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Isoquinoline compounds for hiv treatment

A kind of technology of compound and therapeutic agent, applied in the field of isoquinoline compound used for HIV treatment

Active Publication Date: 2020-05-29
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although effective, many known NNRTIs are deficient because their use is associated with mutations in the HIV virus that can lead to drug resistance

Method used

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  • Isoquinoline compounds for hiv treatment
  • Isoquinoline compounds for hiv treatment
  • Isoquinoline compounds for hiv treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0372] (E)-2-((1-amino-5-(4-(2-cyanovinyl)-2,6-dimethylphenyl)isoquinolin-3-yl)amino)pyrimidine-5- Formonitrile-Compound 1

[0373]

[0374] Step 1: Synthesis of 4-bromo-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (compound 1a)

[0375]

[0376] 4-Bromo-2,3-dihydro-1H-inden-1-one (10g, 47.4mmol, Ark Pharm, Inc.--AK-31085) was dissolved in ether (120mL), ethanol (50mL) and dichloromethane ( 20mL) in the mixture. The reaction mixture was cooled to 0°C and 1M HCl (24 mL, 24 mmol) in ether was added, and then a 15% ethyl nitrite solution (60 mL, 104 mmol) in ethanol was slowly added to the reaction mixture at 0°C over 1 hour. The reaction mixture was vigorously stirred at room temperature for 3 hours and then concentrated under reduced pressure. Ether (50 mL) was added and the mixture was cooled to 0°C. The solid product was filtered and washed twice with ether (2×20 mL) to produce compound 1a. 1 H NMR(400MHz, DMSO-d 6 )δ12.83(s,1H),7.98(d,J=7.8Hz,1H), 7.77(d,J=7.6Hz,1H), 7.62-7.22...

Embodiment 2

[0396] (E)-5-((1-Amino-5-(4-(2-cyanovinyl)-2,6-dimethylphenyl)isoquinolin-3-yl)amino)pyrazine-2 -Formonitrile-Compound 2

[0397]

[0398] (E)-5-((1-Amino-5-(4-(2-cyanovinyl)-2,6-dimethylphenyl)isoquinolin-3-yl)amino)pyrazine-2 -Synthesis of Carbonitrile (Compound 2)

[0399]

[0400] Compound 1f (200mg, 0.60mmol), 5-aminopyrazine-2-carbonitrile (163mg, 1.36mmol, Ark PharmInc, AK-21935), N,N-diisopropylethylamine (835μL, 4.78mmol), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (35mg, 0.06mmol) and palladium(II) acetate (13mg, 0.06mmol) in argon The following are combined in N-methyl-2-pyrrolidone (1 mL). The reaction was heated in a sealed container at 120°C for 4 hours. The reaction mixture was cooled to room temperature and purified by reverse phase chromatography (20-60% aqueous acetonitrile with 0.1% trifluoroacetic acid) to provide the TFA salt of compound 2. 1 HNMR (400MHz, methanol-d 4 )δ8.55(d,J=1.4Hz,1H), 8.36(dd,J=8.1,1.4Hz,1H), 8.31(d,J=1.4Hz,1H),7.73-7.5...

Embodiment 3

[0402] (E)-6-((1-amino-5-(4-(2-cyanovinyl)-2,6-dimethylphenyl)isoquinolin-3-yl)amino)pyridazine-3 -Formonitrile-Compound 3

[0403]

[0404] (E)-6-((1-amino-5-(4-(2-cyanovinyl)-2,6-dimethylphenyl)isoquinolin-3-yl)amino)pyridazine-3 -Synthesis of Carbonitrile (Compound 3)

[0405]

[0406] Compound 1f (200mg, 0.60mmol), 6-aminopyridazine-3-carbonitrile (163mg, 1.36mmol, MatrixScientific, 112287), N,N-diisopropylethylamine (835μL, 4.78mmol), (9, 9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (35mg, 0.06mmol) and palladium(II) acetate (13mg, 0.06mmol) were combined under argon N-methyl-2-pyrrolidone (1 mL). The reaction was heated in a sealed container at 120°C for 4 hours. The reaction mixture was cooled to room temperature and purified by reverse phase chromatography (20-60% aqueous acetonitrile with 0.1% trifluoroacetic acid) to provide the TFA salt of compound 3. 1 H NMR (400MHz, methanol-d 4 )δ8.45-8.31(m,1H),7.94(d,J=9.3Hz,1H),7.81-7.43(m,5H),7.24(d,J=9.3Hz,1H),6.30(...

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Abstract

Described herein are compounds of formula (I) and tautomers and pharmaceutically acceptable salts thereof, compositions and formulations comprising these compounds, and methods of using and preparing these compounds.

Description

[0001] background [0002] Cross references to related applications [0003] This application claims the priority benefit of U.S. Application Serial No. 62 / 096,769 filed on December 24, 2014, the disclosure of which is incorporated herein by reference in its entirety. Background technique [0004] Despite progress in the treatment of HIV and AIDS, HIV infection is still a global health problem. As part of this type of treatment, non-nucleoside reverse transcriptase inhibitors (NNRTI) are often used, especially as part of a highly active antiretroviral therapy (HAART) treatment regimen. Although effective, many known NNRTIs have drawbacks because their use is associated with mutations in the HIV virus that may cause drug resistance. Therefore, there is still a need to further develop an effective NNTRI. [0005] Described herein are compounds of formula (I) and pharmaceutically acceptable salts thereof, compositions and formulations containing these compounds or pharmaceutically acce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/22C07D401/12A61K31/472A61K31/4725A61K31/497A61K31/501A61K31/506A61P31/18
CPCC07D217/22C07D401/12A61P31/18A61K31/4725A61K31/497A61K31/501A61K31/506A61K45/06A61K31/472
Inventor P·扬萨R·L·马克曼Y·E·胡E·兰斯登
Owner GILEAD SCI INC
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