THIOUREA COMPOUNDS

CROSS REFERENCE

Pursuant to 35 U. S. C. $ 1 19(t\s, this application claims priority to U.S. Provisional Application 60/837.782. filed on August 15, 2006. The contents of the provisional application are incorporated by reference.

BACKGROUND

Hepatitis C virus (HCV) infection is estimated to afTect 170 mil! ion 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.

Current treatments based on inierferoπ-aSpha 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 MCV infection.

SUMMARY

This invention is based on the discovery that certain thiourea compounds are effective in treating hepatitis C virus infection. in one aspect, this invention relates to thiourea compounds of formula (1);

ϊn this formula, each of Ri, R>, and R>, independently, is H« Ci-Cj o alky L CV-C _JO alkenyl. CVC n> aikytiyL CVC;<υ cycloalkyl. CVOo cycloalkeny], CVCjo heterocyeloalkyl, Cj-CV ₁ heterocyeloalkenyt, aryl, or heteroaryl; or R( and R?, together with the nitrogen atom to which they are bonded, are CrCyi heterocyeloalkyl; or R; and R?, together with the two nitrogen atoms to which they

are bonded and the carbon atom bonded to both of the two nitrogen atoms, are CS-C _Z0 hereroeyeloalkyt; each of Ai and A:, independently, is aryl or heteroaryS; each of X, Y, and Z, independently, is O, S, S(O), S(O):, N(R ₁₁ ), CfR ₁₁ Ri,), CVGo alky I ₁ C ₂ -Cj ₀ alkenyi, CVC _JO aikynyl, Cj-C> _t ) eycioalkyi, C ₃ -C;o heteroeydoalkyi, aryi. or heteroaryS, in which each of R _a and Rs,, independently, is H, Ci -C so alkyl, CVCso cycloaikyl, Ci-C;o heterocycioalkyi, aryl, or heteroaryi; each of ra and n, independently, is 1 , 2, 3. 4, or 5; and each of J-, y. and 2, independently, is 0 or ϊ .

Referring to formula (S), a subset of the thiourea compounds described above are those in which x is 1 , y is 0, and * is 0. In these compounds, X can be O or NH, A _t can be phenylene, Aj can be phenyl, and each of Rj, Rj, and Rj. independently, can be H or Ci-C us a IKyI optionally substituted with aryl.

Another subset of the thiourea compounds described above are those in which x is t, y is 0, and i is i. In these compounds, X and Z can both be C), each of Ri, R:>, and 3<? can be H, or R _s and Rj, together with the nitrogen atom to which they are hooded, can be Cj-C>o heferocycioalkyi, Aj can be phenylene, and A _? can he heferoaryl, or aryl optionally substituted with halo, aryl, heteroaryl, CN, OR, COOR, or NRRλ in which each of R and R' independently, is H, C>Cκ.> alkyl, or aryl. Referring to formula (I), another subset of the thiourea compounds described above are those in which x is K y is 1 , and z is 1. In these compounds, X and Z can both be O, Y can b« C(R _n Rf;) (in which each of R ₃ and Rj,, independently, can be Cj-C so alkyl J, A, can be phenylene, Aa can be phenyl optionally substituted with aryi, and each of Rj . R:, and R;i can be H,

The term ^k 'alky!" refers to a saturated, linear or branched hydrocarbon moiety, such as -G h, -CH(CH _J J _J , or -CHr- The term "alkenyi" refers to a linear or branched hydrocarbon moiety that contains at least one double bond, such as or -CH=CH-CHb-. The term '"aikynyl" refers to a linear or branched hydrocarbon moiety that contains at least one triple bond, such as -OsC-CHj or The term "cycloalkyl" refers to a saturated, cyclic hydrocarbon moiety, such as cyelohexyl or cycϊohexyiene. The term "cyeloalkenyl" refers to a non-aromatic, cyclic hydrocarbon moiety that contains at least one double bond, such as eyclohexenyl. The term '"heteroeycloalkyi" refers to a saturated, cyclic moiety having at least one

ring heieroatoni (eg,, N, O, or S), sucii as 4~tetrahydropyranyl or 4- tεtrafoydropyranyieπe. The term "neteroeyeloalkenyr 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 ary! moieties include phenyl (PhK phenylene. naphthvL naphtbylene, pyrenyi, aπthryL and phenanthryj. The term "heferoary!" refers to a moiety having one or more aromatic rings mat contain at least one beteroatom (e.g., N, O, or S). Examples of heteroaryl moieties include fury I. futylene, fkiorenyi, pyrroiyl, thienyl, oxazolyl, inmiazolyk ύiiazolyl, pyridyS, pynmklinyi, quinazolinyS. quinoiyl, isocjutnoSyi and indolyi,

