MXPA00011244A - Retroviral protease inhibiting compounds - Google Patents

Abstract

The present invention discloses novel compounds, compositions, and methods for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease. The present invention also relates to compositions and methods for treating a retroviral infection and in particular a HIV infection, and to processes for making such compounds and synthetic intermediates employed in these processes.

Description

COMPOUNDS TO INHIBIT RETROVIRAL PROTEASE TECHNICAL FIELD The present invention relates to novel compounds, compositions and methods for inhibiting retroviral proteases, and in particular for inhibiting human immunodeficiency virus (HIV) protease. The present invention also relates to compositions and methods for treating a retroviral infection, and in particular, an HIV infection, and to processes for making said synthetic intermediates and compounds used in these processes.

BACKGROUND OF THE INVENTION Retroviruses are those viruses that use a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadanvirus and Caulimovirus families. Retroviruses cause a variety of disease states in humans, animals and plants. Some of the most important retroviruses from a pathological point of view include human immunodeficiency virus (HIV-1 and VI H-2), which cause the acquired immunodeficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and human liver carcinomas, human T cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia virus, which cause leukemia in domestic animals. Proteases are enzymes that unfold proteins into specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the renin protease unfolds the peptide angiotesinogen to produce the angiotensin I peptide. Angioteñin I is also split by the protease angiotensin converting enzyme (ACE) to form the angiotensin I I hypotensive peptide. Renin and ACE inhibitors are known to reduce high blood pressure in vivo. A retroviral protease inhibitor will provide a therapeutic agent for diseases caused by the retrovirus. The retrovirus genomes encode a protease that is sensitive to the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See, Wellink, Arch. Virol. 9_8 1 (1988). More commonly, retroviral proteases process gag precursor in core proteins, and also process the pol precursor in reverse transcriptase and retroviral protease. In addition, retroviral proteases are of specific sequence. See, PearI, Nature 328 482 (1987). The correct processing of the precursor polyproteins through the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vitro mutagenesis that produces defective protease viruses leads to the production of immature nucleus forms lacking infectious ability. See, Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, inhibition of retroviral protease provides an attractive target for antiviral therapy. See, Mitsuya, Nature 325 775 (1987). Current treatments for viral diseases usually involve the administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve the administration of compounds such as 3'-azido-3'-deoxyrymidine (AZT), 2 ', 3'-dideoxycytidine (DDC) and 2 \ 3'-dideoxyinosine (DDI) and compounds that treat opportunistic infections caused by immunosuppression that results from infection by VI H. None of the current SI DA treatments have proven to be totally effective in treating and / or reversing the disease. In addition, many of the compounds currently used to treat SIAD cause adverse side effects including low platelet counts, renal toxicity, and spinal cord cytopenia. Recently, inhibitors of VI H protease, ritonavir, saquinavir, nelfinavir and indinavir, have been approved in the United States for the treatment of VI H infections. However, there is a great need for improved VI H protease inhibitors.

COMPENDIUM OF THE INVENTION The present invention comprises retroviral protease inhibitor compounds having the formula V. i wherein R1 is a thiazolyl group having the formula: and R is a group that has the formula: where the group R4 is -WR5. The group R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is selected from the group consisting of -O-, -S-, or - (CH2) n-, where n is from 0 to 6, provided that when W is O, or S then Y is CH. R5 is selected from the group consisting of alkyl and aryl. Optionally, R4 and the ring to which it is attached, taken together can form a bicyclic ring having the formula: The group R6 is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl or (heteroaryl) alkyl, Z is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. The present invention also comprises retroviral protease inhibitor compounds having the formula: II wherein R is a thiazolyl group having the formula: R S. -r N Jl and R2 is a group that has the formula: \ '^ R8 wherein X is -C (O) - or -S (O) 2- and R8 is alkyl, aryl, (aryl) alkyl, alkylamine, dialkylamino, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and R9 is alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. The group Z is -O-, -S-, -CH2- or -N- (R7) -, and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or alkyl ( heteroaryl). The alkyl, aryl, heterocyclic, and heteroaryl groups in the compounds of the invention can be optionally substituted with from 1 to 5 substituents and preferably from 1 to 3 substituents. The substituents are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, aicylamino, dialkylamino and halogen. The invention also includes pharmaceutically acceptable salts, esters or prodrugs of the compounds I and IL DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present description, including definitions, will prevail. The present invention comprises retroviral protease inhibitor compounds having the formula V. wherein R1 is a thiazolyl group having the formula: R is a group that has the formula: where the group R4 is -WR5.

The group R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is selected from the group consisting of -O-, -S-, or - (CH2) n-, where n is from 0 to 6, provided that when W is O, or S then Y is CH. R5 is selected from the group consisting of alkyl and aryl. Optionally, R4 and the ring to which it is attached, taken together can form a bicyclic ring having the formula: provided that when W is O, or S then Y is CH. The group R6 is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl or (heteroaryl) alkyl, A is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. The present invention also comprises retroviral protease inhibitor compounds having the formula IV.

II wherein R1 is a thiazolyl group having the formula: R2 is a group that has the formula: VN '^ R8 wherein X is -C- (O) - or -S (O) -2 and is alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R9 is alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl or (heteroaryl) alkyl. The group Z is -O-, -S-, -CH2- or -N- (R7) -, and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. The alkyl, aryl, heteroaryl, and heterocyclic groups of the compounds of the invention, having the formula I or II, can optionally be substituted with from 1 to 5 substituents and preferably from 1 to 3 substituents. The substituents are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamine, dialkylamino and halogen. The invention also includes pharmaceutically acceptable salts, esters or prodrugs of the compounds I and II. In the compounds of the invention, a R3 group is an alkyl or cycloalkyl group. Most preferred are compounds wherein R3 is alkyl selected from the group consisting of methyl, ethyl, or propyl, or cycloalkyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The most preferred group R3 is isopropy. Preferred Z groups are -O-, or -N (R7) -. When Z is -N (R7) - a preferred R7 group is methyl. In the compounds having the formula _, and R2 is a group having the formula: wherein Y is CH or N and R4 is -W-R5, the preferred R5 group is aryl selected from the group consisting of phenyl, methylenedioxyphenyl and heteroaryl. In compounds where Y is nitrogen, W is - (CH2) n-, R5 is alkyl or aryl, and n is from 0 to 6. In compounds where Y is CH, a preferred group W is -O-, and preferably , R5 is alkyl or aryl selected from the group consisting of phenyl, methylenedioxyphenyl and heteroaryl. The alkyl, aryl, heterocyclic, and heteroaryl groups can be substituted with from 1 to 5 substituents and preferably from 1 to 3 substituents. Examples of substituents, for the alkyl, aryl, heterocyclic and heteroaryl groups, are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. Preferred substituents are fluorine, hydroxy, alkoxy or alkylthio groups. The preferred alkoxy is methoxy. The preferred halogen is fluorine. In a preferred embodiment, the alkyl or aryl groups can be substituted with 1 to 3 groups. Preferred substituents are hydroxy, methoxy or fluorine. Preferred aryl groups include phenyl, such as, for example, methylenedioxyphenyl and heteroaryl such as, for example, furanyl, thienyl, benzothienyl, thiazolyl, and the like. A preferred heteroaryl group is thiazolyl. In a preferred compound N is zero and R 5 is methyl substituted with a thiazolyl group. The group R6 is selected from the group consisting of alkyl, hydroxyalkyl and cycloalkyl. Preferably R6 is a lower alkyl group such as, for example, methyl, ethyl, propyl, butyl and the like. A preferred R6 group is tert-butyl or hydroxybutyl. The group R8 is selected from the group consisting of alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl. A group R8 is (alkyl) amino, such as, for example, (tert-butyl) amino. The preferred R9 group is a lower alkyl group such as, for example, propyl, butyl, pentyl, and the like. The most preferred R9 groups are isopropyl, tert-butyl, isobutyl, 3-methyl-1-butyl, and the like. Very preferred is the iso-butyium group. In a preferred compound of the invention, X is -S (O) 2, Rd is aryl selected from the group consisting of phenyl and heteroaryl and R9 is iso-butyl. In the compounds of the invention, combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. As used herein, the term "stable compound" refers to a compound that is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture and formulation to a suitable therapeutic dosage form for administration . The preferred compounds of the invention are selected from the group consisting of: 2- (1-methylethyl) -4-thiazoyl-Imethi - [(1S) -1 - [[[(1S, 2R) -3 (2S) -4 - (1,3-benzodioxol-5-ylmethyl) -2 - [[(1,1-dimethylethyl) ami] n-n-nyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl ] -2-methyl-propyI] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethyl-etiI) amino] carbonyl ] -4- (f -methylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazoylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) 2 - [[(1,1-dimethyIthiI) amino] carbonyl] -4 - [(4-f luorof eni I) methyl I] 1 -piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] - 4- (5-thienylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylimethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] - 4- [4- (3-hydroxyphenyl) methyl] -1-piperazinyl] -2-hydroxy-1 - (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] - 4- (3-pyridinylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] - 4- (4-pyridinylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-d-imethylethyl) amino] ] carbonyl] -4 - [(4-hydroxyphenyl) methyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) 4- (1H-benzimidazol-2-ylmethyl) -2 - [[( 1,1-dimethylethyl) amino] carbonyl] -1-piperazine iiJ-2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropylcarbamate; 2- (1-Methylethyl) -4-thiazolyImethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethyl-lethyl) amino] carbonyl] -4- (2-quinolinylmethyl) -1-piperazinyl] -2-hydroxy-1 - (phenolmethyl) pro-pil] amino] carbonyl] -2- methyl I propi I] carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl [(1S) -1 - [[[(1S, 2R) -3 - [(2S) 4 - [(3,4-di methoxy) -Ineenyl] -2] - [[(1, 1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy- 1- (nyl methyl I) pro pyl] amino] carbo ni l] -2-m eti I propi i ] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazoylmethyl) - 1-piperazinyl] -2-hydroxy-1- (phenylimethyl) propy] amino] -carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (phenylimethyl) -1- piperazinyl] -2-hydroxyl- (phenylmethyl) propyl] amino] -carbonyl] -2-methy1propyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4 - [(4-hydroxy) 3-methoxyphenyl) methyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) -propiI] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl-jurea; 2-methyl-4-tiazolylmethi - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4- (1,3-benzodioxol-5-ylmethyl) -2- [ [(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2-methy1-4-razoylymethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-d imethoxyl) methyl] -2- [[(1, 1-dimethylethyl) ami] carbon] I] 1 -piperazin-I] -2-hydroxy-1- (phenymethyl) propyl] amino] carbonyl] 2-methylpropyl-j-carbamate; 2-methyI-4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) -amino] carboniI] -4 - [( 4-f luorofenyl) meti I] - 1-piperazyl nyl] -2-hydroxy-1 - (phenylmethyl) propyl] amino] carbonyl] -2-methylpropii] carbamate; 2-ethyl-4-thiazolylmethyl- (lS) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyphenyl) m etiI] -2 - [[(1 , 1-dimethylethyl) amino] carbonyl] -1 piperazinyl] -2-hyd roxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -5-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -4 - [(3,4-dimethoxyphenyl) methyl] -2- [ [(1,1-dimethyl-ethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyI] amino] carbonyl] -2-methylpropyl] carbamate; 2-ethyl-5-thiazolymethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyphenyl) metiI] -2 - [[(1, 1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylimethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2-methyI-5-thiazolyImethyl - [(1S) -1- [t [(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyphenyl) methyl] -2 - [[(1 , 1-di methyl ethyl) amino] carbo nyl] -1-piperazinyl] -2-h id roxy-1 - (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; N, - [(1R) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazoylmethyl) ) -1-piperazinyl] -2-idroxy-1- (phenylmethyl) propyl] amino] -carbonyl] -2-methy1propyl] -N-methyl-N- (5-thiazolylmethyl) urea; N, - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazoylmethyl) - 1-piperazinyl] -2-hydroxy-1 - (phenylmethyl) pro-phenyl] -no] carbonyl] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea; 5-tiazoliImetiI - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbon il] -4- (phenylamide) - 1-piperazinyl] -2-hydroxy I - (fe nylmethyl) propy I] amino] carbonyl] -2-methylpropy] carbamate; 5-thiazolyImethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazole-methyl) - 1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyI] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [[[(1,1-dimethylethyl) amino] carbonyl] (2-methylethyl) p ropi lamin or] -2-hydroxy -1 (phenylmethyl) propyl] amino] ca rbonyl] -2-methyropropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea; 2- (1-methylethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [[[(1,1-dimethylethyl) aminojcarbon ii] (2- methylethyl) propi I amino ] 2-hydroxy-1 - (phenylmethyl) propyl] amino] carb onyl] -2-me ti Ipropiljcarb amato; 2- (1-Methylethyl) -4-thiazoylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (1-methylethyl) amino] -2- hydroxy-1- (phenylimethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (1-methylethyl) amino] -2-h idroxy-1- (phenylmethyl) propyl ] amino] carbonyl] 2-methylpropyl] - N -methyl- N- [2- (1-methyl ethyl) -4-thiazolylmethyl] urea; 2- (1-Methylethyl) -5-thiazolymethyl - [(1S) -1 - [[[(1S, 2R) -3 [(3S) -3 - [[(1,1-dimethylethyl) amino] carbonyl] ( 4aa, 8aa) octahydro-2-isoquinolinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; N * - [(1S) -1-. { [[(1S, 2R) -3 - [(3S) -3 - [[(1,1-dimethylethyl) amino] carbonyl] (4aa, 8aa) octahydro-2-isoquinolinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -5-thiazolylmethyl] urea; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S, 4R) -2 - [[(1,1-dimethyethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) ?) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propyljamino] carbonyl] -2-methyIpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea; 2- (1-Methylethyl) -4-thiazolylmethyl [(1S) -1 - [[[(1S, 2R) -3 [(2S, 4R) -2 - [[(1,1-dimethylethyl) to me not] carbonyl] -4- (5-thiazolyl-methoxy) -1-piperidinyl] -2-h idroxy-1- (phen ylmethyl) propyljam and no] carbonyl] -2-methylpropyl] carbamate; S- [2- (1-Methylethyl) -4-thiazolylmethyl] [(1S) -1 - [[[(1S, 2R) -3 [(2S) -4- (1,3-benzodioxol-5-ylmethyl)] -2 - [[(1,1-dimethylethyl) aminojca rbonyl] -1-piperazinyl] -2-hydroxy-1 (phenylmethyl) propyI] amino] carbonyl] -2-methylpropylcarbamothioate; and 4- (1,3-benzodioxol-5-ylmethyl) -N- (1,1-dimethylethyl) -1 - [(2R, 3S) -3 - [[(2S) -2 - [[3- [2 - (1-methylethyl) -4-thiazolyl] -1-oxopropyl] amino] -3-methyl-1-oxobutyl] amino] -2-hydroxy-4-phenylbutyl] -2-pi? Ezinecarboxamide; or a pharmaceutically acceptable salt, ester or prodrug thereof. The highly preferred compounds of the invention are selected from the group consisting of: 2- (1-Methylethyl) -4-thiazolyImethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -4 - (1,3-benzodioxol-5-ylmethyl) -2 - [[(1,1-dimethyl-ethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] a lno] carbonyl] -2-m eti l prop i I] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (1-methylethyl) amino] -2-hydroxy- 1- (phenylmethyl) propyl] amino] carbo n? IJ-2-methyl propi I carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethyl ethyl) ami no] carbonyl] -4- (5-thien i I meti I) - 1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl [(1S) -1 - [[[(1S, 2R) -3 - [(2S) 4 - [(3,4-di methoxyl) enyl) methyl] -2 - [[(1, 1 -dimeti I eti i) amino] carbon i I - 1 -piperazin i I] -2-hydroxy-1- (phenylmethyl) p ropy] ami no] carbonyl] -2- methy I propi I] carbamate; N * - [(1S) -1 - [[[(1S, 2R) -3 - [(2S, 4R) -2 - [[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazoylme toxi) - 1-piperidinyl] -2-h id roxi-1 - (phenylmethyl) propi I] ami no] carbon nil] -2- methyl I prop i I] - N-met? lN- [2- (1- metUeti!) - 4-thiazole! methyl] urea; and 2- (1-Methylethyl) -5-thiazoIiImetiI - [(1S) -1 - [[[(1S, 2R) -3 - [(3S) -3 - [[(1,1-dimethyl etiI) amino) carbonyl] (4aa, 8aa) octahydro-2-isoquinolinyl] -2-hydroxy-1- (phenylmethyl) pro pil] to my non] carbonyl] 2-methylpropyl] carbamate; or a pharmaceutically acceptable salt, ester or prodrug thereof. The term "alkyl" as used herein, refers to branched straight chain alkyl radicals containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to branched straight chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl , sec-butyl, t-butyl n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like. The alkyl groups can be substituted or unsubstituted with from 1 to 5 substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamine, dialkylamino and halogen. The alkyl groups may be optionally interrupted by one or more heterogeneous atoms selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus. The term "cycloalkyl", as used herein, refers to an aliphatic ring system having from 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexium, and the like. The term "alkoxy" as used herein, refers to groups having the formula -OR 10, wherein R 1 0 is a lower alkyl group. The term "thioalkyl" as used herein, refers to groups having the formula -SR1 1, wherein R 1 1 is a lower alkyl group.

