HIV protease inhibitors

Patent metadata

Field	Value
Publication number	US-9994587-B2
Application number	US-201515123111-A
Country	US
Kind code	B2
Filing date	Mar 2, 2015
Priority date	Mar 6, 2014
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The present invention is directed to 2,6-morpholine derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein Z 1 , Z 2 , V 1 , V 2 , V 3 , R 6 , R 6A , and X are defined herein. The invention also relates to methods of using the 2,6-morpholine derivatives of the invention for the inhibition of HV protease, the inhibition of HV 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. 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 1 is a bond, CH 2 , or O;
V 2 is CH 2 ;
V 3 is CH 2 ; or
alternatively, V 2 and V 3 may come together to form (i) a phenyl group, which is optionally substituted with up to 4 occurrences of X D , or (ii) HetA, wherein V 2 is C or CH and V 3 is C, CH, or N;
X is H or NR 1 R 2 ;
each occurrence of X D is independently selected from halo, hydroxy, ═O, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —S(O) k C 1 -C 4 alkyl, CF3, CN, C 0 -C 4 alkyl-phenyl;
each k is independently 0, 1 or 2;
Z 1 is selected from the group consisting of:

L is a linker selected from
(a) a bond,
(b) —C 1 -C 3 alkylene-,
(c) —C 2 -C 4 alkenylene-,
(d) —CH 2 —CF 2 —
(e) —C(O)—,
(f) —CH2—C(O)—,
(g) —CH2—CH2—C(O)—, and
(h)

L 1 is selected from the group consisting of: S, S(O), S(O) 2 , O, C 1 -C 3 alkylene, and a bond; each r is independently 1, 2, 3 or 4;
Z A is selected from the group consisting of:
(a) hydrogen,
(b) C 1 -C 10 alkyl,
(c) C 2 -C 10 alkenyl,
(d) C 2 -C 10 alkynyl,
(e) C 3 -C 7 cycloalkyl,
(f) AryA,
(g) HetB, and
(h) HetC,

wherein said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, and C 3 -C 7 cycloalkyl, are optionally substituted with 1 to 6 substituents independently selected from the group consisting of: fluoro, hydroxyl, carbomoyl, C 3 -C 6 cycloalkyl, C(O)O—C 1 -C 6 alkyl, C(O)OH, C(O)—C 1 -C 6 alkyl, N(H)—C 1 -C 6 alkyl, N(—C 1 -C 6 alkyl) 2 , AryA, HetB and HetC;
each R 3 is independently H or C 1 -C 6 alkyl;
Z 2 is H; or alternatively Z 1 and Z 2 , together with the carbon atom to which they are attached may form a spirocyclic 3- to 6-membered monocyclic heterocycloalkyl group, a spirocyclic 5- or 6-membered monocyclic heterocycloalkenyl group, or a spirocyclic 3- to 6-membered cycloalkyl group; wherein said 3- to 6-membered monocyclic heterocycloalkyl group, said 5- or 6-membered monocyclic heterocycloalkenyl group, or said 3- to 6-membered cycloalkyl group may be optionally substituted with X A from one up to the maximum number of substitutable positions as allowed by valence;
R 6 is selected from

