HIV protease inhibitors

Patent metadata

Field	Value
Publication number	US-9315475-B2
Application number	US-201314021930-A
Country	US
Kind code	B2
Filing date	Sep 9, 2013
Priority date	Sep 11, 2012
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The compounds encompassed by Formula I include compounds which are HIV protease inhibitors and other compounds which can be metabolized in vivo to HIV protease inhibitors. The compounds and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
V is CH 2 or O;
Y 1 , Y 2 , Y 3 and Y 4 are independently selected from C(R) and N;
each X is independently selected from H and NR 7 R 8 ;
Z is selected from the group consisting of

L is a linker selected from
(a) a bond,
(b) —CH 2 —,
(c) —C(O)—,
(d) —CH 2 —C(O)—** or —C(O)—CH 2 —**,
(e) —CH 2 —CH 2 —C(O)—** or —C(O)—CH 2 —CH 2 —**, and

wherein ** shows the point of attachment to the morpholine and when Z is

 then L is not a bond;
R is selected from H, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-S(O) k —, CF 3 , CN, benzyl, or two R groups on adjacent atoms may be joined together with the atoms to which they are attached to form a fused phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, CF 3 and CN;
each k is independently 0, 1 or 2;
each r and t are independently 1, 2, 3 or 4;
Z A is selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 2-10 alkenyl,
(4) C 3-7 cycloalkyl,
(5) AryA,
(6) HetA,
(7) HetB,

wherein said C 1-10 alkyl, C 2-10 alkenyl and C 3-7 cycloalkyl are optionally substituted with 1 to 6 substituents as allowed by valence independently selected from the group consisting of: fluoro, hydroxy, carbamoyl, C 3-6 cycloalkyl, C(O)O—C 1-6 alkyl, C(O)OH, C(O)—C 1-6 alkyl, N(H)—C 1-6 alkyl, N(—C 1-6 alkyl) 2 , ArylA, HetA and HetB;
each R A is independently H or C 1-6 alkyl;
or Z A and R A and the nitrogen atom to which they are attached may be joined together to form a 5-, 6- or 7-membered mono-cyclic, or 9- or 10-membered bi-cyclic, saturated, aromatic or partially aromatic ring, said ring optionally containing 1 to 3 additional heteroatoms selected from O, S and N, and said ring optionally substituted with from 1 to 3 X A ;
each R 6 independently is:

 wherein the asterisk (*) denotes the point of attachment to the rest of the compound and U 1 is selected from H, C 1-10 alkyl, ArylA, HetA and HetB;
each R 6A independently is H or C 1-6 alkyl;
alternatively, R 6 and R 6A together with the carbon to which they are attached form a C 3-6 cycloalkyl which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with from 1 to 3 X D ;
each X A , each X B , each X C , each X D , each Y B and each Y C are independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 3-6 cycloalkyl,
(3) C 1-6 haloalkyl,
(4) OH,
(5) O—C 1-6 alkyl,
(6) O—C 1-6 haloalkyl,
(7) O—C 3-6 cycloalkyl,
(8) SH,
(9) S—C 1-6 alkyl,
(10) S—C 1-6 haloalkyl,
(11) S—C 3-6 cycloalkyl,
(12) halo,
(13) CN,
(14) NO 2 ,
(15) NH 2 ,
(16) N(H)—C 1-6 alkyl,
(17) N(—C 1-6 alkyl) 2 ,
(18) N(H)C(O)—C 1-6 alkyl,
(19) N(H)CH(O),
(20) CH(O),
(21) C(O)—C 1-6 alkyl,
(22) C(O)OH,
(23) C(O)O—C 1-6 alkyl,
(24) C(O)NH 2 ,
(25) C(O)N(H)—C 1-6 alkyl,
(26) C(O)N(—C 1-6 alkyl) 2 ,
(27) C(O)N(H)C(O)—C 1-6 alkyl,
(28) C(O)N(H)CH(O)
(29) SO 2 H,
(30) SO 2 —C 1-6 alkyl;
(31) phenyl, benzyl or phenoxy, each optionally substituted with 1 to 5 substituents selected from halogen and C 1-6 alkyl,
(32) HetA, —O-HetA or —CH 2 -HetA, optionally substituted with 1 to 5 substituents selected from halogen and C 1-6 alkyl,
(33) trimethylsilyl, and
(34) C 2-6 alkenyl, wherein C 1-6 alkyl in each instance of (1), (3) (5), (6), (9), (10), (16), (17), (18), (21), (23), (25), (26), (27), (30), (31) and (32) above is optionally substituted with 1 to 6 substituents as allowed by valence selected from the group consisting of:
(a) C 1-6 haloalkyl,
(b) OH
(c) O—C 1-6 alkyl,
(d) O—C 1-6 haloalkyl,
(e) O—C 3-6 cycloalkyl,
(f) SH,
(g) S—C 1-6 alkyl,
(h) halo,
(i) CN,
(j) NO 2 ,
(k) NH 2 ,
(l) N(H)—C 1-6 alkyl,
(m) N(—C 1-6 alkyl) 2 ,
(n) C(O)—C 1-6 alkyl,
(o) C(O)OH,
(p) C(O)O—C 1-6 alkyl, and
(q) SO 2 —C 1-6 alkyl;