The term "alkylamino" as used herein, refers to groups having the formula -NH R 12, wherein R 12 is a lower alkyl group. The term "dialkylamino" as used herein, refers to groups having the formula -N (R13) 2, wherein R13 is a lower alkyl group. The term "halo or halogen" as used herein, refers to F, Cl, Br or I. The term "(halo) alkyl" as used herein, refers to a lower alkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl , fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, and the like. The term "aryl" as used herein, refers to a monocyclic or bicyclic, carbocyclic ring system comprising from 6 to 12 carbon atoms and having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups can be substituted or unsubstituted with one to five substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The term "(aryl) alkyl" as used herein, refers to an aryl group as previously defined, attached to a lower alkyl radical, for example, benzyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle", as used herein, refers to any 3 or 4 member ring containing a heterogeneous atom selected from oxygen, nitrogen and sulfur; or a ring of 5, 6 or 7 members containing one, two or three heterogeneous atoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a ring of 5, 6 or 7 members containing one, two or three nitrogen atoms; an oxygen atom; a sulfur atom; a nitrogen atom and a sulfur atom; a nitrogen atom and an oxygen atom; two oxygen atoms in a non-adjacent position; an oxygen atom and a sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent hydrogen atoms and one sulfur atom; not non-adjacent nitrogen atoms and an oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The heterogeneous nitrogen atoms may optionally be quaternized. The term "heterocyclic" also includes bicyclic groups wherein any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, bistetrah? Drofuranyl or benzothienyl) and heterocyclics include: acetydinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazothinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinium, nololyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, py imidyl and benzothienyl. Heterocyclics also include compounds of the formula: wherein X * is -CH2-, -NH- or -O-, Y * is -C (O) - or [-c (R ") 2] v, wherein R" is hydrogen or alkyl of 1 to 4 carbon atoms and v is 1, 2 or 3 and Z * is - - or -NH-; such as 1, 3-benzodioxoyl, 1,4-benzodioxanyl, and the like. The term "methylenedioxyphenyl" refers to a substituent having the formula: Heterocyclic groups can be unsubstituted or substituted with one to five substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. In addition, heterocycles that have nitrogen can be N-protected. The term "alkyl (heterocyclic)" as used herein, refers to a heterocyclic group attached to a lower alkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl, and the like. The term "heteroaryl" as used herein, refers to a heterocyclic group that contains at least one aromatic ring. Examples include examples such as, for example, furaniio, thienyl, benzothienyl, thiazolyl, and the like. The term β (heteroaryl) alkyl "as used herein, refers to a heteroaryl group attached to a lower alkyl radical including, but not limited to, thienylmethyl, thienylethyl, furanylmethyl, and the like. "or" N-protected "as used herein, refers to those groups that are intended to protect the N-terminus of an amino acid or peptide, or protect an amino group against undesirable reactions during synthetic procedures. commonly used are described by T. H. Greene and PG .M.Wuts, Protective Groups in Organic Svnthesis, 2nd Edition, John Wiley &Sons, New York (1991) .The N-protecting groups comprise acyl groups such as formyl , acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromo-acetyl. trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, oc-chloro-butirifo, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl. 4-nitrobenzoyl , and the like, sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-n? trobenciloxicarbonilo, p-bromobenzyloxycarbonyl, 3,4-dimetoxibenciloxicarboniio, 3, 5-dimethoxybenzyloxy carbonyl, 2,4-dimetoxibenciIoxicarbonilo, 4 methoxybenzyloxycarbonyl, 2-nitro-4, 5-di methoxybenzyloxycarbonyl, 3, 4, 5-tri methoxy enciloxicarbonilo, 1 - (p-biphenylyl) -1 -metiletoxicarbonilo, 3, 4, 5-tri methoxy benzyloxycarbonyl, 1 - (p biphenylyl) - 1 -metiletoxicarboniIo, oc, oc-Dimethyl-3, 5-di methoxybenzyloxycarbonyl, benzhidri I oxycarbonyl, t-butiloxicarboniio, diisopropyl yl methoxy coal, isopropyloxycarbonyl, etoxicarbonilc methoxycarbonyl, allyloxycarbonyl, 2, 2,2-trichloroethoxycarbonyl, phenoxycarbonyl , 4-nitro-phenoxycarbonyl, fUorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethyl Isiliphenyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "derivative of activated carboxylic acid" as used herein, refers to halide acids such as acid chlorides and activated esters including, but not limited to, anhydrides derived from formic acid and acetic acid, anhydrides derived from alkoxycarbonyl such as of isobutiloxicarbinilo chloride and the like, esters derived from N-hydroxysuccinimide, esters derived from N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters 2.4 , 5-trichlorophenol, esters derived from thiophenol, anhydrides derived from propylphosphonic acids, and the like. The term "leaving group" as used herein, refers to a group, which is easily displaced from the compound, such as, for example, a halide (eg, Cl, Br ol) or a sulfonate ( for example, mesylate, tosylate, triflate, and the like). As used herein, the terms "S" and "R" configuration are as defined by I U PAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The compounds of the invention may comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are intended to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual diastereomers of the compounds of the invention. This invention is intended to encompass compounds having the formula I or the formula II, when they are prepared through synthetic processes or through metabolic processes. The preparation of the compounds of the invention through metabolic processes includes those that occur in the human or animal body (in vivo) or processes that occur in vitro. The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Loui.s, 'MO, USA); and Fluka Chemical Corp. (Ronkonoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Astma Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrup Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT 06708). Compounds that are not commercially available can be prepared using methods known from the chemical literature. The compounds of the invention can be prepared as shown in schemes I-III. As summarized in Scheme I, a 2-N-protected phenylalaniiepoxide (e.g., with a benzylox: carbor: ion group) is coupled with a protected piperazine compound (e.g., N-Boc), 1 (using, for example, , 1- (3-dimethylaminopropy) -3-ethylcarbodiimide (EDAC), 1-hydroxybenzotriazoI (HOBT), and an amine, such as, triethylamine, and the like, in an inert solvent, (eg, tetrahydrofuran, methylene chloride, and the like) The protected carboxamide product 3 is deprotected (for example, by treatment with hydrogen gas and a hydrogenation catalyst) The amide carboxamide 3a is then coupled with a carboxylic acid, 4, or an activated derivative of the same, using, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodimide (EDAC), 1-hydroxybenzotriazole (HOBT), and triethylamine in an inert solvent, for example, tetrahydrofuran, methylene chloride, and the like, to provide N-protected piperazine, 5. Piperazine is N-despr otegida with trifluoroacetic acid (TFA), and the like) and alkylated (where X1 is a leaving group) to provide the final product, 6.

SCHEME I 3a For piperidyl compounds, where Y is -CH-, the synthesis is presented in scheme 11, shown below. A mono-protected piperidine carbamate, 7, is alkylated to provide compound 8. The alkylated carbamate is N-deprotected (with, for example, trifiuoroacetic acid, and the like), followed by coupling with the epoxide, 9, to provide carboxamide, 10. The carboxamide is N-deprotected to provide compound 10a. Compound 10a is coupled with a carboxylic acid, 4, or an activated derivative thereof, to provide the product 11.

SCHEME II eleven The synthesis of the compounds of the invention having the group -N (R 9) -X-R 8, is summarized in scheme III. The urea, 12, prepared according to the description in J. Med. Chem., 1993, 36, 288-291, is coupled with a carboxylic acid, 4, or an activated derivative thereof, using, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDAC), 1-hydroxybenzotriazoI (HOBT), and triethylamine in an inert solvent, for example, tetrahydrofuran, methylene chloride, and the like to provide the product 13.

SCHEME lll 12 The following examples will serve to further illustrate the preparation of the novel compounds of the invention.

Example 1 2- (1-Methylethyl) -4-thiazolylmethyl-f (1S) -1-rrf (1S.2R) -3-f (2S) -4- (1,3-benzod-oxo-5-ylmethyl) -2M .1 -di meti I eti 0 ami nol carbo ni 11-1 - piperazin i I-2-hydroxy-1 - (phenylmethipropyl-1-aminocarbonyl-2-methylpropincarbamate. 1A. Benzyl-1-r (1S.2R) -3-r (2S) -3-f (2S 4- (1-1-dimethylethyloxy (carbonyl)) - 2-Ff (1,1-di methylethi no) carboni M-1 -piperazine I1-2- hydroxy-1- (phenylmethylpropylcarbamate) The title compound was prepared according to the method described in J. Med. Chem, 1993, 36,288,291, starting with 3.6 g (12 moles) of N-benzyloxycarbonyl-phenylalanylepoxyde and 3.4 g (mmoles) of N-te r-bu ti 1-4- (tert-bu ti I oxy carbo nil) - pipe razin-2 (S) -carboxam ida, prepared with the method described in J. Med. Chem., 1994 37, 3443-3451. 1 B. 1-r (1S.2R) -3-r (2S) -4- (1,1-Dimethylethioxy (carbonin) -2-rr (1,1-dimethyl-etipamino] carbonyl1-1-piperaziniM-2-hydroxy-1- (phen Lmetip propylamine A solution of 2.1 g (3.36 mmoles) of benzyl-1 - [(1S, 2R) -3-t (2S) -4- (1,1-di-2-hydroxy-1- (phenylmethyl) propyl] carbamate in 20 ml of methanol was treated with hydrogen, at more than one atmosphere, in the presence of Pd / C (50 mg, 10%) and stirred for 2 hours.The catalyst was removed through filtration on a pad of celite and the solvent was evaporated under reduced pressure to provide the title compound as a yellow oil (yield: 1.6 g, 99%). 1 C. 2-p-Methylethyl-4-thiazolylmethyl-MS) -1-rrr (1S.2R) -3-r (2S) -4- (1,1-dimethylethyloxy (carbonyl)) -2- [T1, .1 -di-methylethyl] ) am i nolcarbon 11-1-piperazinyl1-2-hydroxy-1 - (phenyl methyl) propi II am i no] carbo or 11-2-m eti I p rop i II carbamate. A solution of 1.5 g (3.3 mmol) of 1 - [(1S, 2R) -3 - [(2S) -4- (1,1-di methylethyl oxy (carbon il)) - 2 - [[1, 1- dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyI] amine in 7 ml of tetrahydrofuran (THF) and 7 ml of methylene chloride was prepared and treated with 1.0 g (3.3 mmol). ) of [(2-isopropyl-4-thiazoyl) methyloxycarbonyl] -L-vain, 642 mg (3.3 mmol) of 1- (3-dimethylaminopropy!) - 3-ethylcarbodiimide (EDAC), 45 mg (0.33 mmol) of 1 -hydroxybenzotriazole (HOBT), and 466 μl (3.3 mmol) d triethylamine. The solution was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with equal portions of a solution of 3 N HCl, 10% aqueous NaHC 3 (20 ml), saturated brine, and dried over MgSO 4. The product was concentrated in vacuo and purified by chromatography on silica gel using methanol: 5% methylene chloride to provide the title compound (yield 2.4 g, 98%). MS: 731 (M + H) + 1 H NMR (DMSO-dβ) d 1.08 (d, J = 7 Hz, 6H), 2.78 (heptet, J = 7 Hz, 1H), 9.06 (br s, 1H), 9.30 (br s, 1H). 1D. 2- (1-Methylene-4-thiazolylmethyl- (1S) -1-frr (1S.2R) -3f (2S) -2-ff (1,1-dimethylethylamino-1-carbonyl-1-piperazin-2-hydroxy-1) - (f eni Im ethyl) pro pilla my nol carbo ni 11-2- me ti 1 propi II carbamate A solution of 2.4 g (3.2 mmoles) of 2- (1-methylethyl) -4-thiazoylmethyl-1 ( 1S) -1 - [[[(1S-2R) -3 - [(2S) -4- (1,1-dimethylethylloxy (carbonyl)) - 2 - [[(1,1-dimethylthi I) -amino) carbonyl] -1-pperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate in 20 ml of dichloromethane was prepared and treated with 2 ml of acid The reaction was verified through TLC.After completion of the reaction the solvent was removed under reduced pressure.The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO and saturated brine.The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound as a light yellow oil (yield: 2.0 g, 90%). 1 E. 2-M-Methylethyl) -4-thiazolylmethyl-rM S) -1 -rrr (1 S.2R) -3r (2S) -4- (1,3-benzodioxol-5-ylmethi-2-IT ( 1.1-dimethylethyl-aminocarbonyl-1-pe pe razinin-2-hydroxy-1 - (phenylmethyl) propylmethylcarbonyl-2-methyl propyl carbamate A solution of 514 mg (0.82 mmol) of 2- (1-methyl ethyl) -4-thiazoylmethyl- (1S) -1 - [[[(1 S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carboni I] - 1 - pipe raziniI ] -2-hydroxy-1 - (fe or I methyl) propi I] ami no] carbo or I] -2-methylpropylJcarbamate in 5 ml of dimethylformamide (DMF) was prepared and treated with 140 mg (0.8 mmol) of chloride of 3, 4-dioxomethylenebenzyl followed by 284 μl (1.6 mmoles) of N, N-diisopropyl ethyl amine, was stirred at room temperature overnight, and was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel, using methanol: methylene chloride to provide the title compound (yield: 502 mg; 81%). MS: 765 (M + H) +. 1 H NMR (CDCl 3) d 0.67 (d, J = 6.3 Hz, 3 H), 0.83 (d, J = 6.3 Hz, 3 H), 1 .37 (s, 9 H), 1 .41 (t, J = 7.5, 6H), 2.05 (hex, J = 6.0 Hz, 1H), 2.26 (m, 1H), 2.41 (m, 1H), 2.58 (m, 2H), 2.73 (m, 3H), 2.83 (m, 2H), 2.90 (m, 1H), 3.33 (AB, J = 15.0 Hz, 2H), 3.46 (s, 2H), 3.80 (m, 1H), 3.93 (m, 1H), 4.22 (septet, J = 4.5 Hz, 1H) ), 5.08 (m, 1H), 5.17 (d, J = 4.5 Hz, 2H), 5.97 (s, 2H), 6.13 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 6.75 (s) , 2H), 7.12-7.22 (m, 7H), 8.19 (br s, 1H).

EXAMPLE 2 2- (1-Methylethyl) -4-thiazolemethyl-r (1S) -1-rrr (1S.2R) -3-r (2S) -2-ri? 1.1-d-methyl-ethyl-amino] -carbon -4- (f -methylmethyl) -1-piperazinyl-1-hydroxy-1- (phenylmethyl) propyl my nolcarbonin-2-methylpropipcarbamate. The title compound was prepared according to the method described in Example 1E, substituting benzyl bromide in place of 3,4-dioxomethylbenzyl chloride. MS: 721 (M + H) \ 1 H NMR (CDCl 3) d 0.68 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J = 6.3, 6H), 2.04 (hextet, J = 6.0 Hz, 1H), 2.28 (dt, J = 9.3, 3.3 Hz, 1H), 2.45 (dt) , J = 12.0, 3.0 Hz, 1H), 2.58 (m, 2H), 2.75 (m, 2H), 2.88 (m, 2H), 3.33 (heptet, J = 6.3 Hz, 1H), 3.37 (m, 1H) , 3.46 (s, 2H), 3.79 (m, 1H), 3.85 (dd, J = 8.4, 6.0 Hz, 1H), 4.22 (septet, J = 4.5 Hz, 1H), 5.11 (dd, J = 10.8, 7.5 Hz, 1H), 5.17 (d, J = 3.3 Hz, 2H), 6.13 (d, J = 9.0 Hz, 2H), 7.12-7.33 (m, 11H), 8.02 (s, 1H), 8.26 (br s, 1 HOUR).

