JP2002515501A - Inhibitory compounds of retroviral protease - Google Patents

Abstract

  (57) [Summary] The present invention discloses novel compounds, compositions, and methods for inhibiting retroviral protease, and specifically for inhibiting human immunodeficiency virus (HIV) protease. The present invention also relates to compositions and methods for treating retroviral infections, specifically HIV infections, and methods for producing compounds and synthetic intermediates used in these methods.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to retroviral proteases, specifically human immunodeficiency virus (
Novel compound compositions and methods for inhibiting HIV) protease. The present invention also relates to compositions and methods for treating retroviral infections, specifically HIV infections, and methods for producing compounds and synthetic intermediates used in these methods.

BACKGROUND OF THE INVENTION [0002] Retroviruses carry ribonucleic acid (RNA) intermediates and R
NA-dependent deoxyribonucleic acid (DNA) polymerase, a virus that utilizes reverse transcriptase. Retroviruses include RNA from the retroviridae family
Viruses include, but are not limited to, hepadnaviruses and DNA viruses of the Caulimovirus family. Retroviruses cause a variety of disease states in humans, animals and plants. Some of the more important retroviruses from a pathological standpoint include the human immunodeficiency virus (AIDS), which causes acquired immunodeficiency syndrome (AIDS) in humans.
HIV-1 and HIV-2), hepatitis B virus causing hepatitis and liver cancer in humans, human T-cell lymphotropic virus I, II, IV and V causing human acute cell leukemia, and bovine causing leukemia in livestock And feline leukemia virus.

[0003] Proteases are enzymes that cleave proteins at specific peptide bonds. Many biological functions are controlled and mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen and the peptide angiotensin I
Generate Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to produce the antihypertensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce hypertension in vivo. Inhibitors of retroviral protease will provide a therapeutic agent for diseases caused by retrovirus.

[0004] The retroviral genome encodes a protease that is responsible for the proteolytic processing of one or more polyprotein precursors, such as the pol and gag gene products. Welllink, Arch. Virol. , Vol. 98, page 1 (1988). Retroviral proteases most commonly process gag precursors into core proteins and also process pol precursors into reverse transcriptase and retroviral protease. In addition, retroviral proteases are sequence-specific. Pearl, Nature, 328 volumes,
See page 482 (1987).

[0005] Correct processing of precursor polyproteins by retroviral proteases is necessary for the construction of infectious virions. In vitro mutagenesis to produce protease deficient virus has been shown to result in the production of immature core forms lacking infectivity. Crawford, J .; Virol. ,
53, 899 pages (1985), Katoh, et al., Virology, 1
45, page 280 (1985). Thus, inhibition of retroviral protease provides an attractive goal for antiviral therapy.
See Mitsuya, Nature, 325, 775 (1987).

[0006] Current treatments for viral diseases generally involve administering compounds that inhibit viral DNA synthesis. Current treatments for AIDS are 3'-azido-
3′-deoxythymidine (AZT), 2 ′, 3′-dideoxycytidine (DDC
) And compounds such as 2 ', 3'-dideoxyinosine (DDI) and HIV
Administer a compound to treat opportunistic infections caused by immunosuppression associated with the infection. None of the current AIDS treatments has proven to be totally effective in treating and / or reversing disease. In addition, many compounds currently used to treat AIDS cause adverse side effects including low platelet count, nephrotoxicity and myelocytopenia.

[0007] Recently, HIV protease inhibitors such as ritonavir, saquinavir, nelfinavir, and indinavir have been approved in the United States for the treatment of HIV infection. However, there is a continuing need for improved HIV protease inhibitors.

SUMMARY OF THE INVENTION The present invention provides a compound having Formula I,

[0009]

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

[0010]

Embedded image R ² is a group having the following formula:

[0011]

Embedded image Includes compounds that inhibit a retroviral protease, wherein the R ⁴ group is -WR ⁵ .

The group R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is
-O -, - S-, or - _{(CH 2) n} - is selected from the group consisting of, n is is a 0 to 6, provided that when W is O or S, is, Y is CH. R ⁵ is
It is selected from the group consisting of alkyl and aryl. Optionally, R ⁴ and the ring to which it is attached may be taken together to form a bicyclic group having the formula:

[0013]

Embedded image The R ⁶ group is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl)
Alkyl, Z is, -O -, - S -, - CH 2 - or -N ^{(R 7)} - a, ^{R 7} is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl , Heteroaryl, or (heteroaryl) alkyl.

The present invention also provides a compound having Formula II,

[0015]

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

[0016]

Embedded image R ² is a group having the following formula:

[0017]

Embedded image In the above formula, X is -C (O) - or -S _{(O) 2} - and is, ^{R 8} is alkyl,
Includes compounds that inhibit a retroviral protease that are aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl.

R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and R ⁹ is alkyl, cycloalkyl,
Aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl. Z group is -O-, -S-, -C
H ₂ — or —N (R ⁷ ) —, wherein R ⁷ is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl.

The alkyl, aryl, heterocyclic and heteroaryl groups in the compounds of the present invention
It may be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents. The substituent is selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The present invention also includes pharmaceutically acceptable salts, esters or prodrugs of compounds I and II.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and references cited herein are hereby incorporated by reference in their entirety. In case of conflict, the present disclosure, including definitions, will control.

The present invention provides a compound having formula I,

[0022]

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

[0023]

Embedded image R ² is a group having the following formula:

[0024]

Embedded image R ⁴ group is -WR ^5, include compounds that inhibit the protease of a retrovirus.

The R ³ group is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is
-O -, - S-, or - _{(CH 2) n} - is selected from the group consisting of, n is is a 0 to 6, provided that when W is O or S, Y is CH. R ⁵ is
It is selected from the group consisting of alkyl and aryl. Optionally, R ⁴ and the ring to which it is attached may together form a bicyclic group having the formula:

[0026]

Embedded image However, when W is O or S, Y is CH. R ⁶ is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl; Z is —O—,
—S—, —CH ₂ — or —N (R ⁷ ) —, wherein R ⁷ is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl). ) Alkyl.

The present invention also provides a compound having Formula II,

[0028]

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

[0029]

Embedded image R ² is a group having the following formula:

[0030]

Embedded image In the above formula, X is -C (O) - or -S _{(O) 2} - and is, ^{R 8} is alkyl,
Includes compounds that inhibit retroviral protease that are aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl.

R³Is hydrogen, alkyl, amino, alkylamino, dialkylamino and
Selected from the group consisting of cycloalkyl;⁹Is alkyl, cycloalkyl,
Aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl)
Reel) alkyl. Z group is -O-, -S-, -CH₂-Or -N (R ⁷ )-And R⁷Is hydrogen, alkyl, aryl, (aryl) alkyl,
Elementary ring, (heterocyclic) alkyl, heteroaryl, or (heteroaryl) alkyl
It is.

The alkyl, aryl, heterocycle and heteroaryl groups in the compounds of the invention having formula I or II are optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents. May be. The substituent is selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The present invention also includes pharmaceutically acceptable salts, esters or prodrugs of compounds I and II.

In the compounds of the present invention, preferred R ³ groups are alkyl or cycloalkyl. More preferred are compounds wherein R ³ 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.
Most preferred R ³ groups is isopropyl.

A preferred Z group is —O— or —N (R ⁷ ) —. Z is -N ^(R 7) -
In a preferred case, R ⁷ is methyl.

In compounds having formula I, R ² is a group having the formula:

[0036]

Embedded image Wherein Y is CH or N, R ⁴ is —W—R ⁵ , and preferred R ⁵ groups are aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl. In, W is compound Y is nitrogen - _{(CH 2) n} -
And R ⁵ is alkyl or aryl, and n is 0-6.

For compounds where Y is CH, preferred W is —O— and R ⁵ is alkyl,
Alternatively, it is preferably an aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl.

The alkyl, aryl, heterocyclic and heteroaryl groups may be substituted with 1 to 5 substituents, preferably 1 to 3 substituents.

In the case of alkyl, aryl, heterocyclic and heteroaryl groups, examples of substituents are
It is selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. Preferred substituents are fluorine, hydroxy, alkoxy, or alkylthio groups. Preferred alkoxy is
Methoxy. The preferred halogen is fluorine.

In a preferred embodiment, an alkyl or aryl group may be substituted with one to three groups. Preferred substituents are hydroxy, methoxy or fluorine. Preferred aryl groups include, for example, phenyl, such as methylenedioxyphenyl, and heteroaryl, such as, for example, furanyl, thienyl, benzothienyl, thiazolyl. A preferred heteroaryl group is thiazolyl. In preferred compounds, n zero, R ⁵ is methyl substituted thiazolyl group.

The R ⁶ group is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl. R ⁶ is preferably a lower alkyl group such as methyl, ethyl, propyl and butyl. Preferred R ⁶ groups are tert-butyl or hydroxybutyl.

The R ⁸ group is selected from the group consisting of alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl. Preferred R ⁸ groups are, for example, (
(alkyl) amino, such as tert-butyl) amino.

Preferred R ⁹ groups are lower alkyl groups such as, for example, propyl, butyl, pentyl and the like. More preferred R ⁹ groups are isopropyl, tert-butyl, isobutyl, 3-methyl-1-butyl and the like. An iso-butyl group is most preferred.

In a preferred compound of the invention, X is —S (O) ₂ —, R ⁸ is aryl selected from the group consisting of phenyl and heteroaryl, and R ⁹ is is
o-butyl.

In the compounds of the present invention, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, the term "stable compound" means a compound that is stable enough to withstand isolation from the reaction mixture in useful purity and formulation into a therapeutic dosage form suitable for administration.

A preferred compound of the present invention is 2- (1-methylethyl) -4-thiazolylmethyl-((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) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (phenylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenyl Methyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-((((
1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino)
Carbonyl) -4-((4-fluorophenyl) methyl) -1-piperazinyl)
-2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl)-
2-methylpropyl) carbamic acid, 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- (Phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -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) carbamic acid, 2- (1-methylethyl) -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) carbamic acid, 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) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4-((4-hydroxyphenyl) methyl) -1-piperazinyl) -2-hydroxy -1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-((((
1S, 2R) -3-((2S) -4- (1H-benzimidazol-2-ylmethyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy -1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (2-quinolinylmethyl) -1-piperazinyl) -2-hydroxy-1- ( Phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2 -Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N '-((1S) -1-((((1S, 2R) -3-((2S)- 2-(((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) 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- (phenylmethyl) -1
-Piperazinyl) -2-hydroxy-1- (phenylmethyl) 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) propyl) amino) carbonyl) -2-methylpropyl) -N
-Methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2-methyl-4-thiazolylmethyl-((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) carbamic acid, 2-methyl-4-thiazolylmethyl-((1S) -1-((((1S, 2R)
-3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-((
(1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-methyl-4-thiazolylmethyl-((1S) -1-((((1S, 2R)
-3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl)
-4-((4-fluorophenyl) methyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-ethyl-4-thiazolylmethyl -(1S) -1-((((1S, 2R)-
3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((
1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -5-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2 -Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-ethyl-5-thiazolylmethyl- (1S) -1-((((1S, 2R)-
3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((
1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-methyl-5-thiazolylmethyl- ((1S) -1-((((1S, 2R)
-3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-((
(1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N ′-((1R) -1-((((1S, 2R) -3-((2S) -2 − (((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl)
Amino) carbonyl) -2-methylpropyl) -N-methyl-N- (5-thiazolylmethyl) urea, N '-((1S) -1-((((1S, 2R) -3-((2S)- 2-(((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl)
Amino) carbonyl) -2-methylpropyl) -N-methyl-N- (5-thiazolylmethyl) urea, 5-thiazolylmethyl-((1S) -1-((((1S, 2R) -3-((2
S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (phenylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl)
Propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 5-thiazolylmethyl- (1S) -1-((((1S, 2R) -3-((2S
) -2-(((1,1-Dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2 -Methylpropyl) carbamic acid, N '-((1S) -1-((((1S, 2R) -3-((((1,1-dimethylethyl) amino) carbonyl) (2-methylethyl) propyl Amino) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) -N-methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2- (1-methylethyl) ) -4-Thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((((1,1-dimethylethyl) amino) carbonyl)
(2-methylethyl) propylamino) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S ) -1-(((((
1S, 2R) -3-(((4-aminophenyl) sulfonyl) (1-methylethyl) amino) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid N '-((1S) -1-((((1S, 2R) -3-(((4-aminophenyl) sulfonyl) (1-methylethyl) amino) -2-hydroxy-1- (phenylmethyl )) Propyl) amino) carbonyl) -2-methylpropyl) -N-methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2- (1-methylethyl) -5-thiazolylmethyl- ( (1S) -1-(((
(1S, 2R) -3-((3S) -3-(((1,1-dimethylethyl) amino) carbonyl) (4aα, 8aα) octahydro-2-isoquinolinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N ′-((1S) -1-((((1S, 2R) -3-((3S) -3 − (((
1,1-dimethylethyl) amino) carbonyl) (4aα, 8aα) 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-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethoxy) -1-piperidinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2- Methylpropyl) -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)
Amino) carbonyl) -4- (5-thiazolylmethoxy) -1-piperidinyl)
-2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl)-
2-methylpropyl) carbamic acid, S- (2- (1-methylethyl) -4-thiazolylmethyl)-((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) carbamothioatenoic acid and 4- (1,3-benzodioxole-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-piperazinecarboxamide, or a pharmaceutically acceptable salt, ester or prodrug thereof. Is selected from

