Substituted 2-alkyl-1-OXO-N-phenyl-3-heteroaryl-1,2,3,4-tetrahydroisoquinoline-4-carboxamides for antimalarial therapies

Patent metadata

Field	Value
Publication number	US-9416124-B2
Application number	US-201214240994-A
Country	US
Kind code	B2
Filing date	Aug 24, 2012
Priority date	Aug 25, 2011
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

In one aspect, the invention relates to novel substituted 2-alkyl-1-oxo-N-phenyl-3-heteroaryl -1,2,3,4-tetrahydroisoquinoline-4-carboxamides; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating and/or preventing malaria. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

The invention claimed is:

1. A compound having a structure represented by a formula:

wherein Ar 1 is selected from 3-pyridinyl, 4-isoxazolyl, N-methyl-4-pyrazolyl, 4-pyrazolyl, 4-isothiazolyl, 5-thiazolyl, 5-pyrimidinyl, or 4-pyridazinyl; R 1 is selected from CF 3 , (CH 3 ) 2 CH or cyclopropyl, R 2 and R 3 are independently selected from H, OCH 3 or F; Ar 2 has a structure represented by a formula:

wherein R 4a , R 4b and R 5 are independently selected from H, CN, F, Cl or OCF 3 , or a pharmaceutically acceptable salt, tautomer, geometrical isomer or optically active form thereof.

2. The compound of claim 1 wherein R1 is CF3.

3. The compound of claim 1 wherein R1is (CH 3 ) 2 CH.

4. The compound of claim 1 wherein R1 is cyclopropyl.

5. The compound according to claim 1 , selected from:
N-(3-cyano-4-fluorophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-(cyclopropylmethyl)-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-7-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-7-methoxy-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-isobutyl-1-oxo-3-(pyridin-3-yl)-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-2-isobutyl-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-6-fluoro-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-butyl-N-(3-cyano-4-fluorophenyl)-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-6-fluoro-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-7-fluoro-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyanophenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-5-fluorophenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(4-fluoro-3-(trifluoromethoxy)phenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-2-isobutyl-1-oxo-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-chloro-5-cyanophenyl)-7-fluoro-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-3-(isothiazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
N-(3-cyano-4-fluorophenyl)-2-isobutyl-1-oxo-3-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; or
N-(3-cyano-4-fluorophenyl)-1-oxo-3-(1H-pyrazol-4-yl-6,7-difluoro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoqu

Assignees

• Guy Rodney Kiplin
• Zhu Fangyi
• Guiguemde Wendyam Armand
• Floyd David
• Knapp Spencer
• Stein Philip
• Castro Steve
• St Jude Children'S Res Hospital
• Medicines For Malaria Venture Mmv
• Univ Rutgers

Inventors

• Guy Rodney Kiplin
• Zhu Fangyi
• Guiguemde Wendyam Armand
• Floyd David
• Knapp Spencer
• Stein Philip
• Castro Steve

Classifications

• A61P33/06

  Antimalarials · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title