λlkyL alkenyi, alkynyi, eyeioaikyk cycioaikenyi, heterocycioaiky.1 heterocycloalketiyl, arj'l, and heteroary] mentioned herein include both substituted and unsubstituted raoieϋes, unless specified otherwise. Possible substiiuents on cycloalkyl. cycloalkenyL helerocycloalkyl, heterocycloaikenyt, aryl. and heteroaryl include, but are not limited to. CVC ^' io alkyl, CVC io aϊkenyk C;-(?in alkynyl, CVCJO cycloalkyl, CVC ^, hεterocycloalkenyl, CVC R ₁ alkoxy, ary), aryloxy. hekroaryi. hekroarySoxy, amino, CVCjo alkylamino, CV C>o dialkyiamino. aryiamino. diarylamino, hydroxy!, halo, fhio, Cj-C i« alkyithio, aryithio, CVC κ> aikylsuifonyl, arylϋuifonyl, acyiamino, aminoacyi. aminofhioacyi, arnidino, guanidine, ureido, cyano, nitro, aoyi, thioacy!, acyloxy, carboxyl, and carboxylic ester. On the- other hand, possible s>ubstituents on alkyl, alkenyi, or alkynyl include all of the above-recited substituents except CI-CR ₁ alkyl. Cyeloalkyl. cycioaikenyi, heteroeyeSoaSkyl heteroeyeSoalkenyl, aryl, and heteroaryl can aiso be fused with each other. In another aspect, this invention features thiourea compounds of formula (I), in which Ri is H, CVC κ> alkyl, CJ-CV _J alkenyi, CVCV alkynyl, CJ-CV _J cycloalkyl, CV CV _J cycloalkenyL CVCV heterocycloalkyϊ, CVC ^' 20 heterocycioaikenyS, aryl, or heteroaryl; each of R: and R?.- independently, is CVCV aSkyL CVCV alkenyi, CVC R ₁ alkynyl, CVCV cycloalkyl, CVCSo cycioaikenyi, t ^' VCV heterocycloalkyl. CVC-V hetcrocycloalkenvL aryl, or heteroaryk or R^ and R _? , together with the two nitrogen atoms to which thev arc bonded and the carbon atom bonded to both of the two

nitrogen aloms, are CVCa! heterυcycioaikyU each of Ai and A;, independently, Ls ary! or heterøaryl; each of X. Y. and Z. independently, is O, S, S(O), S(Ob, N(R _;l ), C(R _s R!r,), CrCio aikyi, C ₂ -CiO aikeπyl, CVC _R1 alkynyi, Cj-C ₂ O cyeioaikyϊ, CVCV heteroeyeloalkyl, aryi, or heteroaryl, in which each Of R ₁ . and Rj,, independently, is H, Ci-C io alkyl. CVCV cyeloalkyi, C)-C ¹ .:!) heteroeycloalkyl, aryi, or heteroaryl; each of m and o, independently, is 0, ! , 2, 3, 4, or 5; and each of λ. y. and 7. independently, Ls 0 or 1.