Example 3 2- (1-Methylene-4-thiazolylmethyl-1 (1S) -1-rrf (1S.2R) -3-r (2S) -2-lf (1,1-dimethylethyl) amino] carbonill-4 -f (f luorof in i I) methi 11-1-piperazin ill-2-hydroxy-1 - (phenyl-methylpropyl-methyl-carbon-carbon-2-methyl-propanecarbamate.) The title compound was prepared according to the method described in Example 1E, replacing 4-fluorobenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride MS: 739 (M + H) +. 1 H NMR (CDCl 3) d 0.67 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J = 7.5, 6H), 2.06 (hextet, J = 6.0 Hz, 1H), 2.30 (m, 1H), 2.48 (m, 1H) , 2.59 (m, 1H), 2.73 (m, 2H), 2.83 (m, 2H), 2.92 (m, 2H), 3.33 (AB, J = 15.0 Hz, 2H), 3.37 (m, 1H), 3.44 ( s, 2H), 3.83 (m, 2H), 4.22 (m, 1H), 5.09 (m, 1H), 5.17 (d, J = 4.8 Hz, 2H), 6.19 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.12-7.22 (m, 9H), 8.09 (br s, 1H).

Example 4 2-p-Methylene-4-thiazolylmethyl-rMS) -1-rr (1S.2R) -3-r (2S) -2-rr (1,1-dimethylethylamino-1-carbonyl-4- (5-thienylmethyl) 1-1-piperazinyl-1-hydroxy-1- (phenylmethyl-1-methylcarbonyl-2-methylpropylcarbamate.) The title compound was prepared according to the method described in Example 1E, replacing 5- (chloromethyl) thiazole in place of 3,4-dioxomethylenebenzyl MS: 728 (M + H) 1 H NMR (CDCl 3) d 0.68 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H), 1.38 (s, 9H) ), 1.41 (d, J = 7.5, 6H), 2.06 (hextet, J = 6.0 Hz, 1H), 2.33 (m, 1H), 2.58 (m, 2H), 2.73 (m, 2H), 2.83 (m, 2H), 2.90 (m, 1H), 3.33 (heptet, J = 4.5 Hz, 1H), 3.36 (m, 1H), 3.73 (d, J = 3.0 Hz, 2H), 3.80 (m, 1H), 3.83 ( dd, J = 7.5, 6.0 Hz, 1H), 4.22 (septet, J = 4.5 Hz, 1H), 5.07 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 4.5 Hz, 2H), 6.15 ( d, J = 7.5 Hz, 1H), 7.12-7.22 (m, 8H), 7.40 (m, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 8.80 (s, 1H).

Example 5 2- (1-Methylethyl-4-thiazolylmethyl-r (1S) -1-rrrMS.2R) -3-r (2S) -2-rr (1,1-dimethylethyl-aminocarbonyl) -4-r4- (3- hydroxyphenyl) methyl] -1-piperazinyl-1-2-hydroxy-1- (phenylmethyl) propyl-1-ylcarbonyl-1-methylpropyl-1-carbamate The title compound was prepared according to the method described in Example 1E, substituting 3-hydroxybenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride MS: 737 (M + H) +.! H NMR (CDCl 3) d 0.67 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H) , 0.96 (m, 1H), 1.37 (s, 9H), 1.40 (d, J = 7.5, 6H), 2.03 (hextet, J = 6.0 Hz, 1H), 2.32 (m, 1H), 2.45 (m, 1H ), 2.61 (m, 2H), 2.76 (m, 2H), 2.85 (m, 2H), 2.89 (m, 2H), 3.32 (m, 1H), 3.37 (s, 1H), 3.42 (m, 1H) , 3.61 (t, J = 8.4 Hz, 1H), 3.87 (m, 2H), 4.22 (m, 1H), 4.63 (s, 1H), 5.16 (s, 2H), 6.36 (m, 1H), 6.78 ( d, J = 7.5 Hz, 2H), 7.12-7.22 (m, 9H), 8.19 (br s, 1H).

Example 6 2- (1-Methylene-4-thiazolylmethyl-f (1S) -1-ffr (1S.2R) -3-r (2S) -2-rf (1,1-dimethylethylcarbonyl-1-4- (3 -pyridinylmethyl) -1-piperazinyl-2-h-idroxy-1- (phenylmethylpropyl-1-aminocarbonyl-1-methylpropylcarbamate.) The title compound was prepared according to the method described in Example 1E, substituting 3-picolyl chloride hypochlorite. instead of 3,4-dioxomethylenebenzyl chloride MS: 722 (M + H) +. 1 H NMR (CDCI) d 0.68 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H) , 1.36 (s, 9H), 1.41 (d, J = 7.5 Hz, 6H), 2.06 (hextet, J = 4.5 Hz, 1H), 2.47 (m, 1H), 2.60 (m, 2H), 2.71 (m, 2H), 2.81 (m, 1H), 2.83 (m, 2H), 2.92 (m, 1H), 3.34 (heptet, J = 4.5 Hz, 1H), 3.35 (m, 1H), 3.51 (s, 2H), 3.81 (m, 1H), 3.85 (m, 1H), 4.22 (m, 1H), 4.75 (m, 1H), 5.07 (d, J = 9.0 Hz, 1H), 5.17 (d, J = 7.8 Hz, 2H ), 6.15 (d, J = 7.8 Hz, 1H), 7.12-7.22 (m, 8H), 7.61 (d, J = 7.8 Hz, 1H) 7.89 (br s, 1H), 8.55 (d, J = 3 Hz , 1H), 8.56 (d, J = 6.0 Hz, 1H).

Example 7 2- (1-Methylethyl-4-thiazolylmethyl-f (1S) -1-frr (1S.2R) -3-f (2S) -2-ir (1,1-dimethylethyl) aminolcarbonyl-4- (4-pyro) Dinylmethyl) -1-piperazinin-2-hydroxy-1- (p-n -methyl) propyl-1-aminolcarbonyl-2-methylpropylcarbamate The title compound was prepared according to the method described in Example 1E, substituting chloride hydrochloride 4-picolyl in place of 3,4-dtoxomethylenebenzyl chloride MS: 722 (M + H) +. 1 H NMR (CDCl 3) d 0.65 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz , 3H), 1.37 (s, 9H), 1.41 (d, J = 7.5, 6H), 2.07 (hextet, J = 6.0 Hz, 1H), 2.37 (m, 1H), 2.57 (m, 1H), 2.62 ( m, 2H), 2.69 (m, 2H), 2.81 (m, 2H), 2.91 (m, 1H), 3.32 (m, 1H), 3.34 (m, 1H), 3.49 (AB, J = 15.0 Hz, 2H ), 3.80 (m, 1H), 3.85 (m, 1H), 4.21 (m, 1H), 4.62 (m, 1H), 5.06 (d, J = 7.5 Hz, 1H), 5.14 (m, 1H), 5.17 (d, J = 4.5 Hz, 2H), 6.14 (d, J = 8.4 Hz, 1H), 7.12-7.22 (m, 8H), 7.77 (br s, 1H), 8.08 (d, J = 6.0 Hz, 2H ).

Example 8 2- (1-Methylethyl-4-thiazolylmethyl-r (1S) -1-rrf (1S.2R) -3-r (2S) -2-ff (1,1-dimethylethylamminol rbonip-4-f (4-hydroxyphenethyl) N-1-piperazine and I1-2-hydroxy-1- (phenylmethylpropyl) aminocarbonyl-2-methylpropylcarbamate The title compound was prepared according to the method described in Example 1E, replacing 4-hydroxybenzyl chloride hydrochloride in place of 3,4-dioxomethylenebenzyl chloride MS: 737 (M + H) \ 1 H NMR (CDCl 3) d 0.68 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J = 7.5, 6H), 2.03 (hextet, J = 4.5 Hz, 1H), 2.27 (dt, J = 7.5, 3.0 Hz, 1H), 2.36 (dd, J = 12.0 , 3.0 Hz, 1H), 2.59 (m, 2H), 2.74 (m, 2H), 2.87 (m, 2H), 2.79 (m, 1H), 2.92 (m, 1H), 3.32 (m, 1H), 3.33 (AB, J = 15.0 Hz, 2H), 3.40 (m, 2H), 3.72 (m, 1H), 3.78 (dd, J = 8.4, 6.0 Hz, 1H), 4.22 (septet, J = 4.5 Hz, 1H) , 5.22 (d, J = 4.5 Hz, 2H), 5.23 (m, 1H), 6.17 (m, 1H), 6.40 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H) , 7.09-7.21 (m, 8H), 8.31 (br s, 1H).

EXAMPLE 9 2-p-Methylethyl-4-thiazolylmethyl-r (1S) -1-rrr (1S.2R) -3-r (2S) -4- (1H-benzimid i azol-2-i I methyl) - 2- [1- (1, 1-dimethylethyl) amino-1-carbonyl-1-piperazylip-2-hydroxy-1- (phenylmethyl) propyl] aminocarbonyl 11-2-methylthiopropyl carbamate. The title compound was prepared according to the method described in Example 1E, substituting 2- (chloromethyl) benzimidazole for 3,4-dioxomethylenebenzyl chloride. MS: 761 (M + H) +. 1 H NMR (CDCl 3) d 0.62 (d, J = 6.3 Hz, 3 H), 0.83 (d, J = 6.3 Hz, 3H), 1.41 (d, J = 7.5, 6H), 1.43 (s, 9H), 2.11 (hextet, J = 4.5 Hz, 1H), 2.52 (m, 1H), 2.57 (dd, J = 12.0, 3.0 Hz , 1H), 2.72 (m, 2H), 2.79 (m, 3H), 3.02 (dd, J = 15.0, 4.5 Hz, 1H), 3.17 (m, 3H), 3.34 (heptet, J = 4.5 Hz, 1H) , 3.85 (m, 2H), 3.95 (d, J = 9.0 Hz, 1H), 4.25 (m, 1H), 4.98 (m, 1H), 5.13 (s, 2H), 5.17 (m, 1H), 6.17 ( m, 1H), 7.12-7.28 (m, 11H), 7.63 (m, 2H).

Example 10 2-p-Methylene-4-thiazolylmethyl-r (1S) -1-rrrpS.2R) -3-f (2S) -2-rr (1.1-dimethyl tile Damin olea rbonill-4- (2 -quinolinylmethyl) -1-pipe razinyl-2-hydroxy-1 - (phenylmethipropinaminolcarbonin-2-methyl-1-propylcarbamate.) The title compound was prepared according to the method described in Example 1E, substituting monohydrochloride 2- (chloromethyl) quinoline instead of 3,4-dioxomethylenebenzyl chloride MS: 772 (M + H) +. 1H NMR (CDCl 3) b 0.67 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.40 (d, J_ = 7.5, 6H), 2.05 ( hextet, J = 6.0 Hz, 1H), 2.50 (m, 1H), 2.61 (m, 2H), 2.70 (m, 1H), 2.71 (m, 2H), 2.85 (m, 2H), 2.92 (m, 1H) ), 3.32 (m, 1H), 3.47 (m, 1H), 3.82 (m, 2H), 3.85 (m, 1H), 4.22 (septet, J = 4.5 Hz, 1H), 4.79 (s, 1H), 5.10 (m, 1H), 5.17 (d, J = 8.4 Hz, 2H), 6.11 (s, 1H), 7.12-7.22 (m, 9H), 7.47 (d, J = 6.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.73 (t, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H).

EXAMPLE 11 2- (1-Methylethyl-4-thiazolylmethyl-r (1S) -1-rrr (1S.2R) -3-r (2S) -4-r (3,4-dimethoxyphenylmethyl-2-ff (1,1-di methylethyl) aminolcarboniH -1-piperazine i II-2-hydroxy-1 - (phen il m eti I) propylated my carbon coal 11-2-m ethyl propy 11 carbamate The title compound was prepared according to the method described in Example 1E, replacing 3,4-dimethoxybenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride. MS: 781 (M + H)? 1H NMR (CDC) d 0.68 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J = 6.3, 6H), 2.05 (hextet, J = 6.0 Hz, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 2.58 (m, 2H), 2.74 (m, 3H), 2.84 (m , 2H), 2.90 (m, 1H), 3.35 (heptet, J = 6.3 Hz, 1H), 3.40 (AB, J = 15.0 Hz, 2H), 3.81 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.21 (m, 1H), 5.08 (m, 1H), 5.17 (d, J = 3.3 Hz, 2H), 6.12 (m, 1H), 6.26 (s, 1H), 6.82 (s, 2H), 7.10-7.22 (m, 8H), 8.21 (br s, 1H).

EXAMPLE 12 N'-r (1S -1 -frr (1S.2R) -3-f (2S) -2-rf (1 .1 -Dimethylethylaminolcarbonin-4- (5-thiazo! Ilmethyl) -1 -p Perazin-p-2-hydroxy-1 - (phenolmethyl) propylamino-1-carbonyl] -2-methylpropyl-N-methyl-N-r2- (1-methylethyl-4-thiazolyl-methyl-urea). 12A. N'-f (1S) -1 -rrr (1 S.2R? -3-r (2S) -2-rr (1 .1 -Dimethylethylamino-1-carbonin-4- (1. 1 -dimeti lethyloxy (carbonyl) ) - 1-piperazinyl-2-hydroxy-1 - (phenylmethyl-propylcarbonyl-2-methylpropyl-1-N-methyl-N-f2- (1-methyl-ethyl-4-thiazolyl-methyl-urea).

A solution of 1.5 g (3.3 mmol) of 1 - [(1 S, 2R) -3 - [(2S) -4- (1,1-dimeti le tyloxy (carboni l)) - 2 - [[( 1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amine in 7 ml of TH F and 7 ml of methylene chloride was prepared and treated with 1.0 g (3.3 mmol) of N-methyI-N - [((((2-isopropyl-4-thiazole I) methyl) am i) carbonyl] -L-valine, 642 mg (3.3 mmol) of EDAC, 45 mg ( 0.33 mmole) of HOBT, and 466 μl (3.3 mmole) of triethylamine. The solution was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with equal portions (15 ml) of a solution of 3 N HCl, 10% aqueous NaHCO3, and saturated brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The mixture was purified by chromatography on silica gel using methanol. 5% methylene chloride to give the title compound (yield: 2.4 g, 98%). 12B. N'-r (1S) -1-rrf (1S.2R) -3-r (2S) -2-rr (1,1-Dimethylenamnamolboncarbonin-1-piperazinill-2-h id roxi-1 - (phenyl) methyl) propyl] amino] carbon ill-2-methyl propyl-m ethi I- N-f2- (1-methyl-ethyl) -4-thiazolylmethylurea A solution of 2.4 g (3.2 mmol) of N '- [(1S) -1 - [(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (1,1-dimethylethyloxy (carbonyl)) - 1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methyl-ethyl) -4-thiazolymethyl] urea in 20 ml of dichloromethane was prepared and treated with 2 ml of trifluoroacetic acid, the reaction was checked by TLC, after the reaction was complete, the solvent was removed under reduced pressure, the residue was dissolved with methylene chloride, washed with saturated NaHCO and saturated brine. The organic layer was dried over MgSO and concentrated in vacuo to provide the title compound as a clear oil (yield: 2.0 g, 90%) .The product was used in Example 12C without further purification. 1. 12C N'-r (1S) -1-frr (1S.2R) -3-f (2S) -2-rr (1,1-Dimethylethylamino-1-carbonyl-1-4- (5-thiazolylmethyl-1-piperazinyl-2-hydroxy -1- (Phenylmethyl) propylaminolcarbonyl-2-methylpropyl-N-methyl-N-f2- (1-methiletip-4-thiazolylmethylurea. The title compound was prepared according to the method described in Example 1E starting with the product, prepared in Example 12B and replacing 5-tα-azolylmethyl chloride in place of 3,4-dioxomethylenebenzyl chloride.

MS: 741 (M + Hf. 1 H NMR (CDC) d 0.75 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H), 1.33 (d, J = 3.0 Hz, 3H), 1.45 (d, J = 3.0 Hz, 3H), 1.47 (s, 9H), 2.18 (m, 1H), 2.40 (dt, J = 7.5, 3.0 Hz, 1H), 2.55 (m, 1H), 2.62 (m , 4H), 2.73 (dd, J = 15.0, 4.5 Hz, 2H), 2.89 (m, 1H), 2.95 (s, 3H), 3.22 (heptet, J = 6.0 Hz, 1H), 3.27 (d, J = 3.0 Hz, 2H), 3.73 (d, J = 3.0 Hz, 2H), 3.87 (m, 1H), 3.99 (dd, J = 6.3, 6.0 Hz, 1H), 4.16 (septet, J = 4.5 Hz, 1H) , 4.37 (s, 2H), 4.61 (br s, 1H), 6.00 (br s, 1H), 6.39 (d, J = 9.0 Hz, 1H), 6.97 (s, 1H), 7.08-7.17 (m, 5H) ), 7.54 (s, 1H), 7.72 (s, 1H), 8.79 (s, 1H).

