HIV protease inhibitors

Patent metadata

Field	Value
Publication number	US-9834526-B2
Application number	US-201415104510-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 19, 2013
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention is directed to 2,5,6-substituted morpholine derivatives 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. 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 1 and Z 2 are independently selected from the group consisting of

or Z 1 and Z 2 may be joined together with the atoms to which they are attached to form HetB;
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;
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, and
(7) HetB,

wherein said C 1-10 alkyl, C 2-10 alkenyl and C 3-7 cycloalky 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 of X A ;
R 6 is selected from:

wherein the asterisk (*) denotes the point of attachment to the rest of the compound and U 1 is selected from (1) H, (2) C 1-10 alkyl, wherein said C 1-10 alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy and C 1-4 alkoxy, (3) C 3-7 cycloalkyl, wherein said C 3-7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy and C 1-4 alkoxy, (4) ArylA, (5) HetA, (6) HetB, (7) C 1-10 alkyl substituted with ArylA, (8) C 1-10 alkyl substituted with HetA, and (9) C 1-10 alkyl substituted with HetB; and Ring B is selected from C 3-7 cycloalky and HetB, wherein C 3-7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, OH, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 alkoxy;
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 of 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 or 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 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 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.

Assignees

• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

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

Classifications

• A61P31/18

  for HIV · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/12

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

• C07D513/04

  Ortho-condensed systems · CPC title