Piperazine derivatives as HIV protease inhibitors

Patent metadata

Field	Value
Publication number	US-9840478-B2
Application number	US-201414908421-A
Country	US
Kind code	B2
Filing date	Jul 29, 2014
Priority date	Jul 31, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention is directed to piperazine derivatives, pharmaceutical compositions comprising the same, and their use in the inhibition of HIV protease, the inhibition of HIV replication, 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.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
Q is —S(O) 2 ;
p is 1;
R 1 is not present or is one substituent selected from (i) —CH 3 unsubstituted or substituted with cyclopropyl, —OC 1-3 alkyl or —O—CH 2 phenyl, (ii) ethyl or (iii) spiro-cyclopropyl;
V is CH 2 ;
X is H, —OH, —NH 2 or —N(H)—C(O)—OC 1-4alkyl;
Ring A is

 or C 3-6 cycloalkyl;
Y 3 is CH or N;
R is H or F;
R 6a is —H;
R 6 is

X B is independently selected at each occurrence from F, Cl, —OCH 3 , —CF 3 or —OCF 3 ;
m is 0, 1 or 2;
Ring B is selected from tetrahydropyranyl or piperidinyl, each optionally substituted with 1 or 2 of methyl;
U 1 is selected from:

 wherein
W 1 is CH or N,
X c is independently selected from F, Cl, —OCH 3 , —CF 3 or —OCF 3 , and
n is 0, 1 or 2,

(2) 1-methylethyl,
(3) tetrahydro-2H-pyran-4-yl unsubstituted or substituted with 1 or 2 of CH 3 , or
(4) —CH 2 -tetrahydro-2H-pyran-4-yl, wherein the tetrahydro-2H-pyran-4-yl is unsubstituted or substituted with 1 or 2 of CH 3 ; and
Z A is
methyl unsubstituted or substituted with cyclopropyl or —CF 3 ,
cyclopropyl,
phenyl or benzyl unsubstituted or substituted with F, Cl, NH 2 , formyl, or —OCH 3 optionally substituted with 1-3 of F,
pyrrolidinyl unsubstituted or substituted with 1 to 3 of F,
piperidinyl unsubstituted or substituted with 1 or 2 of F, —NHC(O)CH 3 , —NHC(O)CF 3 , —NHSO 2 CH 3 , -SO 2 CH 3 , or C 1-4 alkyl,
pyridinyl unsubstituted or substituted with NH 2 ,
pyrazolyl unsubstituted or substituted with methyl,
thiazolyl unsubstituted or substituted with —CH 3 or —NHC(O)CH 3 ,
oxadiazolyl unsubstituted or substituted with —COOC 1-3 alkyl, or
furanyl unsubstituted or substituted with —CH 3 .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
Ring A is

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Ring A is C 3-6 cycloalkyl.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof wherein R 6 is

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof wherein R 6 is

6. The compound according to claim 1 of Formula Ic

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof wherein:
Z A is
methyl unsubstituted or substituted with cyclopropyl or —CF 3 ,
cyclopropyl,
phenyl or benzyl unsubstituted or substituted with F, Cl, NH 2 , formyl, or —OCH 3 optionally substituted with 1-3 of F,
pyrrolidinyl unsubstituted or substituted with 1 or 3 of F, or
pyridinyl unsubstituted or substituted with NH 2 .

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein U 1 is

 one XB group is present and substituted at the 4-position, one or two X C groups are present and substituted at the 3- or 3,5-positions respectively, and the X B group is a different group with respect to either X C group.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,wherein Z A is methyl unsubstituted or substituted with cyclopropyl or —CF 3 .

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z A is cyclopropyl.

