Substituted pyrrolizine compounds and uses thereof

A compound, haloalkyl technology, applied in the field of pyrrolizine compounds, can solve the problem of not clearing HBV infection

Active Publication Date: 2019-05-21
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently available therapies can inhibit viral replication and minimize liver damage; however, no current therapy reliably clears HBV infection

Method used

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  • Substituted pyrrolizine compounds and uses thereof
  • Substituted pyrrolizine compounds and uses thereof
  • Substituted pyrrolizine compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0415] Example 1 : 7-(2-(tert-butylamino)-2-oxoacetyl)-6-chloro-N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrole Oxazine-5-carboxamide (1)

[0416]

[0417] step 1 To a reaction tube with a stirrer was added methyl 3-chloro-1H-pyrrole-2-carboxylate (0.32 g, 2.0 mmol), norbornene (0.38 g, 4.0 mmol), potassium bicarbonate (0.60 g, 6.0 mmol), bis(acetonitrile)palladium(II) dichloride (0.052g, 0.2mmol) and (3-bromopropoxy)(tert-butyl)diphenylsilane (1.51g, 4mmol) in anhydrous dimethyl Acetamide (2 mL) was heated at 90°C for 24 hours. Ethyl acetate (100 mL) was added and filtered. The filtrate was washed with water, brine and dried over sodium sulfate. Removal of solvent and purification of the residue by column (0-80% ethyl acetate in hexanes) gave 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-3-chloro - 1H-pyrrole-2-carboxylic acid methyl ester.

[0418] Step 2: To 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-3-chloro-1H-pyrrole-2-carboxylic acid methyl ester (0.72g, 1....

Embodiment 2

[0425] Example 2 : (R)-N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-5-carboxamide (2)

[0426]

[0427] step 1 : In dichloromethane (150mL) solution of L-proline benzyl ester hydrochloride (8.83g, 36.5mmol) and N-ethyldiisopropylamine (13mL, 75mmol) cooled to 0°C, oxychloride was added dropwise Methyl acetate (5.0 mL, 54 mmol). The reaction mixture was warmed to ambient temperature and stirred for 1 h at which time the reaction mixture was quenched by pouring into cooled saturated aqueous sodium bicarbonate. The aqueous phase was extracted three times into dichloromethane, the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give (2-methoxy-2-oxoacetyl)-L - Proline benzyl ester, which was carried forward without further purification.

[0428] step 2 : (2-methoxy-2-oxoacetyl)-L-proline benzyl ester (10.6g, ...

Embodiment 3

[0436] Example 3 .N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl Base) -6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (3)

[0437]

[0438] Using 1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride instead of R-trifluoroisopropylamine, synthesize N-(3-chloro -4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl -2,3-Dihydro-1H-pyrrolazine-5-carboxamide (3).

[0439] Synthesis of 1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride

[0440]

[0441] step 1 .To 1-amino-3,3-difluorocyclobutane-1-carboxylic acid (990mg, 6.55mmol) in methanol (8mL) solution at 0°C was added 1M aqueous sodium hydroxide solution (7mL, 7mmol), followed by Di-tert-butyl dicarbonate (1.8 g, 8.2 g). The reaction mixture was warmed to ambient temperature, stirred for 14 hours, acidified with dilute aqueous hydrogen chloride, and extracted into ether. The ether phase...

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Abstract

This application relates to substituted fused pyrrole compounds of formula I, and pharmaceutical compositions comprising them which inhibit HBV replication, and methods of making and using them (Formula (I)).

Description

[0001] priority claim [0002] This application claims priority to U.S. Provisional Application No. 62 / 380,063, filed August 26, 2016, and U.S. Provisional Application No. 62 / 416,020, filed November 1, 2016, the entire contents of which are for all purposes Incorporated into this article. technical field [0003] The present application relates generally to certain substituted pyrrolazine compounds, and pharmaceutical compositions, which inhibit HBV replication, and methods of making and using them. Background technique [0004] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA virus. HBV is an infectious disease that affects the liver. Initial symptoms of infection may include vomiting, jaundice, lethargy, dark urine, and abdominal pain. Chronic HBV infection can lead to cirrhosis and liver cancer. Currently available therapies can inhibit viral replication and minimize liver damage; however, there are currently no therapies that can reliably clear...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/407A61K31/433A61K31/4192A61K31/4245A61K31/4439
CPCC07D487/04C07D519/00A61P31/20A61K31/03A61K31/16A61K31/38A61K31/403A61K31/4192A61P1/16A61K31/407A61K31/4196A61K31/4245A61K31/433A61K31/4439A61K31/675A61K45/06C07D405/12C07D409/12C07D495/10
Inventor 杜锦发J·A·卡普兰T·A·吉尔士博格小林哲也S·E·拉泽维斯R·A·李J·W·梅德莱M·L·米歇尔P·A·摩格艾丽边衡正S·L·谢维克N·H·斯夸尔斯W·J·沃金斯
Owner GILEAD SCI INC
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