Patent Abstract:
This invention relates to thiourea compounds of formula (I) shown below:  
                         
Each variable in formula (I) is defined in the specification. These compounds can be used to treat hepatitis C virus infection.

Full Description:
CROSS REFERENCE  
       [0001]     Pursuant to 35 U.S.C. § 119(e), this application claims priority to U.S. Provisional Application 60/837,782, filed on Aug. 15, 2006. The contents of the provisional application are incorporated by reference. 
     
    
     BACKGROUND  
       [0002]     Hepatitis C virus (HCV) infection is estimated to affect 170 million individuals worldwide. This disease is primarily transmitted through contaminated blood products. Although its spread has been slowed as a result of improvement in blood screening in many countries, it remains the leading cause of liver disease-related deaths in the world. For example, it causes about 10,000 deaths annually in the U.S. alone. In the absence of effective therapies, the death rate is expected to triple over the next 2 decades.  
         [0003]     Current treatments based on interferon-alpha have low success rates, particularly for genotype-1 infections predominant in Europe, Japan, and the U.S. Also, they are expensive and poorly received by patients. Thus, there is a need to develop better therapeutic agents for treating HCV infection.  
       SUMMARY  
       [0004]     This invention is based on the discovery that certain thiourea compounds are effective in treating hepatitis C virus infection.  
         [0005]     In one aspect, this invention relates to thiourea compounds of formula (I):  
                         
 
 In this formula, each of R 1 , R 2 , and R 3 , independently, is H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20  cycloalkyl, C 3 -C 20  cycloalkenyl, C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl, aryl, or heteroaryl; or R 1  and R 2 , together with the nitrogen atom to which they are bonded, are C 3 -C 20  heterocycloalkyl; or R 2  and R 3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are C 3 -C 20  heterocycloalkyl; each of A 1  and A 2 , independently, is aryl or heteroaryl; each of X, Y, and Z, independently, is O, S, S(O), S(O) 2 , N(R a ), C(R a R b ), C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20  cycloalkyl, C 1 -C 20  heterocycloalkyl, aryl, or heteroaryl, in which each of R a  and R b , independently, is H, C 1 -C 10  alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20  heterocycloalkyl, aryl, or heteroaryl; each of m and n, independently, is 1, 2, 3, 4, or 5; and each of x, y, and z, independently, is 0 or 1. 
 
         [0006]     Referring to formula (I), a subset of the thiourea compounds described above are those in which x is 1, y is 0, and z is 0. In these compounds, X can be O or NH, A 1  can be phenylene, A 2  can be phenyl, and each of R 1 , R 2 , and R 3 , independently, can be H or C 1 -C 10  alkyl optionally substituted with aryl.  
         [0007]     Another subset of the thiourea compounds described above are those in which x is 1, y is 0, and z is 1. In these compounds, X and Z can both be O, each of R 1 , R 2 , and R 3  can be H, or R 1  and R 2 , together with the nitrogen atom to which they are bonded, can be C 3 -C 20  heterocycloalkyl, A 1  can be phenylene, and A 2  can be heteroaryl, or aryl optionally substituted with halo, aryl, heteroaryl, CN, OR, COOR, or NRR′, in which each of R and R′ independently, is H, C 1 -C 10  alkyl, or aryl. Referring to formula (I), another subset of the thiourea compounds described above are those in which x is 1, y is 1, and z is 1. In these compounds, X and Z can both be O, Y can be C(R a R b ) (in which each of R a  and R b , independently, can be C 1 -C 10  alkyl), A 1  can be phenylene, A 2  can be phenyl optionally substituted with aryl, and each of R 1 , R 2 , and R 3  can be H.  
         [0008]     The term “alkyl” refers to a saturated, linear or branched, hydrocarbon moiety, such as —CH 3 , —CH(CH 3 ) 2 , or —CH 2 —. The term “alkenyl” refers to a linear or branched hydrocarbon moiety that contains at least one double bond, such as —CH═CH—CH 3  or —CH═CH—CH 2 —. The term “alkynyl” refers to a linear or branched hydrocarbon moiety that contains at least one triple bond, such as —C≡C—CH 3  or —C≡C—CH 2 —. The term “cycloalkyl” refers to a saturated, cyclic hydrocarbon moiety, such as cyclohexyl or cyclohexylene. The term “cycloalkenyl” refers to a non-aromatic, cyclic hydrocarbon moiety that contains at least one double bond, such as cyclohexenyl. The term “heterocycloalkyl” refers to a saturated, cyclic moiety having at least one ring heteroatom (e.g., N, O, or S), such as 4-tetrahydropyranyl or 4-tetrahydropyranylene. The term “heterocycloalkenyl” refers to a non-aromatic, cyclic moiety having at least one ring heteroatom (e.g., N, O, or S) and at least one double bond, such as pyranyl. The term “aryl” refers to a hydrocarbon, moiety having one or more aromatic rings. Examples of aryl moieties include phenyl (Ph), phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl 1. The term “heteroaryl” refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, or S). Examples of heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and indolyl.  
         [0009]     Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise. Possible substituents on cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl include, but are not limited to, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10 , alkynyl, C 3 -C 20  cycloalkyl, C 3 -C 20  cycloalkenyl, C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl, C 1 -C 10  alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10  alkylamino, C 1 -C 20  dialkylamino, arylamino, diarylamino, hydroxyl, halo, thio, C 1 -C 10  alkylthio, arylthio, C 1 -C 10  alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl, alkenyl, or alkynyl include all of the above-recited substituents except C 1 -C 10  alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other.  
         [0010]     In another aspect, this invention features thiourea compounds of formula (I), in which R 1  is H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20  cycloalkyl, C 3 -C 20  cycloalkenyl, C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl, aryl, or heteroaryl; each of R 2  and R 3 , independently, is C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20  cycloalkenyl, C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl, aryl, or heteroaryl; or R 2  and R 3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are C 3 -C 20 heterocycloalkyl; each of A 1  and A 2 , independently, is aryl or heteroaryl; each of X, Y, and Z, independently, is O, S, S(O), S(O) 2 , N(R a ), C(R a R b ), C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20  cycloalkyl, C 1 -C 10  heterocycloalkyl, aryl, or heteroaryl, in which each of R a  and R b , independently, is H, C 1 -C 10  alkyl, C 3 -C 20  cycloalkyl, C 1 -C 20  heterocycloalkyl, aryl, or heteroaryl; each of m and n, independently, is 0, 1, 2, 3, 4, or 5; and each of x, y, and z, independently, is 0 or 1.  
         [0011]     Referring to formula (I), a subset of the thiourea compounds described above are those in which x is 1, y is 0, and z is 0. In these compounds, X can be O, A 1  can be phenylene, A 2  can be phenyl, R 1  can be H or C 1 -C 10  alkyl optionally substituted with aryl, and R 2  and R 3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, can be C 3 -C 20  heterocycloalkyl;  
         [0012]     In another aspect, this invention relates to thiourea compounds of formula (II):  
                         
 
 wherein X is O, N(R a ), C(R a R b ), or C(O); each of R 1 , R 2 , and R 3 , independently, is H, C 1 -C 10  alkyl C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20  cycloalkyl, C 3 -C 20  cycloalkenyl C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl, aryl, or heteroaryl; or R 2  and R 3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are C 3 -C 20  heterocycloalkyl; and each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  independently, is H, C 1 -C 10  alkyl C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 20 cycloalkyl C 3 -C 20  cycloalkenyl, C 1 -C 20  heterocycloalkyl, C 1 -C 20  heterocycloalkenyl aryl, heteroaryl halo, N(R c R d), N(R   c )—C(S)—N(R d R e ); N(R c )—C(O)R d , or N(R e )—C(O)O—R d ; in which each of R a , R b , R c , R d , and R e , independently, is H, C 1 -C 10  alkyl C 3 -C 20 cycloalkyl, C 1 -C 20  heterocycloalkyl, aryl, or heteroaryl; provided that if R 10  is at the 3-position, then  
                         
 
 is at the 4-position; and if R 10  is at the 4-position, then  
                         
 
 is at the 3-position. The 3- and 4-positions of the above formula are delineated below:  
                         
 
         [0013]     An embodiment of the just-described compounds features the following formula:  
                         
 
 wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are as just defined. 
 
         [0014]     Referring the above formula, a subset of the thiourea compounds described above are those in which each of R 1 , R 2 , and R 3 , independently, is H, aryl optionally substituted with C 1 -C 20  heterocycloalkyl, heteroaryl, or C 1 -C 10  alkyl optionally substituted with C 1 -C 10  alkoxy, aryl, N(RR′), in which each of R and R′, independently, is H or C 1 -C 10  alkyl. In these compounds, each of R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, can be H, halo, N(R c R d ), N(R c )—C(S)—N(R d R e ); N(R c )—C(O)R d , or N(R c )—C(O)O—R d . For example, each of R 4 , R 5 , R 7 , R 8 , and R 9  can be H and R 6 , can be H, halo, N(R c R d ), N(R c )—C(S)—N(R d R e ), N(R c )—C(O)R d , or N(R c )—C(O)O—R d .  
         [0015]     Another subset of the thiourea compounds described above are those in which each of R 1 , R 2 , and R 3  is H; or R 1  is (CH 2 ) n CH 3 , in which n is 1, 2, 3, 4, 5, or 6, and each of R 2  and R 3  is H.  
         [0016]     In still another aspect, this invention features a method for treating hepatitis C virus infection. The method includes administering to a subject in need thereof an effective amount of one or more thiourea compounds of formula (I) or (II) shown above. The term “treating” or “treatment” refers to administering one or more thiourea compounds to a subject, who has an above-described infection, a symptom of such an infection, or a predisposition, toward such an infection, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the above-described infection, the symptom of it, or the predisposition toward it.  
         [0017]     In addition, this invention encompasses a pharmaceutical composition that contains an effective amount of at least one of the above-mentioned thiourea compounds and a pharmaceutically acceptable carrier.  
         [0018]     The thiourea compounds described above include the compounds themselves, as well as their salts, prodrugs, and solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a thiourea compound. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a thiourea compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The thiourea compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active thiourea compounds. A solvate refers to a complex formed between, an active thiourea compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.  
         [0019]     Also within the scope of this invention is a pharmaceutical composition containing one or more of the above-described thiourea compounds for use in treating HCV infection, as well as this therapeutic use and use of the compounds for the manufacture of a medicament for treating HCV infection.  
         [0020]     The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.  
     
