Carbocyclic nucleoside reverse transcriptase inhibitors

Patent metadata

Field	Value
Publication number	US-11040975-B2
Application number	US-201816212121-A
Country	US
Kind code	B2
Filing date	Dec 6, 2018
Priority date	Dec 8, 2017
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention is directed carbocyclic nucleoside reverse transcriptase inhibitors compounds of Formula Iand their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.

First claim

What is claimed:

1. A compound of structural Formula I

or a pharmaceutically acceptable salt thereof, wherein:
R is

X is —N— or —C(H)—;
R 7 is —CH, —N, —C 1-6 alkyl or —C-aryl;
R 1 is H,

R 2 is H or —CH 2 —O—C 1-6 alkyl;
R 3 is halo, —NH 2 , oxo (═O), —O—C 1-6 alkyl or —O—C(O)—N(phenyl) 2 ;
R 4 is halo or —NR a R b ;
R a and R b are each independently selected from —H, —C 1-6 alkyl or —C(O)—C 1-6 alkyl;
R 5 is —H or —C(O)-phenyl; and
R 6 is —H or —C(O)-phenyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 1 is H,

R 2 is H or —CH 2 —O—C 1-3 alkyl;
R 3 is halo, —NH 2 , oxo, —O—C 1-3 alkyl or —O—C(O)—N(phenyl) 2 ; and
R 4 is halo, —NH 2 or —NH—C(O)—C 1-3 alkyl.

3. The compound of claim 1 that is:
(1S,2S,4R)-4-(6-chloro-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(6-chloro-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(2,6-dichloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(2,6-dichloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol or (1R,2R,4S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol or (1R,2R,4S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
(1S,2S,4R)-4-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
2-amino-9-((1R,3 S,4S)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one and 2-amino-9-((1S,3R,4R)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one;
2-amino-9-((1R,3 S,4S)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one or 2-amino-9-((1S,3R,4R)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one;
2-amino-9-((1R,3 S,4S)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one or 2-amino-9-((1S,3R,4R)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-one;
(1S,2S,4R)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol and (1R,2R,4S)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)cyclopentan-1-ol;
1-((1R,3 S,4S)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-5-methylpyrimidine-2,4(1H,3H)-dione and 1-((1S,3R,4R)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-5-methylpyrimidine-2,4(1H,3H)-dione;
4-amino-1-((1R,3 S,4 S)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cycl opentyl)pyrimidin-2(1H)-one and 4-amino-1-((1S,3R,4R)-3-ethynyl-4-hydroxy-3-(hydroxymethyl)cyclopentyl)pyrimidin-2(1H)-one;
Isopropyl ((S)-(((1S,2S,4R)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate and Isopropyl ((S)-(((1R,2R,4S)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate;
Isopropyl ((S)-(((1S,2S,4R)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate or Isopropyl ((S)-(((1R,2R,4S)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate;
Isopropyl ((S)-(((1S,2S,4R)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate or Isopropyl ((S)-(((1R,2R,4S)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate;
((1S,2S,4R)-4-(6-chloro-2-fluoro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(6-chloro-2-fluoro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(6-amino-2-fluoro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(6-amino-2-fluoro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(2,6-dichloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(2,6-dichloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate or ((1R,2R,4S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-1-ethynyl-2-hydroxy-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-1-ethynyl-2-hydroxy-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopentyl)methyl tetrahydrogen triphosphate;
((1S,2S,4R)-4-(4-amino-2-oxopyrimidin-1(2H)-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate and ((1R,2R,4S)-4-(4-amino-2-oxopyrimidin-1(2H)-yl)-1-ethynyl-2-hydroxycyclopentyl)methyl tetrahydrogen triphosphate;
(1S,2S,4R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-hydroxy-1-(hydroxymethyl)cyclopentane-1-carbonitrile and (1R,2R,4S)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-hydroxy-1-(hydroxymethyl)cycl

Assignees

• Merck Sharp & Dohme
• Idenix Pharmaceuticals Llc

Inventors

• Alexandre Francois-Rene
• Rahali Rachid
• Raheem Izzat
• Parsy Christophe

Classifications

• C07D473/32

  Nitrogen atom · CPC title

• C07D473/40 Primary

  with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6 · CPC title

• C07F9/65616

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title