2-Ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents

Abstract

Compounds which are 2-ureido-1,3-thiazole derivatives of formula (I) wherein R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: i) straight or branched C1-C6 alkyl; ii) C3-C6 cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain; R1 is an optionally substituted group selected from: i) straight or branched C1-C6 alkyl; ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring, iii) aryl or arylcarbonyl; iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain: R2 is hydrogen, a straight or branched C1-C4 alkyl or C2-C4 alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded, R1 and R2 form a substituted or unsubstituted group selected from: i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof; are useful for treating cell proliferative disorders associated with an altered cell dependent kinase activity.

We claim:  
     
         1 . A method of treating, arresting, alleviating, or reducing cell proliferative disorders associated with an altered cell dependent kinase activity in a patient comprising 
 administering a 2-ureido-1,3-thiazole derivative of formula (I)                          wherein    R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii) C 3 -C 6  cycloalkyl;  
 iii) aryl or arylalkyl with from 1 to 6 carbon atoms witliiii the straight or branched alkyl chain;  
   R 1  is an optionally further substituted group selected from: 
 i) straight or branched C 1 -C 6 ;  
 ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring;  
 iii) aryl or arylcarbonyl;  
 iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
   R 2  is hydrogen, a straight or branched C 1 -C 4  alkyl or C 2 -C 4  alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded,    R 1  and R 2  form a substituted or unsubstituted group selected from: 
 i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or  
 ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof to the patient.  
   
     
     
         2 . The method according to  claim 1  wherein the cell proliferative disorder is selected from the group consisting of cancer, Alzheimer's disease, viral infections, auto-immune diseases or neurodegenerative disorders.  
     
     
         3 . The method according to  claim 1  wherein cell proliferative disorder is selected from the group consisting of a carcinoma, squamous cell carcinoma, hematopoietic tumor of myeloid lineage, hematopoietic tumor lymphoid lineage, tumor of mesenchymal origin, tumor of the central nervous system, tumor of the peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.  
     
     
         4 . The method according to  claim 1  wherein the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthrithis glomerulonephritis and post-surgical stenosis and restenosis.  
     
     
         5 . 2-ureido-1,3-thiazole derivative of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii) C 3 -C 6  cycloalkyl;  
 iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
 
 R 1  is an optionally further substituted group selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring;  
 iii) aryl or arylcarbonyl;  
 iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
 
 R 2  is hydrogen, a straight or branched C 1 -C 4  alkyl or C 2 -C 4  alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded,  
 R 1  and R 2  form a substituted or unsubstituted group selected from: 
 i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or  
 ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof; provided that: 
 a) when R is a chlorine atom and R 2  is hydrogen, then R 1  is not methyl, phenyl or trifluoromethylphenyl; and  
 b) when R is methyl and R 2  is hydrogen, then R 1  is not 4-(5-oxazolyl)phenyl.  
 
 
 
     
     
         6 . 2-amino-1,3-thiazole derivative of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii) C 3 -C 6  cycloalkyl;  
 iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
 
 R 1  is an optionally further substituted group selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring;  
 iii) aryl or arylcarbonyl;  
 iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
 
 R 2  is hydrogen, a straight or branched C 1 -C 4  alkyl or C 2 -C 4  alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded,  
 R 1  and R 2  form a substituted or unsubstituted group selected from: 
 i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or  
 ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof, provided that: 
 a) when R is chlorine or bromine and R 2  is hydrogen, then R 1  is not unsubstituted C 1 -C 3  alkyl, phenyl, trifluoromethylphenyl or an optionally substituted phenylcarbonyl;  
 b) when R is methyl and R 2  is hydrogen, then R 1  is not methyl, phenyl or 4-(5-oxazolyl)phenyl;  
 c) when R is nitrophenyl and R 2  is hydrogen, then R 1  is not haloalkyl;  
 d) when R is bromine or chlorine, then R 1  and R 2  are not both methyl groups.  
 
 
 
     
     
         7 . The derivative according to  claim 6 , wvherein R is a halogen atom, a straight or branched C 1 -C 4  alkyl group, a phenyl group, a cycloalkyl groulp; R 2  is hydrogen and R 1  is an optionally substituted group selected from alkyl, aryl or arylakyl.  
     