    
     DETAILED DESCRIPTION  
       [0021]     The table below show 183 exemplary compounds of this invention:  
                                             TABLE 1                                   Molec-       Com-           ular       pound           Weight       No.   Structure   Name   (M + 1)                                                    1                                 [3-(3-Phenyl-propoxy)- phenyl]-thiourea   287               2                                 [3-(4-Phenyl-butoxy)- phenyl]-thiuorea   301               3                                 [3-(5-Phenyl- pentyloxy)-phenyl]- thiourea   315               4                                 [3-(6-Phenyl- hexyloxy)-phenyl]- thiourea   329               5                                 [3-(7-Phenyl- heptyloxy)-phenyl]- thiourea   343               6                                 [3-(8-Phenyl- octyloxy)-phenyl]- thiourea   357               7                                 {3-[5-(4-Bromo- phenoxy)-pentyloxy]- phenyl}-thiourea   409 411               8                                 4-[5-(3-Thioureido- phenoxy)-pentyloxy]- benzoic acid ethyl ester   403               9                                 [3-(5-Phenoxy- pentyloxy)-phenyl]- thiourea   331               10                                 [3-(3-Methyl-5- phenoxy-pentyloxy)- phenyl]-thiourea   345               11                                 [3-(3,3-Dimethyl-5- phenoxy-pentyloxy)- phenyl]-thiourea   359               12                                 {3-[5-(Biphenyl-4- yloxy)-pentyloxy]- phenyl}-thiourea   407               13                                 {3-[5-(Biphenyl-4- yloxy)-3-methyl- pentyloxy]-phenyl}- thiourea   421               14                                 {3-[5-(Biphenyl-4- yloxy)-3,3-dimethyl- pentyloxy]-phenyl}- thiourea   435               15                                 [3-(3-Phenyl- propylamino)-phenyl]- thiourea   286               16                                 [3-(4-Phenyl- butylamino)-phenyl]- thiourea   300               17                                 [3-(5-Phenyl- pentylamino)-phenyl]- thiourea   314               18                                 [3-(6-Phenyl- hexylamino)-phenyl]- thiourea   328               19                                 [3-(7-Phenyl- heptylamino)-phenyl]- thiourea   342               20                                 [3-(8-Phenyl- octylamino)-phenyl]- thiourea   356               21                                 1-Methyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   329               22                                 1-Ethyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   343               23                                 1-[3-(5-Phenyl- pentyloxy)-phenyl]-3- propyl-thiourea   357               24                                 1-Butyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   371               25                                 1-Pentyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   385               26                                 1-Hexyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   399               27                                 1-Heptyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   413               28                                 1-Octyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   427               29                                 1-Phenethyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-thiourea   419               30                                 1-[3-(5-Phenyl- pentyloxy)-phenyl]-3- (3-phenyl-propyl)- thiourea   433               31                                 1-(4-Phenyl-butyl)-3- [3-(5-phenyl- pentyloxy)-phenyl]- thiourea   447               32                                 (2-Methoxy- dibenzofuran-3-yl)- thiourea   273               33                                 (9-Ethyl-9H-carbazol- 3-yl)-thiourea   270               34                                 (9-Oxo-9H-fluoren-2- yl)-thiourea   255               35                                 (7-Bromo-9-oxo-9H- fluoren-2-yl)-thiourea   332 334               36                                 (9-Oxo-9H-fluoren-3- yl)-thiourea   255               37                                 (9H-Fluoren-2-yl)- thiourea   241               38                                 (7-Bromo-9H-fluoren- 2-yl)-thiourea   320               39                                 (7-Dimethylamino-9H- fluoren-2-yl)-thiourea   284               40                                 (7-Diethylamino-9H- fluoren-2-yl)-thiourea   312               41                                 (7-Dipropylamino-9H- fluoren-2-yl)-thiourea   340               42                                 (7-Dibutylamino-9H- fluoren-2-yl)-thiourea   368               43                                 (7-Methylamino-9H- fluoren-2-yl)-thiourea   270               44                                 (7-Ethylamino-9H- fluoren-2-yl)-thiourea   284               45                                 (7-Propylamino-9H- fluoren-2-yl)-thiourea   298               46                                 (7-Butylamino-9H- fluoren-2-yl)-thiourea   312               47                                 [7-(3-Phenyl- propylamino)-9H- fluoren-2-yl]-thiourea   374               48                                 {7-[Bis(3-phenyl- propyl)-amino]-9H- fluoren-2-yl}-thiourea   492               49                                 (7-Amino-9H-fluoren- 2-yl)-thiourea   256               50                                 (7-Thioureido-9H- fluoren-2-yl)-thiourea   315               51                                 1-(7-Bromo-9H- fluoren-2-yl)-3-methyl- thiourea   333 335               52                                 1-(7-Bromo-9H- fluoren-2-yl)-3-ethyl- thiourea   347 349               53                                 1-(7-Bromo-9H- fluoren-2-yl)-3-propyl- thiuorea   361 363               54                                 1-(7-Bromo-9H- fluoren-2-yl)-3-butyl- thiuorea   375 377               55                                 1-(7-Bromo-9H- fluoren-2-yl)-3-pentyl- thiuorea   389 391               56                                 1-(7-Bromo-9H- fluoren-2-yl)-3-hexyl- thiuorea   403 405               57                                 1-(7-Bromo-9H- fluoren-2-yl)-3-heptyl- thiuorea   417 419               58                                 1-(7-Bromo-9H- fluoren-2-yl)-3-octyl- thiuorea   431 433               59                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(3- methoxy-propyl)- thiourea   391 393               60                                 1-(7-Bromo-9H- fluoren-2-yl)-3- isobutyl-thiourea   375 377               61                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(2- dimethylamino-ethyl)- thiuorea   390 392               62                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(2- diethylamino-ethyl)- thiuorea   418 420               63                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(2- dimethylamino- propyl)-thiourea   404 406               64                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(3- phenethyl-thiourea   423 425               65                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(3- phenyl-propyl)- thiuorea   437 439               66                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(4- phenyl-butyl)-thiourea   451 453               67                                 1-Benzyl-3-(7-bromo- 9H-fluoren-2-yl)- thiourea   430 432               68                                 1-(7-Bromo-9H- fluoren-2-yl)-3-phenyl- thiuorea   394 396               69                                 1-(7-Bromo-9H- fluoren-2-yl)-3- pyridin-3-yl-thiourea   395 397               70                                 1-(7-Bromo-9H- fluoren-2-yl)-3-(4- morpholin-4-yl- phenyl)-thiourea   480 482               71                                 1-(7-Bromo-9H- fluoren-2-yl)-3- naphthalen-1-yl- thiourea   445 447               72                                 N-(7-Thioureido-9H- fluoren-2-yl)- butyramide   326               73                                 Cyclohexanecarboxylic acid (7-thioureido-9H- fluoren-2-yl)-amide   366               74                                 Isoxazole-5-carboxylic acid (7-thioureido-9H- fluoren-2-yl)-amide   351               75                                 (7-Thioureido-9H- fluoren-2-yl)-carbamic acid tert-butyl ester   356               76                                 1-(3-Benzyloxy- phenyl)-imidazolidine- 2-thione   285               77                                 1-(3-Benzyloxy- phenyl)-3-butyl- imidazolidine-2-thione   341               78                                 1-(3-Benzyloxy- phenyl)-3-(3-phenyl- propyl)-imidazolidine- 2-thione   403               79                                 1-[3-(5-Phenyl- pentyloxy)-phenyl]- imidazolidine-2-thione   341               80                                 1-Butyl-3-[3-(5- phenyl-pentyloxy)- phenyl]-imidazolidine- 2-thione   397               81                                 1-[3-(5-Phenyl- pentyloxy)-phenyl]-3- (3-phenyl-propyl)- imidazolidine-2-thione   459               82                                 {3-[5-(2,6-Dichloro- phenoxy)-pentyloxy]- phenyl}-thiourea   400               83                                 {3-[5-(4-Fluoro- phenoxy)-pentyloxy]- phenyl}-thiourea   349               84                                 {3-[5-(2-Chloro-4- methoxy-phenoxy)- pentyloxy]-phenyl}- thiourea   395               85                                 {3-[5-(4-Chloro- phenoxy)-pentyloxy]- phenyl}-thiourea   365               86                                 {3-[5-(2,4-Difluoro- phenoxy)-pentyloxy]- phenyl}-thiourea   367               87                                 {3-[5-(2,6-Dichloro-4- fluoro-phenoxy)- pentyloxy]-phenyl}- thiourea   418               88                                 {3-[5-(Pyridin-4- yloxy)-pentyloxy]- phenyl}-thiourea   332               89                                 {3-[5-(Pyridin-3- yloxy)-pentyloxy]- phenyl}-thiourea   332               90                                 {3-[5-(Pyrimidin-4- yloxy)-pentyloxy]- phenyl}-thiourea   333               91                                 4-[5-(3-Thioureido- phenoxy)-pentyloxy]- benzoic acid   375               92                                 {3-[5-(4- Dimethylamino- phenoxy)-pentyloxy]- phenyl}-thiourea   374               93                                 {3-[5-(4-Diethylamino- phenoxy)-pentyloxy]- phenyl}-thiourea   402               94                                 {3-[5-(4-Morpholin-4- yl-phenoxy)- pentyloxy]-phenyl}- thiourea   416               95                                 {3-[5-(4-Piperidin-1- yl-phenoxy)- pentyloxy]-phenyl}- thiourea   414               96                                 (3-{5-[4-(4-Methyl- piperazin-1-yl)- phenoxy]-pentyloxy}- phenyl)-thiourea   429               97                                 {3-[5-(2-Methoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   361               98                                 {3-[5-(3-Methoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   361               99                                 {3-[5-(3,4,5- Trimethoxy-phenoxy)- pentyloxy]-phenyl}- thiourea   421               100                                 {3-[5-(4-Pyrrolidin-1- yl-phenoxy)- pentyloxy]-phenyl}- thiourea   400               101                                 {3-[5-(4′-Methoxy- biphenyl-4-yloxy)- pentyloxy]-phenyl}- thiourea   437               102                                 {3-[5-(4′-Methyl- biphenyl-4-yloxy)- pentyloxy]-phenyl}- thiourea   421               103                                 {3-[5-(4′-Chloro- biphenyl-4-yloxy)- pentyloxy]-phenyl}- thiourea   441               104                                 {3-[5-(4′-Bromo- biphenyl-4-yloxy)- pentyloxy]-phenyl}- thiourea   485 487               105                                 {3-[5-(Naphthalen-1- yloxy)-pentyloxy]- phenyl}-thiourea   381               106                                 {3-[5-(Naphthalen-2- yloxy)-pentyloxy]- phenyl}-thiourea   381               107                                 {3-[5-(4-Thiophen-3- yl-phenoxy)- pentyloxy]-phenyl}- thiourea   413               108                                 {3-[5-(4-Cyano- phenoxy)-pentyloxy]- phenyl}-thiourea   356               109                                 {3-[5-(3-Cyano- phenoxy)-pentyloxy]- phenyl}-thiourea   356               110                                 {3-[5-(2-Cyano- phenoxy)-pentyloxy]- phenyl}-thiourea   356               111                                 {3-[5-(2,6-Dichloro-4- methyl-phenoxy)- pentyloxy]-phenyl}- thiourea   414               112                                 {3-[5-(4- Trifluoromethyl- phenoxy)-pentyloxy]- phenyl}-thiourea   399               113                                 [3-(3-Phenoxy- propoxy)-phenyl]- thiourea   303               114                                 [3-(4-Phenoxy- butoxy)-phenyl]- thiourea   317               115                                 [3-(6-Phenoxy- hexyloxy)-phenyl]- thiourea   345               116                                 [3-(7-Phenoxy- heptyloxy)-phenyl]- thiourea   359               117                                 {4-[3-(Biphenyl-4- yloxy)-propoxy]- phenyl}-thiourea   379               118                                 {3-[4-(Biphenyl-4- yloxy)-butoxy]- phenyl}-thiourea   393               119                                 {3-[6-(Biphenbyl-4- yloxy)-hexyloxy]- phenyl}-thiourea   421               120                                 {3-[7-(Biphenyl-4- yloxy)-heptyloxy]- phenyl}-thiourea   435               121                                 1,1-Dimethyl-3-[3-(5- phenoxy-pentyloxy)- phenyl]-thiourea   359               122                                 1,1-Diethyl-3-[3-(5- phenoxy-pentyloxy)- phenyl]-thiourea   387               123                                 Piperidine-1- carbothioic acid [3-(5- phenoxy-pentyloxy)- phenyl]-amide   399               124                                 Morpholine-4- carbothioic acid [3-(5- phenoxy-pentyloxy)- phenyl]-amide   401               125                                 4-Methyl-piperazine-1- carbothioic acid [3-(5- phenoxy-pentyloxy)- phenyl]-amide   414               126                                 {3-[5-(Quinolin-6- yloxy)-pentyloxy]- phenyl}-thiourea   382               127                                 {3-[5-(Quinolin-5- yloxy)-pentyloxy]- phenyl}-thiourea   382               128                                 {3-[5-(Quinolin-4- yloxy)-pentyloxy]- phenyl}-thiourea   382               129                                 {3-[5-(Isoquinolin-5- yloxy)-pentyloxy]- phenyl}-thiourea   382               130                                 {3-[5-(Quinolin-8- yloxy)-pentyloxy]- phenyl}-thiourea   382               131                                 {3-[5-(Isoquinolin-1- yloxy)-pentyloxy]- phenyl}-thiourea   382               132                                 {3-[5-(1H-Indol-4- yloxy)-pentyloxy]- phenyl}-thiourea   370               133                                 {3-[5-(4-Furan-2-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   397               134                                 {3-[5-(4-Furan-3-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   397               135                                 {3-[5-(4-Thiophen-2- yl-phenoxy)- pentyloxy]-phenyl}- thiourea   413               136                                 (3-{5-[4-(5-Chloro- thiophen-2-yl)- phenoxy]-pentyloxy}- phenyl)-thiourea   447               137                                 {3-[5-(4-Phenoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   423               138                                 {3-[5-(3-Phenoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   423               139                                 {3-[5-(Biphenyl-3- yloxy)-pentyloxy]- phenyl}-thiourea   407               140                                 {3-[5-(Biphenyl-2- yloxy)-pentyloxy]- phenyl}-thiourea   407               141                                 (7-Dibenzylamino-9H- fluoren-2-yl)-thiourea   436               142                                 (7-Benzylamino-9H- fluoren-2-yl)-thiuorea   346               143                                 {3-[5-(4-Methoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   361               144                                 {3-[5-(3,4-Dimethoxy- phenoxy)-pentyloxy]- phenyl}-thiourea   391               145                                 {3-[5-(Pyridin-2- yloxy)-pentyloxy]- phenyl}-thiourea   332               146                                 {3-[5-(4-Pyrrol-1-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   396               147                                 {3-[5-(4-Imidazol-1-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   397               148                                 {3-[5-(4- Thiomorpholin-4-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   432               149                                 {3-[7-(Naphthalen-1- yloxy)-heptyloxy]- phenyl}-thiourea   409               150                                 {3-[8-(Naphthalen-1- yloxy)-octyloxy]- phenyl}-thiourea   423               151                                 4-[5-(3-Thioureido- phenoxy)-pentyloxy]- benzoic acid phenyl ester   451               152                                 [4-(5-Phenyl- pentyloxy)-phenyl]- thiourea   315               153                                 2-[5-(3-Thioureido- phenoxy)-pentyloxy]- benzoic acid phenyl ester   451               154                                 [2-(5-Phenyl- pentyloxy)-phenyl]- thiourea   315               155                                 {3-[5-(3-Phenylamino- phenoxy)-pentyloxy]- phenyl}-thiourea   422               156                                 {3-[5-(3-Benzoyl- phenoxy)-pentyloxy]- phenyl}-thiourea   435               157                                 (3-{5-[3-(Hydroxy- phenyl-methyl)- phenoxy]-pentyloxy}- phenyl)-thiourea   437               158                                 {3-[5-(4-Benzyl- phenoxy)-pentyloxy]- phenyl}-thiourea   421               159                                 {3-[3-(Naphthalen-1- yloxy)-propoxy]- phenyl}-thiourea   353               160                                 {3-[4-(Naphthalen-1- yloxy)-butoxy]- phenyl}-thiourea   367               161                                 [4-(5-Phenoxy- pentyloxy)-phenyl]- thiourea   331               162                                 {3-[5-(4-Methoxy- naphthalen-1-yloxy)- pentyloxy]-phenyl}- thiourea   411               163                                 {3-[6-(Naphthalen-1- yloxy)-hexyloxy]- phenyl}-thiourea   395               164                                 [3-(5-Naphthalen-1-yl- pentyloxy)-phenyl]- thiourea   365               165                                 {3-[5-(4-Chloro- naphthalen-1-yloxy)- pentyloxy]-phenyl}- thiourea   415               166                                 {3-[5-(2-Methyl- naphthalen-1-yloxy)- pentyloxy]-phenyl}- thiourea   395               167                                 {3-[5-(3-Benzyl- phenoxy)-pentyloxy]- phenyl}-thiourea   421               168                                 {3-[5-(4′-Chloro- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   441               169                                 {3-[3-(Biphenyl-2- yloxy)-propoxy]- phenyl}-thiourea   379               170                                 {3-[4-(Biphenyl-2- yloxy)-butoxy]- phenyl}-thiourea   393               171                                 [3-(6-Naphthalen-1-yl- hexyloxy)-phenyl]- thiourea   379               172                                 {4-[5-(2,4-Dichloro- phenoxy)-pentyloxy]- phenyl}-thiourea   340               173                                 {4-[5-(2,4-Difluoro- phenoxy)-pentyloxy]- phenyl}-thiourea   367               174                                 {3-[5-(4′-Fluoro- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   425               175                                 {3-[5-(4′- Trifluoromethyl- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   475               176                                 {3-[5-(4′-Methoxy- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   437               177                                 {3-[5-(4′-Methyl- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   421               178                                 {3-[5-(3′-Methyl- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   421               179                                 {3-[5-(3′,5′-Difluoro- biphenyl-2-yloxy)- pentyloxy]-phenyl}- thiourea   443               180                                 {3-[5-(Naphthalen-1- ylamino)-pentyloxy]- phenyl}-thiourea   380               181                                 {3-[5-(2-Cyclohexyl- phenoxy)-pentyloxy]- phenyl}-thiourea   413               182                                 {3-[5-(4-Cyclohexyl- phenoxy)-pentyloxy]- phenyl}-thiourea   413               183                                 {3-[5-(2-Furan-2-yl- phenoxy)-pentyloxy]- phenyl}-thiourea   397                  
 
