US2001008892A1PendingUtilityA1

Retroviral protease inhibiting compounds

44
Priority: May 15, 1998Filed: Feb 6, 2001Published: Jul 19, 2001
Est. expiryMay 15, 2018(expired)· nominal 20-yr term from priority
Inventors:Xiaoqi ChenDale J. KempfDaniel W. NorbeckFariborz Mohammadi
C07D 417/12C07D 417/14C07D 277/24
44
PatentIndex Score
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Claims

Abstract

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

Claims

exact text as granted — not AI-modified
1 . A compound having formula I:  
                   wherein R 1  is a thiazolyl group having the formula  
                 
   and R 2  is a group having the formula:  
                 
   wherein R 3  is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and Y is CH or N;    R 4  is —W—R 5 ;    W is —O—, —S—, or —(CH 2 ) n —; and R 5  is selected from the group consisting of alkyl, and aryl; n is from 0 to 6; or R 4  and the ring taken together can form a bicyclic group having the formula:  
                 
   with the proviso that when W is O, or S then Y is CH;    R 6  is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl; and    Z is —O—, —S—, —CH 2 — or —N(R 7 )—; and R 7  is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl;    wherein the alkyl, aryl, heterocyclic, and heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino and halogen;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         2 . The compound according to    claim 1   , wherein R 3  is alkyl or cycloalkyl and Z is —O—, or —N(R 7 )—.  
     
     
         3 . The compound according to    claim 2   , wherein R 3  is alkyl.  
     
     
         4 . The compound according to    claim 2   , wherein R 3  is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, 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 compound according to    claim 1   , wherein Z is —N(R 7 )— and R 7  is methyl.  
     
     
         9 . The compound according to    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.  
     
     
         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 1 to 3 hydroxy groups.  
     
     
         12 . The compound according to    claim 9   , wherein R 5  is substituted with 1 to 3 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 according to    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 1 to 3 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 according to    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 R 1  is a thiazolyl group having the formula  
                 
   and R 2  is a group having the formula:  
                 
   wherein R 3  is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and    X is —C(O)— or —S(O) 2 —;    R 8  is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl;    R 9  is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl; and    Z is —O—, —S—, —CH 2 — or —N(R 7 )— wherein R 7  is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl, or (heteroaryl)alkyl;    wherein the alkyl, aryl, heterocyclic, and heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         25 . The compound according to    claim 24   , wherein R 3  is alkyl or cycloalkyl and Z is —O—, or —N(R 7 )—.  
     
     
         26 . The compound according to    claim 25   , wherein R 3  is alkyl.  
     
     
         27 . The compound according to    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 according to    claim 24   , wherein R 8  is selected from the group consisting of alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, or heteroaryl.  
     
     
         33 . The compound according to    claim 24   , wherein X is —S(O) 2 —; R 8  is aryl selected from the group consisting of phenyl, and heteroaryl; and R 9  is lower alkyl.  
     
     
         34 . The compound according to    claim 24   , wherein R 9  is selected from the group consisting of isopropyl, isobutyl, or 3-methyl-1-butyl.  
     
     
         35 . The compound according to    claim 34   , wherein R 9  is iso-butyl.  
     
     
         36 . The compound according to    claim 32   , wherein R 8  is substituted with 1 to 3 amino groups.  
     
     
         37 . The compound selected from the group consisting of 
 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)carbamate;    2-(1-methylethyl)-4-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)carbamate;    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)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-thienylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(4-(3-hydroxyphenyl)methyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(3-pyridinylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(4-pyridinylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-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)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-(1H-benzimidiazol-2-ylmethyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    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)carbamate;    2-(1-methylethyl)-4-thiazolylmethyl ((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    N′-((1S)-1-((((1S,2R)-3-((2S)-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)carbamate;    2-methyl-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    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)carbamate;    2-ethyl-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-methylethyl)-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-ethyl-5-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-methyl-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    N′-((1R)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-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-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(phenylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    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)carbamate;    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;    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)carbamate;    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)carbamate;    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)carbamate;    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)carbamate;    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)carbamothioate; and    4-(1,3-benzodioxol-5-ylmethyl)-N-(1,1-dimethylethyl)-1-((2R,3S)-3-(((2S)-2-((3-(2-(1-methylethyl)-4-thiazolyl)-1-oxopropyl)amino)-3-methyl-1-oxobutyl)amino)-2-hydroxy-4-phenylbutyl)-2-piperazinecarboxamide;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         38 . The compound according to    claim 37   , selected from the group consisting of: 
 2-(1-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)carbamate;    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)carbamate;    2-(1-Methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-thienylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    2-(1-Methylethyl)-4-thiazolylmethyl ((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;    N′-((1S)-1-((((1S,2R)-3-((2S,4R)-2-(((1,1-Dimethylethyl)amino)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)carbamate;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         39 . A pharmaceutical composition for treating an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of    claim 1   .  
     
     
         40 . A pharmaceutical composition for treating an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of    claim 24   .  
     
     
         41 . A method for inhibiting HIV protease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of    claim 1   .  
     
     
         42 . A method for treating an HIV infection comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of    claim 24   .  
     
     
         43 . A pharmaceutical composition for treating an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of    claim 9   .  
     
     
         44 . A pharmaceutical composition for treating an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of    claim 20   .  
     
     
         45 . A pharmaceutical composition for treating an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of    claim 36   .  
     
     
         46 . A process for the preparation of a compound of the formula I:  
                   wherein R 1  is a thiazolyl group having the formula  
                 
   and R 2  is a group having the formula:  
                 
   wherein R 3  is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and Y is CH or N;    R 4  is —W—R 5 ;    W is —O—, —S—, or —(CH 2 ) n —; and R 5  is selected from the group consisting of alkyl, and aryl; n is from 0 to 6; or R 4  and the ring taken together can form a bicyclic group having the formula:  
                 
   with the proviso that when W is O, or S then Y is CH;    R 6  is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl; and    Z 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 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.    
     
     
         47 . A process for the preparation of a compound of the formula II:  
                   wherein R 1  is a thiazolyl group having the formula  
                 
   and R 2  is a group having the formula:  
                 
   wherein R 3  is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl; and    X is —C(O)— or —S(O) 2 —;    R 8  is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl;    R 9  is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl; and    Z is —O—, —S—, —CH 2 — or —N(R 7 )— wherein R 7  is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl;    wherein the alkyl, aryl, heterocyclic, and heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.

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