     
         8 . The derivative according to  claim 6 , wherein 
 R is a halogen atom or is selected from the group consisting of nitro, amino, alkylamino, hydroxyalkylamino, arylamino, C 3 -C 6  cycloalkyl, straight or branched C 1 -C 6  alkyl optionally substituted by hydroxy, alkylthio, alkoxy, amino, alkylamino, alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carboxy, and aryl each optionally substituted by one or more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, N-alkyl-piperazinyl, 4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulfonyl, aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or carboxy, or R is an aryl group optionally substituted by one or more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, N-alkyl-piperazinyl, 4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulphonyl, aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or carboxy;    R 1  is a straight or branched C 1 -C 6  alkyl group or an aryl group, each optionally substituted as above reported for R;    R 2  is a hydrogen atom; and pharmaceutically acceptable salts thereof provided that: 
 a) when R is chlorine or bromine then R 1  is not unsubstituted C 1 -C 3  alkyl, phenyl, trifluoromethylphenyl or an optionally substituted phenylcarbonyl;  
 b) when R is methyl then R 1  is not methyl, phenyl or 4-(5oxazolyl)phenyl;  
 c) when R is nitrophenyl then R 1  is not haloalkyl.  
   
     
     
         9 . A process for preparing the derivative according to  claim 6 , comprising: 
 a) reacting a compound of formula (II) when R 2  is a hydrogen atom                          with a compound of formula (III) wherein R is as defined in  claim 6     R 1 -NCO  (III)    wherein R 1  is as defined in  claim 6;  or    b) reacting a compound of formula (IV) when R 2  is as defined in  claim 6                           with a compound of formula (V) wherein R is as defined in  claim 6                           wherein R 1  and R 2  are as defined in  claim 6;  and optionally converting a 2-ureidol-3-thiazole derivative of formula (I) into another such derivative of formula (I), a salt thereof, or a mixture thereof    
     
     
         10 . A process for preparing the derivative according to  claim 6 , comprising reacting a compound of formula (II)  
       
         
           
           
               
               
           
         
         wherein R is as defined in  claim 6 , with 4-nitrophenyl-chloroformate, or a polymer supported form of it, thus obtaining a compound of formula (VI), or a polymer supported form of it,  
         
           
             
             
                 
                 
             
           
         
         wherein R is as defined in  claim 6;  and reacting a compound of formula (VI) with a compound of formula (V)  
         
           
             
             
                 
                 
             
           
         
         wherein R 1  and R 2  are as defined in  claim 6;  and optionally, converting a 2-ureidol-1,3-thiazole derivative of formula (I), or a polymer supported form of it, into another such derivative of formula (I), a salt thereof or a mixture thereof.  
       
     
     
         11 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or diluent and the derivative of formula (I) according to  claim 1 .  
     
     
         12 . A method of treating, arresting, alleviating, or reducing tumor angiogenesis and metastasis inhibition in a patient, comprising 
 administering a 2-ureido-1,3-thiazole derivative of formula (I)                          wherein    R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: 
 i) straight or branched C 1 -C 6  alkyl;  
 ii.) C 3 -C 6  cycloalkyl;  
 iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
   R 1  is an optionally further substituted group selected from: 
 i) straight or branched C 1 -C 6    
 ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring;  
 iii) aryl or arylcarbonyl;  
 iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;  
   R 2  is hydrogen, a straight or branched C 1 -C 4  alkyl or C 2 -C 4  alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded,    R 1  and R 2  form a substituted or unsubstituted group selected from: 
 i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or  
 ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof to the patient.  
   
     
     