         [0022]     The thiourea compounds described above can be prepared by methods well known in the art, Examples 1-183 below provide detailed descriptions of the preparation of compounds 1-183.  
         [0023]     Scheme I shown below depicts a typical route for synthesizing certain compounds of the invention. Specifically, 3-nitrophenol can first react, with a brominated aromatic compound via a substitution reaction to form an alkoxy-containing compound. The alkoxy-containing compound can then be reduced, (e.g., by hydrogen or tin chloride) to convert the nitro group to an amino group. The compound thus formed can then be treated with thiocarbonyl diimidazole (TCDI) and a base (e.g., ammonia) to form a compound of the invention (e.g., compounds 1-14, 21-31, 82-140, and 143-183).  
                         
 
         [0024]     Certain other compounds of the invention can be prepared from benzene-1,3-diamine. For example, as shown in Scheme II below, one of the amino groups on benzene-1,3-diamine can be first protected with a tert-butyloxycarbonyl (BOC) protecting group. The other amino group on benzene-1,3-diamine can then react with a brominated aromatic compound. The compound thus formed can subsequently be deprotected and then treated with thiocarbonyl diimidazole and a base to form compounds of the invention such as compounds 15-20.  
                         
 
         [0025]     Certain other compounds of the invention can be prepared from a monoamine aromatic compound. For example, as shown in Scheme III below, a monoamino aromatic compound can react with thiocarbonyl diimidazole, followed by ammonia or a primary amine, to form a compound of the invention (e.g., compounds 32-38 and 50-71).  
                         
 
         [0026]     Certain other compounds of the invention can be prepared from a diamine aromatic compound. For example, as shown in Scheme IV below, one amino group on 9H-fluorene-2,7-diamine can first be protected with a BOC protecting group. The other amino group 9H-fluorene-2,7-diamine can then react with a halo-containing compound to form either a compound containing a secondary amino group or a compound containing a tertiary amino group. The compound thus formed can be deprotected (e.g., by reacting with trifluoroacetic acid) and then treated with thiocarbonyl diimidazole and a base to form a compound of the invention (e.g., compounds 39-48, 72-75, 141, and 142).  
                         
 
         [0027]     Certain other compounds of the invention containing an imidazolidinyl ring can be prepared by the method shown in Scheme V. Specifically, an amino-containing compound can first react with 1-chloro-2-isothiocyanatoethane to form a chlorine-containing thiourea compound. The thiourea compound can then react with a base (e.g., triethylamine) to form a compound of the invention containing an imidazolidinyl ring (e.g., compounds 76 and 79). The compound thus formed can optionally react with a halo-containing compound to form another compound of the invention (e.g., compounds 77, 78, 80, and 81).  
                         
 
         [0028]     A thiourea compound synthesized above can be purified by a suitable method such as column chromatography, high-pressure liquid chromatography, or recrystallization.  
         [0029]     Other thiourea compounds can be prepared using other suitable starting materials through the above synthetic routes and others known in the art. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the thiourea compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable thiourea compounds are known in the art and include, for example, those described in R. Larock,  Comprehensive Organic Transformations , VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,  Protective Groups in Organic Synthesis,  2 nd  Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser,  Fieser and Fieser&#39;s Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed.,  Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions thereof.  
         [0030]     The thiourea compounds mentioned herein may contain a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans-isomeric forms. All such isomeric forms are contemplated.  
         [0031]     Also within the scope of this invention is a pharmaceutical composition containing an effective amount, of at least one thiourea compound described above and a pharmaceutical acceptable carrier. Further, this invention covers a method of administering an effective amount of one or more of the thiourea compounds to a patient having hepatitis C virus infection, “An effective amount” refers to the amount of an active thiourea compound that is required to confer a therapeutic effect on the treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.  
         [0032]     To practice the method of the present invention, a composition having one or more thiourea compounds can be administered parenterally, orally, nasally, rectally, topically, or buccally. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.  
         [0033]     A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water. Ringer&#39;s solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.  
         [0034]     A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.  
         [0035]     A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation, for example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.  
         [0036]     A composition having one or more active thiourea compounds can also be administered in the form of suppositories for rectal administration.  
         [0037]     The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active thiourea compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&amp;C Yellow #10.  
         [0038]     The thiourea compounds described above can be preliminarily screened for their efficacy in treating hepatitis C virus infection by an in vitro assay (See Examples 141 and 142 below) and then confirmed by animal experiments and clinic trials. Other methods will also be apparent to those of ordinary skill in the art.  
         [0039]     The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.  
       EXAMPLE 1  
     Preparation, of Compound 1: 1-(3-(5-phenylpentyloxy)phenyl)thiourea  
       [0040]    
       
                 
         
             
             
         
       
     
         [0041]     Potassium carbonate (1.2 g, 8.7 mmol) was added to a stirred suspension of 3-nitrophenol (0.8 g, 5.8 mmol), (5-bromo-pentyl)-benzene (1.32 g, 5.8 mmol), and potassium iodide (0.96 g, 5.8 mmol) in N-methylpyrolidinone (15 mL). The mixture was stirred at 90° C. for 4 hours. After the reaction mixture was cooled to the room temperature, it was quenched with water (30 mL) followed, by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give 1-nitro-3-(5-phenylpentoxy)benzene (1.4 g, 4.93 mmol, yield: 85%) as colorless oil.  
         [0042]     Tin (II) chloride (5.57 g, 24.7 mmol) was added to a solution of 1-nitro-3-(5-phenylpentoxy)benzene (1.4 g, 4.93 mmol) in 35 mL ethanol. The reaction mixture was stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution (50 mL) was added. The resultant mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO 4 , and concentrated to give a crude product as a white solid. The crude product was purified by silica gel column chromatography eluting with ethyl acetate-n-hexane to give 3-(5-phenyl-pentyloxy)-phenylamine (1.03 g, 4.04 mmol, yield: 82%) as a white solid.  
         [0043]     A solution of 3-(5-phenyl-pentyloxy)phenylamine (200 mg, 1.02 mmol) and thiocarbonyl diimidazole (TCDI, 1.90 mg, 1.06 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. After a 25% aqueous ammonia solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was removed and then the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give [3-(5-phenyl-pentyloxy)-phenyl]-thiourea (compound 1) (273 mg, (0.87 mmol, yield: 85%) as a white solid.  
         [0044]     EI-MS (M+1): 315.  
       EXAMPLE 2  
     Preparation of Compound 2: 1-(3-(4-phenylbutoxy)phenyl)thiourea  
       [0045]     Compound 2 was prepared in a manner similar to that described in Example 1.  
         [0046]     EI-MS (M+1): 301.  
       EXAMPLE 3  
     Preparation of Compound 3: 1-(3-(3-phenylpropoxy)phenyl)thiourea  
       [0047]     Compound 3 was prepared in a manner similar to that described in Example 1.  
         [0048]     EI-MS (M+1): 287.  
       EXAMPLE 4  
     Preparation of Compound 4: 1-(3-(6-phenylhexyloxy)phenyl)thiourea  
       [0049]     Compound 4 was prepared in a manner similar to that described in Example 1.  
         [0050]     EI-MS (M+1): 329.  
       EXAMPLE 5  
     Preparation of Compound 5: 1-(3-(7-phenylheptyloxy)phenyl)thiourea  
       [0051]     Compound 5 was prepared in a manner similar to that described in Example 1.  
         [0052]     EI-MS (M+1): 343.  
       EXAMPLE 6  
     Preparation of Compound 6: 1-(3-(8-phenyloctyloxy)phenyl)thiourea  
       [0053]     Compound 6 was prepared in a manner similar to that described in Example 1.  
         [0054]     EI-MS (M+1): 357.  
       EXAMPLE 7  
     Preparation of Compound 7: 1-(3-(5-phenoxypentyloxy)phenyl)thiourea  
       [0055]    
       
                 
         
             
             
         
       
