Substituted thiazoles and the use thereof as inhibitors of plasminogen activator inhibitor-1

Abstract

The present invention relates to the use of aminothiazole derivatives of Formula I of as inhibitors of PAI-1, and to novel classes of aminothiazole derivatives, their synthesis and their use as inhibitors of PAI-1. It has been discovered that compounds of Formula I: or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein Y, Ar 1 , Ar 2 , R 1 , R 2 , Z, m and n are described in the specification, inhibit plasminogen activator inhibitor-1 (PAI-1). These compounds can be used in the prophylaxis or for the treatment of thrombosis, angina pectoris, cerebral infarction, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis and stroke.

What is claimed is:  
     
         1 . A method of inhibiting plasminogen activator inhibitor-1, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Y is —N—, —C(R 3 )— or —CH(R 3 )—, wherein 
 R 3  is selected from the group consisting of hydrogen, cyano, C(CN) 3 , N(CN) 2 , trifluoromethyl, halogen, alkyl, cycloalkyl, aryl and heteroaryl radical, all of which can be optionally substituted;  
 Ar 1  and Ar 2 , which can be the same or different, are an optionally substituted aryl or heteroaryl radical;  
 m is 0 or 1,provided that when Y is —N— or —C(R 3 )—, then m is 1 and when Y is —CH(R 3 )—, then m is 0;  
 R 1  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted; and  
 R 2  is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical;  
 with the provisos that 
 when Y is N, R 1  and R 2  are hydrogen and Ar 2  is an optionally substituted phenyl, then Ar 1  is other than a phenyl group substituted with carboxyalkyl or an alkyl ester of carboxyalkyloxy;  
 when Y is N, R 1  is hydrogen, and Ar 2  and R 2  are both a phenyl group, then Ar 1  is other than a phenyl group substituted with carboxyalkyl; or  
 when Y is N, R 1  and R 2  are hydrogen and Ar 2  is naphthyl, then Ar 1  is other than a phenyl group substituted with carboxyalkyl.  
 
 
 
     
     
         2 . The method according to  claim 1 , wherein Ar 1  and Ar 2  are independently selected from the group consisting of phenyl, biphenyl, naphthyl, tetrahydronaphthyl, thienyl, benzothienyl, furyl, benzofuryl, thiazolyl, imidazolyl, isoxazolyl, pyrrolyl and pyrazolyl, any of which can be optionally substituted.  
     
     
         3 . The method according to  claim 1 , wherein R 1  and R 2  both are hydrogen.  
     
     
         4 . The method according to  claim 1 , wherein the compound administered is a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Ar 21  is an optionally substituted aryl or an optionally substituted heteroaryl radical;  
 Ar 22  is a substituted aryl or an optionally substituted heteroaryl radical;  
 R 21  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted;  
 R 22  is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical,  
 with the provisos that 
 when R 21  and R 22  are hydrogen and Ar 22  is substituted phenyl, then Ar 21  is other than a phenyl group substituted with carboxyalkyl;  
 when R 21  is hydrogen, and Ar 22  and R 22  are both a phenyl group, then Ar 21  is other than a phenyl group substituted with carboxyalkyl; or  
 when R 21  and R 22  are hydrogen and Ar 22  is naphthyl, then Ar 21  is other than a phenyl group substituted with carboxyalkyl.  
 
 
     
     
         5 . The method according to  claim 4 , wherein the aryl or heteroaryl radical is selected from the group consisting of phenyl, biphenyl, naphthyl, tetrahydronapthyl and isoxazolyl.  
     
     
         6 . The method according to  claim 4 , wherein the compound administered is a compound of Formula III:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Ar 31  is an optionally substituted aryl or an optionally substituted heteroaryl radical selected from the group consisting of biphenyl, naphthyl, tetrahydronaphthyl and isoxazolyl; and  
 R 33 -R 37  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR 4 , —NR 4 R 5 , phenoxy, and phenyl(C 1-4 )alkyloxy, wherein R 4  is selected from the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and —C(O)NH-aryl, provided that at least one of R 33 -R 37  is other than hydrogen.  
 
     
     
         7 . The method according to  claim 4 , wherein the compound administered is a compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 48 -R 412  is trifluoro(C 1-6 )alkyl and the substituents that are not trifluoro(C 1-6 )alkyl are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 43 -R 47  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, and benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl, provided that at least one of R 43 -R 47  is other than hydrogen.  
 
     
     
         8 . The method according to  claim 4 , wherein the compound administered is a compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 48 -R 412  is nitro and the substituents that are not nitro are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, cyano, thiol, C 1-6  alkylthiol. C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6 alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 43 -R 47  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6  )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, cyano, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di-C 1-6  alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl, provided that at least one of R 43 -R 47  is other than hydrogen.  
 
     
     
         9 . The method according to  claim 4 , wherein the compound administered is a compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 43 -R 47  is cyano and the substitutents that are not cyano are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6  )alkyl, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 48 -R 412  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl.  
 
     
     
         10 . The method according to  claim 1 , wherein the compound administered is a compound of Formula V:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 R 53 -R 58  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR 4 , —NR 4 R 5 , phenoxy, and benzyloxy, wherein R 4  is selected from the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and —C(O)NH-aryl.  
 