         13 . A compound of formula (I) according to  claim 5 , whenever appropriate in the form of pharmaceutically acceptable salts, selected from the group consisting of: 
 1) N-(5-isopropyl-1,3-thiaz-ol-2-yl)-N′-phenyl-urea;    2) N-(5-bromo-1,3-thiazol-2-yl)-N′-phenyl-urea;    3) N-(5-phenyl-1,3-thiazol-2-yl)-N′-phenyl-urea;    4) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-phenyl-urea;    5) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-sulfamoyl-phenyl)-urea;    6) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-sulfamoyl-phenyl)-urea;    7) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-sulfamoyl-phenyl)-urea;    8) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-sulfamoyl-phenyl)-urea;    9) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-methoxy-phenyl)-urea;    10) N-(5-bromo-1,3-thiazol-2-yl)-N′-(3-methoxy-phenyl)-urea;    11) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(3-methoxy-phenyl)-urea;    12) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(3-methoxy-phenyl)-urea;    13) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-chloro-phenyl)-urea;    14) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-chloro-phenyl)-urea;    15) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-chloro-phenyl)-urea;    16) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-chloro-phenyl)-urea;    17) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-chloro-phenyl)-urea;    18) N-(5-bromo-1,3-thiazol-2-yl)-N′-(3-chloro-phenyl)-urea;    19) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(3-chloro-phenyl)-urea;    20) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(3-chloro-phenyl)-urea;    21) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-chloro-phenyl)-urea;    22) N-(5-bromo-1,3-thiazol-2-yl)-N′-(2-chloro-phenyl)-urea;    23) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(2-chloro-phenyl)-urea;    24) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(2-chloro-phenyl)-urea;    25) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-methoxy-phenyl)-urea;    26) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-methoxy-phenyl)-urea;    27) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-melthoxy-phenyl)-urea;    28) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-methoxy-phenyl)-urea;    29) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-hydroxy-phenyl)-urea;    30) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-hydroxy-phenyl)-urea;    31) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-hydroxy-phenyl)-urea;    32) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-hydroxy-phenyl)-urea;    33) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-hydroxy-phenyl)-urea;    34) N-(5-bromo-1,3-thiazol-2-yl)-N′-(3-hydroxy-phenyl)-urea;    35) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(3-hydroxy-phenyl)-urea;    36) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(3-hydroxy-phenyl)-urea;    37) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-methoxy-phenyl)-urea;    38) N-(5-bromo-1,3-thiazol-2-yl)-N′-(2-methoxy-phenyl)-urea;    39) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(2-methoxy-phenyl)-urea;    40) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(2-methoxy-phenyl)-urea;    41) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-hydroxy-phenyl)-urea;    42) N-(5-bromo-1,3-thiazol-2-yl)-N′-(2-hydroxy-phenyl)-urea;    43) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(2-hydroxy-phenyl)-urea;    44) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(2-hydroxy-phenyl)-urea;    45) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-nitro-phenyl)-urea;    46) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-nitro-phenyl)-urea;    47) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-nitro-phenyl)-urea;    48) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-nitro-phenyl)-urea;    49) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-amino-phenyl)-urea;    50) N-(5-bromo-1,3-thiazol-2-yl)-N′-(4-amino-phenyl)-urea;    51) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(4-amino-phenyl)-urea;    52) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(4-amino-phenyl)-urea;    53) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-nitro-phenyl)-urea;    54) N-(5-bromo-1,3-thiazol-2-yl)-N′-(3-nitro-phenyl)-urea;    55) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(3-nitro-phenyl)-urea;    56) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(3-nitro-phenyl)-urea;    57) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-amino-phenyl)-urea;    58) N-(5-bromo-1,3-thiazol-2-yl)-N′-(3-amino-phenyl)-urea;    59) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(3-amino-phenyl)-urea;    60) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(3-amino-phenyl)-urea;    61) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-benzyl-urea;    62) N-(5-bromo-1,3-thiazol-2-yl)-N′-benzyl-urea;    63) N-(5-phenyl-1,3-thiazol-2-yl)-N′-benzyl-urea;    64) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-benyzl-ure- a;    65) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(pyrid-3-yl)-urea;    66) N-(5-bromo-1,3-thiazol-2-yl)-N′-(pyrid-3-yl)-urea;    67) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(pyrid-3-yl)-urea;    68) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(pyrid-3-yl)-urea;    