     
         [0056]     Potassium carbonate (10.35 g, 75.0 mmol) was added to a stirred suspension of phenol (4.7 g, 50.0 mmol), 1,5-dibromopentane (12.65 g, 55.0 mmol), and potassium iodide (0.83 g, 5.0 mmol) m N-methylpyrrolidinone (100 mL). The reaction mixture was stirred at 90° C. for 4 hours. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give (5-bromopentyloxy)benzene (12.0 g, 49.38 mmol, yield: 98%) as yellow oil.  
         [0057]     Potassium carbonate (10.35 g, 75.0 mmol) was added to a stirred suspension of (5-bromopentyloxy)benzene (12.0 g, 49.38 mmol), 3-nitrophenol (6.95 g, 50.0 mmol), and potassium iodide (0.83 g, 5.0 mmol) in N-methylpyrolidinone (100 mL). The reaction mixture was stirred at 90° C. for 4 hours. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 ml×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give 1-nitro-3-(5-phenoxypentoxy)benzene (11.89 g, 39.5 mmol, yield: 80%) as colorless oil.  
         [0058]     Tin (II) chloride (19.78 g, 87.89 mmol) was added to a solution of 1-nitro-3-(5-phenoxypentoxy)benzene (5.29 g, 17.58 mmol) in 100 mL ethanol. The reaction mixture was stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution (50 mL) was added. The solution was extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with brine, dried over anhydrous MgSO 4 , and concentrated to give a crude product as a white solid. The crude product was purified by silica gel column chromatography eluting with ethyl acetate-n-hexane to give 3-(5-phenoxy-pentyloxy)-phenylamine (4.67 g, 17.22 mmol, yield: 98%) as a light yellow solid.  
         [0059]     A solution of 3-(5-phenoxy-pentyloxy)phenylamine (200 mg, 0.74 mmol) and thiocarbonyl diimidazole (TCDI, 158 mg, 0.89 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. After a 25% ammonia aqueous solution (2 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give [3-(5-phenoxy-pentyloxy)-phenyl]-thiourea (compound 7) (126 mg, 0.38 mmol, yield: 52%) as a white solid.  
         [0060]     EI-MS (M+1): 331.  
       EXAMPLE 8  
     Preparation of Compound 8: ethyl 4-(5-(3-thioureidophenoxy)pentyloxy)-benzoate  
       [0061]     Compound 8 was prepared in a manner similar to that described in Example 7.  
         [0062]     EI-MS (M+1): 403.  
       EXAMPLE 9  
     Preparation of Compound 9: 1-(3-(5-(4-bromophenoxy)pentyloxy)phenyl)-thiourea  
       [0063]     Compound 9 was prepared in a manner similar to that described in Example 7.  
         [0064]     EI-MS (M+1): 409, 411.  
       EXAMPLE 10  
     Preparation of Compound 10: 1-(3-(3-methyl-5-phenoxypentyloxy)phenyl)-thiourea  
       [0065]     Compound 10 was prepared in a manner similar to that described in Example 7.  
         [0066]     EI-MS (M+1): 345.  
       EXAMPLE 11  
     Preparation of Compound 11: 1-(3-(3,3-dimethyl-5-phenoxypentyloxy)-phenyl)thiourea  
       [0067]     Compound 11 was prepared in a manner similar to that described in Example 7.  
         [0068]     EI-MS (M+1): 359.  
       EXAMPLE 12  
     Preparation of Compound 12: 1-(3-(5-(biphenyl-4-yloxy)pentyloxy)phenyl)-thiourea  
       [0069]     Compound 12 was prepared in a manner similar to that described in Example 7.  
         [0070]     EI-MS (M+1): 407.  
       EXAMPLE 13  
     Preparation of Compound 13: 1-(3-(5-(biphenyl-4-yloxy)-3-methylpentyl-oxy)phenyl) thiourea  
       [0071]     Compound 13 was prepared in a manner similar to that described in Example 7.  
         [0072]     EI-MS (M+1): 421.  
       EXAMPLE 14  
     Preparation of Compound 14: 1-(3-(5-(biphenyl-4-yloxy)-3,3-dimethyl-pentyloxy)phenyl)thiourea  
       [0073]     Compound 14 was prepared in a manner similar to that described in Example 7.  
         [0074]     EI-MS (M+1): 435.  
       EXAMPLE 15  
     Preparation of Compound 15: 1-(3-(5-phenylpentylamino)phenyl)thiourea  
       [0075]    
       
                 
         
             
             
         
       
     
         [0076]     (BOC) 2 O (10.1 g, 46.3 mmol) was added to a solution of benzene-1,3-diamine (5.0 g, 46.3 mmol) in dichloromethane (80 mL). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was quenched with, water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give (3-aminophenyl)-carbamic acid tert-butyl ester (4.34 g, 20.8 mmol, yield: 45%) as a white solid.  
         [0077]     Potassium carbonate (0.6 g, 4.35 mmol) was added to a stirred suspension of (3-amino-phenyl)-carbamic acid tert-butyl ester (0.6 g, 2.9 mmol), (5-bromo-pentyl)benzene (0.66 g, 2.9 mmol), and potassium iodide (0.48 g, 2.9 mmol) in N-methylpyrolidinone (14 mL). The reaction mixture was stirred at 90° C. for 4 hours. It was quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give [3-(5-phenyl-pentylamino)-phenyl]-carbamic acid tert-butyl ester (802 mg, 2.26 mmol, yield: 78%) as yellow oil.  
         [0078]     Trifluoroacetic acid (TFA, 2.0 mL, 26.3 mmol) was added to a solution of [3-(5-phenyl-pentylamino)-phenyl]-carbamic acid tert-butyl ester (802 mg, 2.26 mmol) in 10 mL dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give N-(5-phenyl-pentyl)-benzene-1,3-diamine (529 mg, 2.08 mmol, yield: 92%) as light yellow solid.  
         [0079]     A solution of N-(5-phenyl-pentyl)-benzene-1,3-diamine (89 mg, 0.4 mmol) and thiocarbonyl diimidazole (TCDI, 74 mg, 0.42 mmol) in dichloromethane (4 mL) was stirred at room temperature for 2 hours. After a 25% aqueous ammonia solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give [3-(5-phenylpentylamino)-phenyl]-4-thiourea (compound 17) (113 mg, 0.36 mmol, yield: 90%) as a white solid.  
         [0080]     EI-MS (M+1): 314.  
       EXAMPLE 16  
     Preparation of Compound 16: 1-(3-(4-phenylbutylamino)phenyl)thiourea  
       [0081]     Compound 16 was prepared in a manner similar to that described in Example 15.  
         [0082]     EI-MS (M+1): 300.  
       EXAMPLE 17  
     Preparation of Compound 17: 1-(3-(3-phenylpropylamino)phenyl)thiourea  
       [0083]     Compound 17 was prepared in a manner similar to that described in Example 15.  
         [0084]     EI-MS (M+1): 286.  
       EXAMPLE 18  
     Preparation of Compound 18: 1-(3-(6-phenylhexylamino)phenyl)thiourea  
       [0085]     Compound 18 was prepared in a manner similar to that described in Example 15.  
         [0086]     EI-MS (M+1): 328.  
       EXAMPLE 19  
     Preparation of Compound 19: 1-(3-(7-phenylheptylamino)phenyl)thiourea  
       [0087]     Compound 19 was prepared in a manner similar to that described in Example 15.  
         [0088]     EI-MS (M+1): 342.  
       EXAMPLE 20  
     Preparation of Compound 20: 1-(3-(8-phenyloctylamino)phenyl)thiourea  
       [0089]     Compound 20 was prepared in a manner similar to that described in Example 15.  
         [0090]     EI-MS (M+1): 356.  
       EXAMPLE 21  
     Preparation of Compound 21: 1-methyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0091]     Compound 21 was prepared in a manner similar to that described in Example 1.  
         [0092]     EI-MS (M+1): 329.  
       EXAMPLE 22  
     Preparation of Compound 22: ethyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0093]     Compound 22 was prepared in a manner similar to that described in Example 1.  
         [0094]     EI-MS (M+1): 343.  
       EXAMPLE 23  
     Preparation of Compound 23: 1-(3-(5-phenylpentyloxy)phenyl)-3-propyl-thiourea  
       [0095]     Compound 23 was prepared in a manner similar to that described in Example 1.  
         [0096]     EI-MS (M+1): 357.  
       EXAMPLE 24  
     Preparation of Compound 24: 1-butyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0097]     Compound 24 was prepared in a manner similar to that described in Example 1.  
         [0098]     EI-MS (M+1): 371.  
       EXAMPLE 25  
     Preparation of Compound 25: 1-pentyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0099]     Compound 25 was prepared in a manner similar to that described in Example 1.  
         [0100]     EI-MS (M+1): 385.  
       EXAMPLE 26  
     Preparation of Compound 26: 1-hexyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0101]     Compound 26 was prepared in a manner similar to that described in Example 1.  
         [0102]     EI-MS (M+1): 399.  
       EXAMPLE 27  
     Preparation of Compound 27: 1-heptyl-3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0103]     Compound 27 was prepared in a manner similar to that described in Example 1.  
         [0104]     EI-MS (M+1): 413.  
       EXAMPLE 28  
     Preparation of Compound 28: 1-octyl-(3-(3-(5-phenylpentyloxy)phenyl)-thiourea  
       [0105]     Compound 28 was prepared in a manner similar to that described in Example 1.  
         [0106]     EI-MS (M+1): 427.  
       EXAMPLE 29  
     Preparation of Compound 29: 1-phenethyl-3-(3-(5-phenylpentyloxy)-phenyl)thiourea  
       [0107]     Compound 29 was prepared in a manner similar to that described in Example 1.  
         [0108]     EI-MS (M+1): 419.  
       EXAMPLE 30  
     Preparation of Compound 30: 1-(3-(5-phenylpentyloxy)phenyl)-3-(3-phenylpropyl)thiourea  
       [0109]     Compound 30 was prepared in a manner similar to that described in Example 1.  
         [0110]     EI-MS (M+1): 433.  
       EXAMPLE 31  
     Preparation of Compound 31: 1-(4-phenylbutyl)-3-(3-(5-phenylpentyloxy)phenyl)thiourea  
       [0111]     Compound 31 was prepared in a manner similar to that described in Example 1.  
         [0112]     EI-MS (M+1): 447.  
       EXAMPLE 32  
     Preparation of Compound 32: 1-(7-bromo-9H-fluoren-2-yl)thiourea  
       [0113]    
       
                 
         
             
             
         
       
     
         [0114]     A solution of 7-bromo-9H-fluoren-2-ylamine (0.3 g, 1.0 mmol) and thiocarbonyl diimidazole (TCDI, 0.2 g, 1.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. After a 25% aqueous ammonia solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give (7-bromo-9H-fluoren-2-yl)-thiourea (compound 32) (297 mg, 0.93 mmol, yield 93%) as a white solid.  
         [0115]     EI-MS (M+1): 320.  
       EXAMPLE 33  
     Preparation of Compound 33: 1-(9-ethyl-9H-carbazol-3-yl)thiourea  
       [0116]     Compound 33 was prepared in a manner similar to that described in Example 32.  
         [0117]     EI-MS (M+1): 270.  
       EXAMPLE 34  
     Preparation of Compound 34: 1-(9-oxo-9H-fluoren-2-yl)thiourea  
       [0118]     Compound 34 was prepared in a manner similar to that described in Example 32.  
         [0119]     EI-MS (M+1): 255.  
       EXAMPLE 35  
     Preparation of Compound 35: 1-(7-bromo-9-oxo-9H-fluoren-2-yl)thiourea  
       [0120]     Compound 35 was prepared in a manner similar to that described in Example 32.  
         [0121]     EI-MS (M+1): 332, 334.  
       EXAMPLE 36  
     Preparation of Compound 36: 1-(9-oxo-9H-fluoren-3-yl)thiourea  
       [0122]     Compound 36 was prepared in a manner similar to that described in Example 32.  
         [0123]     EI-MS (M+1): 255.  
       EXAMPLE 37  
     Preparation of Compound 37: 1-(9H-fluoren-2-yl)thiourea  
       [0124]     Compound 37 was prepared in a manner similar to that described in Example 32.  
         [0125]     EI-MS (M+1): 241.  
       EXAMPLE 38  
     Preparation of Compound 38: 1-(2-methoxydibenzo[b,d]furan-3-yl)thiourea  
       [0126]     Compound 38 was prepared in a manner similar to that described in Example 32.  
         [0127]     EI-MS (M+1): 273.  
       EXAMPLE 39  
     Preparation of Compound 39: 1 (7-(dipropylamino)-9H-fluoren-2-yl)thiourea  
       [0128]    
       
