1, R2, R3, A1, and A2 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases in which inhibitingROCK1, ROCK2, or ROCK1 / 2 has a therapeutically useful role.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 553,885, filed September 3, 2017, thereby claiming its priority date. [0003] Background of the invention [0004] Members of the Rho-associated coiled-coil kinase family consisting of Rho-associated kinase 1 (ROCK1) and Rho-associated kinase 2 (ROCK2) are serine-threonine kinases activated by Rho GTPases. Both ROCK1 and ROCK2 are involved in a wide range of cellular processes, including actin cytoskeleton organization, smooth muscle cell contraction, adhesion, migration, proliferation, apoptosis, and fibrosis (Loirand, G. Rho Kinases in Health and Disease: From Basic Science to Translational Research. Pharmacol. Rev. 2015, 67(4), 1074-95). The ROCK signaling cascade regulated by fibrotic growth factors, including TGFβ1, angiotensin I, PDGF, and endothelin I, is involved in epithelial-to-mesenchymal transition (Hu, Y.B., Li, X., Liang, G.N...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D403/06C07D403/14
CPCC07D401/14C07D403/14A61P11/00
Inventor 李安虎迪佰恩度·德纳林东星萨提什库玛·盖德海亚郑大云普拉卡什·纳拉扬奎萨·阿里拉沙·帕卡伊萨克·D·戈德伯格
Owner ЭНДЖИОН БАЙОМЕДИКА КОРП
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