69) N-(5-bromo-1,3-thiazol-2-yl)-N′-(pyrid-4-yl)-urea;    70) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(pyrid-4-yl)-urea;    71) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(pyrid-4-yl)-urea;    72) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(pyrid-4-yl)-urea;    73) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(pyrid-2-yl)-urea;    74) N-(5-bromo-1,3-thiazol-2-yl)-N′-(pyrid-2-yl)-urea;    75) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(pyrid-2-yl)-urea;    76) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(pyrid-2-yl)-urea;    77) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(benzothiophen-2-yl)-urea;    78) N-(5-bromo-1,3-thiazol-2-yl)-N′-(benzothiophen-2-yl)-urea;    79) N-(5-phenyl-1,3-thiazol-2-yl)-N′-(benzothiophen-2-yl)-urea; N-(5-cyclopropyl-1,3-thiazol-2-yl)-N′-(benzothiophen-2-yl)-urea;    80) N-(5-isopropyl-1,3-thiazol-2-yl)-4-morpholine carboxamide;    81) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-methlyphenyl)urea;    82) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-fluorophenyl)urea;    83) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-cyanophenyl)urea;    84) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-cyanophenyl)urea;    85) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,6-dimethylphenyl)urea;    86) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-fluorobenzyl)urea;    87) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-acetylphenyl)urea;    88) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-acetylphenyl)urea;    89) 3-({[(5-isopropyl-1,3-thiazol-2-yl)amino[carbonyl}amino)benzoic acid;    90) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-isopropylphenyl)urea;    91) 3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzamide;    92) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-methoxybenzyl)urea;    93) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-butylphenyl)urea;    94) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-trifluromethylphenyl)urea;    95) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-3-bromophenyl)urea;    96) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-cyclohexylphenyl)urea;    97) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-phenoxyphenyl)urea;    98) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-benzyloxyphenyl)urea;    99) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,5-dimethylphenyl)urea;    100) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,3-dimethylphenyl)urea;    101) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-methoxy[1,1′-biphenyl]-4-yl)urea;    102) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-3,4-dihydro-2(1H)-isoquinoline carboxamide;    103) N-benzyl-N′-(5-isopropyl-1,3-thiazol-2-yl)-N-methylurea-;    104) N-(5-isopropyl-1,3-thiazol-2-yl)-6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinoline carboxamide;    105) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(3-chlor-o-4-methyl)-phenyl]urea;    106) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(3-chlo-ro-6-methyl)phenyl]urea;    107) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,5-dim-ethoxyphenyl)urea;    108) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,4-dimethoxy-phenyl)urea;    109) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(2-methoxy-5-chloro-)phenyl]urea;    110) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-((2-chloro-4-methox-yphenyl)urea;    111) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,5-dichlorophenyl-)urea;    112) N-[(1,1′-biphenyl)-2-yl]-N′-(5-isopropyl-1,3-thiazol-2-yl)urea-;    113) N-ethyl-N′-(5-isopropyl-1,3-thiazol-2-yl)-N-phenylurea;    114) N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-2-methoxyphen-yl]acetamide;    115) 2-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino-)-N-phenylbenzamide 116) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-morpholino-phenyl)urea;    117) N-[41-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}am-ino)phenyl]-N-methyl acetamide;    118) N-[2-{[cyclohexyl(methyl)amino]methyl-}phenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    119) N-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-4-methoxyphen-yl]acetamide;    120) N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-methoxyphenyl)-1-piperazine carboxamide;    121) N-(2-furylmethyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    122) N-(4-fluorophenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    123) N-(2-methoxybenzyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    124) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]ure-a;    125) N-(3,4-dimethoxybenzyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    126) N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxamide;    127) n-(5-isopropyl-1,3-thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxamide;    128) N-(5-isopropyl-1,3-thiazol-2-yl)-N- ′-[2-(1-piperidinyl)ethyl]urea;    129) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[-2-(1-morpholinyl)ethyl]urea;    130) 4-(4-flurorphenyl)-N-(5-isopropyl-1,3-th- iazol-2-yl)-1-piperazine carboxamide;    131) N-[4-(4-chlorophenyl)-3-ethyl-5-isoxazolyl]-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    132) 4-[(4-fluorophenyl)(hydroxy)methyl]-N-(5-isopropyl-1,3-thiazol-2-yl)-1-pi-peridine