Example 13 N'-rpS) -1-rrrnS.2R) -3-f (2S) -2-rr (1,1-P-methyl-ethylamino-1-carbonin-4- (phenylmethyl) -1-? I? Erazinin-2-hydroxy-1 - (phenylmethyl) propylaminool carboni 11-2-m eti Ipropyl-N-methyl-N-2 - (1-methylethyl-4-thiazole I metill urea) The title compound was prepared according to the method described in Example 12C , replacing benzyl bromide in place of 5-thiazolylmethyl chloride MS: 734 (M + H) +. 1 H NMR (CDCl 3) d 0.75 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz , 3H), 1.45 (d, J = 7.5 Hz, 6H), 1.46 (s, 9H), 2.15 (hextet, J = 6.3 Hz, 1H), 2.32 (dt, J = 9.0, 3.0 Hz, 1H), 2.51 ( dd, J = 8.4, 3.0 Hz, 1H), 2.59 (dd, J = 8.4, 3.0 Hz, 1H), 2.70 (m, 2H), 2.78 (m, 2H), 2.95 (s, 3H), 3.24 (heptet , J = 7.5 Hz, 1H), 3.32 (t, J = 3.0 Hz, 1H), 3.45 (s, 2H), 3.81 (m, 1H), 4.01 (dd, J = 7.5, 6.0 Hz, 1H), 4.17 (septet, J = 4.5 Hz, 1H), 4.48 (s, 2H), 4.84 (br s, 1H), 5.89 (m, 1H), 6.48 (d, J = 9.0 Hz, 1H), 6.95 (s, 1H) ), 7.07-7.18 (m, 5H), 7.25-7.34 (m, 5H), 8.04 (br s, 1H).

EXAMPLE 14 N'-r (1S) -1-rrr (1S.2R) -3-f (2S) -2-ff (1,1-Dimethylethinylaminolcarbonyl-1-4-r (4-hydroxy-3-methoxyphemptyethyl-1-piperazinip- 2-hydroxy-1- (phenylmethyl) propyl] aminolcarbonin-2-methylpropyl-N-methyl-N-r2- (1-methylethyl) -4-thiazolylmethylurea The title compound was prepared according to the method described in Example 12C, replacing 3-methoxy-4-hydroxybenzyl chloride in place of 5-thiazolymethyl chloride MS: 780 (M + H) +. 1H NMR (CDCl 3) d 0.76 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.36 (d, J = 7.5, 6H), 2.17 (hexet, J = 6.0 Hz, 1H), 2.31 (dt, J = 7.5, 3.0 Hz, 1H), 2.53 (m, 2H), 2.63 (m, 2H), 2.78 (m, 2H), 2.91 (m, 1H), 2.96 (s, 3H), 3.26 (q, J = 7.5 Hz, 2H ), 3.29 (m, 1H), 3.38 (AB, J = 15.0 Hz, 2H), 3.83 (m, 1H), 3.89 (s, 3H), 4.01 (dd, J = 7.5, 6.0 Hz, 1H), 4.17 (septet, J = 4.5 Hz, 1H), 4.38 (s, 2H), 4.77 (m, 1H), 5.58 (s, 1H), 5.92 (m, 1H), 6.38 (d, J = 9.0 Hz, 1H) , 6.77 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 7.12-7.22 (m, 6H), 7 .96 (br s, 1H).

Example 15 2-Metin-4-thiazolylmethyl-1 (1S) -1-rrr (1S.2R) -3-r (2S) -4- (1,3-benzodioxol-5-yl meti 0-2-17 (1.1- dimetylletiDamino 1carbonip-1-piperazinip-2-hydroxy-1- (phenylmethylmethyl-1-car- boyl-2-methylpropylcarbamate, 15A, 2- (1-Methyl) -4-thiazolylmethyl-r (1S) -1-rff (1S.2R) -3 -r (2S) -4- (1,1-di methyl eti l-oxy (carbonyl) -2-17 (1, 1-dimethylethylpaminolcarbonip-1-piperazinip ^ -hydroxyphenylmethylpropylpaminolcarbonyl ^ -methylpropylcarbamate.) The title compound was prepared from according to the method described in Example 1C, substituting [(2-methyl-4-thiazole) methyloxycarbonyl] -L-valine for [(2-isopropyl-4-thiazoyl) methoxycarbonyl] ] -L-valine This was followed by treatment of the product with trifluoroacetic acid according to the method of Example 1D. 15B.2-Methyl-4-thiazolylmethyl-r (1S) -1 -rr (1S.2R) - 3-f (2S) -4- (1,3-Benzodioxol-5-ylmethyl) -2-l7 (1,1-di methylethyl) aminol carboni 11-1 -piperazin il] -2-hydroxy-1 - (phenylmethyl) propillamin oí carbo ni 11-2-methylpropill carbamate. A solution of 98 mg (0.16 mmol) of 2-methyl-4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4- (1,1-dimethylethyloxy) ( carbonyl)) - 2 - [[(1,1-dimethyl-ethyl) amino] carbonyl] -2-methylpropyl] carbamate in 1 ml of DMF was treated with 30 mg (0.18 mmol) of 3,4-dioxomethylenebenzyl chloride followed by 43 μl (0.24 mmoles) of N, N-diisopropylethylamine. The solution was stirred at room temperature overnight. After stirring, the solution was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The mixture was purified by chromatography on silica gel using 5% methylene methochloride to provide the title compound (yield 31 mg, 26%). MS: 737 (M + H)? 1H NMR (CDCl 3) d 0.67 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 2.05 (hextet, J = 4.5 Hz, 1H), 2.26 (m, 1H), 2.41 (dd, J = 12.0, 3.0 Hz, 1H), 2.55 (m, 1H), 2.59 (dd, J = 9., 3, 3.0 Hz, 2H), 2.72 (m, 2H), 2.73 (s, 3H), 2.76 (m, 1H), 2.83 (m, 2H), 2.91 (m, 1H), 3.35 (m, 1H), 3.47 (s, 2H) ), 3.79 (m, 1H), 3.86 (dd, J = 7.5, 6.0 Hz, 1H), 4.22 (m, 1H), 4.93 (m, 1H), 5.62 (m, 2H), 5.65 (d, J = 3.0 Hz, 2H), 5.96 (s, 2H), 6.18 (d, J = 9.0 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 6.78 (d, J = 7.5 Hz, 1H), 7.12-7.22 (m, 6H), 8.19 (br s, 1H).

Example 16 2-Methyl-4-thiazolylmethyl-r (1S) -1-rrr (1S.2R) -3-r (2S) -4- (3,4-dimethoxyl-phenyl) methyH-2-l7 (1.1-dim eti ethyl) ami nol carbonill-1 -piperazin and I1-2-hydroxy-1 - (phenylmethyl) propylaminolcarbonyl-2-methylpropylcarbamate. The title compound was prepared according to the method described in Example 15B, replacing 3,4-dimethoxybenzyl chloride in place of 3,4-dioxomethylbenzene chloride.

MS: 753 (M + H) +. 1H NMR (DMSO-d6) d 0.67 (d, J = 6.3 Hz, 3H), 0.69 (d, J = 6.3 Hz, 3H), 1.23 (s, 9H), 1.78 (hextet, J = 4.5 Hz, 1H) , 2.22 (m, 2H), 2.27 (m, 1H), 2.32 (m, 1H), 2.53 (m, 3H), 2.63 (s, 3H), 2.67 (m, 1H), 2.87 (m, 2H), 2.98 (m, 1H), 3.33 (m, 3H), 3.63 (m, 1H), 3.72 (s, 3H), 3.73 (s, 3H), 4.05 (m, 1H), 4.86 (d, J = 9.0 Hz , 1H), 5.00 (s, 2H), 6.79 (d, J = 7.5 Hz, 1H), 6.87 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 6.0 Hz , 2H), 7.18 (d, J = 6.3 Hz, 2H), 7.26 (d, J = 7.5 Hz, 2H), 7.41 (s, 1H), 7.53 (s, 1H), 7.67 (d, J = 9.0 Hz , 1 HOUR).

Example 17 2-Methyl-4-thiazolylmethyl-r (1S) -1-frr (1S.2R) -3-r (2S) -2-f 1 (1,1-dimethyl-ethyl) aminolcarbon-4-f (4- f luorof eni Dmeti 11-1-piperazinyl-2-hydroxy-1- (phenylmethyl) propylamino] carbonyl] -2-methylopropylcarbamate The title compound was prepared according to the method described in Example 15B, replacing 4-fluorobenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride MS: 711 (M + H) \ 1 H NMR (CDCl 3) d 0.68 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 2.06 (hextet, J = 6.0 Hz, 1H), 2.28 (m, 1H), 2.47 (m, 1H), 2.55 (m, 1H), 2.59 (m, 2H), 2.71 (m, 2H), 2.73 (s, 3H), 2.76 (m, 1H), 2.83 (m, 2H), 2.90 (m, 1H), 3.35 (m, 1H), 3.43 (s, 2H) ), 3.80 (m, 1H), 3.86 (dd, J = 7.5, 6.0 Hz, 1H), 4.22 (septet, J = 4.5 Hz, 1H), 5.10 (m, 1H), 5.14 (s, 2H), 6.15 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 8.4 Hz, 2H), 7.12-7.22 (m, 8H), 8.21 (br s, 1H).

Example 18 2-Ethyl-4-thiazolylmethyl- (1S) -1-fff (1S.2R) -3-r (2S) -4-f (3,4-dimethoxyl-phenethyl-2-rf (1,1-dimethylethyl) aminolcarbonyl- 1-Piperazinyl-2-hydroxy-1- (phenylmethipropylamino-1-carbonyl-2-methylpropylcarbamate. 18. 2-Ethyl-4-thiazolylmethyl- (1S) -1-rrf (1S.2R) -3-r (2S) -4-i1.1-dimethylethyl-oxy (carbonyl) l-2-ff (1, 1- dimethiletipaminolcarbonip-1-piperazinip ^ -hydroxy-1-phenylmethylpropylminolcarbonyl ^ -methylpropylcarbamate The title compound was prepared according to the method of Example 1C, substituting [(2-ethyl-4-thiazolyl) methyloxycarbonyl] -L-valine for of [(2-isopropM-4-thiazolyl) methyloxycarbonyl] -L-valine chloride This was followed by treatment of the product with trifluoroacetic acid according to the method of Example 1D. 18B. 2-Ethyl-4-thiazolylmethyl- (1S) -1-rr (1S.2R) -3-r (2S) -4-r3.4-dimethoxyphenethyl-2-ff (1,1-d-methylethyl-aminol-carbonyl] -1-piperazinyl -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl-2-methylpropylcarbamate The title compound was prepared by reacting 2-ethyl-4-thiazoylmethyl (1S) -1 - [[ [(1S, 2R) -3 - [(2S) -4-t1,1-dimethylethyl-oxy (carbonyl)] - 2 - [[(1,1-dimethyl-1-ethyl) ami] carbon] I] - 1-piperazinyl] -2-hydroxy-1 - (phenylmethyl) pro-pil] amino] -carbonyl] -2-methyl propyl I] carbamate, 98 mg (0.16 mmol), with 3,4-dimethoxybenzyl chloride , 30 mg (0.18 mmol), according to the method described in Example 15B MS: 767 (M + H) +. 1 H NMR (CDCl 3) d 0.67 (d, J = 6.3 Hz, 3 H), 0.84 (d. , J = 6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J = 7.5, 6H), 2.05 (hextet, J = 6.0 Hz, 1H), 2.23 (m, 1H), 2.48 (m, 1H), 2.58 (dd, J = 12.0, 3.0 Hz, 2H), 2.71 (m, 2H), 2.83 (m, 1H), 2.90 (m, 1H), 3.05 (q, J = 7.5 Hz, 2H), 3.31 (m, 1H), 3.35 (m, 1H), 3.40 (AB, .J = 15.0 Hz, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.22 (m, 1H), 4.88 (m, 1H), 5.08 (m, 1H), 5.16 (s, 2H), 6.11 (d, J = 7.5 Hz, 1H), 6.77 (s, 1H), 6.82 (s, 2H), 7.12-7.22 (m, 8H), 8.21 (br s, 1H).

Example 19 2-p-Methylethyl-5-thiazole methyl (1S) -l'-frf (1S.2R) -3-r (2S) -4- (3,4-di methoxy I-faith nil) meti 11 -2-17 (1.1 -di meti le ti i) to my nol carbo ni 11-1 -píperazinIll-2-hid roxi-1 - (phenyl methyl) pro pilla lnolcarbo ni 11-2-methylpropillcarbamate. 19A. 2- (1-Methylethyl-5-thiazolylmethyl-r (1S) -1- (1S.2R) -3-r (2S) -4- (1,1-dimethylethyloxy (carbon-pyr-2-rr (1: 1) dimethylethylcarbonyl-l-pi, ezinipyl-hydroxy-l- ^ enylmethylpropyl-aminocarbonyl-Sm eti-propyl-11-carbamate A solution of 1.5 g (3.3 mmol) of 1 - [(1S, 2R) -3 - [( 2S) -4- (1,1-Di-methylethyloxy (carbonyl)] - 2 - [[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propiI] Amine in 7 ml of THF and 7 ml of methylene chloride was prepared and treated with 1.0 g (3.3 mmoles) of [(2-isopropyl-5-thiazoyl) methyloxycarbonyl] -L-valine, 642 mg (3.3 mmol). of EDAC, 45 mg (0.33 mmoles) of HOBT, and 466 μl (3.3 mmoles) of triethylamine The solution was stirred at room temperature for 6 hours and concentrated in vacuo, the residue was taken up in ethyl acetate, washed with equal portions (15 ml) of a solution of 3 N HCl, 10% aqueous NaHCO3 and saturated brine, dried over MgSO4 and concentrated in vacuo, the resulting mixture was purified through chromat chromatography on silica gel using 5% methano-Methylene chloride to provide the title compound (yield: 2.1 g; 88%). MS: 731 (M + H) +. 1 H NMR (DMSO-de) d 1.08 (d, J = 7 Hz, 6H), 2.78 (heptet, J = 7 Hz, 1H), 9.06 (br s, 1H), 9.30 (br s, 1H). 19B. 2- (1-Methylethyl) -5-thiazolylmethyl-f (1S) -1-frf (1S.2R) -3-r (2S) -4- (3,4-dimethoxy-ifenyl) methyll-2-ff (1.1 -dimeti le ti Da min olea rbon i 11-1 -piperazin i II-2-hydroxy-1 - (phenylmethyl) propyl my carbon nol I1-2- methyl propi 11 carbamate. The title was prepared in two steps: first, 2- (1-methylethyl) -5-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4- (1.1 -dimethylethyloxy (carbon (I)) - 2 - [[(1, 1-dimethylethyl aminocarbonyl-1-piperazinyl) -hydroxy-1-phenylmethylpropyljaminocarbonyl] - methylpropylcarbamate was treated with trifluoroacetic acid according to the method described in Example 1D This was followed by alkylation of the product according to Example 1E, substituting 3,4-dimethylbenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride MS: 781 (+ H) +. CDCI3) d 0.72 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.40 (d, J = 6.3, 6H), 2.01 (hextet, J = 6.0 Hz, 1H), 2.22 (dt, J = 7.5, 3.0 Hz, 1H), 2.43 (m, 1H), 2.55 (m, 2H), 2.73 (m, 3H), 2.88 (m, 2H), 2.93 (m, 1H), 3.30 (heptet, J = 6.3 Hz, 1H), 3.38 (m, 1H), 3.41 (AB, J = 15.0 Hz, 2H), 3.80 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.22 (septet, J = 4.5 Hz, 1H), 5.07 (d, J = 8.4 Hz, 1H), 5.20 (d, J = 3.0 Hz, 2H), 6.06 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 6.82 (s, 2H), 7.12-7.22 (m , 7H), 7.61 (s, 1H), 8.28 (br s, 1H).

EXAMPLE 20 2-Ethyl-5-thiazolylmethyl- (1S) -1-frr (1S.2R) -3-f (2S) -4- (3,4-di methoxy If enyl) methi 11-2 1 (1, 1 - di methylethyl) ami nolcarb or 11-1-piperazin i II-2-hydroxy-1- (phenyl methyl) propi Ham i nolcarbonill-2-m eti I propylcarbamate.