T is O, S, S(O), or SO 2 ;
m is an integer equal to 0, 1, 2, or 3;
n is an integer equal to 0, 1, 2, or 3;
R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl substituted with C 3-6 cycloalkyl, C(O)—R K or SO 2 —R K ;
R 8 is H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
R K is:
(1) C 1-6 alkyl,
(2) C 3-6 cycloalkyl,
(3) C 1-6 alkyl substituted with C 3-6 cycloalkyl,
(4) O—C 1-6 alkyl,
(5) O—C 1-6 alkyl substituted with O—C 1-6 alkyl,
(6) O—C 1-6 fluoroalkyl,
(7) C(O)O—C 1-6 alkyl,
(8) C 1-6 alkyl substituted with C(O)O—C 1-6 alkyl,
(9) C 1-6 alkyl substituted with C(O)OH,
(10) C 1-6 alkyl substituted with C(O)—C 1-6 alkyl,
(11) N(H)—C 1-6 alkyl,
(12) N(—C 1-6 alkyl) 2 ,
(13) C 1-6 alkyl substituted with NH 2 , N(H)—C 1-6 alkyl, or N(—C 1-6 alkyl) 2 ,
(14) AryA,
(15) C 1-6 alkyl substituted with AryA,
(16) O—C 1-6 alkyl substituted with AryA,
(17) HetA,
(18) C 1-6 alkyl substituted with HetA,
(19) O—C 1-6 alkyl substituted with HetA,
(20) HetB,
(21) O-HetB, or
(22) O—C 1-6 alkyl substituted with HetB;

each AryA is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 3 Y B ;
each HetA is a heteroaryl which is independently (i) a 5- or 6-membered monocyclic heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or (ii) is a 9-, 10- or 11-membered bicyclic heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the monocylcic ring (i) or the bicyclic ring (ii) is optionally substituted with from 1 to 3 Y C ; and
each HetB is independently a 4- to 7-membered, saturated or unsaturated, non-aromatic heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O) 2 , and wherein the saturated or unsaturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, CN, C 1-6 alkyl, OH, oxo, O—C 1-6 alkyl, C 1-6 haloalkyl, O—C 1-6 haloalkyl, C(O)NH 2 , C(O)N(H)—C 1-6 alkyl, C(O)N(—C 1-6 alkyl) 2 , C(O)H, C(O)—C 1-6 alkyl, CO 2 H, CO 2 —C 1-6 alkyl, SO 2 H, or SO 2 —C 1-6 alkyl.

2. The compound according to claim 1 wherein R 6 is:

wherein W 1 to W 5 are independently C or N, with the proviso that no more that three are N, and R 6A is H.

3. The compound according to claim 1 wherein Z is

and L is —C(O)—.

4. The compound according to claim 1 wherein Z is

Assignees

• Beaulieu Christian
• Bennett David J
• Bungard Christopher J
• Chang Ronald K
• Crane Sheldon
• Greshock Thomas J
• Hao Li
• Holloway Kate
• Manikowski Jesse J
• Mccauley John A
• Mckay Daniel
• Molinaro Carmela
• Moradei Oscar Miguel
• Nantermet Philippe G
• Nadeau Christian
• Tummanapalli Satyanarayana
• Shipe William
• Singh Sanjay Kumar
• Truong Vouy Linh
• Vijayasaradhi Sivalenka
• Williams Peter D
• Wiscount Catherine M
• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

• Beaulieu Christian
• Bennett David J
• Bungard Christopher J
• Chang Ronald K
• Crane Sheldon
• Greshock Thomas J
• Hao Li
• Holloway Kate
• Manikowski Jesse J
• Mccauley John A
• Mckay Daniel
• Molinaro Carmela
• Moradei Oscar Miguel
• Nantermet Philippe G
• Nadeau Christian
• Tummanapalli Satyanarayana
• Shipe William
• Singh Sanjay Kumar
• Truong Vouy Linh
• Vijayasaradhi Sivalenka
• Williams Peter D
• Wiscount Catherine M

Classifications

• A61P31/18

  for HIV · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D265/30 Primary

  not condensed with other rings · CPC title

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title