Resistance-repellent retroviral protease inhibitors
Resistance-repellent and multidrug resistant retroviral protease inhibitors are provided. Pharmaceutical composition comprising such compounds, and methods of using such compounds to treat HIV infections in mammals, are also provided.
1. A compound of the formula:
wherein:
D′ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl and aralkyl, and is optionally substituted by alkyl, halo, nitro, cyano, CF 3 , halo-C1-C6 alkyl, O-alkyl, or S-alkyl;
R20 is selected from the group consisting of H, alkyl, alkenyl and alkynyl;
R21 is H or is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl, each optionally substituted by one or more halo, haloalkyl, hydroxy, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino, or mono- or dialkylamino, mono- or diarylamino, mono- or di-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- or dialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- or dialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, aiylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, heteroarylsulfinyl or heteroarylsulfonyl; or
R21 and R31 together with the nitrogen atom to which they are attached, form a 3-8 membered unsubstituted or substituted heterocyclyl or heteroaryl ring; or
R20 and R21 together form a 5-8 membered unsubstituted or substituted heterocyclyl or heteroaryl ring;
R31 is hydrogen, or is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl, each optionally substituted by one or more halo, haloalkyl, hydroxy, hydroxyalkyl, R32, —COH, —COR32, —CO2H, —COOR32, —CONH2, —CONHR32, —CONR32R32, —OR32 OCOR32, —OCONHR32, OCONR32R32, cyano, nitro, amino, NHR32, NR32R32, NHCONH2, NHCONHR32, NHCONR32R32, NR32CONH2, NR32CONHR32, NR32CONR32R32, NHCOOR32, NR32COOR32, SR32, SO 2 NH2, SO 2 NHR32, SO 2 NR32R32, SOR32 or SO 2 R32;
where each R32 is independently alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl; and
R30 is selected from the group consisting of hydrogen, OH and NHR, where R is H or is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and heteroaryl; optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino, or mono- or dialkylamino, mono- or diarylamino, mono- or di-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- or dialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- or dialkylsulfonarnido, mono- or diarylsulfonamido, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;
and the pharmaceutically acceptable salts thereof and stereoisomers thereof.
2. A compound selected from the group consisting of:
{1-Benzyl-3-[(3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-dimethylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(ethyl-methyl-amino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[1-(ethyl-methyl-amino)-ethylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[(methyl-propyl-amino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[1-(methyl-propyl-amino)-ethylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-3-[(3-diethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-diethylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-3-[(3-dipropylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-dipropylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-piperidin-1-ylmethylene-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[2-oxo-3-(1-piperidin-1-yl-ethylidene)-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-piperazin-1-ylmethylene-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(3-morpholin-4-ylmethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{3-[(3-Aminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(3-{[3-(1-Amino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-1-benzyl-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[3-(1-methylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-3-[(3-ethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-ethylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{2-oxo-3-[(2,2,2-trifluoro-ethylamino)-methylene]-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{2-oxo-3-[1-(2,2,2-trifluoro-ethylamino)-ethylidene]-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-({3-[(2-hydroxy-ethylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-({3-[1-(2-hydroxy-ethylamino)-ethylidene]-2-oxo-2,3-dihydro-1 