A. 2-Ethyl-5-thiazolylmethyl- (1S) -1-rff (1S.2R) -3-r (2S) -4-f1.1-dimethylethylloxy (carbo nil) 11-2-ff (1, 1) -dimethylethyl) ami no] carboni 11-1 -piperazinyl-2-hydroxy-1- (phenylmethyl) pro pillam i nol carbon and 11-2-methylpropillcarbamate. The title compounds were prepared according to the method described in Example 19A, substituting [(2-ethyl-5-thiazoyl) methyloxycarbonyl] -L-valine for [(2-isopropyl-5-ti azo I il)] I ti I oxi coal i I] L-valine. 20B. 2-Ethyl-5-thiazolylmethyl- (1S) -1-r7i (1S.2R) -3-K2S) -4- (3,4-dimethoxyphenyl) methylene-2-rr (1,1-dimethylethyl) aminolcarbonyl-1-piperazinin -2-h id roxi-1- (fen-ylmethyl) propy-llaminolcarbonyl-2-methylpropillcarbamate.

The title compound was prepared in two steps. First, 2-Eti-5-thiazo-H-methyl-I (1S) -1 - [[[(1S, 2R) -3 - [(2S) -4- (1,1-dimethyethyloxy (carbonyl)] - 2- [ [(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] to my non] carbonyl] -2-methylpropyljcarbamate was treated with trifluoroacetic acid according to the method described in Example 1D This was followed with alkylation of the product according to the method Example 1E, substituting 3,4-dimethylbenzene chloride in place of 3,4-dioxom ethylene benzyl chloride or MS: 767 (M + H) +. 1 H NMR (CDCl 3) d 0.73 (d, J = 6.3 Hz, 3 H), 0.86 (d, J = 6.3 Hz, 3 H), 1.37 (s, 9 H), 1.38 (t, J = 7.5, 3H), 2.02 (m, 1H), 2.23 (dt, J = 7.5, 3.0 Hz, 1H), 2.45 (m, 1H), 2.56 (m, 2H), 2.72 (m, 2H), 2.77 (m, 1H) ), 2.89 (m, 2H), 3.02 (q, J = 7.5 Hz, 2H), 3.39 (t, J = 3.3 Hz, 1H), 3.41 (AB, J = 15.0 Hz, 2H), 3.81 (m, 2H) ), 3.88 (s, 3H), 3.89 (s, 3H), 4.21 (m, 1H), 5.06 (d, J = 9.0 Hz, 1H), 5.20 (d, J = 5.4 Hz, 2H), 6.06 (d) , J = 9.0 Hz, 1H), 6.76 (s, 1H), 6.82 (s, 2H), 7.13-7.23 (m, 7H), 7.6 1 (s, 1H), 8.27 (br s, 1H).

Example 21 2-Methyl-5-thiazolylmethyl-f (1S) -1-rrr (1S.2R) -3-r (2S) -4- (3,4-dimethoxyl-enyl) methyl] -2-f 1 1, 1- dimethylethyl) aminolcarbonip-1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propipaminolcarbonyl-2-methylpropylcarbamate. 21A. 2-Methyl-5-thiazolylmethi-rpSM-rrr (1S.2R) -3-r (2S) -4-M, 1-dimethylethyloxy (carbonyl) 1-2- [f (1, 1-dimethylethylpaminolcarbonyl-1-piperazinyl ^ -hydroxy-l-enylme D-propylminolcarbonyl ^ -m eti I pro pill carbamate The title of the compound was prepared according to the method described in Example 19A, substituting [(2-methyl-5-thiazolyl) methyloxycarbonyl] -L- vain in place of [(2-isopropyl-5-thiazolyl) methyloxycarbon I] - L-valine. 21B. 2-Methyl-5-thiazolylmethyl-f (1S) -1-rrr (1S, 2R) -3-f (2S) -4- (3,4-di methoxy Ife nil) meti 11-2-17 (1.1 -di meti I eti Daminolcarbo ni 11-1 -piperazin i II-2-hydroxy-1- (phenylmethyl) propylaminocarbonyl-1-methylpropylcarbamate The title compound was prepared in two steps: First, 2-methyI-5-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3- [ (2S) -4- [1,1-dimethyethyloxy (carbonyl)] - 2 - [[(1,1-dimethylethyl) amino] carbonyl] -1-pipe razinyl] -2-h idroxy-1 - (phenylmethyl) pro pii] to my no] carbon] -2-methy1propyl] carbamate was treated with trifluoroacetic acid according to the method described in Example 1D.This was followed by alkylation of the product according to the 1E product method, substituting 3,4-dimethylbenzyl chloride in place of 3,4-dioxomethylenebenzyl chloride MS: 753 (M + H) *. 1 H NMR (CDCl 3) d 0.72 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H), 1.46 (s, 9H), 2.01 (hexet, J = 6.0 Hz, 1H), 2.22 (dt, J = 7.5, 3.0 Hz, 1H), 2.43 (dd, J = 12.0, 3.0 Hz , 1H), 2.56 (m, 2H), 2.69 (s, 3H), 2.72 (m, 1H), 2.77 (m, 1H), 2.86 (m, 2H), 2. 92 (m, 1H), 3.39 (t, J = 3.0 Hz, 1H), 3.41 (AB, J = 15.0 Hz, 2H), 3.80 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3H) ), 4.21 (septet, J = 4.5 Hz, 1H), 5.06 (d, J = 9.0 Hz, 1H), 5.19 (AB, J = 9.6 Hz, 2H), 6.07 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 6.82 (s, 2H), 7.12-7.22 (m, 7H), 7.58 (s, 1H), 8.27 (br s, 1H).

EXAMPLE 22 N'-r (1R) -1-rrr (1S.2R) -3-r (2S) -2-ff (1,1-Dimethylethylamino-1-carbonyl-4- (5-t-azolylmethyl-1-piperazinyl-2 -hydroxy-1- (phenylmethyl) propylaminol-carbonyl] -2-methyl propyl-N -methyl- N- (5-thiazolylmethyl) urea. 22A. N, -r (1R) -1-rff (1S.2R) -3-f (2S) -2-fr (1,1-Dimethyletyl) aminolcarbonyl-4-f1.1-di methylethylloxy (carbon 1) ) 1-1 -piperazine i-l-2-h id roxy-1 - (f -methylmethyl) propinaminol-charcoal and H-2-m-ethyl-propyl-ethyl-N- (5-thiazolylmethylurea) The title compound was prepared according to the method described in Example 19A, substituting [N-methyl-N- (5-thiazolyl) methylaminocarbonyl] -D-vaIina in place of [(2-isopropyl-5-thiazoyl) methyloxycarbonyl] -L-valine. N, -r (1R) -1-rrf (1S.2R) -3-((2S) -2-((1,1-Dimethylethyl) aminolcarbonyl 1-4- (5-thiazolylmethyl) -1-piperazinyl] - 2-hydroxy-1- (f-methyl-1-propyl-methylcarbo-nor 11-2-ethyl-propyl-1-N-methyl-N- (5-thiazolylmethyl) The title compound was prepared in two steps: N '- [(1R) -1- [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-Dimethylethyl) amino] carbonyl] -4- [1,1-dimethyIetiOoxi (carbonyl)] -1-piperazinyl] -2-hydroxy-1- (phenylethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-met lN- (5-thiazolylmethyl) urea was treated with trifluoroacetic acid in accordance with method or described in Example 1D. this was followed by alkylation of the product according to the method of Example 1E, substituting 5-thiazolyl chloride in place of 3,4-dioxomethylenebenzyl chloride. MS: 699 (M + H) +. 1 H NMR (CDCl 3) d 0.58 (d, J = 6.3 Hz, 3 H), 0.66 (d, J = 6.3 Hz, 3 H), 1.38 (s, 9 H), 1.75 (m, 1 H), 2.35 (m, 1 H) , 2.60 (m, 2H), 2.70 (m, 2H), 2.85 (m, 2H), 2.86 (s, 3H), 2.92 (m, 3H), 3.30 (t, J = 3.3 Hz, 1H), 3.74 ( s, 2H), 3.88 (m, 1H), 3.97 (dd, J = 8.4, 6.0 Hz, 1H), 4.28 (m, 2H), 4.53 (br s, 1H), 4.65 (d, J = 3.3 Hz, 2H), 5.03 (d, J = 7.5, 1H), 6.09 (d, J = 9.0 Hz, 1H), 7.17-7.27 (m, 5H), 7.73 (s, 2H), 8.73 (s, 1H) and 8.80 (s, 1H).

EXAMPLE 23 N'-r (1S) -1-rrr (1S.2R) -3-f (2S) -2-fr (1,1-Dimethyl-ethyl) aminolcarbonyl-4- (5-ti azoyl-methyl) -1-piperazinill -2-Hydroxy-1 - (phenylmethyl) propylaminol-carbonill-2-methylpropyl- Nm ethyl- - (5-thiazole I meti I) urea. 23A. N'-l (1S) -1-rrf (1S.2R) -3-r (2S) -2-rr (1,1-Dimethylethylnaminolcarbonyl-4-M. 1-dimethylethyloxy (carbonyl) 1-1-piperazinin- 2-Hydroxy-1- (f-methyl-methyl) pro-pilla min i-carbon i 11-2-m eti 1 pro pill-Nm ethyl-N- (5-thiazolylmetinurea) The title compound was prepared according to the method described in Example 19A, substituting [N-methyl- (5-thiazoyl) methylaminocarbonyl] -L-valine for [(2-isopropyl-5-thiazolyl) methyloxycarbonyl] -L-valine. 23B. N'-r (1S) -1-rr (1S.2R) -3-f (2S) -2-rf (1,1-Dimethylethyl) aminolcarboniIl-4- (5-thiazolylmethyl) -1-piperazinyl-2- hydroxy-1- (phenylmethyl) propylaminol-carbonin-2-methylpropin-N-methylN- (5-thiazolylmethyl) urea. The title compound was prepared in two steps. First, N'-E (1R) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- [1 , 1-dimethylethyloxy (carbonyI)] - 1-piperazinyl] -2-hydroxy-1 - (phenylmethyl) propi I] amino] carbony] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea was treated with trifluoroacetic acid according to the method described in Example 1D. This was followed by alkylation of the product according to the method of Example 1E, substituting 5-thiazolyl chloride in place of 3,4-dioxomethylenebenzyl chloride. MS: 699 (M + H) +. 1 H NMR (CDCl 3) d 0.78 (d, J = 6.3 Hz, 3 H), 0.87 (d J = 6.3 Hz, 3 H), 1.49 (s, 9 H), 2.02 (m, 1 H), 2.33 (m, 2 H) , 2.57 (m, 2H), 2.75 (m, 2H), 2.82 (s, 3H), 2.89 (m, 3H), 3.38 (t, J = 3.0 Hz, 1H), 3.73 (d, J = 3.3 Hz, 2H), 3.79 (m, 1H), 4.03 (dd, J = 8.4, 6.3 Hz, 1H), 4.20 (m, 1H), 4.66 (AB, J = 15 Hz, 2H), 4.78 (m, 1H), 4.81 (d, J = 8.4 Hz, 2H), 6.11 (d, J = 9.0 Hz, 1H), 7.11-7.23 (m, 5H), 7.73 (s, 1H), 7.76 (s, 1H), 7.82 (br s, 1H), 8.75 (s, 1H), 8.80 (s, 1H).

Example 24 5-Thiazole-methyl-r (1S) -1-rir (1S.2R) -3-r (2S) -2-rr (1,1-dimethylethyl) aminolcarbonin-4- (phenylmethyl) -1-piperazine -2-hydroxy-1 (phenyl I m ethyl) propylaminolcarbonyl-2-methyl propylcarbamate. 24A. 5-Thiazolylmethyl-r (1S) -1-rrr (1S.2R) -3-r (2S) -2-rf (1,1-dimethylethyl) aminolcarbonyl1-4-f1.1 -dimeti leti loxi (carbo ni 1) 1 -1-piperazinide-2-hydroxy-1- (phenylmethyl) propyl-1-nolcarboni I-2-methylpropyl carbamate. The title compound was prepared according to the method described in Example 19A, substituting [(5-thiazolyl) methyloxycarbonyl] -L-valine, in place of [(2-isopropyl-5-thiazolyl) methyloxycarbonyl] -L-valine . 24B. 5-Thiazolylmethyl-f (1S) -1-rri (1S.2R) -3-r (2S) -2-rr (1,1-di methylethyl) aminocarbon? II-4- (f -methylmethyl) -1-piperazine? Ll -2-hydroxy-1- (phencymethyl) propy-aminolcarbonin-2-me ti I pro pill carbamate. The title compound was prepared in two steps. First, 5-tiazoliImetiI - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethyethyl) amino] carbonyl] -4- [1, 1-di methyl eti loxi (carbo nil)] - 1 -pi pe razinyl] -2-hydroxy-1 - (phenylmethyl) propyl] -a my] carbonyl] -2-methy1propyl] carbamate was treated with trifluoroacetic acid of according to the method described in Example 1D. This was followed by the alkylation of the product according to the method of Example 1E, substituting benzyl bromide in place of 3,4-d-oxymethylbenzyl chloride. MS: 699 (M + H) +. 1 H NMR (CDCl 3) d 0.78 (d, J = 6.3 Hz, 3 H), 0.87 (d, J = 6.3 Hz, 3 H), 1.49 (s, 9 H), 2.02 (m, 1 H), 2.33 (m, 2 H) , 2.57 (m, 2H), 2.75 (m, 2H), 2.82 (s, 3H), 2.89 (m, 3H), 3.38 (t, J = 3.0 Hz, 1H), 3.73 (d, J = 3.3 Hz, 2H), 3.79 (m, 1H), 4.03 (dd, J = 8.4, 6.3 Hz, 1H), 4.20 (m, 1H), 4.66 (AB, J = 15 Hz, 2H), 4.78 (m, 1H), 4.81 (d, J = 8.4 Hz, 2H), 6.11 (d, J = 9.0 Hz, 1H), 7.11-7.23 (m, 5H), 7.73 (s, 1H), 7.76 (s, 1H), 7.82 (br s, 1H), 8.75 (s, 1H), 8.80 (s, 1H).

EXAMPLE 25 5-Thiazolylmethyl-f (1S) -1-rrr (1S.2R) -3-f (2S) -2-ri (1,1-dimethylethylamine-carb or nill-4- (5-thiazoline I meti 0 -1-piperazine i-l-2-hydroxy-1 - (phenyl Im eti) -propyl-aminolcarbonyl-2-methyl propylcarbamate ate The title compound was prepared according to the method described in Example 24B, through of the alkylation of 5-thiazoIiImetiI - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] -carbonyl] -1- piperazinyl] -2-hydroxyl-1- (phenylmethyl) propyl] -amino] carbonyl] -2-methyl-propyl] carbamate with methyl 5-thiazoyl chloride in place of benzyl bromide MS: 686 (M + H) +. 1 H NMR (CDCl 3) d 0.62 (d, J = 6.3 Hz, 3 H), 0.86 (d, J = 6.3 Hz, 3 H), 1.39 (s, 9 H), 2.01 (m, 1 H), 2.30 ( m, 1H), 2.52 (m, 1H), 2.67 (m, 2H), 2.71 (m, 1H), 2.75 (m, 2H), 2.87 (m, 2H), 2.92 (m, 1H), 3.29 (t , J = 3.0 Hz, 1H), 3.74 (d, J = 4.5 Hz, 2H), 4.80 (m, 2H), 4.85 (m, 1H), 4.21 (m, 1H), 5.08 (t, J = 9.0 Hz , 1H), 5.18 (d, J 4.5 Hz, 1H), 6.07 (d, J = 9.6 Hz, 2H), 7.11-7.24 (m, 5H), 7.74 (s, 1H), 7.8 8 (s, 1H), 8.80 (s, 1H), 8.81 (s, 1H).