     
     
         11 . The method according to  claim 1 , wherein the compound administered is a compound of Formula VI:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Ar 1  and R 3  are as defined in  claim 1 .  
 
     
     
         12 . The method according to  claim 1 , wherein the compound administered is selected from the group consisting of 
 3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;    4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)- 1,3-thiazol-2-yl]amino}benzoic acid;    3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoic acid;    [4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;    (3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine;    [4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;    [4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;    (3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl}amine;    2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol;    4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;    4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;    (2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;    4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)-amine;    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;    [4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;    2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;    (4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl )-1,3-thiazol-2-yl]amine;    [4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;    [4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;    3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoic acid;    3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;    [4-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-benzyloxyphenyl)amine;    [4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;    [4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    [4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;    [4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)amine;    (4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine;    (2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine; and    2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazole;    or a solvate, hydrate or a pharmaceutically acceptable salt thereof.    
     
     
         13 . The method according to  claim 1 , wherein one or more of thrombosis, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis or stroke are treated.  
     
     
         14 . A compound having the Formula II:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Ar 21  is an optionally substituted aryl or an optionally substituted heteroaryl radical;  
 Ar 22  is a substituted aryl or an optionally substituted heteroaryl radical;  
 R 21  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted.  
 R 22  is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical,  
 with the provisos that 
 when R 21  and R 22  are hydrogen and Ar 22  is substituted phenyl, then Ar 21  is other than a phenyl group substituted with carboxyalkyl;  
 when R 21  is hydrogen, and Ar 22  and R 22  are both a phenyl group, then Ar 21  is other than a phenyl group substituted with carboxyalkyl;  
 when R 21  and R 22  are hydrogen and Ar 22  is naphthyl, then Ar 21  is other than a phenyl group substituted with carboxyalkyl;  
 when Ar 21  an unsubstituted naphthyl or a naphthyl substituted with halogen, R 21  and R 22  are both hydrogen and Ar 22  is a substituted phenyl group, then the substituents in Ar 22  are not selected from the group consisting of alkyl, haloalkyl, halogen, thiol, and nitro; or  
 when Ar 21  is a phenyl group substituted only with trifluoro(C 1-6 )alkyl, R 21  and R 22  are both hydrogen, and Ar 22  is a phenyl group substituted with halogen or trifluoromethyl, then Ar 22  has another substituent other than hydrogen.  
 
 
     
     
         15 . The compound according to  claim 14 , wherein the aryl or heteroaryl radical is selected from the group consisting of phenyl, biphenyl, naphthyl, tetrahydronapthyl and isoxazolyl.  
     
     
         16 . The compound according to  claim 15 , wherein Ar 22  is a phenyl group substituted with one or more of alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR 4 , —NR 4 R 5 , phenoxy, and benzyloxy, wherein R 4  is selected from the group consisting of alkyl, —C(O)O-alkyl, aroyl, C(O)NH-alkyl and —C(O)NH-aryl.  
     
     
         17 . The compound according to  claim 16 , wherein Ar 22  is a phenyl group substituted with one or more of C 1-6  alkyl, fluoro, chloro, bromo, trifluoro(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, nitro, cyano, carboxy, —C(O)O—(C 1-6 )alkyl and benzyloxy.  
     
     
         18 . The compound according to  claim 17 , wherein Ar 22  is a phenyl group substituted with carboxy, cyano, nitro, trifluoromethyl, 3,5-dichloro, 3,4-dichloro, 2,4-dichloro, 2,4,5-trichloro, 3-chloro-4-bromo, 2,4-difluoro, 2,3,4-trifluoro, hydroxy and hydroxy(C 1-6 )alkyl.  
     
     
         19 . The compound according to  claim 18 , wherein Ar 21  is a phenyl group substituted with 3,4-difluoro, 2,4-difluoro, bromo, trifluoromethyl, 3,4-dichloro, and 2,4-dichloro.  
     
     
         20 . The compound according to  claim 14 , wherein R 21  and R 22  are both hydrogen.  
     
     
         21 . A compound according to  claim 14  having the Formula III:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 Ar 31  is an optionally substituted aryl or an optionally substituted heteroaryl radical selected from the group consisting of biphenyl, naphthyl, tetrahydronaphthyl and isoxazolyl; and  
 R 33 -R 37  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR 4 , —NR 4 R 5 , phenoxy, and phenyl(C 1-4 )alkyloxy, wherein R 4  is selected from the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and —C(O)NH-aryl, provided that at least one of R 33 -R 37  is other than hydrogen,  
 with the proviso that 
 when Ar 31  an unsubstituted naphthyl or a naphthyl substituted with halogen, then one or more of R 33 -R 37  is not selected from the group consisting of alkyl, haloalkyl, halogen, thiol, and nitro.  
 
 
     
     
         22 . The compound according to  claim 21 , wherein Ar 31  is an optionally substituted biphenyl, tetrahydronaphthyl or isoxazolyl.  
     