carboxamide;    133) N-(3-ethynylphenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    134) N-(2-methoxy-3-fluorophenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    135) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-oxo-1-piperidinyl)u-rea;    136) N-(3-acetylaminophenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    137) N-[3-(2-furyl)-1H-pyrazol-5-yl]-N′-(5-isopropyl-1,3-thiazol-2-yl)ure-a;    138) N-{4-[ethyl(isopropyl)amino]phenyl}-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    139) N-(1,3-benzodioxol-5-yl)-N′-(5-isopropyl-1,3-thiazol-2-yl)ur-ea;    140) 5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-1-phenyl-1H-pyrazole-4-carboxamide;    141) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-py-ridinylmethyl)urea;    142) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-pyrazinyl)-urea;    143) n-(5-isopropyl-1,3-thiazol-2-yl)-N′-(5-phenyl-1,3,4-oxadiazol-2-yl)urea;    144) N-(5-isopropyl-1,3-thiazol-2-yl)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidine carboxamide;    145) N-(1,3-benzothiazol-6-yl) N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    146) N-(1,3-dimethyl-1H-pyrazol-5-y-l)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    147) N-(3-phenyl-1-methyl-1H-pyr-azol-5-yl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    148) N-(5-isopropyl-1,3-thiazol-2-yl)-3-hydroxy-1-piperidine carboxamide;    149) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-methyl-1,3-dioxo-2,3-dihydro-1H-is-oindol-5-yl)urea;    150) N-(3-isopropyl-1,3-thiazol-2-yl)-4-benzyl-1-piperaz-ine carboxamide;    151) N-(5-isopropyl-1,3-thiazol-2-yl)-4-methyl-1-piperazi-ne carboxamide;    152) 4-hydroxy-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperidi-ne carboxamide;    153) N-(5-isopropyl-1,3-thiazol-2-yl)-3-azabicyclo[3.2.2]n-onane-3-carboxamide;    154) N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-acetylphen-yl)-1-piperazine carboxmide;    155) 4-[bis(4-fluorophenyl)-N-(5-isopropyl-1,-3-thiazol-2-yl)-1-piperazine carboxamide;    156) N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxamide;    157) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(5,6,7,8-tetrahydro-1-naphtalenyl)ure-a;    158) N-(4-phenyl-2-thiazolyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    159) 4-(4-fluorobenzoyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperidine carboxamide;    160) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-1,3-dihydro-2-benzo-furan-5-yl)urea;    161) N-(5-isopropyl-1,3-thiazol-2-yl)-4′-(2-pyrimidinyl-1-piperazine carboxamide;    162) N-(5-isopropyl-1,3-thiazol-2-yl)-3-oxo-3,4-dihydro-1(2H)-quinoxaline;    163) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(1H-in-dazol-6-yl)urea;    164) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-chlorobenzyl)-urea;    165) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,4-dichlorobenzyl)urea;    166) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-flurobenzyl)urea;    167) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,4-dichlorobenzyl)urea;    168) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,4-difluorobenzyl)urea;    169) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,5-difluorobenzyl)urea;    170) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-2,6-difluorobenzyl)urea;    171) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(4-hydroxy-3-methoxy)benzyl]urea;    172) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(5-methyl-2-furyl)urea;    173) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-methylsulfonylbenzyl)urea;    174) N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-N′-(5-isopropyl-1,3-thiaz-ol-2-yl)urea;    175) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-chlorobenzyl)ure-a;    176) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-pyridinylmethyl)urea;    177) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,5-dimethoxybenzyl)urea;    178) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-pyridinylmethyl)urea;    179) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-trifluorobenzyl)urea;    180) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,4,5-trimethoxybenzyl)urea;    181) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,4-dimethoxybenzyl)urea;    182) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-dimethylaminobenzyl)urea;    183) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,5-dimethoxybenzyl)urea;    184) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(2-chloro-6-phenoxy)benzyl]urea;    185) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(1R,2S)-2-hydroxy-2,3-dihydro-1-H-inden-1-yl]urea;    186) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(3-hydroxy-4-methyl)phenyl]urea;    187) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[4-(1H-benzim-idazol-2-yl)phenyl]urea;    188) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-pheny-l-1H-pyrazol-5-yl)urea;    189) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-methyl-6-quinolinyl)urea;    190) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[4-(cyanometh-yl)phenyl]urea;    191) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-quinolinyl)ure-a;    192) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(1-oxo-2,3-dihydro-1H-inden-5-yl)urea;    193) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-oxo-1,3-dihydro-2-ben-zofuran-5-yl)urea;    194) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(5-oxo-5,6,7,8-tetrahydro-2-naphtalenyl)urea;    195) methyl-3-(<[(5-isopropyl-1,3-thiaz-ol-2-yl)amino]carbonyl}amino)-4-methylbenzoate;    196) methyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)arnino]carbonyllamino)-3-meth-ylbenzoate;    197) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(4-imidazo [1,2-a]pyri-din-2-yl-phenyl)urea;    198) ethyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoate;    199) (2R)-1-benzyl-2-(<[(5-isopropyl-1,3-th-iazol-2-yl)amino]carbonyl}amino)propanamide;    201) 2-chloro-5-({[(5-isoprop-yl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic acid;    202) 3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic acid;    203) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(5-methyl-3-isoxazolyl)urea;    204) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,6-dimethoxyphenyl)urea;    205) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,3-dmethoxybenzyl)urea;    206) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3,4-difluorobenzyl)urea;    207) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,4-dimethylphenyl)urea;    208) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(1H-benzimidazol-5-yl)urea;    209) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(R)-phenylglicinamido]urea;    210) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2-phenoxyacetamido)urea;    211) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[(S)-phenylglicinamido}urea;    212) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-{2-[(1-methyl-1H-imidazol-2-yl)methox-y]phenyl}urea;    213) N-(3-iodophenyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea-;    214) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-[3-(3-methoxy-1-propnyl)phenyl]-urea;    215) N-{3-[3-(dimethylamino)-1-propynyl)phenyl}-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    216) N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbon-yl}amino)phenyl]methanesulfonamide;    217) 2-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)anilino]acetamide;    218) N-[3-(3-hydroxy-1-butyny-l)phenyl]-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    219) N-(imidazo[1,2-a]pyridin-2-yl-methyl)-N′-(5-isopropyl-1,3-thiazol-2-yl)ur-ea;    220) 2-{[{[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}(2-propynyl)amino]methyl}benzenesulfonamide;    221) N-(1H-indol-6yl)-N′-(5-isopropyl-1,3-t-hiazol-2-yl)urea;    222) N-[(1S)-2-hydroxy-1-phenylethyl]-N′-(5-isopropyl-1,-3-thiazol-2-yl)urea;    223) N-(1H-indol-5-yl)-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    224) N-[(1R-2-hydroxy-1-phenylethyl]-N′-(5-isopropyl-1,3-thiazol-2-yl)urea;    225) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-butylurea;    226) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-benzoylurea;    227) N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(2,6-dimethylphenyl)urea;    228) N-(5-methyl-1,3-thiazol-2-yl)-N′-benzylurea;    229) N-(5-methyl-1,3-thiazol-2-yl)-N′-butylurea;    230) N-(5-methyl-1,3-thiazol-2-yl)-4-morpholinecarbox-amide;    231) N-(5-methyl-1,3-thiazol-2-yl)-N′-phenylurea;    232) N-(5-methyl-1,3-thiazol-2-yl)N′-(4-methoxybenzylurea;    233) N-(5-methyl-1,3-thiazol-2-yl)-N′-(4-fluorophenyl)urea;    234) N-[(1-ethyl-2-pyrrolidinyl)methyl]-N′-(5-methyl-1,3-thiazol-2-yl)urea;    235) N-(5-methyl-1,3-thiazol-2-yl)-N′-(5-hydroxy-1H-pyrazol-3-yl)urea;    236) N-(5-methyl-1,3-thiazol-2-yl)-N′-(3-pyridinyl)urea;    237) N-(4-fluorophenyl)-N′-(5-methyl-1,3-thiazol-2-yl)urea.    
     
     
         14 . The method according to  claim 1 , wherein the optionally substituted group of R, R 1 , and R 2  of formula (I) is optionally substituted with at least one member selected from the group consisting of halogen, nitro, oxo, carboxy, cyano, alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylureido, carbonylamino groups, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, oxygen-substituted oximes, alkoxycarbonylalkoxyimino, alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy, aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.  
     
     
         15 . The derivative according to  claim 6 , wherein the optionally substituted group of R, R 1 , and R 2  of formula (I) is opptionally substituted with at least one member selected from the group consisting of halogen, nitro, oxo, carboxy, zyan, alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylureido, carbonylamino groups, formylamino, alkycarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, oxygen-substituted oximes, alkoxycarbonylalkoxyimino, alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy, aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.  
     
     
         16 . The derivative according to  claim 6 , wherein the optionally substituted group of R, R 1 , and R 2  of formula (I) is optionally substituted with at least one member selected from the group consisting of halogen, nitro, oxo, carboxy, cyano, alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylureido, carbonylamino groups, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, oxygen-substituted oximes, alkoxycarbonylalkoxyimino, alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy, aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.