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Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

A technology of pyrrolidinyl and tetrahydropyranyl, which is applied to new HIV inhibitors, uses these compounds in the treatment of HIV infection, and prepares the fields of compounds described below, which can solve problems such as viral drug resistance

Inactive Publication Date: 2018-06-08
VIIV HEALTHCARE UK (NO 5) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treatment failure in most cases due to emergence of viral resistance

Method used

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  • Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
  • Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
  • Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0340]

[0341] (S)-2-(5-(4-(Benzylcarbamoyl)phenyl)-4-(2-azabicyclo[2.2.1]hept-2-yl)-2,6-dimethyl Pyridin-3-yl)-2-(tert-butoxy)acetic acid: Add 0.13 mL of 1M sodium hydroxide (5.14 mg, 0.13 mmol) to (S)-2-(5-(4-(benzylcarbamoyl)phenyl)-4-(2-azabicyclo[2.2. 1] Hept-2-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy) isopropyl acetate (30 mg, 0.05 mmol) in ethanol (2.5 mL) solution and stirred at 90°C for 18 hours. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine and dried (MgSO 4 ). The crude material was purified by preparative HPLC to afford (S)-2-(5-(4-(benzylcarbamoyl)phenyl)-4-(2-azabicyclo[2.2.1]hept-2 -yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid 12.4 mg (45%).

[0342]

[0343]

[0344] 2-(5-Bromo-4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetic acid iso Propyl ester: 1,2,3,4-Tetrahydroisoquinoline, HCl (1.39 g, 8.22 mmol) and DIEA (2.61 mL, ...

Embodiment 2

[0357]

[0358] (S)-2-(tert-butoxy)-2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-(4-fluorophenethoxy )phenyl)- 2,6-Dimethylpyridin-3-yl)acetic acid: Add 0.10 mL of 1M sodium hydroxide (4.0 mg, 0.10 mmol) to (S)-2-(tert-butoxy)-2-(4-(3,4-dihydroisoquinoline-2(1H)- yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl) isopropyl acetate (25 mg, 0.04 mmol) in ethanol (1.5 mL ) and stirred at 90°C for 18 hours. An additional 0.1 mL of sodium hydroxide solution was added and the reaction continued for 18 hours. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine and dried (MgSO 4 ). The crude material was purified by preparative HPLC to give (S)-2-(tert-butoxy)-2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-5- (4-(4-Fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 8.5 mg (37%).

[0359]

[0360]

[0361] 2-(5-bromo-4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2,6-dimethylpyridin-3-...

Embodiment 3

[0375]

[0376] (S)-2-(5-(4-(Benzylcarbamoyl)phenyl)-4-(2-azabicyclo[2.2.1]hept-2-yl)-2,6-dimethyl Pyridin-3-yl)-2-(tert-butoxy)acetic acid: Add 0.40 mL of 1M sodium hydroxide (15.9 mg, 0.40 mmol) to (2S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)- 4-(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2,6-dimethylpyridin-3-yl)isopropyl acetate (60 mg, 0.10 mmol) in ethanol ( 2 mL) and stirred at 90°C for 18 hours. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine and dried (MgSO 4 ). The crude material was purified by prep-HPLC to obtain (S)-2-(5-(4-(benzylcarbamoyl)phenyl)-4-(2-azabicyclo[2.2.1]heptane- 2-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid 21.5 mg (38%).

[0377]

[0378]

[0379] (2S)-2-(5-(4-(Benzylcarbamoyl)phenyl)-4-(hexahydrocyclopenta[c]pyrrole-2(1H)- Base)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate isopropyl ester: Pd(Ph 3 P) 4 (54 mg, 0.047 mmol) ...

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Abstract

Disclosed are compounds of Formula (I), including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibitingHIV integrase and treating those infected with HIV or AIDS. In the compounds of formula (I), R1 is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxy)alkoxyalkyl, or (R6)alkyl; R2 is phenyl substituted with 1 R7 substituent and with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; or R2 is selected from tetrahydroisoquinolinyl, ((Ar1)alkyl)tetrahydroisoquinolinyl, or ((N-alkoxycarbonyl)tetrahydroisoquinolinyl; R3 is is selected from tetrahydroisoquinolinyl or decahydroisoquinolinyl and is substituted with 0-3 substituents selected from halo, alkyl, and haloalkyl; or R3 is a [5-7.3-7.0-2] fused or bridged bicyclic amine and is substituted with 0-3 alkyl substituents; or R3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl and contains a spirocyclic moiety wherein the spirocyclic moiety, including the carbon atom to which it is attached, forms C3-7 cycloalkane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, N-alkylpyrrolidinyl, piperidinyl, N-alkylpiperidinyl, homopiperidinyl, or N-alkylpiperidinyl, and wherein the spirocyclic moiety is substituted with 0-3 halo or alkyl substituents; R4 is selected from alkyl or haloalkyl; R5 is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxy)alkoxyalkyl, or (R6)alkyl; R6is selected from (oxetanyl)oxy, ((oxetanyl)alkoxy)alkyl, (tetrahydropyranyloxy)alkyl, (tetrahydropyranyl)alkoxy)alkyl, or (Rg)(R9)N; R7 is selected from (Ar1)alkoxy or ((Ar1)alkyl)HNCO; R8 is selected from hydrogen, alkyl, (cycloalkyl)alkyl, alkoxyalkyl, (tetrahydropyanyl)alkyl, tetrahydropyanyl, or alkoxyphenyl; R9 is selected from hydrogen or alkyl; or (R8)(R9)N taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, (spirocyclobutyl)piperidinyl, piperazinyl, or morpholinyl; and Ar1 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

Description

[0001] Cross References to Related Inventions [0002] This application claims the benefit of US Provisional Application Serial No. 62 / 202,521 filed August 7, 2015. field of invention [0003] The present invention relates to compounds, compositions and methods for the treatment of human immunodeficiency virus (HIV) infection. More specifically, the invention provides novel HIV inhibitors, pharmaceutical compositions containing such compounds and methods of using these compounds in the treatment of HIV infection. The invention also relates to processes for the preparation of the compounds described hereinafter. Background of the invention [0004] Human immunodeficiency virus (HIV) has been identified as the causative agent of acquired immunodeficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and inability to fight off life-threatening opportunistic infections. Recent statistics indicate that an estimated 35.3 million people worldw...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/444A61P31/18
CPCA61K45/06A61K31/5365C07D401/04A61P31/18C07D401/14C07D407/14C07D471/10C07D493/10A61K2300/00A61K31/444A61K31/46
Inventor J.F.卡多B.N.奈杜J.L.罗迈尼P.西瓦普拉卡萨姆D.R.圣劳伦特
Owner VIIV HEALTHCARE UK (NO 5) LTD