Referring to formula IS), a subset of the thiourea compounds described above are those in which x is I , y is 0, and * is 0. In these compounds, X can be C), A _t can be phenySeπe, A; can be phenyl. R; can be H or CvC jø alkyl optionally substituted with ary K and R> and R,;, 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 CVCno heterøeycloalkyi; in another aspect, this invention relates to thiourea compounds of formula (Ii):

wherein X is C), N(R ₁₁ ), C(R ₁₁ R ₁ ,), or C(O); each of Ru R _; , and R ₃ . independently, is M, Ci-Ci _P alkyl, CVCni alkenyi, CVC to alkynyi, cycioaikyl, CVCj ₁ .) cycloalkenyl. CVC:n heierocycloalkyl. CVC ^s hctorocycloalkenyi. aryi, or heleroaryl; or R^ and R _λ « together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are CVCV heieroeyetoatkyk and each of R ₄ . R _> Rf), R7, Rs, Ri), and Rip, independently, is IL CI -CV _J alkyl. CVCj ₁₁ alkenyl, CV Cio alkynyi, CVQo cycioalkyl, C3-CV cycloalkenyi. CVC;o heterocycloaJkyi, heterocycloalkenyl ary!. heteroaryi. halo. N(R ₁ -Rj). N(RVC(S)^N(R ₁₁ R ₀ ); N(RV C(O)R ₁ -), or N(I^)-C(O)O-R _t1 ; in which each of R,, R ₅ ,- K, R^ and R ₄ -, independently, is H, CVCV _J alkyl, CVCV. cycioalkyl, CVOo heterocycSoalkyl, aryj, or heteroaryi;

provided that if Rκ> is at the Vposttion, then ^2 ^3 is at the 4-posilion; and if

^R ^N ^λ N-

RiO is at lhe 4-posiιion, then ^R 2 ^R 3 is at the 3-position. The 3~ and 4~poss?ions of the above formula are delineated below:

An embodiment of the just-describee! compound's, features (he following formula:

wherein X, Kj, Rj, R.u K^, Rs R<>, R?, Ks, and Ra are as just defined.

Referring the above formula, a subset of the thiourea compounds described above are those in which each of Ri, R>, and R^, independently, is H. aryl optionally substituted with Ci-Ca heterocycloalkyt, heteroaryt, or CVC ^' κ» alkyl optionally substituted with CYCfo alkoxy, aryi. N(RR'), in which each of R and R\ independently, is i-\ or CVC) _G alkyl, In these compounds, each of R ₄ ., R ₅ , R^, R-. Rs, and Rv, independently, can be H. halo, N(R ₁ -Rj). N ^f (R _v .)-C(O)R ₄ , or N(Rc)-C(OjO-Rd. For example, each of R.u Rí, _< R ;. R&, and RQ can be H and R<, can he H, halo, N< R ₁ -Rd), N(R ₁ O-C(S)-N(RdR ₁ .), N(R,.)-C(O)Rα. or N(R ₁ -J-C(OP-Rj.

Another subset of the thiourea compounds described above are those in which each of R:, R2. and R.~, is H; or R i is (CH^) _n CH.;, in which n is I , 2, 3, 4, 5, or 6, and each of R? and R? ts H, 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 Ci) or (JD shown above. The term "treating" or "treatment" refers to administering one or mure 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. 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.

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, methanesuifonate. trifiuoroaeetate, acetate, roalate, tosylate, tartrate, fumurate, giutamate, glueuronate, lactate, giutarate, and maleate. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxyiate) on a thiourea compound. Suitable cations, include sodium ion, potassium ion, magnesium ion, caicium ion, and an ammonium cation such as tetraraethySammonium ion. The thiourea compounds also include those salts containing quaternary ¹ 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, isopropa.no!. ethyl acetate, acetic acid, and eihatiolamine.

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 FlCV infection.

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 w-ill be apparent from the description and from the claims.

DETAILED DESCRI PTlON

The table beiow show 183 exemplary compounds of this invention:

I ^' abie l :

The thiourea compounds described above can be prepared fay methods well known in the art. Examples 1-183 below provide detailed descriptions of the preparation of compounds 1 -583,

Scheme ϊ shown below depicts a typical route for synthesizing certain compounds of the invention. Specifically, 3-oitropheoot can first react with a brominated aromatic compound via a substitution reaction to form an alkoxy- containing compound. The aikoxy-contaiπing 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 diitrtidazole (7 ^' CDi) 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).