The most preferred compound of the present invention is 2- (1-methylethyl) -4-thiazolylmethyl-[(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] carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[(
1S, 2R) -3-[[(4-Aminophenyl) sulfonyl] (1-methylethyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid 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- (Phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2 -Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid, N '-[(1S) -1-[[[(1S, 2R) -3-[(2S, 4R ) -2-
[[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2- Methylpropyl] -N-methyl-N- [2
-(1-methylethyl) -4-thiazolylmethyl] urea and 2- (1-methylethyl) -5-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(3S) -3-[[(1,1-dimethylethyl) amino] carbonyl] (4aα, 8aα) octahydro-2-isoquinolinyl] -2-
Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid, or a pharmaceutically acceptable salt, ester or prodrug thereof.

As used herein, the term “alkyl” refers to a straight or branched chain alkyl group containing 1 to 12 carbon atoms. The term "lower alkyl" means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. -Butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like, but are not limited thereto. The alkyl group may be unsubstituted or substituted with 1 to 5 substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
The alkyl group may be optionally interrupted by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus.

As used herein, the term “cycloalkyl” refers to an aliphatic ring system having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl .

The term “alkoxy,” as used herein, refers to a group having the formula —OR ¹⁰ , wherein R ¹⁰ is a lower alkyl group.

The term "thioalkyl" as used herein has the formula ^{-SR 11,} refers to the group ^{R 1 1} is a lower alkyl group.

The term “alkylamino” as used herein has the formula —NHR ¹² ;
R ¹² represents a lower alkyl group.

The term “dialkylamino,” as used herein, refers to a group having the formula —N (R ¹³ ) ₂ , wherein R ¹³ is independently a lower alkyl group.

As used herein, the term “halo or halogen” means 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 have been replaced with halogen, and includes trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl , Fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like, but are not limited thereto.

As used herein, the term “aryl” refers to a mono- or bicyclic carbocyclic ring system containing 6 to 12 carbon atoms and having one or more aromatic rings, phenyl, naphthyl , Tetrahydronaphthyl, indanyl, indenyl and the like, but are not limited thereto. An aryl group is unsubstituted or hydroxy,
It may be substituted with 1 to 5 substituents independently selected from alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.

As used herein, the term “(aryl) alkyl” refers to an aryl group as defined above for a lower alkyl group, for example, benzyl.

As used herein, the term “heterocyclic ring” or “heterocyclic” or “heterocycle” refers to any three or four membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, Or 1, independently selected from the group consisting of nitrogen, oxygen and sulfur,
Means a 5-, 6- or 7-membered ring containing 2 or 3 heteroatoms or a 5-membered ring containing 4 nitrogen atoms; 1, 2 or 3 nitrogen atoms, 1 oxygen atom, 1 A sulfur atom, one nitrogen and one sulfur atom, one nitrogen and one oxygen atom, two oxygen atoms that are not in adjacent positions, one oxygen and one oxygen that is not in adjacent positions Sulfur atom, two non-adjacent sulfur atoms, two sulfur atoms and one nitrogen atom in adjacent positions, two nitrogen atoms and one sulfur atom, two non-adjacent atoms Included are 5, 6 or 7 membered rings containing one nitrogen atom and one sulfur atom, two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0 to 2 double bonds, and the 6- and 7-membered rings have 0 to 3 double bonds. The nitrogen heteroatom may be optionally quaternized. The term "heterocyclic" also includes bicyclic groups wherein said heterocyclic ring is fused to a benzene or cyclohexane ring or other heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinoyl). Ryl, benzofuryl, bistetrahydrofuranyl or benzothienyl). Heterocycles include azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolyl, oxazolyl, oxazinyl, oxazolinyl , Morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, tetrazolyl , Thiadiazori Include pyrrolyl, pyrimidyl and benzothienyl. Heterocycles also include compounds of the formula:

[0059]

Embedded image In the above formula, ^{X *} _is, -CH 2 _-, - is NH- or -O-, ^{Y *} is, -C (O
) - or _{[-C (R ") 2 -} ] v (R" is hydrogen or _C 1 -C ₄ alkyl,
v is 1, 2 or 3), and includes 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like in which Z ^* is -O- or -NH-.

The term “methylenedioxyphenyl” refers to a substituent having the formula:

[0061]

Embedded image The heterocyclic group may be unsubstituted or substituted with 1 to 5 substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. Further, the nitrogen containing heterocycle may be N
It may be protected.

As used herein, the term “(heterocycle) alkyl” refers to a heterocyclic group attached to a lower alkyl group, including but not limited to pyrrolidinylmethyl, morpholinylmethyl, and the like. It is not something to be done.

As used herein, the term “heteroaryl” refers to a heterocyclic group that contains at least one aromatic ring. Examples include, for example, groups such as furanyl, thienyl, benzothienyl, thiazolyl, and the like.

As used herein, the term “(heteroaryl) alkyl” refers to a heteroaryl group attached to a lower alkyl group, including, but not limited to, thienylmethyl, thienylethyl, furanylmethyl, and the like. is not.

As used herein, the term “N-protecting group” or “N-protected” refers to a group that protects the N-terminus of an amino acid or peptide, or protects an amino group from unwanted reactions during synthetic procedures. Means A commonly used N protecting group is T
. H. Greene and P.M. G. FIG. M. Wuts, "Protective G
loops in Organic Synthesis ", 2nd edition, John
Wiley & Sons, New York (1991).
N protecting groups include formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, Acyl groups such as 4-chlorobenzoyl, 4-bromobenzoyl and 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl and p-toluenesulfonyl; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p -Nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbo Le, 2,4-dimethoxybenzyl oxycarbonyl, 4-
Methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-
(P-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3
, 5-Dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl Carbamic acid ester-forming groups such as, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; and alkyls such as benzyl, triphenylmethyl, and benzyloxymethyl. And silyl groups such as trimethylsilyl. Preferred N protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the term “activated carboxylic acid derivative” refers to acid halides, such as acid chlorides, and active esters, including an anhydride derived from formic acid and acetic acid. An anhydride derived from an alkoxycarbonyl halide such as isobutyloxycarbonyl chloride, an ester derived from N-hydroxysuccinimide, an ester derived from N-hydroxyphthalimide, an ester derived from N-hydroxybenzotriazole, Esters derived from hydroxy-5-norbornene-2,3-dicarboxamide, esters derived from 2,4,5-trichlorophenol, esters derived from thiophenol, anhydrides derived from propylphosphonic acid Etc. are included, It is not limited to these.

The term “leaving group” as used herein includes, for example, a halide (eg, Cl 2
, Br or I) or a sulfonic acid ester (eg, mesylate, tosylate, triflate, etc.).

As used herein, the terms “S” and “R” configuration refer to IUPAC
1974 Recommendations for Section E, F
elemental Stereochemistry, Pure Appl
. Chem. 45, pages 13-30, 1976.

The compounds of the present invention may contain asymmetrically substituted carbon atoms. Thus, all stereoisomers of the compounds of the present invention are meant to be included in the present invention, and include racemic mixtures, diastereomeric mixtures, and single diastereomers of the compounds of the present invention.

The present invention is intended to include compounds having Formula I or Formula II prepared by synthetic or metabolic processes. Preparation of the compounds of the invention by metabolic processes includes processes occurring in humans or animals (in vivo), or processes occurring in vitro.

The reagents required for the synthesis of the compounds of the invention are Aldrich Chemical
Co. (Milwaukee, WI, USA), Sigma Chemical
Co. (St. Louis, MO, USA), Fluka Chemical
Corp .. (Ronkonkoma, NY, USA), Alfa Aesar
(Ward Hill, MA01835-9953), Eastman Ch
electronic Company (Rochester, New York 146)
52-3512), Lancaster Synthesis Inc. (Wi
ndham, NH03087-9977), Spectrum Chemica
l Manufacturing Corp. (Janssen Chemic
al) (New Brunswick, nJ08901), Pfaltz an
It is readily available from many commercial sources, such as d Bauer (Waterbury, CT. 06708). Compounds that are not commercially available can be prepared by using methods known in the chemical literature.

The compounds of the present invention can be prepared as shown in Schemes I-III.
As outlined in Scheme I, an N-protected (eg, via a benzyloxycarbonyl group) phenylalanyl epoxide 2 is coupled to an N-protected (eg, N-Boc) piperazine compound 1 (eg, 1- (3- Dimethylaminopropyl)-
3-ethylcarbodiimide (EDAC), 1-hydroxybenzotriazole (
HOBT), amines such as triethylamine, for example, tetrahydrofuran,
Used in an inert solvent such as methylene chloride). Deprotect the protected carboxamide product 3 (eg, by treatment with hydrogen gas and a hydrogenation catalyst). Amine carboxamides 3a can be converted to, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDAC), 1-hydroxybenzotriazole (HOBT), and triethylamine to, for example, tetrahydrofuran,
When used in an inert solvent such as methylene chloride and coupled to carboxylic acid 4 or an active derivative thereof, N-protected piperazine 5 is obtained. This piperazine is deprotected by N (
Alkylation (for example, with trifluoroacetic acid (TFA) or the like) (X ¹ is a leaving group) gives the final product 6.

[0073]

Embedded image

The synthesis of piperidinyl compounds where Y is —CH— is outlined in Scheme II below. Alkylation of the monoprotected piperidine carbamic acid ester 7 gives compound 8. N-deprotection of the alkylated carbamate (eg, with trifluoroacetic acid, etc.) followed by conjugation with epoxide 9 affords carboxamide 10. N-deprotection of the carboxamide gives compound 10a. When compound 10a is combined with carboxylic acid 4 or an active derivative thereof,
The product 11 is obtained.

[0075]

Embedded image

The synthesis of compounds of the invention having a —N (R ⁹ ) —X—R ⁸ group is outlined in Scheme III. J. Med. Chem. , 36 volumes, 288-291 pages, 199
Urea 12 prepared according to the three year description can be prepared, for example, by adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDAC), 1-hydroxybenzotriazole (HOBT), and triethylamine to, for example, tetrahydrofuran, methylene chloride. When used in an inert solvent such as, for example, and coupled with carboxylic acid 4 or an active derivative thereof, product 13 is obtained.

[0077]

Embedded image

The following examples serve to further illustrate the preparation of the novel compounds of the present invention.

Example 1 2- (1-methylethyl) -4-thiazolylmethyl-[(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] carbamic acid.

1A. Benzyl-1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl]- 1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] carbamic acid.