wherein the asterisk (*) denotes the point of attachment to the rest of the compound and U1 is selected from (1) H, (2) C 1 -C 10 alkyl, wherein said C 1 -C 10 alkyl is optionally substituted with 1 to 4 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy and C 1 -C 4 alkoxy, (3) C 3 -C 7 cycloalkyl, wherein said C 3 -C 7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy and C 1 -C 4 alkoxy, (4) AryA, (5) HetB, (6) HetC, (7) C 1 -C 10 alkyl substituted with AryA, (8) C 1 -C 10 alkyl substituted with HetB, and (9) C 1 -C 10 alkyl substituted with HetC; and Ring B is selected from C 3 -C 7 cycloalkyl, HetB, and HetC, wherein C 3 -C 7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, C 1 -C 4 fluorolkyl and C 1 -C 4 alkoxy;
R 6A is selected from H or C 1 -C 6 alkyl;
alternatively, R 6 and R 6A together with the carbon to which they are attached form a C 3 -C 6 cycloalkyl, which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with from 1 to 3 X E ;
each occurrence of X A , X B , X C , X E , Y B and Y C are independently selected from the group consisting of:
(1) C 1 -C 6 alkyl,
(2) C 3 -C 6 cycloalkyl,
(3) C 1 -C 6 haloalkyl,
(4) OH,
(5) O—C 1 -C 6 alkyl,
(6) O—C 1 -C 6 haloalkyl,
(7) O—C 3 -C 6 cycloalkyl,
(8) SH,
(9) S—C 1 -C 6 alkyl,
(10) S—C 1 -C 6 haloalkyl,
(11) S—C 3 -C 6 cycloalkyl,
(12) halo,
(13) CN,
(14) NO 2 ,
(15) NH 2 ,
(16) N(H)—C 1 -C 6 alkyl,
(17) N(—C 1 -C 6 alkyl)2,
(18) N(H)C(O)—C 1 -C 6 alkyl,
(19) N(H)CH(O),
(20) CH(O),
(21) C(O)—C 1 -C 6 alkyl,
(22) C(O)OH,
(23) C(O)O—C 1 -C 6 alkyl,
(24) C(O)NH 2 ,
(25) C(O)N(H)—C 1 -C 6 alkyl,
(26) C(O)N(—C 1 -C 6 alkyl) 2 ,
(27) C(O)N(H)C(O)—C 1 -C 6 alkyl,
(28) C(O)N(H)CH(O)
(29) SO 2 H,
(30) SO 2 — C 1 -C 6 alkyl;
(31) phenyl, benzyl or phenoxy, each optionally substituted with 1 to 5 substituents independently selected from halo and C 1 -C 6 alkyl,
(32) HetD, —O-HetD or —CH 2 —HetD,
(33) trimethylsilyl,
(34) C 2 -C 6 alkenyl, and
(35) SO 2 —NH 2

wherein C 1 -C 6 alkyl in each instance of (1), (3) (5), (6), (9), (10), (16), (17), (18), (21), (23), (25), (26), (27), (30), and (31) and C 2 -C 6 alkenyl of (34) above is optionally substituted with 1 to 6 substituents independently selected from the group consisting of:
(a) C 1 -C 6 haloalkyl,
(b) OH
(c) O—C 1 -C 6 alkyl,
(d) O—C 1 -C 6 haloalkyl,
(e) O—C 3 -C 6 cycloalkyl,
(f) SH,
(g) S—C 1 -C 6 alkyl,
(h) halo,
(i) CN,
(j) NO 2 ,
(k) NH 2 ,
(l) N(H)—C1-6 alkyl,
(m) N(—C 1 -C 6 alkyl) 2 ,
(n) C(O)—C 1 -C 6 alkyl,
(o) C(O)OH,
(p) C(O)O—C 1 -C 6 alkyl, and
(q) SO 2 — C 1 -C 6 alkyl;

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

each AryA is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with Y B from one up to the maximum number of substitutable positions as allowed by valence;
each HetA is an independently a 5- or 6-membered monocyclic heteroaryl containing from 1 to 4 N, wherein the moncyclic ring is optionally substituted with up to 3 occurrences of X D ;
each HetB is a heteroaryl which is independently (i) a 5- or 6-membered monocyclic heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a 9-, 10- or 11-membered bicyclic heteroaromatic ring containing from 1 to 6 heteroatoms independently selected from N, O and S; wherein the monocyclic ring (i) or the bicyclic ring (ii) is optionally substituted with Y C from one up to the maximum number of substitutable positions as allowed by valence; and

Assignees

• Merck Canada Inc
• Merck Sharp & Dohme

Inventors

• Mccauley John A
• Bennett David Jonathan
• Bungard Christopher J
• Greshock Thomas J
• Holloway M Katharine
• Williams Peter D
• Beaulieu Christian
• Crane Sheldon
• Lessard Stephanie
• Mckay Daniel
• Molinaro Carmela
• Moradei Oscar Miguel
• Sivalenka Vijayasaradhi
• Truong Vouy Linh
• Tummanapalli Satyanarayana

Classifications

• A61K31/5375

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

• C07D498/10 Primary

  Spiro-condensed systems · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title