11. A compound selected from the group consisting of:
2S-Amino-3,3-di-(4-fluorophenyl)-N-(5-fluoro-4-(2-(1-methylsulfonylpiperazin-2-yl)ethyl)pyridin-3-yl)propanamide;
Methyl ((S)-1-((3-fluoro-2-(2-((S)-1-(phenylsulfonyl)piperazin-2-yl)ethyl)phenyl)amino)-3,3-bis(3-fluorophenyl)-1-oxopropan-2-yl)carbamate;
(S)-2-Amino-N-(5-fluoro-4-(2-((S)-1-(phenylsulfonyl)piperazin-2-yl)ethyl)pyridine-3-yl)-3,3-bis(3-fluorophenyl)propanamide;
Methyl ((1S,2S)-1-(4-chlorophenyl)-3-((3-fluoro-2-(2((S)-1-(phenylsulfonyl)piperizin-2-yl)ethyl)phenyl)amino)-1-(6-methoxypyridin-3-yl)-3-oxopropan-2-yl)carbamate;
(2S,3S)-2-amino-3-(4-chlorophenyl)-N-(3-fluoro-2-(2-((S)-1-(phenylsulfonyl)piperazin-2-yl)ethyl)phenyl)-3-(5-(trifluoromethyl)pyridine-3-yl)propanamide;
Methyl ((2S,3R)-1-((3-fluoro-2-(2-((2S,6S)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl)ethyl)phenyl)amino)-3-(4-fluorophenyl)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)carbamate;
Methyl ((2S,3R)-3-(4-chlorophenyl)-1-((5-fluoro-4-(2-((2S,6S)-6-methyl-1-(phenylsulfonyl)piperzin-2-yl)ethyl)pyridin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate;
(2S,3R)-2-Amino-3-(4-chlorophenyl)-N-(5-fluoro-4-(2-((2S,6S)-1-((4-methoxyphenyl)sulfonyl)-6-methylpiperazin-2-yl)ethyl)pyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;
(S)-2-Amino-N-(3-fluoro-2-(2-((2S,6S)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl)ethyl)phenyl)-3,3-bis(3-fluorophenyl)propanamide;
Methyl ((1S,2S)-1-(4-chlorophenyl)-3-((4-(2-((2S,6S)-1-(cyclopropylsulfonyl)-6-methylpiperazin-2-yl)ethyl)-5-fluoropyridin-3-yl)amino)-1-(3-fluorophenyl)-3-oxopropan-2-yl)carbamate;
Methyl (1R,2S)-1-(4-chlorophenyl)-3-(2-(2-((2S,6S)-1-(cyclopropylsulfonyl)-6-methylpiperazin-2-yl)ethyl)-3-fluorophenylamino)-3-oxo-1-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate;
(βS)-β-(3,5-difluorophenyl)-4-fluoro-N-(5-fluoro-4-{2-[(2S,6R)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl]ethyl}pyridin-3-yl)-L-phenylalaninamide;
(βS)-4-chloro-N-(3-fluoro-2-{2-[(2S,6R)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl]ethyl}phenyl)-β-(6-methoxypyridin-3-yl)-L-phenylalaninamide;
(βS)—N-(4-{2-[(2S,6R)-1-(cyclopropylsulfonyl)-6-methylpiperazin-2-yl]ethyl}-5-fluoropyridin-3-yl)-β-(3,5-difluorophenyl)-4-fluoro-L-phenylalaninamide;
(βS)-β-(3,5-difluorophenyl)-4-fluoro-N-[3-fluoro-2-(2-{(2S,6R)-1-[(4-methoxyphenyl)sulfonyl]-6-methylpiperazin-2-yl}ethyl)phenyl]-L-phenylalaninamide;
(βR)-4-chloro-N-(5-fluoro-4-{2-[(2S,6R)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl]ethyl}pyridin-3-yl)-Nα-(methoxy carbonyl)-β-(1-methylethyl)-L-phenylalaninamide;
Methyl ((1R,2S)-1-(4-chlorophenyl)-3-((3-fluoro-2-(2-((2S,6R)-1-((4-fluorophenyl)sulfonyl)-6-methylpiperazin-2-yl)ethyl)phenyl)amino)-3-oxo-1-(tetrahydro-2H-pyran-4-yl)propan-2-yl)carbamate;
Methyl ((1S,2S)-1-(4-chlorophenyl)-3-((3-fluoro-2-(2-((S)-5-phenylsulfonyl)-5,8-diazaspiro[2.6]nonan-6-yl)ethyl)phenylamino)-1-(6-methoxypyridin-3-yl)-3-oxopropan-2-yl)carbamate;
Methyl ((2S,3R)-1-((3-fluoro-2-(2-((S)-5-(phenylsulfonyl)-5,8-diazaspiro[2.6]nonan-6-yl)ethyl)phenyl)amino)-3-(4-fluorophenyl)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)carbamate;
N-(4-{2-[1-(benzylsulfonyl)piperazin-2-yl]ethyl}-5-fluoropyridin-3-yl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalaninamide
(S)-2-amino-N-(5-fluoro-4-(2-((S)-1-(phenylsulfonyl)piperazin-2-yl)ethyl)pyridin-3-yl)-3,3-bis(4-fluorophenyl)p

Assignees

• Merck Sharp & Dohme
• Msd R&D (China) Co Ltd

Inventors

• Williams Peter D
• Mccauley John A
• Bennett David Jonathan
• Bungard Christopher J
• Chang Lehua
• Dwyer Michael P
• Holloway M Katharine
• Keertikar Kartik M
• Loughran H Marie
• Manikowski Jessie J
• Morriello Gregori J
• Shen Dong-Ming
• Sherer Edward C
• Schultz Jurgen
• Waddell Sherman T
• Wiscount Catherine M
• Zorn Nicolas
• Chu Xin-Jie
• Tummanapalli Satyanarayana
• Sivalenka Vijayasaradhi
• Hu Bin
• Ji Tao
• Zhong Bin

Classifications

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P31/18

  for HIV · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title