                 
         
             
             
         
       
     
         [0129]     Sodium carbonate (1.06 g, 10.0 mmol) was added to a solution of 9H-fluorene-2,7-diamine (1.0 g, 5.0 mmol) and (BOC) 2 O (1.4 mL, 7.5 mmol) in 1,4-dioxane (20 mL) and H 2 O (10 mL). The reaction mixture was stirred at room temperature overnight. It was then quenched with saturated ammonium chloride aqueous solution (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give (7-amino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (640 mg, 2.16 mmol yield: 43%) as a yellow solid.  
         [0130]     Potassium carbonate (120 mg, 0.87 mmol) was added to a stirred suspension of (7-amino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (200 mg, 0.67 mmol), n-propyl iodide (114 mg, 0.67 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at refluxing temperature for 4 hours. It was then quenched with a saturated ammonium chloride aqueous solution (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give ((7-propylamino-9H-fluoren-2-yl)-carbamic acid, tert-butyl ester (91 mg, 0.27 mmol, yield: 40%) as a light brown solid and (7-dipropylamino-9H-fluoren-2-yl)carbamic acid tert-butyl ester (114 mg, 0.30 mmol, yield: 45%) as a light brown solid.  
         [0131]     Trifluoroacetic acid (TFA, 2.0 mL, 26.3 mmol) was added to a solution of (7-dipropylamino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (270 mg, 0.71 mmol) in 20 mL dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic Savers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give N,N-dipropyl-9H-fluorene-2,7-diamine (220 mg, 0.78 mmol, yield: 91%) as a light brown solid.  
         [0132]     A solution of N,N-dipropyl-9H-fluorene-2,7-diamine (220 mg, 0.78 mmol) and thiocarbonyl diimidazole (TCDI, 163 mg, 0.92 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. After a 25% ammonia aqueous solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give (7-dipropylamino-9H-fluoren-2-yl)-thiourea (compound 39) (231 mg, 0.69 mmol, yield; 88%) as a white solid.  
         [0133]     EI-MS (M+1): 340.  
       EXAMPLE 40  
     Preparation of Compound 40: 1-(7-(diethylamino)-9H-fluoren-2-yl)thiourea  
       [0134]     Compound 40 was prepared in a manner similar to that described in Example 39.  
         [0135]     EI-MS (M+1): 312.  
       EXAMPLE 41  
     Preparation of Compound 41: 1-(7-(dimethylamino)-9H-fluoren-2-yl)thiourea  
       [0136]     Compound 41 was prepared in a manner similar to that described in Example 39.  
         [0137]     EI-MS (M+1): 284.  
       EXAMPLE 42  
     Preparation of Compound 42: 1-(7-(dibutylamino)-9H-fluoren-2-yl)thiourea  
       [0138]     Compound 42 was prepared in a manner similar to that described in Example 39.  
         [0139]     EI-MS (M+1): 368.  
       EXAMPLE 43  
     Preparation of Compound 43: 1-(7-(propylamino)-9H-fluoren-2-yl)thiourea  
       [0140]    
       
                 
         
             
             
         
       
     
         [0141]     Trifluoroacetic acid (TFA, 2.0 mL, 26.3 mmol) was added to a solution of (7-propylamino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (91 mg, 0.27 mmol) prepared in Example 39 in 10 mL dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give N 2 -propyl-9H-fluorene-2,7-diamine (60 mg, 0.25 mmol, yield: 92%) as a light brown solid.  
         [0142]     A solution of N 2 -propyl-9H-fluorene-2,7-diamine (60 mg, 0.25 mmol) and thiocarbonyl diimidazole (53 mg, 0.30 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. After a 25% ammonia aqueous solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue was purified by silica gel column chromatography eluting with methanol-dichloromethane to give (7-propylamino-9H-fluoren-2-yl)-thiourea (compound 43) (68 mg, 0.23 mmol, yield: 90%) as a white solid.  
         [0143]     EI-MS (M+1): 298.  
       EXAMPLE 44  
     Preparation of Compound 44: 1-(7-(ethylamino)-9H-fluoren-2-yl)thiourea  
       [0144]     Compound 44 was prepared in a manner similar to that described in Example 43.  
         [0145]     EI-MS (M+1): 284.  
       EXAMPLE 45  
     Preparation of Compound 45: 1-(7-(methylamino)-9H-fluoren-2-yl)thiourea  
       [0146]     Compound 45 was prepared in a manner similar to that described in Example 43.  
         [0147]     EI-MS (M+1): 270.  
       EXAMPLE 46  
     Preparation of Compound 46: 1-(7-(butylamino)-9H-fluoren-2-yl)thiourea  
       [0148]     Compound 46 was prepared in a manner similar to that described in Example 43.  
         [0149]     EI-MS (M+1): 312.  
       EXAMPLE 47  
     Preparation of Compound 47: 1-(7-(3-phenylpropylamino)-9H-fluoren-2-yl)thiourea  
       [0150]     Compound 47 was prepared in a manner similar to that described in Example 43.  
         [0151]     EI-MS (M+1): 374.  
       EXAMPLE 48  
     Preparation of Compound 48: 1-(7-(bis(3-phenylpropyl)amino)-9H-fluoren-2-yl)thiourea  
       [0152]     Compound 48 was prepared in a manner similar to that described in Example 43.  
         [0153]     EI-MS (M+1): 492.  
       EXAMPLE 49  
     Preparation of Compound 49: 1-(7-amino-9H-fluoren-2-yl)thiourea  
       [0154]    
       
                 
         
             
             
         
       
     
         [0155]     Sodium carbonate (1.06 g, 10.0 mmol) was added to a solution of 9H-fluorene-2,7-diamine (1.0 g, 5.0 mmol) and (BOC) 2 O (1.4 mL, 7.5 mmol) in dioxane (20 mL) and H 2 O (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. It was then quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give (7-amino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (640 mg, 2.16 mmol, yield: 43%) as a yellow solid.  
         [0156]     A solution of (7-amino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (116 mg, 0.39 mmol) and thiocarbonyl diimidazole (81 mg, 0.45 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. After a 25% ammonia aqueous solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography eluting with methanol-dichloromethane to give (7-thioureido-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (118 mg, 0.33 mmol, yield: 85%) as a white solid.  
         [0157]     Trifluoroacetic acid (TFA, 2.0 mL, 26.3 mmol) was added to a solution of (7-thioureido-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (75 mg, 0.21 mmol) in 2 mL dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give (7-amino-9-1H-fluoren-2-yl)-thiourea (compound 49) (51 mg, 0.20 mmol, yield: 95%) as a white solid.  
         [0158]     EI-MS (M+1): 256.  
       EXAMPLE 50  
     Preparation of Compound 50: 1,1′-(9H-fluorene-2,7-diyl)dithiourea  
       [0159]     Compound 50 was prepared in a manner similar to that described in Example 32.  
         [0160]     EI-MS (M+1): 315.  
       EXAMPLE 51  
     Preparation of Compound 51: 1-(7-bromo-9H-fluoren-2-yl)-3-methylthiourea  
       [0161]     Compound 51 was prepared in a manner similar to that described in Example 32.  
         [0162]     EI-MS (M+1): 333, 335.  
       EXAMPLE 52  
     Preparation of Compound 52: 1-(7-bromo-9H-fluoren-2-yl)-3-ethylthiourea  
       [0163]     Compound 52 was prepared in a manner similar to that described in Example 32.  
         [0164]     EI-MS (M+1): 347, 349.  
       EXAMPLE 53  
     Preparation of Compound 53: 1-(7-bromo-9H-fluoren-2-yl)-3-propylthiourea  
       [0165]     Compound 53 was prepared in a manner similar to that described in Example 32.  
         [0166]     EI-MS (M+1): 361, 363.  
       EXAMPLE 54  
     Preparation of Compound 54: 1-(7-bromo-9H-fluoren-2-yl)-3-butylthiourea  
       [0167]     Compound 54 was prepared in a manner similar to that described in Example 32.  
         [0168]     EI-MS (M+1): 375, 377.  
       EXAMPLE 55  
     Preparation of Compound 55: 1-(7-bromo-9H-fluoren-2-yl)-3-pentyl-thiourea  
       [0169]     Compound 55 was prepared in a manner similar to that described in Example 32.  
         [0170]     EI-MS (M+1): 389, 391.  
       EXAMPLE 56  
     Preparation of Compound 56: 1-(7-bromo-9H-fluoren-2-yl)-3-hexylthiourea  
       [0171]     Compound 56 was prepared in a manner similar to that described in Example 32.  
         [0172]     EI-MS (M+1): 403, 405.  
       EXAMPLE 57  
     Preparation of Compound 57: 1-(7-bromo-9H-fluoren-2-yl)-3-heptyl-thiourea  
       [0173]     Compound 57 was prepared in a manner similar to that described in Example 32.  
         [0174]     EI-MS (M+1): 417, 419.  
       EXAMPLE 58  
     Preparation of Compound 58: 1-(7-bromo-9H-fluoren-2-yl)-3-octylthiourea  
       [0175]     Compound 58 was prepared in a manner similar to that described in Example 32.  
         [0176]     EI-MS (M+1): 431, 433.  
       EXAMPLE 59  
     Preparation of Compound 59: 1-(7-bromo-9H-fluoren-2-yl)-3-(3-methoxypropyl)thiourea  
       [0177]     Compound 59 was prepared in a manner similar to that described in Example 32.  
         [0178]     EI-MS (M+1): 391, 393.  
       EXAMPLE 60  
     Preparation of Compound 60: 1-(7-bromo-9H-fluoren-2-yl)-3-isobutyl-thiourea  
       [0179]     Compound 60 was prepared in a manner similar to that described in Example 32.  
         [0180]     EI-MS (M+1): 375, 377.  
       EXAMPLE 61  
     Preparation of Compound 61: 1-(7-bromo-9H-fluoren-2-yl)-3-(2-(dimethylamino)ethyl)thiourea  
       [0181]     Compound 61 was prepared in a manner similar to that described in Example 32.  
         [0182]     EI-MS (M+1): 390, 392.  
       EXAMPLE 62  
     Preparation of Compound 62: 1-(7-bromo-9H-fluoren-2-yl)-3-(2-(diethylamino)ethyl)thiourea  
       [0183]     Compound 62 was prepared in a manner similar to that described in Example 32.  
         [0184]     EI-MS (M+1): 418, 420.  
       EXAMPLE 63  
     Preparation of Compound 63: 1-(7-bromo-9H-fluoren-2-yl)-3-(3-(dimethylamino)propyl)thiourea  
       [0185]     Compound 63 was prepared in a manner similar to that described in Example 32.  
         [0186]     EI-MS (M+1): 404, 406.  
       EXAMPLE 64  
     Preparation of Compound 64: 1-(7-bromo-9H-fluoren-2-yl)-3-phenethyl-thiourea  
       [0187]     Compound 64 was prepared in a manner similar to that described in Example 32.  
         [0188]     EI-MS (M+1): 423, 425.  
       EXAMPLE 65  
     Preparation of Compound 65: 1-(7-bromo-9H-fluoren-2-yl)-3-(3-phenylpropyl)thiourea  
       [0189]     Compound 65 was prepared in a manner similar to that described in Example 32.  
         [0190]     EI-MS (M+1): 437, 439.  
       EXAMPLE 66  
     Preparation of Compound 66: 1-(7-bromo-9H-fluoren-2-yl)-3-(4-phenylbutyl)thiourea  
       [0191]     Compound 66 was prepared in a manner similar to that described in Example 32.  
         [0192]     EI-MS (M+1): 451, 453.  
       EXAMPLE 67  
     Preparation of Compound 67: 1-benzyl-3-(7-bromo-9H-fluoren-2-yl)thiourea  
       [0193]     Compound 67 was prepared in a manner similar to that described in Example 32.  
         [0194]     EI-MS (M+1): 430, 432.  
       EXAMPLE 68  
     Preparation of Compound 68: 1-(7-bromo-9H-fluoren-2-yl)-3-phenyl-thiourea  
       [0195]     Compound 68 was prepared in a manner similar to that described in Example 32.  
         [0196]     EI-MS (M+1): 394, 396.  
       EXAMPLE 69  
     Preparation of Compound 69: 1-(7-bromo-9H-fluoren-2-yl)-3-(pyridin-3-yl)thiourea  
       [0197]     Compound 69 was prepared in a manner similar to that described in Example 32.  
         [0198]     EI-MS (M+1): 395, 397.  
       EXAMPLE 70  
     Preparation of Compound 70: 1-(7-bromo-9H-fluoren-2-yl)-3-(4-morpholinophenyl)thiourea  
       [0199]     Compound 70 was prepared in a manner similar to that described in Example 32.  
         [0200]     EI-MS (M+1): 480, 482.  
       EXAMPLE 71  
     Preparation of Compound 71: 1-(7-bromo-9H-fluoren-2-yl)-3-(naphthalen-1-yl)thiourea  
       [0201]     Compound 71 was prepared in a manner similar to that described in Example 32.  
         [0202]     EI-MS (M+1): 445, 447.  
       EXAMPLE 72  
     Preparation of Compound 72: N-(7-thioureido-9H-fluoren-2-yl)butyramide  
       [0203]    
       