Scheme i

Certain other compounds of the invention can be prepared from benzene- 1 ,3- diamine. For example, as shown in Scheme SI below, one of the amino groups on benzene-1 , 3-diamine can be first protected with a fcrf-butyloxycarbonyl (BOC) protecting group. The other amino group on benzene- 1,3-di amine can then react with a brominaled aromatic compound. The compound thus formed can subsequently be deprotecled and then treated with thiocarbonyS diimidazoie and a base to form compounds of the invention such as compounds i 5-20.

Scheme i!

TFA

Certain other compounds of the invention can be prepared from a monoamine aromatic compound. For example, as shown in Scheme TTϊ below, a monoamine aromatic compound can reset with fhioearbonyl di imidazole, followed by ammonia or a primary amine, to form a compound of the invention (e.g., compounds 32-38 and 50-71).

Compounds 32-38 and 50-71: X=O. CH ₂ , C{0). N(ESi, R ₈ =H. Br, or NH _?<

R ₇ =H, Br, or NHC(S)NH ₂ . and R-H, alkyl, aryl, or heieroaryi.

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-f!i!orene-2.7-diamioe 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 trifluoroacetie acid _. ) and then treated with ibiocarbony! diimidazole a.od a base to form a compound of the invention (e.g., compounds 39-48, 72-75, J 41 , and 142).

Scheme JV

Certain other compounds of the invention containing an imidazoUdiny! ring can be prepared by the method shown in Scheme V. Specificaiiy, an amino- contaiπing compound can first react with J -chioro-2-fSothiocyanatoethane Jo form a ehiorine-eoiitaiπiiig thiourea compound. The thiourea compound can then react with a base {e.g., triethylarmne) to form a compound of the invention containing an iraidazoSidinyi 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 S l).

Scheme V

and 81 :

A thiourea compound synthesized above can be purified by a suitable method such as column chromatography, high-pressure liquid chromatography, or recrysiatlization.

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 de-protection) 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); TλV. Greene and P.O. M. Wins, Protective Groups in Organic Synthesis, 2" ^ύ Ed., John Wiley and Sons ( 1991 ); L. Fieser and M Fieser, Fieser and Fieser 's Reagents Jar Organic Sytuhesis, John Wiley and Sons ( 1994); and L. Paquette, ed., Em:yvlopedia of Reagents for Organic Synthesis, John Wiley and Sons ( 1995) and subsequent editions thereof. The thiourea compounds mentioned herein may contain a non-aromatic double bond and one or more asymmetric centers. T hus, they ea.n occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and eis- or trans- isomeric forms. Ail such isomeric forms are contemplated.

Aiso 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, To practice the method of the present invention, a composition having one or more thiourea compounds can be administered pareπteralty. orally, nasally, reeta!l>\ topically, or bueeally. The term "parenteral" as used herein refers to subcutaneous, intracutaneous, intravenous, intrmuscuiar, intraarticular, intraarterial, jntrasynovial, intrasteraaL intrathecal, intralesionai, or intracranial injection, as well as any suitable infusion technique.

A sterile injectable composition can be a solution or suspension in a non-toxic parenteral!}' acceptable diiueoi or solvent, such as a solution in 1 ,3-butaπediol Among the acceptable vehicles and solvents that can be employed are mannitoi, water, Ringer'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 diglyeerides). Fatty acid, such as oleic acid and its giyeeride derivatives are useful in the preparation of injeetabies. as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethyiated versions. These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, earboxymethyl 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. 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 com 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,

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, linorocarbons, and/or other soiubϋizing or dispersing agents known in the art,

A composition having one or more active thiourea compounds can also be administered in the form of suppositories for rectal administration. The carrier in the pharmaceutical composition must be "acceptable" in the sense that if 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 utilised 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&C Yellow # 10.

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 skii! in the art.

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 entirely.

Example J : Preparation of Compound 1 ; ! -(3-( ^' 5-pheriyipentyfoxy)pJienyl}thu>urea

>

Compound 1

Potassium carbonate (1.2 g, 8.7 mmol) was added to a stirred suspension of 3- nitrophenoi (0,8 g, 5,8 mmoi), (S-bτomo-perityi)-benzene ( ! .32 g, 5.8 mmoi), and potassium iodide (0.96 g, 5.8 mmol) in λ'-methylpyroiidiiione (I S mL). The mixture was stirred at 9ffC for 4 hours. After the reaction mixture was cooled to the room temperature, if was quenched with wafer (30 mL) followed by extraction with ethyl acetate (30 mL. x 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 i~nitro-3-(5~pheoylpentoxy)benzeoe ( 1.4 g, 4.93 mmol, yield: 85%) as colotiess oil.

