Piperazine derivatives as hiv protease inhibitors

Patent metadata

Field	Value
Publication number	US-2016159752-A1
Application number	US-201414908421-A
Country	US
Kind code	A1
Filing date	Jul 29, 2014
Priority date	Jul 31, 2013
Publication date	Jun 9, 2016
Grant date	—

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

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from C 3-7 cycloalkyl or

wherein C 3-7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH;
p is an integer equal to 1 or 2;
Q is N(H)S(O) 2 —**, N(C 1-4 alkyl)S(O) 2 —**, —S(O) 2 —, —C(O)—, —O—C 1-6 alkylenyl-C(O)—** or CH 2 —, wherein the double asterisk (**) is the point of attachment of Q to the nitrogen atom in the piperazine or 1,4-diazepane ring depicted in Formula I;
V is CH 2 or O;
Y 1 , Y 2 , Y 3 and Y 4 are independently selected from C(R) and N;
X is selected from H, OR 8 and NR 7 R 8 ;
each R is independently selected from H, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, 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, C 1-4 alkoxyC 1-4 alkyl, CF 3 and CN;
each k is independently 0, 1 or 2;
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) ArylA,
(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, ArylA-O—, HetA, HetA-O—, HetB and HetB-O—;
each R 1 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected from halogen, OC(O)NH 2 , OC(O)N(H)—C 1-6 alkyl or OC(O)N(—C 1-6 alkyl) 2 , or two R 1 groups on adjacent carbon atoms or the same carbon atom may be joined together with the atoms to which they are attached to form a fused 3- to 6-membered nonaromatic cyclic ring;
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 and C 1-4 alkoxyl;

R 6A is selected from H or C 1-6 alkyl;
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 1-6 fluoroalkyl
(3) C 3-6 cycloalkyl,
(4) C 1-6 alkyl substituted with C 3-6 cycloalkyl,
(5) O—C 1-6 alkyl,
(6) O—C 1-6 alkyl substituted with O—C 1-6 alkyl,
(7) O—C 1-6 fluoroalkyl,
(8) C(O)O—C 1-6 alkyl,
(9) C 1-6 alkyl substituted with C(O)O—C 1-6 alkyl,
(10) C 1-6 alkyl substituted with C(O)OH,
(11) C 1-6 alkyl substituted with C(O)—C 1-6 alkyl,
(12) N(H)—C 1-6 alkyl,
(13) N(—C 1-6 alkyl) 2 ,
(14) C 1-6 alkyl substituted with NH 2 , N(H)—C 1-6 alkyl, or N(—C 1-6 alkyl) 2 ,
(15) ArylA,
(16) C 1-6 alkyl substituted with ArylA,
(17) O—C 1-6 alkyl substituted with ArylA,
(18) HetA,
(19) C 1-6 alkyl substituted with HetA,
(20) O—C 1-6 alkyl substituted with HetA,
(21) HetB,
(22) O-HetB, or
(23) O—C 1-6 alkyl substituted with HetB;

each ArylA is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 4 Y B ;
each HetA is a heteroaromatic ring system 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 4 Y C ; and
each HetB is independently a 4- to 7-membered monocyclic, or 9-, 10- or 11-membered bicyclic, saturated or unsaturated, non-aromatic heterocyclic ring system 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 4 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, N(H)SO 2 —C 1-6 alkyl, N(H)C(O)—C 1-6 alkyl, SO 2 H, SO 2 —C 1-6 alkyl, C(O)N(H)—C 1-6 haloalkyl, C(O)N(—C 1-6 alkyl)(—C 1-6 haloalkyl), C(O)N(—C 1-6 haloalkyl) 2 , C(O)—C 1-6 haloalkyl, CO 2 —C 1-6 haloalkyl, N(H)SO 2 —C 1-6 haloalkyl, N(H)C(O)—C 1-6 haloalkyl, or SO 2 —C 1-6 haloalkyl.

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

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D401/14

  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

• C07D405/14

  containing three or more hetero rings · CPC title