                 
         
             
             
         
       
     
         [0204]     Triethylamine (37 mg, 0.37 mmol) was added to a solution of (7-amino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (100 mg, 0.34 mmol) and n-butyryl chloride (36 mg, 0.34 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 4 hours, it was then quenched with excess saturated ammonium chloride aqueous solution (30 mL), followed by extraction with dichloromethane (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel to give (7-butyrylamino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (99 mg, 0.27 mmol, yield: 80%) as a white solid.  
         [0205]     Trifluoroacetic acid (TFA, 2.0 mL, 26.3 mmol) was added to a solution of (7-butyrylamino-9H-fluoren-2-yl)-carbamic acid tert-butyl ester (99 mg, 0.27 mmol) in 2 mL dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. It was then quenched with water (30 mL), followed by extraction with ethyl acetate (30 ml×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give N-(7-amino-9H-fluoren-2-yl)-butyramide (69 mg, 0.26 mmol, yield: 95%) as a yellow solid.  
         [0206]     A solution of N-(7-amino-9H-fluoren-2-yl)-butyramide (69 mg, 0.26 mmol) and thiocarbonyl diimidazole (55 mg, 0.30 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. After a 25% ammonia aqueous solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature overnight. The solvent was removed and then the residue thus obtained was purified by silica gel column chromatography eluding with methanol-dichloromethane to give N-(7-thioureido-9H-fluoren-2-yl)-butyramide (compound 72) (75 mg, 0.23 mmol, yield: 90%) as a white solid.  
         [0207]     EI-MS (M+1): 326.  
       EXAMPLE 73  
     Preparation of Compound 73: N-(7-thioureido-9H-fluoren-2-yl)-cyclohexanecarboxamide  
       [0208]     Compound 73 was prepared in a manner similar to that described in Example 72.  
         [0209]     EI-MS (M+1): 366.  
       EXAMPLE 74  
     Preparation of Compound 74: N-(7-thioureido-9H-fluoren-2-yl)isoxazole-5-carboxamide  
       [0210]     Compound 74 was prepared in a manner similar to that described in Example 72.  
         [0211]     EI-MS (M+1): 351.  
       EXAMPLE 75  
     Preparation of Compound 75: tert-butyl 7-thioureido-9H-fluoren-2-ylcarbamate  
       [0212]     Compound 75 was prepared in a manner similar to that described in Example 72.  
         [0213]     EI-MS (M+1): 356.  
       EXAMPLE 76  
     Preparation of Compound 76: 1-(3-(benzyloxy)phenyl)imidazolidine-2-thione  
       [0214]    
       
                 
         
             
             
         
       
     
         [0215]     2-Chloroethyl isothiocyanate (293 mg, 2.4 mmol) was added to a solution of 3-benzyloxy-phenylamine (398 mg, 2.0 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature overnight, it was quenched with water (30 mL), followed by extraction with dichloromethane (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give 1-(3-benzyloxyphenyl)-3-(2-chloro-ethyl)-thiourea (627 mg, 1.96 mmol, yield: 98%) as colorless oil.  
         [0216]     Triethylamine (2.0 mL, excess) was added to a solution of 1-(3-benzyloxyphenyl)-3-(2-chloro-ethyl)-thiourea (187 mg, 0.58 mmol) in dry THF (3 mL). The reaction mixture was stirred at refluxing temperature for 6 hours. It was then quenched with a saturated ammonium chloride aqueous solution (30 mL), followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gel to give 1-(3-benzyloxy-phenyl)-imidazolidine-2-thione (compound 76) as a white solid (150 mg, 0.52 mmol, yield: 90%).  
         [0217]     EI-MS (M+1): 285.  
       EXAMPLE 77  
     Preparation of Compound 77: 1-(3-(benzyloxy)phenyl)-3-butyl-imidazolidine-2-thione  
       [0218]    
       
                 
         
             
             
         
       