Tin (Ii) chloride (5.57 g. 24.7 mmol) was added to a solution of i -nitro-3-(5- pheny]peoio.\y)benzene (1.4 g, 4.93 minof) in 35 ml. ethane] . The reaction mixture was stirred at 70 ¹¹ C tor 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 x 50 ml..}. The combined organic phases were washed with brine, dried over anhydrous MgSOj, and concentrated to give a crude product as a white solid. The crude product was purified by silica gel column chromatography eϊuting with ethyl acetate-w-hexarte to give 3-(5- phetiyl-penryloxy j-pherryiaroine ( 1.03 g, 4.04 mmoi, yield: 82%) as a white solid,

A solution of 3~(5-phenyl-pentyloxy)-phenyIamine (200 mg, ϊ ,02 mmol) and thiocarbonyi diimidazole (TCDl, 190 mg, 1.06 mmol) in diehiororøethane ( 10 nil.) 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 ihen the residue thus obtained was purified by silica gel column chromatography eiining with methanoi-dichioromethane to give j3-(5-phenyi-pentyloxy)-pbenjfl]-thfoui"ea (compound 1) (273 mg, 0.8? mmol, yield: 85 %) as a white solid. Ei-MS (VI-H ); 315.

Example 2: Preparation of Compound 2; H3-{4-phenyibιitoxy}phenyi)thiourea

Compound 2 was prepared in a manner similar to that described in Example I .

Ei-MS (M-H ): 301.

Example 3: Preparation of Compound 3: i -(3-{3-pheiiyipropoxy )pheny!}{hio»rea

Compound 3 was prepared in a manner similar to that described in Example I .

Example 4: Preparation of Compound 4; ] -{3~(6-phei]yihe.\yloxy}phenyi)thtourea

Compound 4 was prepared in a manner similar to that described in Example I . Ei-MS (M-H ): 329.

Example 5: Preparation of Compound 5: i ~(3-(7-phenyiheptyiøxy}pnenyi}thiourea Compound 5 was prepared in a manner simiiar to that described in Example \ .

Hl-MS (M t O: 343.

Example 6: Preparation of Compound 6: ! -(3-(8-phenyioctyloxy)pheny!jthiourea

Compound 6 was prepared in a manner similar to lhai described in Example I . Ei-MS (M-H ): 357.

Example 7: Preparation of Compound 7: H3~(5-pfoenoxypentyk)xy)phenyl)thioιtrea

TCOi , CH ₂ Ct ₂ NH ₃ iaqj

O' .,'^ ₀ λ. λ NH, r.t. r.t.

Compound ?

Potassium carbonate (10,35 g, 75,0 mmol) was added to a stirred suspeπsioo of phenol (4.7 g, 50.0 mmol), L5-dibromopentane ( 12.65 g, 55.0 mmol), and potassium iodide (0.83 g, 5.0 mmol} in N~mcthyipyrolidinonc ( 100 niL). The reaction mixture was stirred at 9CfC for 4 hours. It was then quenched with water (30 rnlλ foiiowed by extraction with ethyl acetate (30 nil. x 3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on sϋica gei to give (5- brømopentyioxy)benzene ( 12.0 g, 49.38 mmol, yield; 98%) as yellow oil.