The title compound is described in Med. Chem. , 36 volumes, 288-291 pages, 1
According to the method described in 993, 3.6 g (12 mmol) of N-benzyloxycarbonyl-phenylalanyl epoxide and J.I. Med. Chem. Nt prepared according to the method described in Vol.
tert-butyl-4- (tert-butyloxycarbonyl) -piperazine-2
Prepared starting from 3.4 g (12 mmol) of (S) -carboxamide.

1B. 1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1- Piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amine.

Benzyl-1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino]
Carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl)
A solution of 2.1 g (3.6 mmol) of propyl] carbamic acid in 20 ml of methanol is treated with hydrogen at 1 atm or more in the presence of Pd / C (50 mg, 10%),
Stir for 2 hours. The catalyst was removed on a celite pad by filtration and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (1.6 g, 99% yield).

1C. 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1- [
[[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (
Carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl]-
1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
A solution of 1.5 g (3.3 mmol) of amine in 7 ml of tetrahydrofuran (THF) and 7 ml of methylene chloride was prepared, and [(2-isopropyl-4-thiazolyl) was prepared.
Methyloxycarbonyl] -L-valine 1.0 g (3.3 mmol), 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide (EDAC) 642 m
g (3.3 mmol), 1-hydroxybenzotriazole (HOBT) 45 m
g (3.3 mmol), and 466 μl (3.3 mmol) of triethylamine
Processed. The solution was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with the same amount of a 3N HCl solution, 10% aqueous NaHCO ₃ (20 mL) and saturated brine, and dried over MgSO ₄ . Concentration in vacuo and purification of the product by chromatography on silica gel using 5% methanol: methylene chloride afforded the title compound (2.4 g, 98%).

MS: 731 (M + H) ⁺ .

¹ H NMR (DMSO-d ₆ ) δ 1.08 (d, J = 7 Hz, 6H);
78 (sevenfold line, J = 7 Hz, 1H), 9.06 (brs, 1H), 9.30 (
br s, 1H).

1D. 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1- [
[[(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino ] Carbonyl] -2-methylpropyl] carbamic acid.

2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[(
1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2 A solution of 2.4 g (3.2 mmol) of -hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid in 20 ml of dichloromethane was prepared and treated with 2 ml of trifluoroacetic acid. T
The reaction was monitored by LC. After the completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a light yellow oil (2.0 g, 90% yield).

1E. 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-
[[[(1S, 2R) -3-[(2S) -4- (1,3-benzodioxole-
5-ylmethyl) -2-[[(1,1-dimethylethyl) amino] carbonyl]
-1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[(
1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino]
Carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl)
Propyl] amino] carbonyl] -2-methylpropyl] carbamic acid 514 m
g (0.82 mmol) in 5 ml of dimethylformamide (DMF) was prepared, and 140 mg (0.8 mmol) of 3,4-dioxomethylenebenzyl chloride, followed by 284 μl (1.6 mmol) of N, N-diisopropylethylamine. Treated, stirred at room temperature overnight, and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. 5%
The residue was purified by chromatography on silica gel using methanol: methylene chloride to give the title compound (yield 502 mg, 81%).

MS: 765 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.41 (t, J
= 7.5, 6H), 2.05 (six lines, 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 (sevenfold line, 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-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4- (phenylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenyl Methyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with benzyl bromide.

MS: 721 (M + H) ⁺ .

¹ H NMR (CDCl ₃ ) δ 0.68 (d, J = 6.3 Hz, 3H);
84 (d, J = 6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J
= 6.3 Hz, 6H), 2.04 (six wires, 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 (sevenfold line, 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 (sevenfold line, J = 4.5 Hz, 1H), 5.1
1 (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 to 7.33 (m,
11H), 8.02 (s, 1H), 8.26 (br s, 1H).

Example 3 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[(
1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino]
Carbonyl] -4-[(4-fluorophenyl) methyl] -1-piperazinyl]
-2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]-
2-Methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, substituting 4-fluorobenzyl chloride for 3,4-dioxomethylenebenzyl chloride.

MS: 739 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H);
84 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J
= 7.5 Hz, 6H), 2.06 (six wires, 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), 3.8
3 (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- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thienylmethyl) -1-piperazinyl] -2-hydroxy-1- (Phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 5- (chloromethyl) thiazole.

MS: 728 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.68 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 1.38 (s, 9H), 1.41 (d, J
= 7.5 Hz, 6H), 2.06 (six lines, 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 (sevenfold line, 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 (sevenfold line, J = 4.5 Hz, 1H), 5.07 (d, J = 7.5 Hz) , 1H), 5.1
7 (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-[(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] carbamic acid.

The title compound was prepared according to the method described in Example 1E, substituting 3-hydroxybenzyl chloride for 3,4-dioxomethylenebenzyl chloride.

MS: 737 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 0.96 (m, 1H), 1.37 (s, 9
H), 1.40 (d, J = 7.5, 6H), 2.03 (hexet, 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 to 7.22 (m, 9H), 8.1
9 (br s, 1H).

Example 6 2- (1-methylethyl) -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] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 3-picolyl chloride hydrochloride.

MS: 722 (M + H) ^<+> .

¹ H NMR (CDCl) δ 0.68 (d, J = 6.3 Hz, 3H), 0.8
3 (d, J = 6.3 Hz, 3H), 1.36 (s, 9H), 1.41 (d, J =
7.5 Hz, 6H), 2.06 (six lines, J = 4.5 Hz, 1H), 2.47 (
m, 1H), 2.60 (m, 2H), 2.71 (m, 2H), 2.81 (m, 1
H), 2.83 (m, 2H), 2.92 (m, 1H), 3.34 (sevenfold line, 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 H)
z, 2H), 6.15 (d, J = 7.8 Hz, 1H), 7.12 to 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-[(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] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 4-picolyl chloride hydrochloride.

MS: 722 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.65 (d, J = 6.3 Hz, 3H);
94 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.41 (d, J
= 7.5 Hz, 6H), 2.07 (six lines, 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), 3.8
0 (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 (brs, 1H), 8.08 (
d, J = 6.0 Hz, 2H).

Example 8 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4-[(4-hydroxyphenyl) methyl] -1-piperazinyl] -2-hydroxy -1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 4-hydroxybenzyl chloride hydrochloride.

MS: 737 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.68 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J
= 7.5, 6H), 2.03 (six lines, J = 4.5 Hz, 1H), 2.27 (d
t, 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), 3.7
2 (m, 1H), 3.78 (dd, J = 8.4, 6.0 Hz, 1H), 4.22
(Sevenfold line, 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 to 7.21 (m,
8H), 8.31 (brs, 1H).

Example 9 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[((
1S, 2R) -3-[(2S) -4- (1H-benzimidazol-2-ylmethyl) -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy -1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

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 ) δ 0.62 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 1.41 (d, J = 7.5 Hz, 6H),
1.43 (s, 9H), 2.11 (six lines, 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 (sevenfold line, J = 4.5 Hz, 1
H), 3.85 (m, 2H), 3.95 (d, J = 9.0 Hz, 1H), 4.2
5 (m, 1H), 4.98 (m, 1H), 5.13 (s, 2H), 5.17 (m
, 1H), 6.17 (m, 1H), 7.12 to 7.28 (m, 11H), 7.6
3 (m, 2H).

Example 10 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4- (2-quinolinylmethyl) -1-piperazinyl] -2-hydroxy-1- ( Phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, substituting 3,4-dioxomethylenebenzyl chloride for 2- (chloromethyl) quinoline monohydrochloride.

MS: 772 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H);
83 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.40 (d, J
= 7.5 Hz, 6H), 2.05 (six lines, 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 (sevenfold line, 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-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2 -Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 3,4-dimethoxybenzyl chloride.

MS: 781 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 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 Hz, 6H), 2.05 (six lines, 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 (sevenfold line, 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 ′-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(
1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
Amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-
Methylethyl) -4-thiazolylmethyl] urea.

12A. 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-methylethyl) -4-thiazolylmethyl] urea.

1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
A solution of 1.5 g (3.3 mmol) of amine in 7 ml of THF and 7 ml of methylene chloride was prepared, and N-methyl-N-[(((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl] -L-valine was prepared. 0 g (3.3 mmol), EDA
Treated with 642 mg (3.3 mmol) of C, 45 mg (0.33 mmol) of HOBT, and 466 μl (3.3 mmol) of triethylamine. The solution was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with the same amount (15 ml) of a 3N HCl solution, 10% aqueous NaHCO ₃ , and saturated saline. The organic layer was dried over MgSO _4, and concentrated in vacuo. The mixture was purified by chromatography on silica gel using 5% methanol: methylene chloride to give the title compound (2.4 g, 98%).

12B. N '-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2
-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl]
-2-hydroxy-1- (phenylmethyl) 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- (1,1-dimethylethyloxy (carbonyl))-1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2 -Methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea 2.4 g
A solution of (3.2 mmol) in 20 ml of dichloromethane was prepared and treated with 2 ml of trifluoroacetic acid. The reaction was monitored by TLC. After the completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a light oil (2.0 g, 90% yield). The product was used in Example 12C without further purification.

12C. N '-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2
-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl ] -N-methyl-N- [2
-(1-Methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared starting from the product prepared in Example 12B, following the procedure described in Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with 5-thiazolylmethyl chloride.

MS: 741 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 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 (sevenfold line, 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 (sevenfold line, J = 4.5 Hz, 1H), 4.3
7 (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 ′-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(
1,1-dimethylethyl) amino] carbonyl] -4- (phenylmethyl) -1
-Piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared according to the procedure described in Example 12C, substituting benzyl bromide for 5-thiazolylmethyl chloride.

MS: 734 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.75 (d, J = 6.3 Hz, 3H);
88 (d, J = 6.3 Hz, 3H), 1.45 (d, J = 7.5 Hz, 6H),
1.46 (s, 9H), 2.15 (Hex, J = 6.3 Hz, 1H), 2.32
(Dt, J = 9.0, 3.0 Hz, 1H), 2.51 (dd, J = 8.4, 3.H).
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 (sevenfold line, J = 7.5 Hz, 1H), 3.32 (t, J = 3. 0 Hz, 1H), 3.4
5 (s, 2H), 3.81 (m, 1H), 4.01 (dd, J = 7.5, 6.0
Hz, 1H), 4.17 (sevenfold line, J = 4.5 Hz, 1H), 4.48 (s, 2
H), 4.84 (br s, 1H), 5.89 (m, 1H), 6.48 (d, J
= 9.0 Hz, 1H), 6.95 (s, 1H), 7.07 to 7.18 (m, 5H
), 7.25-7.34 (m, 5H), 8.04 (brs, 1H).

Example 14 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) propyl] amino] carbonyl] -2-methylpropyl] -N
-Methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared according to the method described in Example 12C, substituting 3-methoxy-4-hydroxybenzyl chloride for 5-thiazolylmethyl chloride.

MS: 780 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 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 (six lines, J = 6.0 Hz, 1H), 2.31 (d
t, 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 (sevenfold line, J
= 4.5 Hz, 1H), 4.38 (s, 2H), 4.77 (m, 1H), 5.5
8 (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-Methyl-4-thiazolylmethyl-[(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] carbamic acid.

15A. 2-methyl-4-thiazolylmethyl- (1S) -1-[[[(1S,
2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl)
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

According to the method of Example 1C, the title compound was obtained by converting [(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine into [(2-methyl-4-thiazolyl) methyloxycarbonyl] -L- Prepared in place of valine. Subsequently, the product was treated with trifluoroacetic acid according to the method of Example 1D.

15B. 2-methyl-4-thiazolylmethyl-[(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] carbamic acid.

2-Methyl-4-thiazolylmethyl- (1S) -1-[[[(1S, 2R)-
3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-
[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl]-
2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2
-Methylpropyl] carbamic acid 98 mg (0.16 mmol) in DMF 1 ml
The solution was treated with 3,4-dioxomethylenebenzyl chloride (30 mg, 0.18 mmol).
And then N, N-diisopropylethylamine 43 μl (0.24 mmol)
Processed. The solution was stirred overnight at room temperature. After stirring, the solution was partitioned between ethyl acetate and 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% methanol: methylene chloride to give the title compound (yield 31 mg, 26%).

