Antiviral beta-amino acid ester phosphodiamide compounds

Patent metadata

Field	Value
Publication number	US-9822138-B2
Application number	US-201615231365-A
Country	US
Kind code	B2
Filing date	Aug 8, 2016
Priority date	Aug 10, 2015
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Compounds of Formula I:

and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.

First claim

What is claimed is:

1. A compound of structural Formula I:

or pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently H or —C 1-4 alkyl;
R 3 is —C 1-10 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R A is an L-amino acid ester residue of formula (i), a D-amino acid ester residue of formula (ii), or a geminally di-substituted amino acid ester residue of formula (iv):

R 4 is (a) —C 1-4 alkyl, (b) —C 1-4 alkyl substituted with —OH, —SH, —SCH 3 , —NH 2 , —NH—C(═NH)—NH 2 , (c) —CH 2 -phenyl, (d) —CH 2 -phenol, (e) —(CH 2 ) 1-2 —COOH, (f) —(CH 2 ) 1-2 —CONH 2 , (g) —CH 2 -1H-indole, (h) —CH 2 -imidazole, (i) aryl or (j) heteroaryl;
R 5 and R 6 are each CH 3 ; and
R 9 is —C 1-10 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein one of R 1 and R 2 is H, and the other is H or —C 1-4 alkyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R 3 is —C 3-8 alkyl.

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

R 4 is —C 1-4 alkyl; and
R9 is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 1 is H or —C 1-4 alkyl;
R 2 is H or —C 1-4 alkyl,
R 3 is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R 4 is —CH 3 ;
R 5 and R 6 are both —CH 3 ;
and
R 9 is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
one of R 1 and R 2 is H, and the other is methyl or i-propyl;
R 3 is i-propyl;
R 4 is —CH 3 ;
and
R 9 is —C 3-8 alkyl, cyclobutyl, cyclopentyl or cyclohexyl.

8. The compound of claim 1 that is:
1-methylethyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
1-methylethyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
1-methylethyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
1-methylethyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
1-methylethyl (3S)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate;
1-methylethyl (3S)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate;
1-methylethyl (3R)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate;
1-methylethyl (3R)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate;
1-methylethyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2R)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
1-methylethyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2R)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclopentyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclopentyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclobutyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclobutyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclohexyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
cyclohexyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
2-methylpropyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
2-methylpropyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
butyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
butyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
pentyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
pentyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
heptyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
heptyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate;
isopropyl (3R)-3-(((S)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)butanoate;
isopropyl (3R)-3-(((R)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)butanoate;
1-methylethyl (3S)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1R)-2-(cyclobutyloxy)-1-methyl-2-oxoethyl]amino}phosphoryl]amino}butanoate;
1-methylethyl (3S)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1R)-2-(cyclobutyloxy)-1-methyl-2-oxoethyl]amino}phosphoryl]amino}butanoate;
cyclobutyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclobutyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclohexyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclohexyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclopentyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclopentyl N—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate;
cyclobutyl N—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alan

Assignees

• Merck Sharp & Dohme

Inventors

• Vachal Petr
• Raheem Izzat
• Guo Zhiqiang
• Hartingh Timothy John

Classifications

• C07F9/65616 Primary

  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

• C07F9/16

  Esters of thiophosphoric acids or thiophosphorous acids · CPC title

• A61P43/00

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

• A61P31/18

  for HIV · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title