Potassium carbonate (10.35 g, 75.0 mmol) was added to a stirred suspension of {5-bromopenryloxy)beozene (12.0 g, 49.38 mmol), 3-nttrophenol (6,95 g, 50,0 mmol}, and potassium iodide {0.83 g, 5.0 tnmol) in N-roethylpyrolidinooe ( i OO mL). The reaction mixture was stirred at 9O ⁰ C for 4 hours. It was then quenched with water (30 nil. ), followed by extraction with ethyl acetate { 30 mL x 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 ] -nstro-3-C5~ phetrøxypenioxy) benzene ( 1 1.89 g, 39.5 mmol, yield; 80%) as colorless oil. Tin (11) chloride (19.78 g, 87.89 mmol) was added to a solution of i-mtro-3-

(5-phenoxypeiuoxy) benzene (5.29 g, 1 7.58 mrnoi) in 100 mL ethanol The reaction

mixture was stirred at ?0"C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution (50 ml..) w as added. The solution was extracted with ethyl acetate (3 x SO ml,), and the combined organic phases were washed with brine, dried over anhydrous MgSCIj, and concentrated to give a crude product as a white solid. The crude product was purified by silica gel column chromatography elυttrig with ethyi aetHate-n-hexane to give 3-{5~ phenoxy-pentyioxy )-phenyiamme (4.6? g, i 7.22 mmol, yield; 9H%) as a iight yellow solid.

A solution of 3~{5-phcnoxy-pentyloxy)phenylamine (200 mg, 0,74 mmoi) and tliiocarbonyl diimktoolc (TCDf, 158 rng, 0.89 mmol) hi dicSiSorarnethane (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 roethanol-dichiorornethane to give p~{5-pheno.\y-pentyk>xyVphenyl]-thiourea {compound 7) ( J26 nig, 0.38 mmol, yield: 52%} as a white solid.

Ei-MS (M-M ): 331 .

Example 8: Preparation of Compound S: ethyl 4-(5-(3-thioureidophenoxy)p<mtyloxy}- benzoate

Compound S was prepared in a manner similar to that described in Hxampk 7, Bl-MS (M-H ): 403.

Example Q: Preparation of Compound °: 1 -(3-(5~(4- bromophenoxy}penty!oxy)pheoyi}-ihtourea

Compound 9 was prepared in a manner similar to that described in Example 7, EI-MS (Mt I): 400, 41 1.

IiMiBβkJi? ^; Preparation of Compound i f): l -(3-(3-methyS-5~ phenoxypentyloxy)phenyl)-thio«rea

Compound 10 was prepared ^" m a manner similar to that described in Example

?.

Ei-MS (M-M ): 345.

Example J J : Preparation of Compound i i ; 5 -(3-(33-dimethyl-5-phenoxypenty!oxy )- phenyUthiourea

Compound i 1 was prepared in a manner similar to that described in Example 7.

El-MS (M-H ): 359.

Example i 2: Preparation of Compound 12: ] -(3-(S-(bipherty]-4- yioxy)pentyloxy)phenyl)-thiourea

Compound 12 was prepared in a manner similar to that described in Example

7, Ei-MS (M -H ): 407.

Example i 3: Preparation of Compound 13: l-(3-(5-(bipht:oyl-4-ylox.y)-3- methyiρentyl~oxy)pheny] )thiourea

Compound 13 was prepared in a manner similar to that described in Example 7,

Hi-MS (M t I): 421 .

Example ! 4: Preparation of Compound 14: l-(3-p-{biphenyl-4-ylσxy)~3,3~dimethyi- pentyloxy)phenyijthioυrea Compound. 14 was prepared in a manner ^■ similar to that described m Example

ES-MS ( M t { }: 435.

IiMiBβkJ.5 ^; Preparation of Compound 1 5: l -(3~(5- pheiiy!penlyiasninϋ ^' )pheny5)di!ourca

Compound ( 5

(BOCfeO (K ⁾ J g. 46.3 rniiiftl) was added to a solution of benzene- i ,3-diamjne (5,0 g, 46,3 rømoi) in dichlorornethane (SO 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 mi... x 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-amino- phenyl)-carbamic acid tat-hυtyi ester (4.34 g, 20.8 mniol, yield: 45%) as a white solid. Potassium carbonate (0.6 g\ 4,35 mmoϊ) was added to a stirred suspension of

(3-ammo-phenylj-carbamie acid tert-butyi ester (0.6 g. 2.9 mmol), (5-brotno-pentyl)- benzene (0.66 g, 2.9 mmol), and potassium iodide (0.48 g, 2.9 nimαi) in N- methylpyrolidiπotie ( 14 mL). The reaction mixture was stirred at 9O ⁰ C tor 4 hours. It was quenched with water (30 mL), followed by extraction with ethyl acetate (30 mL x 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-phenyi-penty!amino)-phenyi]-carbamic acid tert-bυtyl ester < 802 nig, 2.26 mmol, yield: 78%) as yellow oil.