EXAMPLE 26 N'-r (1S) -1-rrr (1S.2R) -3-rrr (1,1-D-methylethylaminocarbonyl (2-methyl-ethyl) pro-cell min. 1-2- hi roxy- 1 - (phenylmethyl ) pro pill ami nolcarbo or 11-2-methylpropin-N-methyl-N-r2- (1-methylethyl) -4-thiazolylmethylurea The title compound was prepared according to the method described in Example 12A, coupling N-methyl-N - [(((2-isopropyl-4-thiazoIiI) methyl) amino) -carbonyl] -L-vaIine with N- (3S-amino-2R-hydroxy-4-f enylbu ti I) - N - (2-methyl propyl) -N '- (1,1-di methylethyl) urea, produced according to the method described in J. Med. Chem., 1993, 36,288-291, Elemental Analysis: Theory: C: 62.34 , H: 8.44, N: 13.64 Found: C: 59.60, H: 7.37, N: 12.86 Example 27 2- (1-Methylethyl) -4-thiazolylmethyl-r (1S) -1-rrf (1S.2R) -3-fyr (1,1-dimethylethyl-amino-1-carbonyl-1 (2-methylethyl) -propylaminol-2-h) droxi-1 - (phenylmethyl) propyl-aminolcarbonyl] -2-methylpropylcarbamate The title compound was prepared according to the method described in Example 26, coupling N- [2-isopropyl-4-thiazoyl) methyloxycarbonyl ] -L-vain with N- (3S-amino-2R-hydroxy-4-phenylbutyl) -N- (2-methylpropii) -N '- (1,1-dimethylethyl) urea, prepared according to the method described in J. Med. Chem., 1993, 36,288-291 Elemental Analysis: Theory: C: 61:69, H: 8.13, N: 11.61 Found: C: 60.80, H: 8.21, N: 11.18 Example 28 2- (1-Methylethyl) -4-thiazolylmethyl-f (1S) -1-rrf (1S.2R) -3-ff (4-aminophenol) -sulfonin (1-methylethyl) amino-2-hydroxy -1- (phenylmethyl) propyl-aminol-carbonyl-2-methylpropyl] carbamate. The title compound was prepared in two steps. First, N-isobutyI-2 (R) -hydroxy-3 (S) -amino-4-phenyl- (4'-nitrophenyl) sulfonamide, prepared according to the method described in J. Am. Chem. Soc., 1995 , 117, 1181-1182, was coupled with [(2-isopropyl-4-t-azoyl) methyloxycarbonyl] -L-valine according to the method described in Example 1C. this was followed by hydrogenation of the product over Pd / C under 1 atmosphere of hydrogen. The catalyst was removed by filtration on a pad of celite and the solvent was evaporated under reduced pressure to provide the title compound as a white foam. MS: 674 (M + H) +. 1 H NMR (DMSO-dβ) d 0.65 (d, J = 6.3 Hz, 3H), 0.67 (d, J = 6.3 Hz, 3H), 0.77 (d, J = 6.0 HZ, 3H), 0.81 (t, J = 6.0 HZ, 3H), 1.32 (d, J = 6.3 Hz, 6H), 1.77 (m, 1H), 1.90 (m, 1H), 2.60 (m, 2H), 2.65 (m, 1H), 2.72 (m, 1H), 2.83 (d, J = 7.5 Hz , 1H), 2.89 (d, J = 9.0 Hz, 1H), 3.00 (m, 2H), 3.25 (m, 1H), 3.61 (m, 1H), 3.75 (dd, J = 9.0, 6.3 Hz, 1H) , 3.94 (m, 1H), 4.96 (d, J = 6.3 Hz, 1H), 5.02 (s, 2H), 5.98 (s, 2H), 6.60 (t, J = 9.0 Hz, 2H), 7.10 (m, 2H), 7.15-7.22 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H).

EXAMPLE 29 N'-r (1S) -1-frr (1S.2R) -3-rrf (4-Aminophenyl) sulfonyl (1-methylethyl) aminol-2-hydroxy-1- (phenylmethyl) propylaminolcarbonyl-2-methylpropin- N-methyl-N-f2- (1-methylethyl) -4-thiazolylmethylurea. The title compound was prepared in two steps. First, N-iso pro pil-2 (R) -hydroxy-3 (S) -amino-4-phenyl- (4'-nitrophenyl) sulfonamide was coupled with N-methyl-N - [(((2-isopropyl -4-thiazoIiI) methyl) amino) carbonyl] -L-valine according to the method described in Example 12A. This was followed by hydrogenation of the product over Pd / C under 1 atmosphere of hydrogen. The catalyst was removed by filtration on a pad of celite and the solvent was evaporated under reduced pressure to provide the title compound as a white foam. MS: 674 (M + H) +. Elemental Analysis: Theory: C: 58.93, H: 7.14, N: 12.50 Found: C: 58.30, H: 7.28, N: 12.11 Example 30 2- (1-Methylethyl) -5-thiazolylmethyl-r (1S) -1 -f fr (1S.2R) -3-yl (1,1-dimethylethyl) ami nol (4a .8aa) octah id ro-2-isoquinolyl-2-hydroxy-1-phenyl ethyl) propylaminecarbonyl-2- methylpropyl carbamate. The title compound was prepared according to the method described in Example 1C, coupling 2 ~ (3 (S) -amino-2 (R) -hydroxy-4-phenyl-butyl) -N-tert-butylcahydro- (4aS, 8aS ) -isoquinolin-3 (S) -carboxamide with [(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine, prepared according to the method described in J. Org. Chem., 1994, 59, 3656-3664. Elemental Analysis: Theory: C: 65.01, H: 8.35, N: 10.25 Found: C: 63.70, H: 8.19, N: 10.05 Example 31 N'-G? SI-I-GGT? S.2R) -3-G (3S) -3, GM.I-. Dimethylethyl) aminolcarbonin (4aa.8aa) -octahydro-2-isoquinolinyl-2-hydroxy-1- (phenylmethyl) pro inaminolcarbonin-2-methylpropyl-N-methyl-N-f2- (1-methylethyl) -4-thiazolymethyl-1urea. The title compound was synthesized according to the method described in Example 12A by coupling 2- (3 (S) -amino-2 (R) -hydroxy-4-faith nylbuyl) -N- tert-bu tyl ca hydro - (4 aS, 8aS) -isoquinolin-3 (S) -carboxamide with N-methyl- N - [(((2-isopropyl-4-thiazolyl) methyl) am i no) -carbonyl)] - L-vainine which was prepared according to the method described in J. Org. Chem., 1994, 59, 3656-3664.

Elemental Analysis: Theory: C: 65.52, H: 8.62, N: 12.07 Found: C: 64.50, H: 8.72, N: 12.09 Example 32 ^ fd S) -1-rff (1 S.2 R) -3-f (2S.4R) -2f f (1,1 -Dimeti letiDaminolcarbon ill-4- (5-thiazolyl methoxy) -1-piperidinin -2-hydroxy-1 - (phenylmethylpropyl) nol-carbonyl-1-2-methylpropyl-N-methyl-N-f2- (1-methylethyl) -4-thiazolylmethylurea, 32A. 1-cis-N- (1,1-dimethylethyl) -1- (1,1-dimethylethyloxycarbonin-4- (5-thiazolylmethyl) pyridine-2-carboxamide cis- N- (1,1-Dimethylethyl) -1- was prepared (1, 1 -di me ti I eti loxi coal i I) -4-hydroxy-piper? Dina-2-carboxamide according to the methods described in EP 560268 A1, the hydroxy-carboxamide compound was treated with sodium hydride and 5-thiazolylmethyl chloride in DMF at 0 ° C to provide the title compound. 32B. 1-cis-N- (1,1-Dimethylethyl) -4- (5-thioazoylmethyloxy) piperidine-2-carboxamide. A solution of 1.24 g of 1-cis-N- (1,1-dimethylethyl) -1- (1,1-dimethyI-β-oxocarbonyl) -4- (5-thiazolylmethyloxy) piperidine-2-carboxamide in 10 ml of THF, it was prepared. The solution was treated with 3 N HCl, and stirred at room temperature for 1 hour. After stirring, the reaction was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with brine, dried with Na2SO4 and evaporated to dryness to provide 836 mg of the desired product. 32C. N'-r (1S) -1-rrr (1S.2R) -3-r (2S.4R) -2rr (1,1-Dimethylethyl) arninol-carbonin-4- (5-thiazole I methoxy) -1-piperid in il] -2-hydroxy-1- (phenylmethyl) propmamine. The title compound was synthesized in two steps. N '- [(1S) -1 - [[[(1S, 2R) -3-t (2S, 4R) -2 [[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazoylmethoxy) -1-piperidine iI] -2-hydroxy-1- (phenylmethyl) propyI] amine was prepared according to the method described in Example 1A, using t-butyloxycarbonyl phenylalanyl-p-roxide by replacing N-benzyloxycarbonyl phenylalanyl-epoxide followed by column purification. The resulting product was treated with trifluoroacetic acid (TFA) in methylene chloride at room temperature. 32D. N'-r (1S) -1-rrr (1S.2R) -3-r (2S.4R) -2rr (1,1-Dimethylethyl) aminol-carbonyl-1-4- (5-thiazoliI-methoxy) -1-piperid i nill-2-hydroxy-1 - (phenylmethyl) propylaminole-carbonill-2-m ethyl propyl- N -methyl- N -f2- (1 -methylethyl) -4-thiololylmethylurea. The title compound was synthesized by the method described in Example 12A using 32D. N '- [(1S) -1 - [[[(1 S, 2R) -3 - [(2S, 4R) -2 [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazoyl) methoxy) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propylamine and N-methyl-N - [(((2-isopropyl-4-azoyl) methyl) amine) carbonyl ] - L-valina. MS: 756 (M + H) +. 1 H NMR (CDCl 3) d 0.65 (d, J = 6.3 Hz, 3 H), 0.92 (d, J = 6.3 Hz, 3 H), 1.32 (d, J = 3.0 HZ, 3 H), 1.34 (d, J = 3.0 Hz , 2H), 1.35 (s, 9H), 1.53 (m, 1H), 1.58 (m, 1H), 1.91 (m, 1H), 2.20 - 2.37 (m, 4H), 2.67 (m, 1H), 2.69 ( m, 1H), 2.80 (dd, J = 11.4, 3.0 Hz, 1H), 2.87 (dd, J = 15.0, 3.3 Hz, 1H), 2.97 (s, 3H), 3.21 (heptet, J = 6.3 Hz, 1H) ), 3.40 (t, J = 4.5 Hz, 1H), 3.44 (m, 1H), 3.91 (t, J = 5.7 Hz, 1H), 4.03 (m, 2H), 4.12 (m, 1H), 4.35 (AB , J = 15.0 Hz, 2H), 4.78 (AB, J = 12.0 Hz, 2H). 6.48 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 7.00 (s, 1H), 7.09-7.18 (m, 6H), 7.78 (s, 1H), 8.79 (s, 1H).

EXAMPLE 33 2- (1-Methylethyl) -4-thiazolyl "ethyl-f (1S) -1-rir (1S.2R) -3-f (2S.4R) -2-rr (1,1-dimethylethyl) aminocarbonyl 1-4 - (5-thiazolyl methoxy) -1- piperid i or 11-2-hydroxy-1- (phenylmethyl) propylmaminolcarbon i 11-2-methyl propylcarbamate The title compound was prepared according to the procedure described in Example 32C, using N - [(2-isopropyl-4-thiazoIH) methyloxycarbonyl!] - L-valine instead of N-methyl-N - [(((2-isopropyl-4-thiazole [] methyl) amino) carbonyl] -L-vaiine as a coupling reagent.

Example 34 S-r2-p-Methylethyl) -4-thiazolylmethyl-r (1S) -1-rr (1S.2R) -3-r (2S) -4- (1,3-benzodioxol-5-ylmethyl) ) -2-rf (1,1-dimethyl) amino) carbonill-1-piperazinyl-2-hydroxy-1- (phenylmethyl) propinaminolcarbonin-2-methylpropylcarbamothioate. 34 A. 2-lsopropyl-4- (methanesulfonyloxymethyl) thiazole. A solution of 1.2 mmol of 4- (hydroxymethyl) -2-isopropylthiazole and 1.3 mmol of diisopropylethylamine in 20 ml of dichloromethane was cooled to -20 ° C and treated dropwise with 1.3 mmol of methanesuiphenyl chloride. The resulting mixture was stirred for 1 hour, quenched with aqueous citric acid, separated, dried over Na2SO4, and concentrated in vacuo to provide the title compound. 34B. 2-lsopropyl-4- (mercaptomethyl) thiazole. A mixture of 0.8 mmol of the product prepared in the Example 34A and 1.0 mmoles of sodium disulphide hydrate in 20 ml of THF was heated to reflux until the thin layer chromatography analysis indicated the consumption of starting material. The resulting mixture was allowed to cool, concentrate in vacuo, partition between dichloromethane and water, dry over Na2SO4 and concentrate to provide the crude compound. 34C. N - ((2-isopropyl-4-thiazolyl) thiomethoxycarbonyl) -valine methyl ester. A solution of 2.18 g (15 mmol) of 2-lsopropyl-4- (mercaptomethyl) thiazole, 15.8 mmol of a-isocyanato-valine methyl ester and 1.5 mmol of 4-dimethylaminopyridine in 75 ml of dichloromethane was heated to reflux for approximately 5 hours. The resulting solution was washed successfully with 10% citric acid, aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Chromatography of the silica gel from the residue using 5% ethyl acetate in chloroform will provide the title compound. 34D. N - ((2-lsopropyl-4-thiazolyl) thiomethoxycarbonyl) valine. A solution of the product, prepared in Example 34C in dioxane, was treated with 0.50 M aqueous LiOH. The resulting solution was stirred at room temperature for approximately 30 minutes, treated with 1 M HCl and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO4, and concentrated in vacuo to provide the title compound. 34E. S-r2- (1-Methylethyl) -4-thiazotylmetill-rM S) -1 -riip S.2R) -2-rrp. 1-dimethylethyl) amino) carbo nill-4-ffd, 1-di-methyl-methyl) -carbonyl-1-piperazinin-2-hydroxy-1- (phenylmethyl) propyl-1-aminocarbonyl-2-methylpropylcarbamothioate. The title compound was prepared according to the method described in Example 1 C, substituting N - ((2-lsopropyl-4-thiazoliI) thiomethoxycarbonyl) valine for [(2-isopropyl-4-thiazole)] methyloxycarbonylI-L-valine. 34F. S-r2- (1 -Methylethyl) -4-thiazolylmethyl-f (1S) -1-lff (1S.2R) -3-f (2S) -2-17 (1, 1-di-methyl) eti Dami no) carbonyl] -1 - pipe razinill-2-h id roxi-1 - (fen ilmetil) pro pilla mi no] carbon ill-2-methyl pro pillcarbamothioate. The title compound was prepared according to the method described in Example 1 D, substituting S- [2- (1-methylethyl) -4-thiazo! I [meti: - [(1S) -1 - [[[( 1S, 2R) -3 - [(2S) -4- (1,1-dimethylethyloxy (carbonyl)) - 2 - [[H. l-dipetiletiOmino-JCarbonin-l-piperazinin-hydroxy-l-phenylmethiopropinaminolcarbonin ^ -methylpropincarbamothioate in place of 2-.1-methylethyl) -4-thiazolylmethyl] (1S) -1 - [[[(1S, 2R) -3- [ (2S) -4- (1,1-dimethylethyloxy (carbonyl)) - 2 - [[(1,1-dimethylethyl) amino) carbonyl] -1-pipe-reason? I] -2-hydroxy-1 - ( phenylmethyl) prop i I] to my non] carbonyl] -2-methypropyl] carbamate. 34G. S-T2- 1-Methylene-4-thiazolylmethyl (1S) -1-rtf (1S.2R) -3-r (2S) -4- (1,3-benzodioxc-5-ylmethyl) -2-ff (1.1 -dimethyethyl) amino) carbonin-1-pip erazinir-2-hydroxyl-1 - (phenylmethyl) pro pyl] at min oley or 11-2-methyropropylcarbamothioate. The title post was prepared according to the method described in Example 1E, substituting S- [2- (1-methyethyl) -4-t? Azolümet; - [(1S) -1 - [[[( 1S, 2R) -2 - [[(1,1-dimethylethyl) aminocarbonyl-l-piperazinyl-hydroxy-1-phenylmethylpropyl-aminocarbonyl] -methylpropylcarbamothioate in place of 2- (1-methylethyl) -4-thiazolylmethyl] - (1S) -1 - [[[('3.2R) -3 - [(2S) -2 - [[(1, 1 -di etílet¡l) amíno) carboníl] -1 -pipe razi ni T -2 -hydroxy - 1- (Phenethylmethyl) propyl] amino] ca rbo ni l] -2-methylpropiFcarbamate.