MS: 737 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H), 0.
84 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 2.05 (hexet, 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, 1
H), 7.12-7.22 (m, 6H), 8.19 (br s, 1H).

Example 16 2-Methyl-4-thiazolylmethyl-[(1S) -1-[[[(1S, 2R)
-3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[
(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-
Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 15B, replacing 3,4-dioxomethylenebenzyl chloride with 3,4-dimethoxybenzyl chloride.

MS: 753 (M + H) ^<+> .

¹ H NMR (DMSO-d ₆ ) δ 0.67 (d, J = 6.3 Hz, 3H),
0.69 (d, J = 6.3 Hz, 3H), 1.23 (s, 9H), 1.78 (hexet, 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, 3
H), 4.05 (m, 1H), 4.86 (d, J = 9.0 Hz, 1H), 5.0
0 (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 H)
z, 2H), 7.41 (s, 1H), 7.53 (s, 1H), 7.67 (d, J
= 9.0 Hz, 1H).

Example 17 2-methyl-4-thiazolylmethyl-[(1S) -1-[[[(1S, 2R)
-3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl]
4-[(4-Fluorophenyl) methyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 15B, substituting 4-fluorobenzyl chloride for 3,4-dioxomethylenebenzyl chloride.

MS: 711 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.68 (d, J = 6.3 Hz, 3H), 0.
84 (d, J = 6.3 Hz, 3H), 1.35 (s, 9H), 2.06 (hexet, 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 (sevenfold line, 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), 7.0.
12-7.22 (m, 8H), 8.21 (br s, 1H).

Example 18 2-ethyl-4-thiazolylmethyl- (1S) -1-[[[(1S, 2R)-
3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(
1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

18A. 2-ethyl-4-thiazolylmethyl- (1S) -1-[[[(1S,
2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl)
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

According to the method of Example 1C, the title compound was obtained by converting [(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine into [(2-ethyl-4-thiazolyl) methyloxycarbonyl] -L- Prepared in place of valine. Subsequently, the product was treated with trifluoroacetic acid according to the method of Example 1D.

18B. 2-ethyl-4-thiazolylmethyl- (1S) -1-[[[(1S,
2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2
-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl]
-2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]-
2-Methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 15 (B), 2-ethyl-4-thiazolylmethyl- (1S) -1-[[[(1S, 2R) -3-[(2S) -4 − (
1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (
98 mg (0.16 mmol) of phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid was added to 3,4-dimethoxybenzyl chloride 30
mg (0.18 mmol).

MS: 767 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.67 (d, J = 6.3 Hz, 3H), 0.
84 (d, J = 6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J
= 7.5 Hz, 6H), 2.05 (six lines, 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),
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- (1-methylethyl) -5-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2 -Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

19A. 2- (1-methylethyl) -5-thiazolylmethyl-[(1S) -1
-[[[(1S, 2R) -3-[(2S) -4- [1,1-dimethylethyloxy (carbonyl)]-2-[[(1,1-dimethylethyl) amino] carbonyl] -1 -Piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
Amino] carbonyl] -2-methylpropyl] carbamic acid.

1-[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
A solution of 1.5 g (3.3 mmol) of an amine in 7 ml of THF and 7 ml of methylene chloride was prepared. .3mm
ol), HOBT 45 mg (0.33 mmol), and triethylamine 46
Treated with 6 μl (3.3 mmol). The solution was stirred at room temperature for 6 hours and concentrated in vacuo. The residue is taken up in ethyl acetate and the same amount (15 mL) of 3N HCl solution, 10%
Washed with aqueous NaHCO ₃ and brine, dried over MgSO ₄ and concentrated in vacuo. The resulting mixture was purified by chromatography on silica gel using 5% methanol: methylene chloride to give the title compound (yield 2.1 g,
88%).

MS: 731 (M + H) ^<+> .

¹ H NMR (DMSO-d ₆ ) δ 1.08 (d, J = 7 Hz, 6H), 2.
78 (sevenfold line, J = 7 Hz, 1H), 9.06 (brs, 1H), 9.30 (
br s, 1H).

19B. 2- (1-methylethyl) -5-thiazolylmethyl-[(1S) -1
-[[[(1S, 2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(1,1-dimethylethyl) amino] carbonyl] -1
-Piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared in two steps. First, 2- (1-methylethyl) -5-thiazolylmethyl-[(1S) -1-[[[(1S, 2R) -3-[(2S) -4
-[1,1-dimethylethyloxy (carbonyl)]-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1
-(Phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl]
The carbamic acid was treated with trifluoroacetic acid according to the method described in Example 1D. Subsequently, according to the method of Example 1E, the product was alkylated by replacing 3,4-dioxomethylenebenzyl chloride with 3,4-dimethylbenzyl chloride.

MS: 781 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 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 Hz, 6H), 2.01 (six lines, 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, 1
H), 3.30 (sevenfold line, 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 (sevenfold line, 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 to 7.22 (m, 7H), 7.61 (s, 1H),
8.28 (br s, 1H).

Example 20 2-ethyl-5-thiazolylmethyl- (1S) -1-[[[(1S, 2R)-
3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[(
1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

20A. 2-ethyl-5-thiazolylmethyl- (1S) -1-[[[(1S,
2R) -3-[(2S) -4- [1,1-dimethylethyloxy (carbonyl)
] -2-[[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 19A, [[2-isopropyl-5
-Thiazolyl) methyloxycarbonyl] -L-valine was converted to [(2-ethyl-5-
Thiazolyl) methyloxycarbonyl] -L-valine.

20B. 2-ethyl-5-thiazolylmethyl- (1S) -1-[[[(1S,
2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2
-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl]
-2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]-
2-Methylpropyl] carbamic acid.

The title compound was prepared in two steps. First, 2-ethyl-5-thiazolylmethyl-[(1S) -1-[[[(1S, 2R) -3-[(2S) -4- [1,1-dimethylethyloxy (carbonyl)]-2- [[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid was added to Example 1D. Treated with trifluoroacetic acid according to the method described. Subsequently, according to the method of Example 1E, the product was alkylated by replacing 3,4-dioxomethylenebenzyl chloride with 3,4-dimethylbenzyl chloride.

MS: 767 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.73 (d, J = 6.3 Hz, 3H), 0.
86 (d, J = 6.3 Hz, 3H), 1.37 (s, 9H), 1.38 (t, J
= 7.5 Hz, 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), 7.61 (s, 1H), 8.27 (br s, 1H).

Example 21 2-methyl-5-thiazolylmethyl-[(1S) -1-[[[(1S, 2R)
-3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl] -2-[[
(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-
Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

21A. 2-methyl-5-thiazolylmethyl-[(1S) -1-[[[(1S
, 2R) -3-[(2S) -4- [1,1-dimethylethyloxy (carbonyl)]-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2- Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 19A, [(2-isopropyl-5
-Thiazolyl) methyloxycarbonyl] -L-valine to [(2-methyl-5-
Thiazolyl) methyloxycarbonyl] -L-valine.

21B. 2-methyl-5-thiazolylmethyl-[(1S) -1-[[[(1S
, 2R) -3-[(2S) -4-[(3,4-dimethoxyphenyl) methyl]-
2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]
-2-methylpropyl] carbamic acid.

The title compound was prepared in two steps. First, 2-methyl-5-thiazolylmethyl-[(1S) -1-[[[(1S, 2R) -3-[(2S) -4- [1,1-dimethylethyloxy (carbonyl)]-2- [[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid was added to Example 1D. Treated with trifluoroacetic acid according to the method described. Subsequently, according to the method of Example 1E, the product was alkylated by replacing 3,4-dioxomethylenebenzyl chloride with 3,4-dimethylbenzyl chloride.

MS: 753 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.72 (d, J = 6.3 Hz, 3H);
86 (d, J = 6.3 Hz, 3H), 1.46 (s, 9H), 2.01 (six lines, J = 6.0 Hz, 1H), 2.22 (dt, J = 7.5) , 3.0Hz, 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, 1
H), 3.41 (AB, J = 15.0 Hz, 2H), 3.80 (m, 2H), 3
. 87 (s, 3H), 3.88 (s, 3H), 4.21 (sevenfold line, J = 4.5H)
z, 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, 1
H), 6.82 (s, 2H), 7.12 to 7.22 (m, 7H), 7.58 (s)
, 1H), 8.27 (br s, 1H).

Example 22 N ′-[(1R) -1-[[[(1S, 2R) -3-[(2S) -2-[[(
1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
Amino] carbonyl] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea.

22A. N '-[(1R) -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- (5-thiazolylmethyl) urea.

The title compound was prepared according to the method described in Example 19A [[2-isopropyl-5
-Thiazolyl) methyloxycarbonyl] -L-valine was converted to [N-methyl- (5-
Thiazolyl) methylaminocarbonyl] -D-valine.

22B. N '-[(1R) -1-[[[(1S, 2R) -3-[(2S) -2
-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl ] -N-methyl-N- (5
-Thiazolylmethyl) urea.

The title compound was prepared in two steps. First, N '-[(1R) -1-[[[(1
S, 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- (5-thiazolylmethyl)
Urea was treated with trifluoroacetic acid according to the method described in Example 1D. Subsequently, according to the method of Example 1E, 3,4-dioxomethylenebenzyl chloride was converted to 5-chloromethane.
The product was alkylated by replacement with thiazolyl.

MS: 699 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.58 (d, J = 6.3 Hz, 3H), 0.
66 (d, J = 6.3 Hz, 3H), 1.38 (s, 9H), 1.75 (m, 1
H), 2.35 (m, 1H), 2.60 (m, 2H), 2.70 (m, 2H),
2.85 (m, 2H), 2.86 (s, 3H), 2.92 (m, 3H), 3.3
0 (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 Hz, 1H), 6.09 (d, J = 9.0 Hz, 1H),
7.17 to 7.27 (m, 5H), 7.73 (s, 2H), 8.73 (s, 1H
), 8.80 (s, 1H).

Example 23 N ′-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(
1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl]
Amino] carbonyl] -2-methylpropyl] -N-methyl-N- (5-thiazolylmethyl) urea.

23A. 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- (5-thiazolylmethyl) urea.

The title compound was prepared according to the method described in Example 19A [[2-isopropyl-5
-Thiazolyl) methyloxycarbonyl] -L-valine was converted to [N-methyl- (5-
Thiazolyl) methylaminocarbonyl] -L-valine.

23B. N '-[(1S) -1-[[[(1S, 2R) -3-[(2S) -2
-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl ] -N-methyl-N- (5
-Thiazolylmethyl) urea.

The title compound was prepared in two steps. First, N '-[(1S) -1-[[[(1
S, 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- (5-thiazolylmethyl)
Urea was treated with trifluoroacetic acid according to the method described in Example 1D. Subsequently, according to the method of Example 1E, 3,4-dioxomethylenebenzyl chloride was converted to 5-chloromethane.
The product was alkylated by replacement with thiazolyl.

MS: 699 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.78 (d, J = 6.3 Hz, 3H);
87 (d, J = 6.3 Hz, 3H), 1.49 (s, 9H), 2.02 (m, 1
H), 2.33 (m, 2H), 2.57 (m, 2H), 2.75 (m, 2H),
2.75 (m, 2H), 2.82 (s, 3H), 2.89 (m, 3H), 3.3
8 (t, J = 3.0 Hz, 1H), 3.73 (d, J = 3.3 Hz, 2H), 3
. 3. 79 (m, 1H), 4.03 (dd, J = 8.4, 6.3 Hz, 1H);
20 (m, 1H), 4.66 (AB, J = 15 Hz, 2H), 4.78 (m, 1H)
H), 4.81 (d, J = 8.4 Hz, 2H), 6.11 (d, J = 9.0 Hz)
, 1H), 7.11 to 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-Thiazolylmethyl-[(1S) -1-[[[(1S, 2R) -3-[(2
S) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -4- (phenylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl)
Propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

24A. 5-thiazolylmethyl-[(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] carbamic acid.