H-indole-5-sulfonyl}-isobutyl-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[(2-methoxy-ethylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo [2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[1-(2-methoxy-ethylamino)-ethylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(2-dimethylamino-ethylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[1-(2-dimethylamino-ethylamino)-ethylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[3-(isopropylamino-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[3-(1-isopropylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-propylaminomethylene-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[2-oxo-3-(1-propylamino-ethylidene)-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-pyrrolidin-2-ylidene-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-3-[(3-butylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-butylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[3-(isobutylamino-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[3-(1-isobutylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(tert-butylamino-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-tert-butylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(2,2-dimethyl-propylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[1-(2,2-dimethyl-propylamino)-ethylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[(2-methyl-butylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[(3-methyl-butylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(3,3-dimethyl-butylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{3-[(1-isopropyl-2-methyl-propylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-phenylaminomethylene-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(benzylamino-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-3-{[3-(1-benzylamino-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(cyclohexylmethyl-amino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-oxo-3-{[(pyridin-4-ylmethyl)-amino]-methylene}-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
(1-Benzyl-2-hydroxy-3-{isobutyl-[2-oxo-3-(phenethylamino-methylene)-2,3-dihydro-1H-indole-5-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-3-({3-[(2-cyclohex-1-enyl-ethylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{2-oxo-3-[(2-pyridin-2-yl-ethylamino)-methylene]-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{2-oxo-3-[(2-phenyl-propylamino)-methylene]-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
[1-Benzyl-2-hydroxy-3-(isobutyl-{2-oxo-3-[(4-phenyl-butylamino)-methylene]-2,3-dihydro-1H-indole-5-sulfonyl}-amino)-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester;
{1-Benzyl-2-hydroxy-3-[isobutyl-(3-nonylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester; and
(1-Benzyl-2-hydroxy-3-{[3-(1-hydroxy-ethylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl]-isobutyl-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester and the pharmaceutically acceptable salts thereof, as single stereoisomers or mixtures of stereoisomers.
3. A compound that is shown in the table:
Compound
R
R′
R″
21
H
Me
Me
25
Me
Me
Me
26
H
Me
Et
27
Me
Me
Et
28
H
Me
Pr
29
Me
Me
Pr
30
H
Et
Et
31
Me
Et
Et
32
H
Pr
Pr
33
Me
Pr
Pr
34
H
CH2CH2CH2CH2CH2
35
Me
CH2CH2CH2CH2CH2
36
H
CH2CH2NHCH2CH2
37