Example 35 4- (1,3-Benzodioxol-5-ylmethyl) -N- (1-1-dimethylethyl) -1-r (2R-3S) -3-fr (2S) -2-ff3-f2- (1-rr6tilethyl) ) -4-thiazolin-1-oxopropylamino] -3-methyl-1-oxobutipar- 'no1-2-hydroxy-4-phenylbutyne-2-piperazinecarboxamide). 35A. 2-lsopropylthiazole-4-carboxaldehyde. A solution of 3.1 g (15.6 mmol) of ethyl 2-isopropylthiazo I-4-carboxylate in 50 ml of dichloromethane was cooled under an N2 atmosphere at -78 ° C and treated dropwise with 15.6 ml (23.4 mmol) of a solution of 1.5 M diisobutylaluminium hydride in toluene for a period of 1.5 hours. After being stirred for a further 0.5 hours, the solution was quenched with 5 ml of methanol followed by 15 ml of the Rochelle aqueous salt. The resulting mixture was partitioned between chloroform and the Rochelle aqueous salt, dried over Na2SO4, and concentrated to provide 1.3 g (56%) of the desired crude compound Rf 0.47 (20% ethyl acetate in hexane). 1 H NMR (CDCl 3) d 1.45 (d, J = 7 Hz, 6 H), 3.39 (heptet, J = 7 Hz, 1 H), 8.07 (s, 1 H), 10.00 (s, 1 H) . Mass spectrum: (M + H) + = 156. 35B. 3- (2-lsopropyl-4-thiazolyl) propenoate of (E) -ethyl. A 60% NaH slurry (18 mmol) in mineral oil was washed with hexane, decanted under an N2 atmosphere, and diluted with 25 ml of TH F. The resulting mixture was cooled to 0 ° C, treated in portions with 3.24 ml (16.4 mmoles) of triethylphosphonoacetate. After the addition, the solution was stirred for 10 minutes, treated with 1.37 g (8.84 mmol) of 2-isopropylamine-4-carboxaldehyde in 25 ml of THF, followed by heating to room temperature for 25 minutes, and it was quenched with 10 ml of saturated aqueous NH4CI. The mixture was extracted with three 100 ml portions of ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5-10% ethyl acetate in hexane provided 1.61 g (81%) of the desired compound, Rf 0.64 (20% ethyl acetate in hexane). 1 H NMR (CDCl 3) d 1 .33 (t, J = 7 Hz, 3 H), 1.42 (d, J = 7 Hz, 6 H), 3.32 (heptet, J = 7 Hz, 1 H), 4.26 ( q, J = 7 Hz, 2 H), 6.75 (d, J = 15 Hz, 1 H), 7.29 (s, 1 H), 7.57 (d, J = 15 Hz, 1 H). 35C. 3- (2-l soproyl-4-thiazolyl) propanoate methyl. A solution of 225 mg (1 mmol) of (E) ethyl 3- (2-lsopropyl-4-thiazolyl) -propenoic acid in 10 ml of freshly distilled methanol (from calcium hydride) and 1 ml of dry THF are added. treated with 49 mg (2 mmol) of magnesium. The mixture was stirred for 20 minutes and the magnesium was consumed. The resulting solution was drained over cold aqueous HCl, basified to a pH of 8 with NaHCO3, extracted with ethyl acetate, dried over Na2SO4, and concentrated. Silica gel chromatography using 10% ethyl acetate in hexane gives a mixture of the desired compound and methyl 3- (2-isopropyl-4-thiazolyl) propanoate. 35D. 3- (2-Isopropyl-4-ti-azoyl) propanoic acid. A solution of the product, prepared in Example 35C in dioxane was treated with 0.50 M aqueous LiOH. The resulting solution was stirred at room temperature for approximately 30 minutes, treated with 8.7 ml of 1 M HCl and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO4, and concentrated in vacuo to provide the title compound. 35E. N '- (1.1 -Dimethylethyl) -4-fr (1. 1 -dimethylethyl) carboninoxyl 1-r (2R.3S) -3-rr (2S) -2-rr3-r2- (1 -methylethyl) -4- thiazoHp-1-oxopropylamino-1-3-methyl-1-oxo-butyl] aminol-2-hydroxy-4-phenylbutyn-2-piperazinecarboxamide. A solution of 3- (2-isopropyl-4-thiazolyl) propanoic acid, 1.1 equivalents of a-isocyanate-valine methyl ester and 4-dimethylaminopyridine (catalytic) in d-chloromethane was heated to reflux for about 5 hours. The resulting solution was washed successively with 10% citric acid, aqueous NaHCO3, and brine, dried over Na2SO, and concentrated in vacuo. Chromatography of silica gel of the residue using 5% ethyl acetate in chloroform to provide the title compound. 35F. N, - (1 .1 -Dimethylethyl-1 -r (2R.3S) -3-rr (2S) -2-rf3-f2- (1-methylthiol) -4-thiazolyl-1-1-oxopropyl-1-aminol-3 methyl-1-oxobutinaminol-2-hydroxy-4-phenylbutin-2-piperazinecarboxamide The title compound was prepared according to the method described with method 1 C, substituting N - ((2-lsopropyl-4-thiazoH) propionyl ) vain in place of [(2-isopropyl-4-thiazoyl) methyloxycarbonyl] -L-valine. 35G. N '- (1,1-Dimethylethyl) -1-r (2R.3S) -3-rr (2S) -2-rr (2- (1-methylethn-4-thiazolyl) -1-oxopropyl-amino-3-methyl -1-oxobutinaminol-2-hydroxy-4-phenylbutyl-2-piperazinecarboxamide The title compound was prepared according to the method described in Example 1D, replacing 4- (1,1-dimethyethyloxy (carbonyl)) - N - (1, 1-dimethylethyl) -1 - [(2R, 3S) -3 - [[(2S) -2 [[3- [2- (1-methylethyl) -4-thiazolyl] -1-oxopropyl] amino ] -3-methyl-1-oxobutyl] amino] -2-hydroxy-4-phenylbutyl] -2-piperazinecarboxamide in place of 2- (1-methyIeti!) - 4-thiazoylmethyl- (1S) - [[[(1S , 2R) -3 - [(2S) -4- (1,1-dimethylethylloxy- (carbonyl)) - 2 - [[(1,1-dimethyl-ethyl) amino] carbonyl] -1-piperazinyl] -2 -hydroxy-1- (phenylmethyl) propyI] amino] -carbonyl] -2-methylpropyl] carbamate. 35H. 4- (1,3-Benzodioxol-5-ylmetin-N- (1-1 -dimethylethyl) -1-1 (2 R-3S) -3-rr (2S) -2-rr3-r2- (1-methylethyl) - 4-thiazolyl-1-oxopropylamino-3-methyl-1-oxobutyl-1-amino-2-hydroxy-4-phenylbutyl-1-piperazinecarboxamide). The title compound was prepared according to the method described in Example 1E, substituting N '- (1,1-dimethylethyl) -1 - [(2R, 3S) -3 - [[(2S) -2 - [[ 3- (2- (1-Methylethyl) -4-thiazoyl] -1-oxopropyI] amino] -3-methyl-1-oxobutyl] amino] -2-hydroxy-4-phenylbutyl] -2-piperazinecarboxamide instead of 2- (1-Methylethyl) -4-thiazolylmethii- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-di methylethyl)] not my] carboni I] - 1 -pipe razi ni I] -2-hi droxy- 1 - (phenyl m ethyl) prop i I] mino] carboni l] -2-methyl-prop i Ijcarbamate.

Fluorogenic assay for classifying inhibitors of HIV protease The inhibitory potency of the compounds of the invention can be determined by the following method: A compound of the invention was dissolved in DMSO. A small aliquot was diluted with DMSO at 100 times the final concentration desired for testing. The test was performed in a 6 X 50 mm tube in a total volume of 300 microliters. The final concentrations of the components in the reaction pH regulator are: 1.25 mm of sodium acetate, 1 M of sodium chloride, 5 mM of dithiothreitol, 0.5 mg / ml of bovine serum albumin, 1 .3 μM of fluorogenic substrate, 2% (v / v) of dimethyl sulfoxide, pH 4.5. After adding the inhibitor, the reaction mixture was placed in a fluorometer cell holder and incubated at 30 ° C for several seconds. The reaction was initiated by the addition of a small aliquot of cold VI H protease. The fluorescence intensity (340 nM excitation, 490 nM emission) was recorded as a function of time. The reaction rate was determined during the first 6 to 8 minutes. The observed speed is directly proportional to the substrate moles divided by unit of time, the inhibition percentage is 100 X (1 - (speed in the presence of? inhibitor) / (speed in the absence of the inhibitor)). Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-lle-Val-Gln-EDAN S where DABCYL = 4- (4-dimethylamino-phenyI) azobenzoic acid and .EDANS = 5 - ((2-aminoethyl) ) amino) -naphthalene- 1 -syphonic. All compounds tested at 1.0 nM were found to have an IC50 of 100%. The test compounds were then tested at a concentration of 0.5 nM. The results are reported as percent inhibition in Table 1, below.TABLE 1 Table 1 shows the inhibitory potencies of the compounds of the invention against VI H-1 protease.

Antiviral Activity The anti-VlH activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, and others (Antimycrob, Agents Chemother, 1991, 35, 2209). IC5Q is the concentration of the compound that provides 50% inhibition of the cytopathic effect of HIV. The LC50 is the concentration of the compound at which 50% of the cells remain viable.

Table 2 The compounds of the present invention can be used in the form of salts derived from organic or inorganic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , tartrate, thiocyanate, p-toluenesulfonate, and a decanoate. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halide such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkylsulfates such as dimethyl, diethyl, dibutii, and diamyl sulfates, long chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearium, aralkyl halides such as benzyl and phenethyl bromides, and others. In this way, products dispersible in water or soluble in oil are obtained. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate. The compounds of the present invention can also be used in the form of esters. Examples of such esters include a substituted hydroxyl compound of the formula I or II which has been asylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R14C (O) or R14C (S) - wherein R14 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula RaC (Rb) (Rd) -C (O) - or Ra -C (R °) (Rd) -C (S) - wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is -N (Re) (Rf), ORe or -SRe where Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino acyl residue having the formula R 15 NH (CH 2) 2 N HCH 2 C (O) - or R 15 NH (CH 2) 2 OCH 2 C (O) - wherein R 15 is hydrogen, lower alkyl, aralkyl, cycloalkylalkyl, alkanoyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are glycine and lysine, however, other amino acid residues can also be used, including those wherein the amino acyl group is -C (O) CH2NR 1? 6e rR, 1 7 wherein R1 S and R17 are independently selected from hydrogen and lower alkyl, or the group -NR? SR i 7 in cyclopene R1 6 1 7] taken together, form a nitrogen containing a heterocyclic ring . These esters serve as prodrugs of the compounds of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase the solubility for intravenous administration of the compounds. Other pro-drugs include a hydroxyl-substituted compound of the formula I or II, wherein the hydroxyl group is functionalized with a substituent of the formula -CH (R18) OC (O) R19 or -CH (R18) OC (S) R19 wherein R19 is lower alkyl, haloalkyl, alkoxy, thioaicoxy or haioalkoxy; and R18 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Said drugs can be prepared according to the Schreiber method (Tetrahedron Lett, 1993, 24, 2363) through ozonolysis of the corresponding metalilic ether in methane followed by treatment with acetic anhydride. The prodrugs of this invention are metabolized in vivo to provide the substituted hydroxyl compound of formula I or II. The preparation of the pro-drug esters is carried out by reacting a hydroxyl-substituted compound of the formula I or II with an activated amino acyl derivative, phosphoryl, hemisuccinyl or acyl as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. The prodrugs of the invention can also be prepared through the alkylation of the hydroxyl group with alkyl (halo) esters, transacetylation with bis (alkanoyl) acetals or the condenzation of the hydroxyl group with an activated aldehyde followed by the hemiacetal acylation as an intermediate. The compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and particularly in humans). The compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human immunodeficiency virus (HIV). The compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially the acquired immunodeficiency syndrome or an HIV infection in a human or other mammal. The total daily dose administered to a human or other host mammal in individual or divided doses may be in amounts of, for example, 0.001 to 300 mg / kg body weight daily, and more usually 0.1 to 10 mg. The unit dose compositions may quantities of their submultiples to develop the daily dose. The amount of the active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. However, it should be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, the time of administration, the route of administration, the rate of excretion, the combination of drug, and the severity of the particular disease that is in therapy. The compounds of the present invention may be administered orally, parenterally, sub-surgically, by inhalation, rectally or topically in unit dose formulations containing conventional, non-toxic pharmaceutically acceptable carriers, auxiliaries, and carriers as desired. Topical administration may also involve the use of transdermal administration, such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example, as an aqueous solution., 3-propanodiol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and an isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable products. Suppositories for rectal administration of the drug can be prepared by mixing the drug with an unsuitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures, but liquid at rectal temperature and, therefore, will melt in the rectum and they will release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound can be mixed with at least one diluent such as sucrose, lactose or starch. Said dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. The tablets and pills can also be prepared with enteric covers. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Said compositions may also comprise auxiliaries, such as, wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfume-providing agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids and other lipid substances. Liposomes are formed through mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidols (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV; Academic Press, New York, N .Y. (1976), p. 33 et seq. Although the compounds of the invention can be administered as a single active pharmaceutical agent, they can also be used in combination with one or more immunomodulatory agents, antivirals and other agents against infections or vaccines. Other antiviral agents that will be administered in combination with a compound of the present invention include AL-721, beta interferon, polyimanoacetate, reverse transcriptase inhibitors (e.g., dideoxycytine (DDC), dideoxyinosine (DDI), BCH-189, AzdU, carbovir , DDA, D4C, D4T, DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thiadidexycytidine, PMEA, zidovudine (AZT), and the like), non-nucleoside reverse transcriptase inhibitors ( example, R82193, L-697,661, BI-RG-587 (nevirapine), DMP-266, and the like), retroviral protease inhibitors (e.g., HIV protease inhibitors such as ritonavir, ABT-378, saqu? navir, nelfinavir, indinavir, VX-478 (amprenavir), SC-52151, KNI-227, KNI-272, U-140690, DMP-450, and the like), composed of HEPT, L, 697, 639, R82150, U-87201 E, and the like), TAT inhibitors (e.g., RO-24-7429 and the like), trisodium phosphonoformate, HPA-23, eflonithin, Peptide T, Reticulose (nucieofosfoprot) eina), ansamycin LM 427, trimetrexate, UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cilobut-G, cidobut-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, L-693.999, BV ara-U , tricyclonal antibodies of CMV, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, viradabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4 / CD4-IgG, CD4-PE40, butyl-DNJ, hypericin, oxamic acid, dextrtan sulfate and pentosan poiisulfate. The immunomodulators can be administered in combination with a compound of the present invention and include bromopyrimine, Ampligen, alpha-interferon anti- human antibody, colony stimulation factor CL246,738, Imreg-1, lmreg-2, diethithiocarbamate, interleukin- 2, alpha-interferon, inosine-pranobex, methionine-enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8 + infusion , alpha interferon immunoglobulin, IGF-1, anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosin, IVIG, HIVIG, passive immunotherapy, and hyperimmunization of polio vaccine. Other anti-infection agents that can be administered in combination with a compound of the present invention include pentamidine isethionate. Any of a variety of HIV or AIDS vaccines (eg, gp120 (recombinant), Env 2-3 (gp 120), H IVAC-1 e (gp120), gp160 (recombinant), VaxSyn H IV-1 (gp 160) ), immuno-Ag (gp 160), HG P-30, VI H Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a compound of the present invention Other agents that can be used in combination with the compounds of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721, carrisin, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2 -oxothiazolidin-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoietin, fusidic acid, glucan, HPA-23, human growth hormone, hydroxychloroquine, isacador, L-ofloxasine or other quinolone antibiotics, lentinan, carbonate lithium, MM-1, monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PA1, panax ginseng, pentofilin, pentoxifylline, T peptide, p-extract ino, poiimanoacetate, reticulosa, retrogen, ribavirin, ribozomas, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, thymosin alfa-one, thymo-stimulin, UA001, uridine, vitamin B12 and " wobemugos ". Other agents that can be used in combination with the compounds of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin, and the like. Other agents that may be used in combination with the compounds of this invention are antibacterial such as amikacin sulfate, azithromycin, ciprofloxacin, tosofloxacin, clarithromycin, clofazimine, ethambutol, sionazide, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65, and the like Other agents that may be used in combination with the compounds of this invention are anti-neoplastic such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD, (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (w / Ieucovin, rescue) doxorubicin, cyclophosphamide, etoposide / mechlorethamide, vincristine, prednisone and procarbazine), vincristine, vinblastine, angiohibines, pentosan polysulfate, platelet factor 4 and SP-PG, and the like. Other agents that can be used in combination with the compounds of this invention are drugs for treating neurological diseases such as T peptide, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetin, heparin and cytosine arabinoside, and the like. Other agents that may be used in combination with the compounds of this invention are antimicrobial agents such as albendazoi azithromycin, cyarithromycin, cyandamicin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, faar, furazolidone, L, 671, 329, letrazuril, metronidazole , paromycin, pefloxacin, pentamidine, piritrexime, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP / SMX, trimetrexate and WR 6026, and the like. Among the preferred compounds for treating VI H or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors and other HIV protease inhibitors. It will be understood that the agents that can be combined with the compounds of the present invention for the treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but rather include in the beginning any agent useful for the treatment or prophylaxis of AIDS or an HIV infection. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are provided at the same time or at different times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. For those skilled in the art, variations and changes are obvious and are intended to be within the scope and nature of the invention, which are defined in the appended claims.