The title compound was prepared according to the method described in Example 19A, [[2-isopropyl-5
-Thiazolyl) methyloxycarbonyl] -L-valine to [(5-thiazolyl)
[Methyloxycarbonyl] -L-valine.

24B. 5-thiazolylmethyl-[(1S) -1-[[[(1S, 2R) -3
-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4
-(Phenylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared in two steps. First, 5-thiazolylmethyl-[(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] carbamic acid was prepared according to Example 1D.
Treated with trifluoroacetic acid according to the method described in Subsequently, the product was alkylated according to the method of Example 1E, replacing 3,4-dioxomethylenebenzyl chloride with benzyl bromide.

MS: 699 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.78 (d, J = 6.3 Hz, 3H);
87 (d, J = 6.3 Hz, 3H), 1.49 (s, 9H), 2.02 (m, 1
H), 2.33 (m, 2H), 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- (1S) -1-[[[(1S, 2R) -3-[(2S
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethyl) -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2 -Methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 24B, using 5-thiazolylmethyl- [
(1S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-
Prepared by alkylating 1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid with 5-thiazolylmethyl chloride instead of benzyl bromide.

MS: 686 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) δ 0.62 (d, J = 6.3 Hz, 3H), 0.
86 (d, J = 6.3 Hz, 3H), 1.39 (s, 9H), 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), 2.9
2 (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 to 7.2
4 (m, 5H), 7.74 (s, 1H), 7.88 (s, 1H), 8.80 (s
, 1H), 8.81 (s, 1H).

Example 26 N ′-[(1S) -1-[[[(1S, 2R) -3-[[[(1,1-dimethylethyl) amino] carbonyl] (2-methylethyl) propylamino ] -2-
Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared according to the method described in Example 12A using N-methyl-N-[(((
2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl] -L-valine is described in J. Am. Med. Chem. N- (3S-Amino-2R-hydroxy-4-phenylbutyl) prepared according to Vol. 36, 288-291, 1993.
Prepared by conjugation with -N- (2-methylpropyl) -N '-(1,1-dimethylethyl) urea.

Elemental analysis Theoretical value: C: 62.34, H: 8.44, N: 13.64 Actual values: C: 59.60, H: 7.37, N: 12.86 Example 27 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[[[(1,1-dimethylethyl) amino] carbonyl]
(2-Methylethyl) propylamino] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 26 using N-[(2-isopropyl-
4-Thiazolyl) methyloxycarbonyl] -L-valine is described in J. Am. Med. Che
m. , 36, 288-291, 1993.
-Amino-2R-hydroxy-4-phenylbutyl) -N- (2-methylpropyl) -N '-(1,1-dimethylethyl) urea.

Elemental analysis Theoretical value: C: 61.69, H: 8.13, N: 11.61 Actual value: C: 60.80, H: 8.21, N: 11.18 Example 28 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-[[[(
1S, 2R) -3-[[(4-Aminophenyl) sulfonyl] (1-methylethyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid .

The title compound was prepared in two steps. First, J.I. Am. Chem. Soc. , 1
Vol. 17, pages 1181-1182, N-isobutyl-2 (R) -hydroxy-3 (S) -amino-4-phenyl- (prepared according to the method described in 1995.
4'-Nitrophenyl) sulfonamide was prepared according to the method described in Example 1C [
(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine. Subsequently, the product was hydrogenated on Pd / C in 1 atm of hydrogen. The catalyst was removed on a celite pad by filtration and the solvent was evaporated under reduced pressure to give the title compound as a white foam.

MS: 674 (M + H) ^<+> .

¹ H NMR (DMSO-d ₆ ) δ 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 = 7.5H
z, 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 to 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 ′-[(1S) -1-[[[(1S, 2R) -3-[[(4-aminophenyl) sulfonyl] (1-methylethyl) amino] -2-hydroxy- 1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl-N- [2- (1-methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared in two steps. First, according to the method described in Example 12A,
N-isopropyl-2 (R) -hydroxy-3 (S) -amino-4-phenyl-
(4′-Nitrophenyl) sulfonamide was coupled with N-methyl-N-[(((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl] -L-valine. Subsequently, the product was hydrogenated on Pd / C in 1 atm of hydrogen. The catalyst was removed on a celite pad by filtration and the solvent was evaporated under reduced pressure to give the title compound as a white foam.

MS: 674 (M + H) _<+> .

Elemental analysis Theoretical: C: 58.93, H: 7.14, N: 12.50 Found: C: 58.30, H: 7.28, N: 12.11 Example 30 2- (1-methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(3S) -3-[[(1,1-dimethylethyl) amino] carbonyl] (4aα, 8aα) octahydro-2-isoquinolinyl] -2-
Hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid.

The title compound was prepared according to the method described in Example 1C, using 2- (3 (S) -amino-2
(R) -Hydroxy-4-phenylbutyl) -N-tert-butyldecahydro- (4aS, 8aS) -isoquinoline-3 (S) -carboxamide was obtained according to J. Am. Or
g. Chem. 59, 3656-3664, 1994, prepared by conjugation with [(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine.

Elemental analysis Theoretical value: C: 65.01, H: 8.35, N: 10.25 Actual value: C: 63.70, H: 8.19, N: 10.05 Example 31 N ' -[(1S) -1-[[[(1S, 2R) -3-[(3S) -3-[[(
1,1-dimethylethyl) amino] carbonyl] (4aα, 8aα) octahydro-2-isoquinolinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] -N-methyl- N- [2- (1
-Methylethyl) -5-thiazolylmethyl] urea.

The title compound was prepared according to the method described in Example 12A, using 2- (3 (S) -amino-
2 (R) -Hydroxy-4-phenylbutyl) -N-tert-butyldecahydro- (4aS, 8aS) -isoquinoline-3 (S) -carboxamide was prepared as described in
Org. Chem. Vol. 59, pp. 3656-3664, 1994. N-methyl-N-[(((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl] -L-valine prepared according to the method described in 1994. Prepared by

Elemental analysis Theoretical value: C: 65.52, H: 8.62, N: 12.07 Actual value: C: 64.50, H: 8.72, N: 12.09 Example 32 N ′ -[(1S) -1-[[[(1S, 2R) -3-[(2S, 4R) -2-
[[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2- Methylpropyl] -N-methyl-N- [2
-(1-Methylethyl) -4-thiazolylmethyl] urea.

32A. 1-cis-N- (1,1-dimethylethyl) -1- (1,1-dimethylethyloxycarbonyl) -4- (5-thiazolylmethyloxy) piperidine-2-carboxamide.

1-cis-N- (1,1-dimethylethyl) -1- (1,1-dimethylethyloxycarbonyl) -4-hydroxy-piperidine-2-carboxamide was prepared according to the method described in EP 560 268 A1. did. Treatment of the hydroxy-carboxamide compound with sodium hydride and 5-thiazolylmethyl chloride in DMF at 0 ° C. provided the title compound.

32B. 1-cis-N- (1,1-dimethylethyl) -4- (5-thiazolylmethyloxy) piperidine-2-carboxamide.

1-cis-N- (1,1-dimethylethyl) -1- (1,1-dimethylethyloxycarbonyl) -4- (5-thiazolylmethyloxy) piperidine-2-
A solution of 1.24 g of carboxamide in 10 ml of THF was prepared. Mix 3N
Treated with 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 over Na ₂ SO ₄ and evaporated to dryness to give 836 mg of the desired product.

[0241] 32C. N '-[(1S) -1-[[[(1S, 2R) -3-[(2S, 4R
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propyl] amine.

The title compound was synthesized in two steps. N '-[(1S) -1-[[[(1S, 2
R) -3-[(2S, 4R) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1 -(Phenylmethyl) propyl] amine was prepared according to the method described in Example 1A, using t-butyloxycarbonylphenylalanyl epoxide instead of N-benzyloxycarbonylphenylalanyl epoxide, followed by column purification. The resulting product was treated with trifluoroacetic acid (TFA) in methylene chloride at room temperature.

32D. N '-[(1S) -1-[[[(1S, 2R) -3-[(2S, 4R
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl ] -2-Methylpropyl] -N-methyl-
N- [2- (1-Methylethyl) -4-thiazolylmethyl] urea.

The title compound was prepared according to the method described in Example 12A using N ′-[(1S) -1- [
[[(1S, 2R) -3-[(2S, 4R) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl]- It was synthesized using 2-hydroxy-1- (phenylmethyl) propyl] amine and N-methyl-N-[(((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl] -L-valine.

MS: 756 (M + H) ^<+> .

¹ H NMR (CDCl ₃ ) d 0.65 (d, J = 6.3 Hz, 3H), 0.
92 (d, J = 6.3 Hz, 3H), 1.32 (d, J = 3.0 HZ, 3H),
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 to 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 Hz, 3
. 3 Hz, 1 H), 2.97 (s, 3 H), 3.21 (sevenfold line, 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 = 1
2.0 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.61 (s,
1H), 7.00 (s, 1H), 7.09 to 7.18 (m, 6H), 7.78 (
s, 1H), 8.79 (s, 1H).

Example 33 2- (1-Methylethyl) -4-thiazolylmethyl-[(1S) -1-[[[
(1S, 2R) -3-[(2S, 4R) -2-[[(1,1-dimethylethyl)
Amino] carbonyl] -4- (5-thiazolylmethoxy) -1-piperidinyl]
-2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]-
2-Methylpropyl] carbamic acid.

The title compound was prepared as described in Example 32C using N as a coupling reagent.
-Methyl-N-[(((2-isopropyl-4-thiazolyl) methyl) amino)
Prepared using N-[(2-isopropyl-4-thiazolyl) methyloxycarbonyl] -L-valine instead of carbonyl] -L-valine.

Example 34 S- [2- (1-Methylethyl) -4-thiazolylmethyl]-[(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] carbamothioic acid.

34A. 2-Isopropyl-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 is cooled to −20 ° C., and treated dropwise with 1.3 mmol of methanesulfonyl chloride. The resulting mixture is stirred for 1 hour, quenched with aqueous citric acid, separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

34B. 2-Isopropyl-4- (mercaptomethyl) thiazole.

A mixture of 0.8 mmol of the product prepared in Example 34A and 1.0 mmol of sodium hydrosulfide hydrate in 20 ml of THF is heated to reflux until analysis by thin layer chromatography indicates consumption of the starting material. The resulting mixture was allowed to cool, concentrated in vacuo, distributed between dichloromethane and water, dried over Na ₂ SO _4, and concentrated, the crude compound is obtained.

34C. N-((2-isopropyl-4-thiazolyl) thiomethoxycarbonyl) valine methyl ester.

2.18 g of 2-isopropyl-4- (mercaptomethyl) thiazole (15 m
mol), 15.8 mmol of α-isocyanato-valine methyl ester and 4
Dimethylaminopyridine (1.5 mmol) in dichloromethane (75 ml)
Heat to reflux for hours. The resulting mixture is washed sequentially with 10% citric acid, aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel using 5% ethyl acetate in chloroform to give the title compound.

34D. N-((2-isopropyl-4-thiazolyl) thiomethoxycarbonyl) valine.

A solution of the product prepared in Example 34 in dioxane is treated with 0.50 M aqueous LiOH. The resulting solution is stirred at ambient temperature for about 30 minutes, treated with 1M HCl and concentrated in vacuo. The residue is taken up in dichloromethane, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

34E. S- [2- (1-methylethyl) -4-thiazolylmethyl]-[(1
S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -4-[[(1,1-dimethylethyl) [Carbonyl] oxy] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamothioic acid.

The title compound was prepared according to the method described in Example 1C, [(2-isopropyl-4-
Thiazolyl) methyloxycarbonyl] -L-valine is replaced by N-((2-isopropyl-4-thiazolyl) thiomethoxycarbonyl) valine.

34F. S- [2- (1-methylethyl) -4-thiazolylmethyl]-[(1
S) -1-[[[(1S, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1-
(Phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamothioic acid.