H
CH2CH2OCH2CH2
38
H
H
H
39
Me
H
H
40
H
H
Me
41
Me
H
Me
42
H
H
Et
43
Me
H
Et
44
H
H
CH 2 CF 3
45
Me
H
CH 2 CF 3
46
H
H
CH 2 CH 2 OH
47
Me
H
CH 2 CH 2 OH
48
H
H
CH 2 CH 2 OMe
49
Me
H
CH 2 CH 2 OMe
50
H
H
CH 2 CH 2 NMe 2
51
Me
H
CH 2 CH 2 NMe 2
52
H
H
iPr
53
Me
H
iPr
54
H
H
Pr
55
Me
H
Pr
56
—CH 2 CH 2 —
H
—CH 2 linked to R
57
H
H
Bu
59
Me
H
Bu
60
H
H
iBu
61
Me
H
iBu
62
H
H
tBu
63
Me
H
tBu
22
H
H
CH 2 tBu
64
Me
H
CH 2 tBu
65
H
H
2-Me-Bu
66
H
H
CH 2 CH 2 i-Pr
67
H
H
CH 2 CH 2 tBu
68
H
H
CH(iPr) 2
69
H
H
Ph
70
H
H
CH 2 Ph
71
Me
H
CH 2 Ph
72
H
H
CH 2 C 6 H 11
73
H
H
CH 2 -4-Pyr
74
H
H
(CH 2 ) 2 Ph
75
H
H
CH 2 CH 2 C 6 H 10
76
H
H
(CH 2 ) 2 -2-Pyr
77
H
H
CH 2 CH(Me)Ph
78
H
H
(CH 2 ) 4 Ph
79
H
H
(CH 2 ) 8 CH 3
81
H
H
(CH2)2OPh
82
H
H
2-CH2CH2NMe-pyrollidine
83
Me
H
(CH2)2-2-Pyridyl
84
H
Et
CH2-4-Pyridyl
85
H
CH2-2-Pyridyl
CH2-2-Pyridyl
86
H
Et
CH2-2-Pyridyl
87
H
H
(CH2)2-3-Pyridyl
88
H
(CH2)5 linked to R
89
H
H
(CH2)3OEt
90
H
H
(CH2)2-4-Pyridyl
91
H
Me
(CH2)2-2-Pyridyl
92
H
H
(CH2)6OH
93
H
C6H11
CH2-2-Pyridyl
94
H
H
(CH2)2SEt
95
H
(CH2)4 linked to R
96
H
H
CH2CH2-4-morpholinyl
97
H
H
s-Bu
98
H
H
CH(Me)iPr
99
H
CH2CH2CH2
CH(CO2Et)CH2 linked to R′
100
H
H
CH(Et)2
101
H
H
CH2cyclopropyl
102
H
Me
cyclohexyl
103
H
H
CH2CH(Et)2
104
H
H
CH(Me)CH2iPr
105
H
H
CH(Me)(CH2)2iPr
106
H
Et
Pr
107
H
H
cyclohexyl
108
H
H
1-Me-Bu
109
H
Me
Bu
110
H
H
cyclopentyl
111
H
Me
iBu
112
H
H
6-Et-2-Pyridyl
113
H
iBu
iBu
114
H
H
cyclobutyl
115
H
Et
iPr
116
H
allyl
cyclopentyl
117
H
H
CH2CH2NHCO2tBu
118
H
Et
Bu
119
H
H
CH2CF2CF3
120
H
Et
isobutenyl
121
H
H
CH2CH2NHPh
122
H
Pr
2-Bu
123
H
H
CH2-2-benzimidazolyl
124
H
H
CH2-2-(5-Me-Pyrazinyl)
125
H
H
CH2CF2CF2CF3
126
H
H
(CH2)2-4-NH2Ph
127
H
H
(CH2)2-4-OHPh
128
H
H
CH2-3,5-(OMe)-4Me-2-Pyridyl
129
H
H
CH2-(2-Me-4-thiazolyl)
130
H
H
CH2-2-quinolinyl
131
Me
H
CH2cyclohexyl
132
H
H
CH2CO2tBu
133
H
H
CH(iPr)CO2Et
134
H
H
CH(CH2Ph)CO2Me
135
H
H
CH(CH2-4-ClPh)CO2Et
136
H
H
CH2CO2CH2Ph
137
H
H
(CH2)2CO2CH2Ph
138
H
CH2Ph
CH2CO2Et
139
H
CH2CH(CO2Me)CH2 linked to R′
140
H
H
CO2Et(NCO2Et)
141
H
H
CO2Et
142
H
H
Ac
143
H
H
Cyclopropyl
144
H
H
CH2-5-benzofuranyl.
4. The compound of claim 1 , wherein the compound is present as a single stereoisomer.
5. A pharmaceutical composition comprising, as an active ingredient, the compound of claim 1 .
6. The pharmaceutical composition of claim 5 , wherein the composition is a solid formulation adapted for oral administration.
7. The pharmaceutical composition of claim 5 , wherein the composition is a liquid formulation adapted for oral or parenteral administration.
8. A pharmaceutical composition comprising the compound of claim 1 , wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.
9. The compound of claim 5 bound in a complex with wild type or a drug resistant mutant form of HIV-1 protease
10. A pharmaceutical composition, comprising the compound of claim 1 and another agent selected from the group consisting of an antiretroviral agent, an HIV inhibitor, an HIV protease inhibitor and an HIV reverse transcriptase inhibitor.
11. A method of treating a patient suffering from HIV infection, comprising administering to said patient the compound of claim 1 .
12. A method of treating a patient suffering from HIV infection, comprising administering to said patient a composition of claim 10 .
13. The method of claim 12 , wherein said patient is suffering from a multi-drug resistant HIV infection.
14. A method of inhibiting an HIV protease, comprising contacting the HIV protease with the compound of claim 1 .
15. A method of inhibiting an HIV protease, comprising contacting the HIV protease with a composition of claim 9 .
16. The method of claim 15 , further comprising administering a cytochrome P450 inhibitor.
17. The compound of claim 1 , wherein the compound is present as a mixture of stereoisomers.