Claims (47)

1. A compound that has the formula V. wherein R1 is a thiazolyl group having the formula: and R is a group that has the formula: wherein R is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; And it is CH or N; 4 is -W-R5; VV is -O-, -S-, or - (CH2) n-; and R5 is selected from the group consisting of alkyl, and aryl; N is from 0 to 6; or R4 and the ring taken together can form a bicyclic group having the formula: provided that when W is O, or S, then Y is CH; R6 is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl; heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; and Z is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; wherein the alkyl, aryl, heterocyclic, and heteroaryl groups may be optionally substituted with 1 to 5 substituents of the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, and halogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. The compound according to claim 1, wherein R3 the alkyl or cycloalkyl and Z is -O-, or -N (R7) -.

3. The compound according to claim 2, wherein R3 is alkyl.

4. The compound according to claim 2, wherein R3 is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. The compound according to claim 3, wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropy.

6. The compound according to claim 5, wherein R3 is isopropyl.

7. The compound according to claim 1, wherein Z is -O-.

8. The compound according to claim 1, wherein Z is -N (R7) - and R7 is methyl.

9. The compound according to claim 1, wherein Y is nitrogen, W is -CH2- and R5 is aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl.

10. The compound according to claim 9, wherein R5 is substituted with fluorine.

The compound according to claim 9, wherein R5 is substituted with 1 to 3 hydroxy groups.

12. The compound according to claim 9, wherein R5 is substituted with 1 to 3 alkoxy or alkylthio groups.

13. The compound according to claim 9, wherein R5 is substituted with two alkoxy groups.

14. The compound according to claim 9, wherein R5 is substituted with at least one hydroxy group and at least one methoxy group.

15. The compound according to claim 1, wherein Y is CH, and R5 is alkyl or aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl.

16. The compound according to claim 15, wherein R5 is substituted with 1 to 3 alkoxy or alkylthio groups.

17. The compound according to claim 15, wherein R5 is substituted with a hydroxy group.

18. The compound according to claim 15, wherein R5 is substituted with a methoxy group.

19. The compound according to claim 15, wherein W is -O-.

20. The compound according to claim 19, wherein R5 is methyl substituted with a thiazolyl group.

21. The compound according to claim 1, wherein R6 is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl.

22. The compound according to claim 21, wherein R6 is lower alkyl selected from the group consisting of methyl, ethyl, propyl, or butyl.

23. The compound according to claim 22, wherein R6 is tert-butyl or hydroxybutyl.

24. A compound having the formula IV. Item wherein R1 is a thiazolyl group having the formula: and R is a group that has the formula: V "^ 8 wherein R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and X is -C (O) - or -S (O) 2-; R8 is alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; R9 is alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl) alkyl; and Z is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl) alkyl; wherein the alkyl, aryl, heterocyclic, and heteroaryl groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino, and halogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.

25. The compound according to claim 24, wherein R3 the alkyl or cycloalkyl and Z is -O-, or -N (R7) -.

26. The compound according to claim 25, wherein R3 is alkyl.

27. The compound according to claim 25, wherein R3 is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

28. The compound according to claim 26, wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl or propyl.

29. The compound according to claim 27, wherein R3 is isopropyl.

30. The compound according to claim 25, wherein Z is -O-.

31 The compound according to claim 25, wherein Z is -N (R7) - and R7 is methyl.

32. The compound according to claim 24, wherein R8 is selected from the group consisting of alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino or heteroaryl.

33. The compound according to claim 24, wherein X is -S (O) 2-; R8 is aryl selected from the group consisting of phenyl, and heteroaryl; and R is lower alkyl.

34. The compound according to claim 24, wherein R9 is selected from the group consisting of isopropyl, isobutyl, or 3-methyl-1-butyl.

35. The compound according to claim 34, wherein R9 is iso-butyl.

36. The compound according to claim 32, wherein R8 is substituted with 1 to 3 amino groups.

37. The compound selected from the group consisting of: 2- (1-methylethyl) -4-thiazolemethyl - [(1S) -1 - [[[(1S, 2R) -3 (2S) -4- (1 , 3-benzodioxol-5-ylmethyl) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methyl -prop?!] carbamate; 2- (1-Methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethyl-etl) amine] ] carbonyl] -4- (phenylmethyl) -1 piperazi ni l] -2-hyd roxy- 1- (phenylmethyl) propyljam i no] carbon il] -2-m ethyl propyl I] carbamate; 2- (1-methyletiI) -4-thiazolylmethyl- (1S) -1-t [[(1S, 2R) -3 - [(2S) 2 - [[(1,1-di methylethi) am i no ] ca rbo ni l] -4 - [(4-f luorof eni l) met¡ I] 1 -piperazi ni l] -2-hydroxy- 1 - (phen? l meti I) prop il] amino] carbonyl] 2 -m ethyl propy I] carbamate; 2- (1-methyethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-d imetiIetiI) amino] carbonyl] -4- (5-thieni I meti 1) 1 -piperazi ni l] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; 2- (1-Methyethyl) -4-thiazolemethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethylethyl) amino] ] carbonyl] -4- [4- (3-hydroxyphenyl) methyI] -1-piperazinyl] -2-hydroxy-1- (phenyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-methyethyl) -4-thiazoylmethylI - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethyIetiI) amine] ] carboniI] -4- (3-pyridinylmethyl) -1 -piperazi or 1] -2-hydroxy-1 - (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethM - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dim ethylethyl) ami] carbon] il] -4- (4-pyridinylmethyl) -1-piperazyl-1] -2-hydroxy-1 - (phenylmethyl) propyl] amino] carbonii] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazoylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4 - [(4-Hydroxyphenyl) methyl] -1-p-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl carba kill; 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) 4- (1H-benzimidiazol-2-ylmethyl) -2- [ [(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropylcarbamate; 2- (1-Methyethyl) -4-thiazoylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -2 - [[(1,1-dimethyIetiI) amino] carbon il] -4- (2qui nol inylmethyl) -1 -piperazi ni l] -2-hi droxi -1- (phenylmethyl) pro pyl] am i no] carbonyl] -2-metiIprop il] carbamate; 2- (1-methyethyl) -4-thiazoyl-Imethi [(1S) -1 - [[[(1S, 2R) -3 - [(2S) 4 - [(3,4-dimethoxylfenyl) ) methyl] -2 - [[(1,1-dimethyl-lethyl) amino] carbonyl] -1-piperazi or I] -2-hydroxy-1- (phenylimethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolyl) metll) -1-p? perazin? I] -2-h id roxy- 1 - (phenylmethyl) prop il] amino] -carboniI] -2-methylpropiI] -N-methyl-N- [2- (1- methylethyl) -4-thiazolylmethyl] urea; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethyethyl) amino] carbonyl] -4- (phen ilmethyl) -1-piperazinyl] -2-hydroxyl l- (f -methylmethyl) propyl] amino] -carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl ]urea; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4 - [(4-hydroxy) 3-methoxyphenyl) methyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) -propiI] amino] carbonyl] -2-methylpropyl] - N -methyl- N- [2- (1-methyl-ethyl) -4-thiazolylmethyl] urea; 2-methyI-4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4- (1,3-benzodioxol-5-iImetI) -2- [ [(1,1-dimethylethyl) amino] carbonyl] -1-piperazine or l] -2-h idroxy-1- (phenylimethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2-methyI-4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyl-enyl) methyl] - 2 - [[ (1,1-dimethylethyl) amino] carbonyl] -1-piperazyl or I] -2-hydroxy-1- (pheny1ethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; 2-methyI-4-thiazolyImethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) -amino] carboni] -4- [ (4-f luorofenyl) useful] -1-piperazyl-1] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methypropylcarbamate; 2-Ethyl-4-thiazoyl-methyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyphenyl) me thi] -2 - [[(1 , 1-dimethylethyl) amino] carboni I] -1 piperazinyl] -2-hydroxy-1- (f -methyl) propyl] amino] carbonyl] -2-methylpropyl] carbam ato; 2- (1-Methylethyl) -5-thiazoylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(2S) -4 - [(3,4-dimethoxyIphenyll) meth] -2 - [[(1, 1-dimethyl-eti I) at min o] cabobo nyl] - 1-pperazinyl] -2-h-droxy- 1 - (phenyl I methyl) propi I] amino ] carbonyl] -2-methylpropylcarbamate; 2-eIiI-5-thiazoI-ImetiI- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxylfenii) met? I] -2 - [[(1,1-dimethylethyl) am i no] carbonyl] -1-piperazyl nILJ-2-hydroxy-1- (phencymethyl) propyl] amino] carbonyl] -2-methyl propylcarbamate; 2-methi-5-thiazoylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -4 - [(3,4-dimethoxyphenyl) methyl] -2 - [[ (1,1-di methylethyl) to mino] carbonyl] -1-piperazinyl] -2- hydroxy- 1- (phenylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; N '- [(1R) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-t azoleyl methyl) -1-piperazinyl] -2-hydroxy-1 - (phenylmethyl) propyl] amyl] -carbonyl] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea; N, - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethyethyl) amino] carbonyl] -4- (5-thiazolymethyl) - 1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea; 5-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbon] I] -4- ( phenylmethyl) -1-piperazinyl] -2-hydroxyl- (phenylimethyl) propyl] amino] carbonyl] -2-methylpropy] carbamate; 5-thiazoIiImethyl- (1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amino] carbo niIl-4- (5-thiazolyl) eti I ) - 1 -piperazi ni l] -2-h id roxy- 1- (faith nyl methyl) propiI] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [[[(1,1-dimethylethyl) amino] carbonyl] (2-methylethyl) propylamine] -2-hydroxy-1 (phenylmethyl) ) propyI] amino] carbonyl] -2-methyl propyl] -N-methyl- N- [2- (1-methylethyl) -4-thiazole-ylmethyl] -urea; 2- (1-methyIetiI) -4-thiazoiylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [[[(1,1-dimethylethyl) amino] carboni I] (2-m) eti I eti I) propylamino] 2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-methylethyl) -4-thiazoylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) suiofonyl] (1-methylethyl) amino] -2-hydroxy- 1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) sulfoniI] (1-methylethii) amino] -2-hydroxy-1 - (phenylmethyl) propyl] amino carbonyl] 2-methylpropyl] -N-methyl-N- [2- (1-methyl-ethyl) -4-thiazoIi-methyl] urea; 2- (1-meti! EtiI) -5-yiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 [(3S) -3 - [[(1,1-dimetiIet:;) aminc carbonyl] (4aa, 8aa) octahydro-2-isoquinolinyl] -2-hydroxy-1- (phenyl-ethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; N '- [(1S) - - [[[(1S.2R) -3 - [(3S) -3 - [[(1,1-dimethylethyl) amino] carbonyl] (4aa, 8aa) octah: ro -2-isoquinolinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl-2-methy1propyl] -N-methyl-N- [2- (1-methylethyl) -5-thiazolylmethyl] urea; N * - [(1S) - * - [[[(lS 2R) -3 - [(2S, 4R) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazo! 7-methox '; - 1-piperidinyl] -2-hyd roxy- (f -methylmethyl) propyljamino] -carbon or -2-met:? PropiI] -N-methyl-N- [2- (1-methylethyl) - 4-thiazoxymethyl] urea; 2- (1-methyl), ethyl) -t-azolylmethi [(1S) -1 - [[[(1S, 2R) -3 [(2Sl4R) -2 - [[(1,1-dimet? Ie : ",) amirc] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1 - (f orilyl) p rcoiI] to my no] ca nbo nil] -2- methyl propyl ] carbamate; S- [2- (1-r-ethyl-ethyl-4-thiazolymethyl] [(1 S) -1 - [[[(1 S, 2R) -3 [(2S) -4- (1, 3- benzodichloxol-5'-ethyl) -2 - [[(1,1-dimethylethyl) amino] carbonyl] -1-piperazyr; I] -2-; droxy-1 (phenylmethyl) propyl] amino] carbonyl] - 2-Methylprocyl] car amothioate and 4- (1,3-benzodicxol-5-ylmethyl) -N - (1,1-di methylethyl) -1 - [(2 R, 3S) -3 - [[(2S) -2- [[3- [2- (1-methylene: l) -4-thiazole] -1-oxopropyl] amino] -3-methyl-1-oxobutyl] amino] -2-hydroxy-4- phenylbutyl] -2-piperazinecarboxamide, or a pharmaceutically acceptable salt, ester or prodrug thereof

38. The compound according to claim 37, selected from the group consisting of: 2- (1-Me: eti!) - -i-: iazoIiImethyl - [(1 S) -1 - [[[(1 S, 2R) -3 [(2S) -4- (1, 3-benzodioxol-5-ylmethyl) -2 - [[(1 , l-dimethyl-eti-O-aminolcarboni-l-piperazinylj -hydroxy-l-phenylmethio propylaminocarbonyl] - methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl- (1S) -1 - [[[(1S, 2R) -3 - [[(4-aminophenyl) suiofon]] (1-methylethyl) amino] -2- hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; 2- (1-Methylethyl) -4-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(2S) -2 - [[(1,1-dimethylethyl) amin or] carbonii ] -4- (5-thienylmethyl) -1-pipe-razinyl] -2-hydroxy-1 - (phenylmethyl) pro-pil] amino] -carbonyl] 2-methyl-pro-piljcarbamate; 2- (1-Methyethyl) -4-thiazolylmethyl [(1S) -1 - [[[(1S, 2R) -3 - [(2S) 4 - [(3,4-d? Methoxylpheni) methy] -2- [[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate; N '- [(1S) -1 - [[[(1S, 2R) -3 - [(2S, 4R) -2 - [[(1,1-Dimethylethyl) amino] carbonii] -4- (5 -thiazole-1-ethoxy) -1-piperidinyl] -2-hydroxy-1 - (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -Nm ethyl- N- [2- (1-methyl-ethyl) -4- thiazolylmethyl] urea; and 2- (1-Methyethyl) -5-thiazolylmethyl - [(1S) -1 - [[[(1S, 2R) -3 - [(3S) -3 - [[(1,1-dimethyl etiI) amino) carbonyl] (4aa, 8aa) octahydro-2-isoquinoliniI] -2-hydroxy-1 - (fe nylmethyl) propyl] amino] carbonyl] 2-methylpropyl] carbamate; or a pharmaceutically acceptable salt, ester or prodrug thereof.

39. A pharmaceutical composition for the treatment of an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.

40. A pharmaceutical composition for the treatment of an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 24.

41. A method for inhibiting HIV protease comprising administering to a mammal in need of such treatment. a therapeutically effective amount of a compound of claim 1.

42. A method for inhibiting HIV protease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 24.

43. A pharmaceutical composition for the treatment of an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 9.

44. A pharmaceutical composition for the treatment of an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 20.

45. A pharmaceutical composition for the treatment of an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 36.

46. A process for the preparation of a compound of the formula I: wherein R1 is a thiazolyl group having the formula: and R2 is a group that has the formula: wherein R3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkyl amino, and cycloalkyl; And it is CH or N; R4 is -W-R5; W is -O-, -S-, or - (CH2) "-; and R5 is selected from the group consisting of alkyl, and aryl; N is from 0 to 6; or R4 and the ring taken together can form a bicyclic group having the formula: * > 101 provided that when W is O, or S, then Y is CH; Rd is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl; heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; 5 and Z is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; wherein the alkyl, aryl, heterocyclic, and heteroaryl groups can be optionally substituted with 1 to 5 substituents of the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, and halogen.

47. A process for the preparation of a compound of formula II: 15 ti wherein R 1 is a thiazolyl group having the formula: S and R2 is a group that has the formula: 'N' ^ 8 wherein R is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and X is -C (O) - or -S (O) 2-; R8 is alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocyclic, alkyl (heterocyclic), heteroaryl, or (heteroaryl) alkyl; Rs is alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl) alkyl; and Z is -O-, -S-, -CH2- or -N (R7) -; and R7 is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl) alkyl; wherein the alkyl, aryl, heterocyclic, and heteroaryl groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino, and halogen.