The title compound was prepared according to the method described in Example 1D, using 2- (1-methylethyl)-
4-thiazolylmethyl- (1S) -1-[[[(1S, 2R) -3-[(2S)
-4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-
Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid is converted to S- [2- (1-methylethyl)- 4-thiazolylmethyl]
-[(1S) -1-[[[(1S, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl)) 2-[[(1,1-dimethylethyl) Amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamothioic acid.

34G. S- [2- (1-methylethyl) -4-thiazolylmethyl]-[(1
S) -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] carbamothioic acid.

The title compound was prepared according to the method described in Example IE, 2- (1-methylethyl)-
4-thiazolylmethyl- (1S) -1-[[[(1S, 2R) -3-[(2S)
2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamic acid was converted to S- [2- (1-methylethyl) -4
-Thiazolylmethyl]-[(1S) -1-[[[(1S, 2R) -3-[(2S
) -2-[[(1,1-Dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamothioic acid Prepare in place of

Example 35 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-piperazinecarboxamide.

35A. 2-isopropylthiazole-4-carboxaldehyde.

3.1 g (15.6 mm) of ethyl 2-isopropylthiazole-4-carboxylate
ol) in 50 ml of dichloromethane was cooled to −78 ° C. in nitrogen and 15.6 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene (23.4 mm).
ol) was added dropwise over 1.5 hours. After stirring for a further 0.5 h, the solution was quenched with 5 ml of methanol followed by 15 ml of aqueous Rochelle salt. The resulting mixture is partitioned between chloroform and aqueous Rochelle salt, Na ₂ S
Dried over O ₄ and concentrated to give 1.37 g (56%) of the crude desired compound with R _f 0.47 (20% ethyl acetate in hexane).

¹ H NMR (CDCl ₃ ) d 1.45 (d, J = 7 Hz, 6H), 3.39
(Sevenfold line, J = 7 Hz, 1H), 8.07 (s, 1H), 10.00 (s, 1H)
).

Mass spectrum: (M + H) ⁺ = 156. 35B. (E) Ethyl 3- (2-isopropyl-4-thiazolyl) propenoate.

A 60% mineral oil slurry of NaH (18 mmol) was washed with hexane, decanted in a nitrogen atmosphere, and diluted with 25 ml of THF. The resulting mixture was cooled to 0 ° C. and treated little by little with 3.24 ml (16.4 mmol) of triethyl phosphonoacetate. After the addition, the solution was stirred for 10 minutes, treated with and dissolved in 25 ml of THF 2-isopropyl-thiazole-4-carboxaldehyde 1.37 g (8.84 mmol), warmed to ambient temperature for 25 min, quenched with saturated aqueous _NH 4 Cl100ml did. The mixture was extracted three times with 100 ml of ethyl acetate, dried over Na ₂ SO ₄ 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 with an _{Rf of} 0.64 (20% ethyl acetate in hexane).

¹ H NMR (CDCl ₃ ) d 1.33 (t, J = 7 Hz, 3H), 1.42
(D, J = 7 Hz, 6H), 3.32 (sevenfold line, J = 7 Hz, 1H), 4.26
(Q, J = 7 Hz, 2H), 6.75 (d, J = 15 Hz, 1H), 7.29 (
s, 1H), 7.57 (d, J = 15 Hz, 1H).

[0271] 35C. Methyl 3- (2-isopropyl-4-thiazolyl) propanoate.

(E) Ethyl 3- (2-isopropyl-4-thiazolyl) propenoate 225m
g (1 mmol) of freshly distilled methanol (from calcium hydride) 10 m
and 1 ml of dry THF solution were mixed with 49 mg (2 mmol) of magnesium shavings.
To process. The mixture is stirred for 20 minutes and the magnesium is consumed. The resulting solution is poured into cold aqueous HCl, basified to pH 8 with NaHCO ₃ , extracted with ethyl acetate, dried over Na ₂ SO ₄ and concentrated. 10 dissolved in hexane
Silica gel chromatography using% ethyl acetate gives a mixture of the desired compound and methyl 3- (2-isopropyl-4-thiazolinyl) propanoate.

35D. 3- (2-isopropyl-4-thiazolyl) propanoic acid.

A solution of the product prepared in Example 35C in dioxane was added to 0.50 M aqueous LiOH
To process. The resulting solution is stirred at ambient temperature for about 30 minutes and 1M HCl 8.7
Work up with ml and concentrate in vacuo. The residue is taken up in dichloromethane, washed with water,
Dry over a ₂ SO ₄ and concentrate in vacuo to give the title compound.

35E. N- (1,1-dimethylethyl) -4-[[(1,1-dimethylethyl) carbonyl] oxy] -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.

3- (2-isopropyl-4-thiazolyl) propanoic acid, α-isocyanato-
Valine methyl ester 1.1 equivalents and 4-dimethylaminopyridine (catalytic amount)
Is heated to reflux for about 5 hours. The resulting solution is washed sequentially with 10% citric acid, aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel using 5% ethyl acetate in chloroform to give the title compound.

35F. 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.

The title compound was prepared according to the method described in Example 1C, [[2-isopropyl-4-
Thiazolyl) methyloxycarbonyl] -L-valine is replaced by N-((2-isopropyl-4-thiazolyl) propionyl) valine.

35G. 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.

The title compound was prepared according to the method described in Example 1D, using (1S) -1-[[[(1S
, 2R) -3-[(2S) -4- (1,1-dimethylethyloxy (carbonyl))-2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2- 2- (1-methylethyl) -4-thiazolylmethyl hydroxy-1- (phenylmethyl) propyl] amino] carbonyl] -2-methylpropyl] carbamate is converted to 4- (1,1-dimethylethyloxy (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-
[Phenylphenyl] -2-piperazinecarboxamide.

35H. 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-piperazinecarboxamide .

The title compound was prepared according to the method described in Example 1E, using (1S) -1-[[[(1S
, 2R) -3-[(2S) -2-[[(1,1-dimethylethyl) amino] carbonyl] -1-piperazinyl] -2-hydroxy-1- (phenylmethyl) propyl] amino] carbonyl]- 2-Methylpropyl] carbamic acid 2- (1-methylethyl) -4-thiazolylmethyl is converted to 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.

Fluorescence Assay for Screening HIV Protease Inhibitors The inhibitory potency of the compounds of the present invention can be measured by the following method.

A compound of the present invention is dissolved in DMSO. Dilute a small amount with DMSO to make 100 times the final concentration desired for the test. The test was performed with a total volume of 300 ml and 6 x 50
Perform in a mm tube. The final concentration of each component in the reaction buffer was sodium acetate 125
mM, sodium chloride 1M, dithiothreitol 5mM, bovine serum albumin 0
. 5 mg / ml, fluorogenic substrate 1.3 μM, dimethyl sulfoxide 2% (v / v
), PH 4.5. After addition of the inhibitor, the reaction mixture is placed in the cell holder of the fluorometer and incubated at 30 ° C. for several minutes. The reaction is started by adding a small amount of cold HIV protease. Fluorescence intensity (excitation 340 nM, emission 490 nM
) Is recorded as a function of time. The reaction rate is measured for the first 6 to 8 minutes. Observation rate is directly proportional to the number of moles of substrate cleaved per unit time. Percent inhibition is 100 × (1− (rate in the presence of inhibitor) / (rate in the absence of inhibitor))
).

Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-I
le-Val-Gln-EDANS (Dabcyl = 4- (4-dimethylaminophenyl) azobenzoic acid and EDANS = 5-((2-aminoethyl) amino) naphthalene-1-sulfonic acid). All compounds tested at 1.0 nM had 1
It was found to have an IC ₅₀ of 00%. The test compound was then
Tested at a concentration of M. The results are reported in Table 1 below as percent inhibition.

[0286]

[Table 1] Table 1 shows the inhibitory potency of the compounds of the invention on HIV-1 protease.

Antiviral Activity The anti-HIV activity of the compounds of the present invention is determined by the method of Kempf et al. (Antimicrob.
Agents Chemother. 35, 2209, 1991)
Can be measured in MT4 cells. IC ₅₀ is the concentration of compound that produces 50% inhibition of the cytopathic effect of HIV. LC ₅₀ is 5
0% is the concentration of the compound that is viable.

[0288]

[Table 2]

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: Acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camformate, camphorsulfonate, digluconate, cyclopentanepropion Acid salt, dodecyl sulfate, ethane sulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydrogen iodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate Salt, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluate Nsuruhon, and undecanoate. Also, nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfate, decyl, lauryl, and myristyl. And long-chain halides such as stearyl chloride, bromide and iodide, and aralkyl halides such as benzyl and phenethyl bromide. This gives a product that is soluble or dispersible in water or oil.

Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic salts such as hydrochloric, sulfuric, and phosphoric acid, oxalic acid, maleic acid, succinic acid, and citric acid, and the like. Contains organic salts. Other salts include salts with alkali or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or other organic bases.

Preferred salts of the compounds of the present invention include the hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate salts.

The compounds of the present invention can also be used in the form of an ester. Such an d
Examples of steles include protected or unprotected amino acid residues, phosphate functions,
Mysuccinic acid residue, formula R¹⁴C (O)-or R¹⁴C (S)-(R¹⁴Is hydrogen
, Lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyal
Acyl, thioalkoxyalkyl or haloalkoxy) acyl residues of the formula R^a−
C (R^b) (R^d) -C (O)-or R^a-C (R^b) (R^d) -C (S)-
(R^bAnd R^dIs independently selected from hydrogen or lower alkyl;^aIs-
N (R^e) (R^f), OR^eOr -SR^eAnd R^eAnd R^fIs independently hydrogen
, An acyl residue of the formula R^FifteenN
H (CH₂)₂NHCH₂C (O)-or R^FifteenNH (CH₂)₂OCH₂C
(O)-(R^FifteenIs hydrogen, lower alkyl, arylalkyl, cycloalkyl
Having an alkyl, alkanoyl, benzoyl or α-aminoacyl group)
Includes hydroxyl-substituted compounds of formulas I and II acylated with a no-acyl residue.
I will. Particularly interesting amino acid esters are glycine and lysine. Only
While the aminoacyl group is -C (O) CH₂NR¹⁶R¹⁷(R¹⁶And R ¹⁷ Are independently selected from hydrogen and lower alkyl, or a group -NR¹⁶R¹⁷ (R¹⁶R¹⁷Together form a nitrogen-containing heterocyclic ring))
Acid residues can also be used. These esters are the prodrugs of the compounds of the present invention.
It acts as a package and helps increase the solubility of these substances in the gastrointestinal tract.
stand. These esters also increase solubility when the compound is administered intravenously.
Also useful. Other prodrugs include a hydroxyl group of the formula -CH (R¹⁸) O
C (O) R¹⁹Or -CH (R¹⁸) OC (S) R¹⁹(R¹⁹Is the lower al
Kill, haloalkyl, alkoxy, thioalkoxy or haloalkoxy, R^{1 8} Is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocar
Substitution of bonyl, alkylaminocarbonyl or dialkylaminocarbonyl)
Includes hydroxy-substituted compounds of Formula I or II functionalized with a group. This
Prodrugs such as Schreiber (Tetrahedron Le
tt. 24, 2363, 1983).
The ozonolysis of the corresponding methallyl ether, followed by treatment with acetic anhydride
Can be prepared.

The prodrugs of the invention are metabolized in vivo to give hydroxyl substituted compounds of formula I or II. The preparation of prodrug esters is based on Formula I or II
By reacting a hydroxyl-substituted compound with an activated aminoacyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to give the desired prodrug ester. The prodrugs of the present invention may also be alkylated of a hydroxy group with a (halo) alkyl ester, an acetal exchange reaction with a bis (alkanoyl) acetal, or condensation of a hydroxyl group with an active aldehyde, followed by acylation of the intermediate hemiacetal. Can be prepared by

The compounds of the present invention may be administered in vitro or in vivo, particularly in mammals,
Specifically in humans) and retroviral proteases, specifically HIV
Useful for inhibiting proteases. The compounds of the present invention may also be used in vivo
o is useful for inhibiting retroviruses, particularly human immunodeficiency virus (HIV). The compounds of the present invention are also useful for treating or preventing retroviral diseases, particularly acquired immunodeficiency syndrome or HIV infection in humans or other mammals.