     
         [0219]     A suspension of Compound 76, i.e., 1-(3-benzyloxy-phenyl)-imidazolidine-2-thione (71 mg, 0.25 mmol) and potassium tert-butoxide (56 mg, 0.50 mmol) in acetonitrile (1 mL) was cooled in an ice bath and stirred at 0° C. for 30 minutes, followed by addition of a solution of n-butyl bromide (41 mg, 0.30 mmol) in acetonitrile (1 mL). After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water, followed by extraction with ethyl acetate (20 mL×3). The organic layers were combined and washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude mixture thus obtained was purified with silica gel column chromatography to yield 1-(3-benzyloxy-phenyl)-3-butyl-imidazolidine-2-thione (compound 77) as yellow oil (59 mg, 0.18 mmol, yield: 72%).  
         [0220]     EI-MS (M+1): 341.  
       EXAMPLE 78  
     Preparation of Compound 78: 1-(3-benzyloxy-phenyl)-3-(3-phenyl-propyl)-imidazolidine-2-thione  
       [0221]     Compound 78 was prepared in a manner similar to that described in Example 77.  
         [0222]     EI-MS (M+1): 403.  
       EXAMPLE 79  
     Preparation of Compound 79: 1-[3-(5-phenyl-pentyloxy)-phenyl]-imidazolidine-2-thione  
       [0223]     Compound 79 was prepared in a manner similar to that described in Example 76.  
         [0224]     EI-MS (M+1): 341.  
       EXAMPLE 80  
     Preparation of Compound 80: 1-butyl-3-[3-(5-phenyl-pentyloxy)-phenyl]imidazolidine-2-thione  
       [0225]     Compound 80 was prepared in a manner similar to that described in Example 77.  
         [0226]     EI-MS (M+1): 397.  
       EXAMPLE 81  
     Preparation of Compound 81: 1-[3-(5-phenyl-pentyloxy)-phenyl]-3-(3-phenyl-propyl)-imidazoline-2-thione  
       [0227]     Compound 81 was prepared in a manner similar to that, described in Example 77.  
         [0228]     EI-MS (M+1): 459.  
       EXAMPLE 82  
     Preparation of Compound 82: {3-[5-(2,6-dichloro-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0229]     Compound 82 was prepared in a manner similar to that described in Example 7.  
         [0230]     EI-MS (M+1): 400.  
       EXAMPLE 83  
     Preparation of Compound 83: {3-[5-(4-fluoro-phenoxy)-pentyloxy]phenyl}-thiourea  
       [0231]     Compound 83 was prepared in a manner similar to that described in Example 7.  
         [0232]     EI-MS (M+1): 349.  
       EXAMPLE 84  
     Preparation of Compound 84: {3-[5-(2-chloro-4-methoxy-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0233]     Compound 84 was prepared in a manner similar to that described in Example 7.  
         [0234]     EI-MS (M+1): 395.  
       EXAMPLE 85  
     Preparation of Compound 85: {3-[5-(4-chloro-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0235]     Compound 85 was prepared in a manner similar to that described in Example 7.  
         [0236]     EI-MS (M+1): 365.  
       EXAMPLE 86  
     Preparation of Compound 86: {3-[5-(2,4-difluorophenoxy)-pentyloxy]-phenyl}-thiourea  
       [0237]     Compound 86 was prepared in a manner similar to that described in Example 7.  
         [0238]     EI-MS (M+1): 367.  
       EXAMPLE 87  
     Preparation of Compound 87: {3-[5-(2,6-dichloro-4-fluoro-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0239]     Compound 87 was prepared in a manner similar to that described in Example 7.  
         [0240]     EI-MS (M+1): 418.  
       EXAMPLE 88  
     Preparation of Compound 88: {3-[5-(pyridin-4-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0241]     Compound 88 was prepared in a manner similar to that described in Example 7.  
         [0242]     EI-MS (M+1): 332.  
       EXAMPLE 89  
     Preparation of Compound 89: {3-[5-(pyridin-3-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0243]     Compound 89 was prepared in a manner similar to that described in Example 7.  
         [0244]     EI-MS (M+1): 332.  
       EXAMPLE 90  
     Preparation of Compound 90: {3-[5-(pyrimidin-4-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0245]     Compound 90 was prepared in a manner similar to that described in Example 7.  
         [0246]     EI-MS (M+1): 333.  
       EXAMPLE 91  
     Preparation of Compound 91: 4-[5-(3-thioureido-phenoxy)-pentyloxy]-benzoic acid  
       [0247]     Compound 91 was prepared in a manner similar to that described in Example 7.  
         [0248]     EI-MS (M+1): 375.  
       EXAMPLE 92  
     Preparation of Compound 92: {3-[5-(4-dimethylamino-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0249]     Compound 92 was prepared in a manner similar to that described in Example 7.  
         [0250]     EI-MS (M+1): 374.  
       EXAMPLE 93  
     Preparation of Compound 93: {3-[5-(4-diethylamino-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0251]     Compound 93 was prepared in a manner similar to that described in Example 7.  
         [0252]     EI-MS (M+1): 402.  
       EXAMPLE 94  
     Preparation of Compound 94: {3-[5-(4-morpholin-4-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0253]     Compound 94 was prepared in a manner similar to that described in Example 7.  
         [0254]     EI-MS (M+1): 416.  
       EXAMPLE 95  
     Preparation of Compound 95: {3-[5-(4-piperidin-1-yl-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0255]     Compound 95 was prepared in a manner similar to that described in Example 7.  
         [0256]     EI-MS (M+1): 414.  
       EXAMPLE 96  
     Preparation of Compound 96: (3-{5-[4-(4-methyl-piperazin-1-yl)phenoxy]-pentyloxy}-phenyl)-thiourea  
       [0257]     Compound 96 was prepared in a manner similar to that described in Example 7.  
         [0258]     EI-MS (M+1): 429.  
       EXAMPLE 97  
     Preparation of Compound 97: {3-[5-(2-methoxy-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0259]     Compound 97 was prepared in a manner similar to that described in Example 7.  
         [0260]     EI-MS (M+1): 361.  
       EXAMPLE 98  
     Preparation of Compound 98: {3-[5-(3-methoxy-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0261]     Compound 98 was prepared in a manner similar to that described in Example 7.  
         [0262]     EI-MS (M+1): 361.  
       EXAMPLE 99  
     Preparation of Compound 99: {3-[5-(3,4,5-trimethoxy-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0263]     Compound 99 was prepared in a manner similar to that described in Example 7.  
         [0264]     EI-MS (M+1): 421.  
       EXAMPLE 100  
     Preparation of Compound 100: {3-[5-(4-pyrrolidin-1-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0265]     Compound 100 was prepared in a manner similar to that described in Example 7.  
         [0266]     EI-MS (M+1): 400.  
       EXAMPLE 101  
     Preparation of Compound 101: {3-[5-(4′-methoxy-biphenyl-4-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0267]     Compound 101 was prepared in a manner similar to that described in Example 7.  
         [0268]     EI-MS (M+1): 437.  
       EXAMPLE 102  
     Preparation of Compound 102: {3-[5-(4′-methyl-biphenyl-4-yloxy)pentyloxy]-phenyl}-thiourea  
       [0269]     Compound 102 was prepared in a manner similar to that described in Example 7.  
         [0270]     EI-MS (M+1): 421.  
       EXAMPLE 103  
     Preparation of Compound 103: {3-[5-(4′-chloro-biphenyl-4-yloxy)pentyloxy]-phenyl}-thiourea  
       [0271]     Compound 103 was prepared in a manner similar to that described in Example 7.  
         [0272]     EI-MS (M+1): 441.  
       EXAMPLE 104  
     Preparation of Compound 104: {3-[5-(4′-bromo-biphenyl-4-yloxy)pentyloxy]-phenyl}-thiourea  
       [0273]     Compound 104 was prepared in a manner similar to that described in Example 7.  
         [0274]     EI-MS (M+1): 485, 487.  
       EXAMPLE 105  
     Preparation of Compound 105: {3-[5-(naphthalen-1-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0275]     Compound 105 was prepared in a manner similar to that described in Example 7.  
         [0276]     EI-MS (M+1): 381.  
       EXAMPLE 106  
     Preparation of Compound 106: {3-[5-(naphthalen-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0277]     Compound 106 was prepared in a manner similar to that described in Example 7.  
         [0278]     EI-MS (M+1): 381.  
       EXAMPLE 107  
     Preparation of Compound 107: {3-[5-(4-thiophen-3-yl-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0279]     Compound 107 was prepared in a manner similar to that described in Example 7.  
         [0280]     EI-MS (M+1); 413.  
       EXAMPLE 108  
     Preparation of Compound 108: {3-[5-(4-cyano-phenoxy)-pentyloxy]phenyl}-thiourea  
       [0281]     Compound 108 was prepared in a manner similar to that described in Example 7.  
         [0282]     EI-MS (M+1): 356.  
       EXAMPLE 109  
     Preparation of Compound 109: {3-[5-(3-cyano-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0283]     Compound 109 was prepared in a manner similar to that described in Example 7.  
         [0284]     EI-MS (M+1): 356.  
       EXAMPLE 110  
     Preparation of Compound 110: {3-[5-(2-cyano-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0285]     Compound 110 was prepared in a manner similar to that described in Example 7.  
         [0286]     EI-MS (M+1): 356.  
       EXAMPLE 111  
     Preparation of Compound 111: {3-[5-(2,6-dichloro-4-methyl-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0287]     Compound 111 was prepared in a manner similar to that described in Example 7.  
         [0288]     EI-MS (M+1): 414.  
       EXAMPLE 112  
     Preparation of Compound 112: {3-[5-(4-trifluoromethyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0289]     Compound 112 was prepared in a manner similar to that described in Example 7.  
         [0290]     EI-MS (M+1): 399.  
       EXAMPLE 113  
     Preparation of Compound 113: [3-(3-phenoxy-propoxy)-phenyl]-thiourea  
       [0291]     Compound 113 was prepared in a manner similar to that described in Example 7.  
         [0292]     EI-MS (M+1): 303.  
       EXAMPLE 114  
     Preparation of Compound 114; [3-(4-phenoxy-butoxy)-phenyl]-thiourea  
       [0293]     Compound 114 was prepared in a manner similar to that described in Example 7.  
         [0294]     EI-MS (M+1): 317.  
       EXAMPLE 115  
     Preparation of Compound 115: [3-(6-phenoxy-hexyloxy)-phenyl]-thiourea  
       [0295]     Compound 115 was prepared in a manner similar to that described in Example 7.  
         [0296]     EI-MS (M+1): 345.  
       EXAMPLE 116  
     Preparation of Compound 116: [3-(7-phenoxy-heptyloxy)-phenyl]-thiourea  
       [0297]     Compound 116 was prepared in a manner similar to that described in Example 7.  
         [0298]     EI-MS (M+1): 359.  
       EXAMPLE 117  
     Preparation of Compound 117: {3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-thiourea  
       [0299]     Compound 117 was prepared in a manner similar to that described in Example 7.  
         [0300]     EI-MS (M+1): 379.  
       EXAMPLE 118  
     Preparation of Compound 118: {3-[4-(biphenyl-4-yloxy)-butoxy]-phenyl}-thiourea  
       [0301]     Compound 118 was prepared in a manner similar to that described in Example 7.  
         [0302]     EI-MS (M+1): 393.  
       EXAMPLE 119  
     Preparation of Compound 119: {3-[6-(biphenyl-4-yloxy)-hexyloxy]-phenyl}-thiourea  
       [0303]     Compound 119 was prepared in a manner similar to that described in Example 7.  
         [0304]     EI-MS (M+1): 421.  
       EXAMPLE 120  
     Preparation of Compound 120: {3-[7-(biphenyl-4-yloxy)-heptyloxy]-phenyl}-thiourea  
       [0305]     Compound 120 was prepared in a manner similar to that described in Example 7.  
         [0306]     EI-MS (M+1): 435.  
       EXAMPLE 121  
     Preparation of Compound 121: 1,1-dimethyl-3-[3-(5-phenoxy-pentyloxy)phenyl]-thiourea  
       [0307]     Compound 121 was prepared in a manner similar to that described in Example 1.  
         [0308]     EI-MS (M+1): 359.  
       EXAMPLE 122  
     Preparation of Compound 122: 1,1-Diethyl-3-[3-(5-phenoxy-pentyloxy)phenyl]-thiourea  
       [0309]     Compound 122 was prepared in a manner similar to that described in Example 1.  
         [0310]     EI-MS (M+1): 387.  
       EXAMPLE 123  
     Preparation of Compound 123: piperidine-1-carbothioic acid [3-(5-phenoxy-pentyloxy)phenyl]-amide  
       [0311]     Compound 123 was prepared in a manner similar to that described in Example 1.  
         [0312]     EI-MS (M+1): 399.  
       EXAMPLE 124  
     Preparation of Compound 124; morpholine-4-carbothioic acid [3-(5-phenoxy-pentyloxy)-phenyl]-amide  
       [0313]     Compound 124 was prepared in a manner similar to that described in Example 1.  
         [0314]     EI-MS (M+1): 401.  
       EXAMPLE 125  
     Preparation of Compound 125: 4-methyl-piperazine-1-carbothioic acid [3-(5-phenoxy-pentyloxy)phenyl]-amide  
       [0315]     Compound 125 was prepared in a manner similar to that described in Example 1.  
         [0316]     EI-MS (M+1): 414.  
       EXAMPLE 126  
     Preparation of Compound 126: {3-[5-(quinolin-6-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0317]     Compound 126 was prepared in a manner similar to that described in Example 1.  
         [0318]     EI-MS (M+1): 382.  
       EXAMPLE 127  
     Preparation of Compound 127: {3-[5-(quinolin-5-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0319]     Compound 127 was prepared in a manner similar to that described in Example 1.  
         [0320]     EI-MS (M+1): 382.  
       EXAMPLE 128  
     Preparation of Compound 128: {3-[5-(quinolin-4-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0321]     Compound 128 was prepared in a manner similar to that described in Example 1.  
         [0322]     EI-MS (M+1): 382.  
       EXAMPLE 129  
     Preparation of Compound 129: {3-[5-(isoquinolin-5-yloxy)pentyloxy]-phenyl}-thiourea  
       [0323]     Compound 129 was prepared in a manner similar to that described in Example 1.  
         [0324]     EI-MS (M+1): 382.  
       EXAMPLE 130  
     Preparation of Compound 130: {3-[5-(quinolin-8-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0325]     Compound 130 was prepared in a manner similar to that described in Example 1.  
         [0326]     EI-MS (M+1): 382.  
       EXAMPLE 131  
     Preparation of Compound 131: {3-[5-(isoquinolin-1-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0327]     Compound 131 was prepared in a manner similar to that described in Example 1.  
         [0328]     EI-MS (M+1): 382.  
       EXAMPLE 132  
     Preparation of Compound 132: {3-[5-(1H-indol-4-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0329]     Compound 132 was prepared in a manner similar to that described in Example 1.  
         [0330]     EI-MS (M+1): 370.  
       EXAMPLE 133  
     Preparation of Compound 133: {3-[5-(4-furan-2-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0331]     Compound 133 was prepared in a manner similar to that described in Example 1.  
         [0332]     EI-MS (M+1): 397.  
       EXAMPLE 134  
     Preparation of Compound 134: {3-[5-(4-furan-3-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0333]     Compound 134 was prepared in a manner similar to that described in Example 1.  
         [0334]     EI-MS (M+1): 397.  
       EXAMPLE 135  
     Preparation of Compound 135: {3-[5-(4-thiophen-2-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0335]     Compound 135 was prepared in a manner similar to that described in Example 1.  
         [0336]     EI-MS (M+1): 413.  
       EXAMPLE 136  