     
         23 . The compound according to  claim 22 , wherein Ar 31  is an optionally substituted biphenyl or tetrahydronaphthyl.  
     
     
         24 . The compound according to  claim 21 , wherein the optional substituent on Ar 31  is selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, hydroxy, nitro, cyano, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, and carboxy.  
     
     
         25 . The compound according to  claim 21 , wherein R 33 -R 37  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, and benzyloxy.  
     
     
         26 . The compound according to  claim 25 , wherein R 33 -R 37  are independently selected from the group consisting of hydrogen, C 1-4 alkyl, halogen, halo(C 1-4 )alkyl, trifluoro(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, amino, amino(C 1-4 )alkyl, C 1-4 alkoxy, nitro, cyano, C 1-4 acylamino, C 1-4 acyloxy, carboxy, carboxy(C 1-4 )alkyl, —C(O)O—C 1-4 alkyl, —C(O)NH—C 1-4 alkyl, C 1-4 alkylamino, di(C 1-4 )alkylamino;, phenoxy, and benzyloxy.  
     
     
         27 . The compound according to  claim 26 , wherein R 33 -R 37  are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, nitro, cyano, methoxy, carboxy, and benzyloxy.  
     
     
         28 . A compound according to  claim 14  having the Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 48 -R 412  is trifluoro(C 1-6 )alkyl and the substituents that are not trifluoro(C 1-6 )alkyl are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 43 -R 47  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alky, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, and benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 ) alkyl, and —NHC(O)(C 1-3 )alkyl, provided that at least one of R 43 -R 47  is other than hydrogen,  
 with the proviso that 
 when one of R 48 -R 412  is trifluoro(C 1-6 )alkyl and the other substituents are hydrogen and one of R 43 -R 47  is halogen or trifluoromethyl, then at least one of R 43 -R 47  that is not halogen or trifluoromethyl, is other than hydrogen.  
 
 
     
     
         29 . A compound according to  claim 14  having the Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 48 -R 412  is nitro and the substituents that are not nitro are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O-C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 43 -R 47  are independently selected from the group consisting of hydrogen. C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, cyano, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di-C 1-6  alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl, provided that at least one of R 43 -R 47  is other than hydrogen.  
 
     
     
         30 . A compound according to  claim 14  having the Formula IV:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 at least one of R 43 -R 47  is cyano and the substitutents that are not cyano are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl; and  
 R 48 -R 412  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, halo(C 1-6 )alkyl, hydroxy, hydroxy(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  alkoxy(C 1-6 )alkyl, nitro, cyano, thiol, C 1-6  alkylthiol, C 1-6  acylamino, C 1-6  acyloxy, carboxy, carboxy(C 1-6 )alkyl, —C(O)O—C 1-6  alkyl, —C(O)NH—C 1-6  alkyl, C 1-6  alkylamino, di(C 1-6 )alkylamino, phenoxy, benzyloxy, —C(O)O(C 1-3 )alkyl, —O—C(O)(C 1-3 )alkyl, and —NHC(O)(C 1-3 )alkyl.  
 
     
     
         31 . A compound having the Formula V:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 R 53 -R 58  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR 4 , —NR 4 R 5 , phenoxy, and benzyloxy, wherein R 4  is selected from the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and —C(O)NH-aryl.  
 
     
     
         32 . A compound having the Formula VI:  
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein 
 R 3  is selected from the group consisting of hydrogen, cyano, C(CN) 3 , N(CN) 2 , trifluoromethyl, halogen, alkyl, cycloalkyl, aryl and heteroaryl radical, all of which can be optionally substituted; and  
 Ar 1  is an optionally substituted aryl or an optionally substituted heteroaryl radical.  
 
     
     
         33 . The compound according to  claim 32 , wherein Ar 1  selected from the group consisting of phenyl, biphenyl, naphthyl, tetrahydronaphthyl, thienyl, benzothienyl, furyl, benzofuryl, thiazolyl, imidazolyl, isoxazolyl, pyrrolyl and pyrazolyl, any of which can be optionally substituted.  
     
     
         34 . The compound according to  claim 33 , wherein Ar 1  is selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl, biphenyl and isoxazolyl.  
     
     
         35 . A compound selected from the group consisting of 
 3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;    4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoic acid;    3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoic acid;    [4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;    (3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine:    [4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;    [4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;    (3,5-dichlorophenyl){4-[4-(trifluoromethyl)pheny](1,3-thiazol-2-yl}amine;    2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol:    4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;    4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;    (2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;    4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)-amine;    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;    [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;    [4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine:    4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;    2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;    (4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl)-1,3-thiazol-2-yl]amine;    [4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine:    [4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;    [4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;    3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoic acid;    3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;    [4-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-benzyloxyphenyl)amine;    [4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;    [4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;    [4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;    [4-(3-chloro-4-methylphenyl)-5-methyl- 1,3-thiazol-2-yl](3-hydroxyphenyl)amine;    (4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine;    (2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethyl ester)-1,3-thiazol-2-yl]amine; and    2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydroiiaphthyl)-1,3-thiazole;    or a solvate, hydrate or a pharmaceutically acceptable salt thereof.