The total daily dose administered to a human or other mammalian host in single or divided doses can be
0.001 to 300 mg / kg of body weight daily, usually 0.1 to 10 mg. Dosage unit compositions may contain such amounts of submultiples to make up the daily dose.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

However, specific dosages for a particular patient will depend on the activity, age, weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, of the particular compound used. It will be appreciated that various factors will vary, including the severity of the particular disease being treated.

The compounds of the present invention can be administered orally, parenterally, sublingually, by inhalation spray, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and the desired vehicle.
It can be administered rectally or topically. Topical administration also includes the use of transdermal administration, such as transdermal patches or ion implantation 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 may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug are solid at normal temperature but liquid at rectal temperature and suitable nonirritating agents such as cocoa butter and polyethylene glycol, which melt in the rectum to release the drug. It can be prepared by mixing an excipient and a drug.

[0301] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also usually comprise, in addition to the inert diluent, additional substances such as a lubricating agent such as magnesium stearate. In the case of capsules, tablets, or pills, the dosage form may also contain buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, including inert diluents commonly used in the art, such as water. And elixirs. Such compositions may also contain adjuvants such as wetting, emulsifying and suspending agents, and sweetening, flavoring, and flavoring 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 or other lipid substances. Liposomes are formed by mono- or multi-lamellar 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 present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholine (lecithin), natural and synthetic.

[0304] Methods for forming liposomes are known in the art. For example, Presco
tt, "Methods in Cell Biology", Volume XIV,
Academic Press, New York, N.W. Y. , Page 33 et seq. (1976).

The compounds of the present invention can be administered as the sole active agent, but can also be used in combination with one or more immunomodulators, antivirals, other anti-infectives or vaccines. Other antiviral agents administered in combination with the compounds of the present invention include:
AL-721, beta interferon, polymannoacetate (polyma
nonoate), a reverse transcriptase inhibitor (eg, dideoxycytidine (D
DC), dideoxyinosine (DDI), BCH-189, AzdU, carbovir, DDA, D4C, D4T, DP-AZT, FLT (fluorothymidine), B
CH-189, 5-halo-3′-thia-dideoxycytidine, PMEA, zidovudine (AZT), etc., non-nucleoside reverse transcriptase inhibitors (eg, R8219)
3, L-697,661, BI-RG-587 (nevirapine), DMP-266
), Retroviral protease inhibitors (eg, ritonavir, ABT-3)
78, saquinavir, nelfinavir, indinavir, VX-478 (amprenavir), SC-52151, KNI-227, KNI-272, U-14069
0, DMP-450, etc.), HEPT compound, L, 697, 639, R8215
0, U-87201E, etc.), TAT inhibitors (eg, RO-24-7429, etc.), trisodium phosphonoformate, HPA-23, eflonitin (efloni)
thin), peptide T, reticulose (nucleophosphoprotein), ansamycin LM427, trimetrexate, UA
001, Ribavirin, alpha interferon, oxetanosine, oxetanosine-G, cylobut-G, cyclobat
t) -A, Alla-M, BW882C87, Foscarnet, BW256U87
, BW348U87, L-693989, BV Ara-U, CMV triclonal antibody, FIAC, HOE-602, HPPMC, MSL-109, TI-23
, Trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4 / CD4-IgG, CD
4-PE40, butyl-DNJ, hypericin, oxamyristate, dextran sulfate and pentosan polysulfate. Examples of immunomodulators that can be administered in combination with the compound of the present invention include bropyrimine, ampligen, anti-human alpha interferon antibody, colony stimulating factor, CL246, 738, Imreg-
1, Imreg-2, diethyl dithiocarbamate, interleukin-2, alpha-interferon, inosine pranovex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone,
Tumor necrosis factor, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8 + injection, alpha interferon immunoglobulin, IGF-1, anti-Leu-3A, autovaccine therapy, biostimulation, extracorporeal Photophoresis (photo
phoresis), FK-565, FK-506, G-CSF, GM-CSF
, Hyperthermia, isopinosine, IVIG, HIVIG
, Passive immunotherapy and polio vaccine hyperimmunity. Other anti-infectives that can be administered in combination with the compounds of the present invention include pentamidine isethionate. Various HIV or AIDS vaccines (eg, gp120 (recombinant), Env2-3 (gp120), HIVAC-1e (gp120), gp16
0 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag
(Gp160), HGP-30, HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)) can be used in combination with the compound of the present invention.

Other agents that can be used in combination with the compounds of the present invention include Ansamycin L
M427, aprinic acid, ABPP, AI-721, carysyn (carrisyn)
), AS-101, avarol, azimexone (azimexo)
n), colchicine, compound Q, CS-85, N-acetylcysteine, (2-oxothiazolidine-4-carboxylic acid), D-penicillamine, diphenylhydantoin, EL-10, erythropoietin, fusidic acid, glucan, HPA -23
, Human growth hormone, hydroxychloroquine, iscador,
L-ofloxacin or other quinolone antibiotic, lentinan, lithium carbonate,
MM-1, monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax carrot,
Pentofilline, pentoxifylline, peptide T, pine cone extract, polymannoacetate, reticulose, retrogen (re
trogen), ribavirin, ribozyme, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, thymosin alpha 1, thymostimulin
, UA001, uridine, vitamin B12 and ubemugosu (wobemugo)
s).

Other agents that can be used in combination with the compounds of the present invention include amphotericin B
, Clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin.

Other agents that can be used in combination with the compounds of the present invention include amikacin sulfate,
Azithromycin, ciprofloxacin, tosfloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyratinamide, rifabutin, rifampin, streptomycin and TLC G-65.

Other agents that can be used in combination with the compounds of the present invention include alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamido). , Vincristine and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (
w / leucovin rescue, doxorubicin, cyclophosphamide, etoposide / mechlorethamine, vincristine,
Prednisone and procarbazine), vincristine, vinblastine, angioinhibin, pentosan polysulfate, platelet factor 4 and SP-PG.

Other agents that can be used in combination with the compounds of the present invention include peptide T, ritalin, lithium, elavir, phenytoin, carbamazipine, mexitetine for treating neurological disorders.
), Heparin and cytosine arabinoside.

Other agents that can be used in combination with the compounds of the present invention include albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fancidar, Furazolidone, L, 671, 329, letrazuril
, Metronidazole, paromycin, pefloxacin,
Antiprotozoal drugs such as pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP / SMX, trimetrexate and WR6026.

Preferred agents for the treatment of HIV or AIDS in combination with the compounds of the present invention include:
There are reverse transcriptase inhibitors and other HIV protease inhibitors.

The agents that can be used in combination with the compounds of the present invention for the treatment or prevention of AIDS or HIV infection are not limited to those listed above, but are in principle AIDS
Or it will be understood that any agent useful for treating or preventing HIV infection is included.

When administered in combination, the agents can be formulated as separate compositions that are administered at the same time or different times, or the agents can be administered as a single composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes obvious to one skilled in the art are intended to be included within the scope and nature of the invention as defined in the appended claims.

[Procedure amendment]

[Submission date] November 16, 2000 (2000.11.16)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

Embedded image R ² is a group having the following formula:

Embedded image R ³ is hydrogen, alkyl, amino, alkylamino, selected from the group consisting of dialkylamino and cycloalkyl, Y is CH or N, ^{R 4} is a ^{-W-R 5,} W is - O -, - S-, or - _{(CH 2) n} -, and, ^{R 5} is alkyl,
And n is from 0 to 6, or R ⁴ and the ring together form a bicyclic group having the formula:

Embedded image However, when W is O or S, Y is CH and R ⁶ is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl). aryl) alkyl, Z is, -O -, - S -, - CH 2 - or -N ^(R 7) -, and ^{R 7} is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, ( Heteroaryl) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein the alkyl, aryl, heterocycle, and heteroaryl groups are optionally selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, and halogen Or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 5 substituents Or prodrugs.

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

Embedded image R ² is a group having the following formula:

Embedded image R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; X is —C (O) — or —S (O) ₂ —; and R ⁸ is alkyl , Aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein R ⁹ is alkyl, cycloalkyl, aryl, (aryl) alkyl , heterocycle, a (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl,, Z is, -O -, - S -, - CH 2 - or ^{-N (R 7) -, {} R 7 is ,hydrogen,
Alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein the alkyl, aryl, heterocycle and heteroaryl groups are optionally hydroxy,
It may be substituted with 1 to 5 substituents selected from the group consisting of alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

Embedded image R ² is a group having the following formula:

Embedded image R ³ is hydrogen, alkyl, amino, alkylamino, selected from the group consisting of dialkylamino and cycloalkyl, Y is CH or N, ^{R 4} is a ^{-W-R 5,} W is - O -, - S-, or - _{(CH 2) n} -, and, ^{R 5} is alkyl,
And n is from 0 to 6, or R ⁴ and the ring together form a bicyclic group having the formula:

Embedded image Provided that when W is O or S, Y is CH; R ⁶ is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocycle, heteroaryl, or (heteroaryl) alkyl; Is —O—, —S—, —CH ₂ — or —N (R ⁷ ) —, and R ⁷ is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, heteroaryl, or (heteroaryl). ) Alkyl, wherein the alkyl, aryl, heterocyclic and heteroaryl groups are optionally hydroxy,
A method for preparing a compound optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.

Embedded image Wherein R ¹ is a thiazolyl group having the formula:

Embedded image R ² is a group having the following formula:

Embedded image R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; X is —C (O) — or —S (O) ₂ —; and R ⁸ is alkyl , Aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein R ⁹ is alkyl, cycloalkyl, aryl, (aryl) alkyl , heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl,, Z is, -O -, - S -, - CH 2 - or -N ^{(R 7)} - a and, ^{R 7} Is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) An alkyl, alkyl, aryl, heterocyclic and heteroaryl groups is optionally hydroxy,
A method for preparing a compound optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 43/00 111 A61P 43/00 111 C07D 277/24 C07D 277/24 277/26 277/26 277/28 277/28 277/30 277/30 417/12 417/12 417/14 417/14 (72) Inventor Kemph, Dale J. United States, Illinois 60048, Libertyville, Tyler Court 256 (72) Inventor Norbetsk, Daniel Dubrillo United States, Illinois 60030, Glaze Lake, Walton Lane 816 (72) Inventor Mohamaz Day, Faribauds United States, Illinois 60045, Lake Forrest, Parliament Court 1741 F-term (reference) 4C033 AD03 AD04 AD06 AD08 AD13 AD17 AD20 4C063 AA01 AA03 BB07 BB0 9 CC62 CC81 DD10 DD34 EE01 4C086 AA01 AA02 AA03 BC82 CB09 GA07 MA01 MA04 NA14 ZB33 ZC20 ZC55

Claims (47)