     Preparation of Compound 136: (3-{5-[4-(5-chloro-thiophen-2-yl)phenoxy]-pentyloxy}-phenyl)-thiourea  
       [0337]     Compound 136 was prepared in a manner similar to that described in Example 1.  
         [0338]     EI-MS (M+1): 447.  
       EXAMPLE 137  
     Preparation of Compound 137: {3-[5-(4-phenoxy-phenoxy)pentyloxy]-phenyl}-thiourea  
       [0339]     Compound 137 was prepared in a manner similar to that described in Example 1.  
         [0340]     EI-MS (M+1): 423.  
       EXAMPLE 138  
     Preparation of Compound 138: {3-[5-(3-phenoxy-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0341]     Compound 138 was prepared in a manner similar to that described in Example 1.  
         [0342]     EI-MS (M+1): 423.  
       EXAMPLE 139  
     Preparation of Compound 139: {3-[5-(biphenyl-3-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0343]     Compound 139 was prepared in a manner similar to that described in Example 1.  
         [0344]     EI-MS (M+1): 407.  
       EXAMPLE 140  
     Preparation of Compound 140: {3-[5-(biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0345]     Compound 140 was prepared in a manner similar to that described in Example 1.  
         [0346]     EI-MS (M+1): 407.  
       EXAMPLE 141  
     Preparation of Compound 141: (7-Dibenzylamino-9H-fluoren-2-yl)-thiourea  
       [0347]     Compound 141 was prepared in a manner similar to that described in Example 39.  
         [0348]     EI-MS (M+1): 436.  
       EXAMPLE 142  
     Preparation of Compound 142: (7-Benzylamino-9H-fluoren-2-yl)-thiourea  
       [0349]     Compound 142 was prepared in a manner similar to that described in Example 39.  
         [0350]     EI-MS (M+1): 346.  
       EXAMPLE 143  
     Preparation of Compound 143: {3-[5-(4-Methoxy-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0351]     Compound 143 was prepared in a manner similar to that described in Example 7.  
         [0352]     EI-MS (M+1): 361.  
       EXAMPLE 144  
     Preparation of Compound 144: {3-[5-(3,4-Dimethoxy-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0353]     Compound 144 was prepared in a manner similar to that described in Example 7.  
         [0354]     EI-MS (M+1): 391.  
       EXAMPLE 145  
     Preparation of Compound 145: {3-[5-(Pyridin-2-yloxy)pentyloxy]-phenyl}-thiourea  
       [0355]     Compound 145 was prepared in a manner similar to that described in Example 7.  
         [0356]     EI-MS (M+1): 382.  
       EXAMPLE 146  
     Preparation of Compound 146: {3-[5-(4-Pyrrol-1-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0357]     Compound 146 was prepared in a manner similar to that described in Example 7.  
         [0358]     EI-MS (M+1): 382.  
       EXAMPLE 147  
     Preparation of Compound 147: {3-[5-(4-Imidazol-1-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0359]     Compound 147 was prepared in a manner similar to that described in Example 7.  
         [0360]     EI-MS (M+1): 397.  
       EXAMPLE 148  
     Preparation of Compound 148: {3-[5-(4-Thiomorpholin-4-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0361]     Compound 148 was prepared in a manner similar to that described in Example 7.  
         [0362]     EI-MS (M+1): 432.  
       EXAMPLE 149  
     Preparation of Compound 149: {3-[7-(Naphthalen-1-yloxy)-heptyloxy]-phenyl}-thiourea  
       [0363]     Compound 149 was prepared in a manner similar to that described in Example 7.  
         [0364]     EI-MS (M+1): 409.  
       EXAMPLE 150  
     Preparation of Compound 150: {3-[8-(Naphthalen 1-yloxy)-octyloxyl]-phenyl}-thiourea  
       [0365]     Compound 150 was prepared in a manner similar to that described in Example 7.  
         [0366]     EI-MS (M+1): 423.  
       EXAMPLE 151  
     Preparation of Compound 151: 4-[5-(3-Thioureido-phenoxy)-pentyloxy]-benzoic acid phenyl ester  
       [0367]     Compound 151 was prepared in a manner similar to that described in Example 7.  
         [0368]     EI-MS (M+1): 451.  
       EXAMPLE 152  
     Preparation of Compound 152: [4-(5-Phenyl-pentyloxy)-phenyl]-thiourea  
       [0369]     Compound 152 was prepared in a manner similar to that described in Example 7.  
         [0370]     EI-MS (M+1): 315.  
       EXAMPLE 153  
     Preparation of Compound 153: 2-[5-(3-Thioureido-phenoxy)-pentyloxy]-benzoic acid phenyl ester  
       [0371]     Compound 153 was prepared in a manner similar to that described in Example 7.  
         [0372]     EI-MS (M+1): 451.  
       EXAMPLE 154  
     Preparation of Compound 154: [2-(5-Phenyl-pentyloxy)-phenyl]-thiourea  
       [0373]     Compound 154 was prepared in a manner similar to that described in Example 7.  
         [0374]     EI-MS (M+1): 315.  
       EXAMPLE 135  
     Preparation of Compound 155: {3-[5-(3-Phenylamino-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0375]     Compound 155 was prepared in a manner similar to that described in Example 7.  
         [0376]     EI-MS (M+1): 422.  
       EXAMPLE 156  
     Preparation of Compound 156: {3-[5-(3-Benzoyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0377]     Compound 156 was prepared in a manner similar to that described in Example 7.  
         [0378]     EI-MS (M+1): 435.  
       EXAMPLE 157  
     Preparation of Compound 157: (3-{5-[3-(Hydroxy-phenyl-methyl)-phenoxy]-pentyloxy}-phenyl)-thiourea  
       [0379]     Compound 157 was prepared in a manner similar to that described in Example 7.  
         [0380]     EI-MS (M+1): 437.  
       EXAMPLE 158  
     Preparation of Compound 158: {3-[5-(4-Benzyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0381]     Compound 158 was prepared in a manner similar to that described in Example 7.  
         [0382]     EI-MS (M+1): 421.  
       EXAMPLE 159  
     Preparation of Compound 159: {3-[3-(Naphthalen-1-yloxy)-propoxy]-phenyl}-thiourea  
       [0383]     Compound 159 was prepared in a manner similar to that described in Example 7.  
         [0384]     EI-MS (M+1): 353.  
       EXAMPLE 160  
     Preparation of Compound 160: {3-[4-(Naphthalen-1-yloxy)-butoxy]-phenyl}-thiourea  
       [0385]     Compound 160 was prepared in a manner similar to that described in Example 7.  
         [0386]     EI-MS (M+1): 367.  
       EXAMPLE 161  
     Preparation of Compound 161: [4-(5-Phenoxy-pentyloxy)-phenyl]-thiourea  
       [0387]     Compound 161 was prepared in a manner similar to that described in Example 7.  
         [0388]     EI-MS (M+1): 381.  
       EXAMPLE 162  
     Preparation of Compound 162: {3-[5-(4-Methoxy-naphthalen-1-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0389]     Compound 162 was prepared in a manner similar to that described in Example 7.  
         [0390]     EI-MS (M+1): 411.  
       EXAMPLE 163  
     Preparation of Compound 163: {3-[6-(Naphthalen-1-yloxy)-hexyloxy]-phenyl}-thiourea  
       [0391]     Compound 163 was prepared in a manner similar to that described in Example 7.  
         [0392]     EI-MS (M+1): 395.  
       EXAMPLE 164  
     Preparation of Compound 164: [3-(5-Naphthalen-1-yl-pentyloxy)-phenyl]-thiourea  
       [0393]     Compound 164 was prepared in a manner similar to that described in Example 7.  
         [0394]     EI-MS (M+1): 365.  
       EXAMPLE 165  
     Preparation of Compound 165: {3-[5-(4-Chloro-naphthalen-1-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0395]     Compound 165 was prepared in a manner similar to that described in Example 7.  
         [0396]     EI-MS (M+1): 415.  
       EXAMPLE 166  
     Preparation of Compound 166: {3-[5-(2-Methyl-naphthalen-1-yloxy)pentyloxy]phenyl}-thiourea  
       [0397]     Compound 166 was prepared in a manner similar to that described in Example 7.  
         [0398]     EI-MS (M+1): 395.  
       EXAMPLE 167  
     Preparation of Compound 167: {3-[5-(3-Benzyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0399]     Compound 167 was prepared in a manner similar to that described in Example 7.  
         [0400]     EI-MS (M+1): 421.  
       EXAMPLE 168  
     Preparation of Compound 168: {3-[5-(4′-Chloro-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0401]     Compound 168 was prepared in a manner similar to that described in Example 7.  
         [0402]     EI-MS (M+1): 441.  
       EXAMPLE 169  
     Preparation of Compound 169: {3-[3-(Biphenyl-2-yloxy)-propoxy]-phenyl}-thiourea  
       [0403]     Compound 169 was prepared in a manner similar to that described in Example 7.  
         [0404]     EI-MS (M+1): 379.  
       EXAMPLE 170  
     Preparation of Compound 170: {3-[4-(Biphenyl-2-yloxy)-butoxy]-phenyl}-thiourea  
       [0405]     Compound 170 was prepared in a manner similar to that described in Example 7.  
         [0406]     EI-MS (M+1): 393.  
       EXAMPLE 171  
     Preparation of Compound 171: [3-(6-Naphthalen-1-yl-hexyloxy)-phenyl]-thiourea  
       [0407]     Compound 171 was prepared in a manner similar to that described in Example 7.  
         [0408]     EI-MS (M+1): 379.  
       EXAMPLE 172  
     Preparation of Compound 172: {4-[5-(2,4-Dichloro-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0409]     Compound 172 was prepared in a manner similar to that described in Example 7.  
         [0410]     EI-MS (M+1): 340.  
       EXAMPLE 173  
     Preparation of Compound 173: {4-[5-(2,4-Difluoro-phenoxy)-pentyloxy]phenyl}-thiourea  
       [0411]     Compound 173 was prepared in a manner similar to that described in Example 7.  
         [0412]     EI-MS (M+1): 367.  
       EXAMPLE 174  
     Preparation of Compound 174: {3-[5-(4′-Fluoro-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0413]     Compound 174 was prepared in a manner similar to that described in Example 7.  
         [0414]     EI-MS (M+1): 425.  
       EXAMPLE 175  
     Preparation of Compound 175: {3-[5-(4′-Trifluoromethyl-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0415]     Compound 175 was prepared in a manner similar to that described in Example 7.  
         [0416]     EI-MS (M+1): 475.  
       EXAMPLE 176  
     Preparation of Compound 176: {3-[5-(4′-Methoxy-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0417]     Compound 176 was prepared in a manner similar to that described in Example 7.  
         [0418]     EI-MS (M+1): 437.  
       EXAMPLE 177  
     Preparation of Compound 177: {3-[5-(4′-Methyl-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0419]     Compound 177 was prepared in a manner similar to that described in Example 7.  
         [0420]     EI-MS (M+1): 421.  
       EXAMPLE 178  
     Preparation of Compound 178: {3-[5-(3′-Methyl-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0421]     Compound 178 was prepared in a manner similar to that described in Example 7.  
         [0422]     EI-MS (M+1): 421.  
       EXAMPLE 179  
     Preparation of Compound 179: {3-[5-(3,5-Difluoro-biphenyl-2-yloxy)-pentyloxy]-phenyl}-thiourea  
       [0423]     Compound 179 was prepared in a manner similar to that described in Example 7.  
         [0424]     EI-MS (M+1): 443.  
       EXAMPLE 180  
     Preparation of Compound 180: {3-[5-(Naphthalen-1-ylamino)-pentyloxy]-phenyl}-thiourea  
       [0425]     Compound 180 was prepared in a manner similar to that described in Example 7.  
         [0426]     EI-MS (M+1): 380.  
       EXAMPLE 181  
     Preparation of Compound 181: {3-[5-(2-Cyclohexyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0427]     Compound 181 was prepared in a manner similar to that described in Example 7.  
         [0428]     EI-MS (M+1): 413.  
       EXAMPLE 182  
     Preparation of Compound 182: {3-[5-(4-Cyclohexyl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0429]     Compound 182 was prepared in a manner similar to that described in Example 7.  
         [0430]     EI-MS (M+1): 413.  
       EXAMPLE 183  
     Preparation of Compound 183: {3-[5-(2-Furan-2-yl-phenoxy)-pentyloxy]-phenyl}-thiourea  
       [0431]     Compound 183 was prepared in a manner similar to that described in Example 7.  
         [0432]     EI-MS (M+1): 397.  
       EXAMPLE 184  
     Assay for Inhibition of HCV Replication  
       [0433]     Dulbecco&#39;s modified Eagle&#39;s medium (DMEM) high glucose, fetal bovine serum (FBS), G418 (geneticin), and blasticidin were purchased from Invitrogen (Carlsbad, Calif.). A reporter cell line, Ava5-EG(Δ4AB)SEAP, for HCV drug screening was derived from HCV replicon cells (Ava5). See, e.g., Lee et al.,  Anal. Biochem.  316:162-70 and Lee et al.,  J. Viral. Methods  116:27-33. EG(Δ4AB)SEAP is a reporter gene consisting of enhanced green fluorescent protein (EG), an NS3-NS4A protease decapeptide recognition sequence (Δ4AB), and secreted alkaline phosphatase (SEAP). See, e.g., Lee et al.,  Anal. Biochem.  316:162-70. A reporter gene, EG(Δ4AB)SEAP, was stably integrated in the Ava5 cells to generate Ava5-EG(Δ4AB)SEAP cells. The cells were cultured in a medium containing 500 μg/ml G418 (geneticin) and 10 μg/ml blasticidin in a 5% CO 2  incubator.  
         [0434]     Ava5-EG(Δ4AB)SEAP cells were seeded in 96-well plates (5×10 3  cells/100 μl/well). After incubation for 1 day, the cells were treated with various concentrations of a test compound for 48 hours. Each culture medium was replenished with a fresh medium containing the test compound at the same concentration to remove the accumulated SEAP. The cells were then incubated for another 24 hours. The culture medium was collected and subjected to SEAP activity assays. The SEAP activities were measured using the Phospha-Light assay kit (Tropix, Foster, Calif., USA) according to manufacturer&#39;s instructions. Of note, SEAP activity in the culture medium, can be used to reflect anti-HCV activity. See, e.g., Lee et al.,  J. Virol. Methods  116:27-33.  
         [0435]     Compounds 1-42, 45-62, 64-91, 93-135, and 137-183 were tested for their efficacy in inhibiting HCV replication. Unexpectedly, 119 test compounds showed low EC 50  values (i.e., the concentration of a test compound at which 50% HCV replication is inhibited) between 0.001 μM and 1 μM. Among them, 63 test compounds showed EC 50  values as low as between 0.001 μM and 0.1 μM.  
       EXAMPLE 185  
     Cytotoxicity Assay  
       [0436]     Cell viability was determined by the MTS assay similar to that described in Cory et al.,  Cancer Commun.  3:207-12. In short Ava5-EG(Δ4AB)SEAP cells were seeded in 96-well plates (5×10 3  cells/100 μl/well). 100 μL/well solution containing phenol red-free DMEM, MTS (tetrazolium compound [3-(4,5-dimethylthiozol-2-yl)&gt;5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]; Promega, Madison, Wis.) and phenazine methosulfate (PMS; Sigma, St. Louis, Mo.) at a ratio of 80:20:1 to each well. The cells were incubated with test compounds for 1-4 hours at 37° C. in a humidified, 5% CO 2  incubator and the absorbance was then measured at 490 nm.  
         [0437]     Compounds 1-42, 45-62, 64-91, 93-135, and 137-183 were tested in the above cytotoxicity assay. Unexpectedly, all test compounds showed CC 50  values (i.e., the concentration of a test compound at which 50% of the cells are killed) above 1 μM. Specifically, 67 of the tested compounds showed CC 50  values above 50 μM, 88 of the tested compounds showed CC 50  values between 10 μM and 50 μM, and 23 of the test compounds showed CC 50  values between 1 μM and 10 μM. Most of the effective compounds exerted little cytotoxicity.  
       OTHER EMBODIMENTS  
       [0438]     All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.  
         [0439]     From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Technology Classification (CPC): 2