Piperazine derivatives as HIV protease inhibitors

Patent metadata

Field	Value
Publication number	US-10138255-B2
Application number	US-201515124635-A
Country	US
Kind code	B2
Filing date	Mar 6, 2015
Priority date	Mar 10, 2014
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention is directed to compounds of Formula I 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 structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is O or CH 2 ;
Ring A is

wherein * indicates the point of attachment to X* in Formula I and ** indicates the point of attachment to N** in Formula I;
one, two or three of Y 1 , y 2 , y 3 and Y 4 are N and the others are C(R);
HetAr is:
(a) a 5-membered (including the two carbons that are the points of attachment to X* and N** in Formula I) monocyclic heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or
(b) a 9-, 10- or 11-membered (including the two carbons that are the points of attachment to X* and N** in Formula I) bicyclic heteroaromatic ring system containing from 1 to 4 heteroatoms independently selected from N, O and S;

p is an integer selected from 1, 2 or 3;
R is independently selected at each occurrence from,
(a) —H,
(b) halo, —OH, —SH, —CN, —NO 2 , or —N(R 3a ) 2 ,
(c) —C 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl or —O—C 1-3 alkyl-phenyl,
(d) —OC 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl or —O—C 1-3 alkyl-phenyl,
(e) —C 1-6 alkyl-O—C 1-3 alkyl unsubstituted or substituted with 1 to 6 of —F,
(f) —C(O)OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F, or
(g) —C(O)C 1-6 alkyl unsubstituted or substituted with 1-6 of —F;

Z 1 is

R a and R b are independently selected from —H and —C 1-3 alkyl;
R c is —C 1-3 alkyl or —C 3-6 cycloalkyl and R c is unsubstituted or substituted with 1-3 of —F;
R d is —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F or —C 3-6 cycloalkyl unsubstituted or substituted with 1-3 of —F;
m is the integer 1;
Z 2 is —H or —NHR 3 ;
R 2a is
(a) —C 1-6 alkyl unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-3 of —F; or —OR c ;
(b) —C 3-6 cycloalkyl unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —C 1-3 alkyl —OR c ; —OR d ; —COOH; or —C(O)OR d ;
(c) phenyl unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —C 1-3 alkyl-O—R c ; —OR d ; —COOH; —C(O)OR d ; or —C 3-6 cycloalkyl unsubstituted or substituted with 1-3 of —F;

wherein the tetrahydropyran is unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F;
(e) pyridinyl unsubstituted or substituted with one to four substituents independently selected at each occurrence from
(i) halo, (ii) —OH,
(iii) —C 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl, or —O—C 1-3 alkyl-phenyl,
(iv) —OC 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl, or —O—C 1-3 alkyl-phenyl,
(v) —C 1-6 alkyl-O—C 1-3 alkyl unsubstituted or substituted with 1 to 6 of —F,
(vi) ═O (oxo),
(vii) —C(O)OC 1-6 alkyl optionally substituted with 1-6 of —F, or
(viii) —C(O)C 1-6 alkyl optionally substituted with 1-6 of —F;

(f) pyrimidinyl, unsubstituted or substituted with one to four substituents independently selected at each occurrence from
(i) halo, (ii) —OH,
(iii) —C 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl, or —O—C 1-3 alkyl-phenyl,
(iv) —OC 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, or (ii) —OH, —C(O)OC 1-6 alkyl, —O—C 1-6 alkyl, or —O—C 1-3 alkyl-phenyl,
(v) —C 1-6 alkyl-O—C 1-3 alkyl unsubstituted or substituted with 1 to 6 of —F,
(vi) ═O (oxo),
(vii) —C(O)OC 1-6 alkyl optionally substituted with 1-6 of —F, or
(viii) —C(O)C 1-6 alkyl optionally substituted with 1-6 of —F;

unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —C 3-6 cycloalkyl unsubstituted or substituted with 1-3 of —F;

(i) morpholinyl;
(j) piperidinyl, unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F;
—OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —C(O)OR 1 ;
(k) pyrazinyl, unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —C(O)OR 1 ;
(l) thiazolyl, unsubstituted or substituted with one to three substituents independently selected at each occurrence from halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —C(O)OR 1 ;
(m) pyrazolyl, unsubstituted or substituted halo; —OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —C(O)OR 1 ; or

R 1 is (i) —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F, phenyl or —C 3-6 cycloalkyl, or (ii) —S(O) 2 —C 1-6 alkyl;
R 2b is —H, —C 1-6 alkyl or —OC 1-6 alkyl, wherein each of —C 1-6 alkyl or —OC 1-6 alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, —OH, or —OC 1-6 alkyl;
or R 2a and R 2b are joined together with the carbon to which they are both attached to form (a) —C 3-6 cycloalkyl, (b) piperidinyl, or (c) tetrahydro-(2H)-furanyl;
wherein each of cycloalkyl, piperidinyl and tetrahydro-(2H)-furan is unsubstituted or substituted with one to four substituents independently selected at each occurrence from halo;
—OH; —C 1-6 alkyl unsubstituted or substituted with 1-6 of —F; —OC 1-6 alkyl unsubstituted or substituted with 1-6 of —F; or —COOC 1-3 alkyl unsubstituted or substituted with 1-6 of —F;

R 3 and R 3a are independently selected at each occurrence from
(a) —H,
(b) —C 1-6 alkyl unsubstituted or substituted with (i) 1 to 6 of —F, (ii) —OH, (iii) —C(O)OC 1-3 alkyl, (iv) —O—C 1-3 alkyl, or (v) —O—C 1-3 alkyl-phenyl,
(c) —C(O)OC 1-6 alkyl unsubstituted or substituted with (i) 1-6 of —F, (ii) —C 3-6 cycloalkyl or (iii) —NH 2 , or
(d) —C(O)C 1-6 alkyl unsubstituted or substituted with (i) 1-6 of —F, (ii) —C 3-6 cycloalkyl or (iii) —NH 2 ;
n is an integer selected from 1, 2 or 3;
R 4 is independently selected at each occu

Assignees

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

Inventors

• Williams Peter D
• Mccauley John A
• Bungard Christopher J
• Bennett David Jonathan
• Waddell Sherman T
• Morriello Gregori J
• Chang Lehua
• Dwyer Michael P
• Holloway M Katharine
• Crespo Alejandro
• Chu Xin-Jie
• Wiscount Catherine
• Loughran H Marie
• Manikowski Jesse J
• Schulz Jurgen
• Keertikar Kartik M
• Hu Bin
• Zhong Bin
• Ji Tao

Classifications

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• A61P31/18

  for HIV · CPC title

• C07D513/08 Primary

  Bridged systems · CPC title

• A61K45/06

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