[Claims] 1. A compound having the formula I, which comprises In the above formula, R ¹ is a thiazolyl group having the following formula: R ² is a group having the following formula: R ³ is hydrogen, alkyl, amino, alkylamino, selected from the group consisting of dialkylamino and cycloalkyl, Y is CH or N, ^{R 4} is a ^{-W-R 5,} W is - O -, - S-, or - _{(CH 2) n} -, and, ^{R 5} is alkyl,
And n is from 0 to 6, or R ⁴ and the ring together form a bicyclic group having the formula: However, when W is O or S, Y is CH and R ⁶ is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl). Aryl) alkyl, wherein Z is —O—, —S—, —CH ₂ — or —N (R ⁷ ) —, and R ⁷ is hydrogen, alkyl, aryl, (aryl) alkyl, heterocyclic, Heteroalkyl) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein the alkyl, aryl, heterocyclic and heteroaryl groups are optionally hydroxy,
A compound optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, amino, alkylamino, dialkylamino and halogen, or a pharmaceutically acceptable salt, ester or prodrug thereof. 2. R ³ is alkyl or cycloalkyl and Z is —O
-, or -N ^{(R 7)} - in which A compound according to claim 1. 3. The compound according to claim 2, wherein R ³ is alkyl. 4. R ³ is cyclopropyl, cyclobutyl, cyclopentyl,
3. The compound according to claim 2, which is a cycloalkyl selected from the group consisting of and cyclohexyl. 5. The compound according to claim 3, wherein R ³ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl. 6. The compound according to claim 5, wherein R ³ is isopropyl. 7. The compound according to claim 1, wherein Z is -O-. 8. The method of claim 1, wherein Z is —N (R ⁷ ) — and R ⁷ is methyl.
The compound according to the above. 9. The method of claim 1, wherein Y is nitrogen, W is —CH ₂ —, and R ⁵ is aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl. Compound. 10. The compound according to claim 9, wherein R ⁵ is substituted with fluorine. 11. The compound according to claim 9, wherein R ⁵ is substituted with one to three hydroxy groups. 12. The compound according to claim 9, wherein R ⁵ is substituted with one to three alkoxy or alkylthio groups. 13. The compound according to claim 9, wherein R ⁵ is substituted with two alkoxy groups. 14. The compound according to claim 9, wherein R ⁵ is substituted with at least one hydroxy group and at least one methoxy group. 15. The compound of claim 1, wherein Y is CH and R ⁵ is alkyl or aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl. 16. The compound according to claim 15, wherein R ⁵ is substituted with one to three alkoxy or alkylthio groups. 17. The compound according to claim 15, wherein R ⁵ is substituted with a hydroxy group. 18. The compound according to claim 15, wherein R ⁵ 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 R ⁵ is methyl substituted with a thiazolyl group. 21. The compound according to claim 1, wherein R ⁶ is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl. 22. The compound of claim 21, wherein R ⁶ is lower alkyl selected from the group consisting of methyl, ethyl, propyl, or butyl. 23. The compound according to claim 22, wherein R ⁶ is tert-butyl or hydroxybutyl. 24. A compound having formula II wherein: In the above formula, R ¹ is a thiazolyl group having the following formula: R ² is a group having the following formula: R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; X is —C (O) — or —S (O) ₂ —; and R ⁸ is alkyl , Aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein R ⁹ is alkyl, cycloalkyl, aryl, (aryl) alkyl , heterocycle, a (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl,, Z is, -O -, - S -, - CH 2 - or ^{-N (R 7) -, {} R 7 is ,hydrogen,
Alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein the alkyl, aryl, heterocycle and heteroaryl groups are optionally hydroxy,
It may be substituted with 1 to 5 substituents selected from the group consisting of alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen
Or a pharmaceutically acceptable salt, ester or prodrug thereof. 25. R ³ is alkyl or cycloalkyl and Z is-
O- or -N ^{(R 7)} - A compound according to claim 24. 26. The compound according to claim 25, wherein R ³ is alkyl. 27. The compound of claim 25, wherein R ³ is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 28. The compound according to claim 26, wherein R ³ is selected from the group consisting of hydrogen, methyl, ethyl, or propyl. 29. The compound according to claim 27, wherein R ³ is isopropyl. 30. The compound according to claim 25, wherein Z is -O-. 31. The compound according to claim 25, wherein Z is —N (R ⁷ ) — and R ⁷ is methyl. 32. The compound of claim 24, wherein R ⁸ is selected from the group consisting of alkyl, aryl, (aryl) alkyl, alkylamino, dialkylamino, or heteroaryl. 33. The method of claim 24, wherein X is —S (O) ₂ —, R ⁸ is aryl selected from the group consisting of phenyl, and heteroaryl, and R ⁹ is lower alkyl. Compound. 34. R ⁹ is isopropyl, isobutyl, or 3-methyl-
25. The compound according to claim 24, wherein the compound is selected from the group consisting of 1-butyl. 35. The compound according to claim 34, wherein R ⁹ is isobutyl. 36. The compound according to claim 32, wherein R ⁸ is substituted with one to three amino groups. 37. 2- (1-methylethyl) -4-thiazolylmethyl-((1
S) -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) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-(( 1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (phenylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenyl Methyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-((((
1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino)
Carbonyl) -4-((4-fluorophenyl) methyl) -1-piperazinyl)
-2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl)-
2-methylpropyl) carbamic acid, 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- (Phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -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) carbamic acid, 2- (1-methylethyl) -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) carbamic acid, 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) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4-((4-hydroxyphenyl) methyl) -1-piperazinyl) -2-hydroxy -1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-((((
1S, 2R) -3-((2S) -4- (1H-benzimidazol-2-ylmethyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy -1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (2-quinolinylmethyl) -1-piperazinyl) -2-hydroxy-1- ( Phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2 -Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N '-((1S) -1-((((1S, 2R) -3-((2S)- 2-(((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) 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- (phenylmethyl) -1
-Piperazinyl) -2-hydroxy-1- (phenylmethyl) 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) propyl) amino) carbonyl) -2-methylpropyl) -N
-Methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2-methyl-4-thiazolylmethyl-((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) carbamic acid, 2-methyl-4-thiazolylmethyl-((1S) -1-((((1S, 2R)
-3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-((
(1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-methyl-4-thiazolylmethyl-((1S) -1-((((1S, 2R)
-3-((2S) -2-(((1,1-dimethylethyl) amino) carbonyl)
-4-((4-fluorophenyl) methyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-ethyl-4-thiazolylmethyl -(1S) -1-((((1S, 2R)-
3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((
1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -5-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2 -Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-ethyl-5-thiazolylmethyl- (1S) -1-((((1S, 2R)-
3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((
1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2-methyl-5-thiazolylmethyl- ((1S) -1-((((1S, 2R)
-3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-((
(1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N ′-((1R) -1-((((1S, 2R) -3-((2S) -2 − (((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl)
Amino) carbonyl) -2-methylpropyl) -N-methyl-N- (5-thiazolylmethyl) urea, N '-((1S) -1-((((1S, 2R) -3-((2S)- 2-(((
1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl)
Amino) carbonyl) -2-methylpropyl) -N-methyl-N- (5-thiazolylmethyl) urea, 5-thiazolylmethyl-((1S) -1-((((1S, 2R) -3-((2
S) -2-(((1,1-dimethylethyl) amino) carbonyl) -4- (phenylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl)
Propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 5-thiazolylmethyl- (1S) -1-((((1S, 2R) -3-((2S
) -2-(((1,1-Dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethyl) -1-piperazinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2 -Methylpropyl) carbamic acid, N '-((1S) -1-((((1S, 2R) -3-((((1,1-dimethylethyl) amino) carbonyl) (2-methylethyl) propyl Amino) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) -N-methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2- (1-methylethyl) ) -4-Thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((((1,1-dimethylethyl) amino) carbonyl)
(2-methylethyl) propylamino) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S ) -1-(((((
1S, 2R) -3-(((4-aminophenyl) sulfonyl) (1-methylethyl) amino) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid N '-((1S) -1-((((1S, 2R) -3-(((4-aminophenyl) sulfonyl) (1-methylethyl) amino) -2-hydroxy-1- (phenylmethyl )) Propyl) amino) carbonyl) -2-methylpropyl) -N-methyl-N- (2- (1-methylethyl) -4-thiazolylmethyl) urea, 2- (1-methylethyl) -5-thiazolylmethyl- ( (1S) -1-(((
(1S, 2R) -3-((3S) -3-(((1,1-dimethylethyl) amino) carbonyl) (4aα, 8aα) octahydro-2-isoquinolinyl) -2-
Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N ′-((1S) -1-((((1S, 2R) -3-((3S) -3 − (((
1,1-dimethylethyl) amino) carbonyl) (4aα, 8aα) 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-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethoxy) -1-piperidinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2- Methylpropyl) -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)
Amino) carbonyl) -4- (5-thiazolylmethoxy) -1-piperidinyl)
-2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl)-
2-methylpropyl) carbamic acid, S- (2- (1-methylethyl) -4-thiazolylmethyl)-((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) carbamothioatenoic acid and 4- (1,3-benzodioxole-5- Ylmethyl) -N- (1,1-dimethylethyl) -1-((2R, 3S) -3-(((2S) -2-((3- (2-
(1-methylethyl) -4-thiazolyl) -1-oxopropyl) amino) -3
A compound selected from the group consisting of -methyl-1-oxobutyl) amino) -2-hydroxy-4-phenylbutyl) -2-piperazinecarboxamide, or a pharmaceutically acceptable salt, ester or prodrug thereof. 38. 2- (1-methylethyl) -4-thiazolylmethyl-((
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) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl- (1S) -1-((((
1S, 2R) -3-(((4-aminophenyl) sulfonyl) (1-methylethyl) amino) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid , 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- (Phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, 2- (1-methylethyl) -4-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((2S) -4-((3,4-dimethoxyphenyl) methyl) -2-(((1,1-dimethylethyl) amino) carbonyl) -1-piperazinyl) -2 -Hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, N ′-((1S) -1-((((1S, 2R) -3-((2S, 4R ) -2-
(((1,1-dimethylethyl) amino) carbonyl) -4- (5-thiazolylmethoxy) -1-piperidinyl) -2-hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2- Methylpropyl) -N-methyl-N- (2
-(1-methylethyl) -4-thiazolylmethyl) urea, and 2- (1-methylethyl) -5-thiazolylmethyl-((1S) -1-(((
(1S, 2R) -3-((3S) -3-(((1,1-dimethylethyl) amino) carbonyl) (4aα, 8aα) octahydro-2-isoquinolinyl) -2-
38. The compound of claim 37, selected from the group consisting of hydroxy-1- (phenylmethyl) propyl) amino) carbonyl) -2-methylpropyl) carbamic acid, or a pharmaceutically acceptable salt, ester or pro-form thereof. drag. 39. A pharmaceutical composition for treating HIV infection, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 1. 40. A pharmaceutical composition for treating HIV infection, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 24. 41. A method for inhibiting HIV protease comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment. 42. A method for treating HIV infection, comprising administering a therapeutically effective amount of a compound of claim 24 to a mammal in need of such treatment. 43. A pharmaceutical composition for treating HIV infection, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 9. 44. A pharmaceutical composition for treating HIV infection, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 20. 45. A pharmaceutical composition for treating HIV infection, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 36. 46. A compound having formula I, wherein: In the above formula, R ¹ is a thiazolyl group having the following formula: R ² is a group having the following formula: R ³ is hydrogen, alkyl, amino, alkylamino, selected from the group consisting of dialkylamino and cycloalkyl, Y is CH or N, ^{R 4} is a ^{-W-R 5,} W is - O -, - S-, or - _{(CH 2) n} -, and, ^{R 5} is alkyl,
And n is from 0 to 6, or R ⁴ and the ring together form a bicyclic group having the formula: Provided that when W is O or S, Y is CH; and R ⁶ is hydrogen, alkyl, cycloalkyl, aryl, (aryl) alkyl, heterocyclic, (heterocyclic) alkyl, heteroaryl, or (heteroaryl). ) alkyl, Z is, -O -, - S -, - CH 2 - or -N ^{(R 7)} - a and, ^{R 7} is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, ( Heteroaryl) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein the alkyl, aryl, heterocycle, and heteroaryl groups are optionally selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, and halogen A method for preparing a compound optionally substituted with 1 to 5 substituents. 47. A compound having Formula II, wherein: In the above formula, R ¹ is a thiazolyl group having the following formula: R ² is a group having the following formula: R ³ is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; X is —C (O) — or —S (O) ₂ —; and R ⁸ is alkyl , Aryl, (aryl) alkyl, alkylamino, dialkylamino, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, wherein R ⁹ is alkyl, cycloalkyl, aryl, (aryl) alkyl , heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl,, Z is, -O -, - S -, - CH 2 - or -N ^{(R 7)} - a and, ^{R 7} Is hydrogen, alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) Alkyl, aryl, heterocyclic and heteroaryl groups are optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen For preparing compounds which may have been prepared.