Trifluoroaeetic acid (TFA, 2.0 mL. 263 mmol) was added to a solution of [3- ( ^' 5-pherjy!-penr.y1fimsno)-phenyl]-cfirbamic acid tert-butyi ester {802 rag, 2.26 mrao!) in 10 rat dichloromethane. The reaction mixture was stirred at room temperature for \ hour. It was then quenched with water (30 mL). followed by

extraction with ethyl acetate (30 mL x 3 ). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected to column chromatography on silica gei ks give N -(5-phe«yi-pentyI )- benzene- 1,3- dianiine (529 mg. 2.08 mmol, yield: 92%) as light yellow solid.

5 A soiuϋon of N-(5-pheiiy1-penιyi}-benzene-K3-diami)ie (89 ing, 0.4 mmol) and thiocarbonyl diimidazoie (TCDl, 74 mg. 0,42 mmot) in dichloroniethane (4 ml.) was stirred at room temperature for 2 hours. After a 25% aqueous ammonia solution (2.0 nil.., excess} was added, the reaction mixture was stirred at room temperature overnight. The solvent was then removed and the residue thus obtained was purified 10 by silica gel column chromatography dating with mcthanoi-dichloromethane to give |3-(5-phenyi-peotylamiiioVphenyi]-{.hioιsre3 (compound 37.) ( 5 13 mg. 036 mmol, yield: 90%; as a white solid.

^5 Example Kx Preparation of Compound 16: t~(J~(4-pheny1hutyianiino}phenyl)fl]iourea

Compound 16 was prepared in a manner similar to that described in Example 15.

FS-MS (M-M ): 300.

20 iixamj>leJJ7: Preparation of Compound 17: l -(3-(3- pheny lpropylami no )pheny l)thiou rca

Compound 17 was prepared in a manner similar to that described in Example 15.

Ei-MS (M-H i: 286. 25

Example 18: Preparation of Compound ! 8: 1 -(3-(6- phe«ylhexy!amino)phcn.y1}thiourea

Compound 18 was prepared in a manner similar to that described in Example 15. 30 El-MS (M-H ): 328.

Example J 9: Preparation of Compound 19: t-( ^' 3~(7- phenyiheptyiamino)pheny1)tfoiourea

Compound 19 was prepared in a manner similar to thai described in Example

15. Ri-MS (Vl-H ): 342.

Example 20: Preparation of Compound 20: l -(3-(8"pheny!octylamino)pheiiy!)thiourea

Compound 20 was prepared in a manner similar to that described in Example I5. Ei-MS (M-H ): 356.

Example 21 : Preparation of Compound 25 : 1 -methyl-3-{3-{5- phenylpeiUyioxy)pheny!)-thiourea

Compound 21 was prepared in a manner similar to that described in Example 1.

El-MS (M-H ): 329.

Example 22: Preparation of Compound 22: l -ethyl~3-{3-(5-pheny{penty1oxy)phenyl}- thiourea

Compound 22 was prepared in a manner similar to that described in Example L

Ei-MS (M-H ): 343.

.&Ml ^! ?iR.k.22: Preparation of Compound 23: l -(3-{S-phenylpentylαxy)phenyl)-3- propyi-- thiourea

Compound 23 was prepared in a manner similar to that described in Example 1.

Ei-MS (M-H ): 357.

Example .2-4: Preparation of Compound 24: l-butyS-3-(3-{5~pheo%-lpentv!oxy)piieiiylj- thioυrεa

Compound 24 was prepared in a manner similar to thai described in Example 1. Ei-MS (M* J ): J?1.

Example 23: Preparation of Compound 25: l -pen{yt-3-(3-(5- phtmylpenty!oxy)phenyiVthiourea

Compound 25 was prepared in a manner similar to that described in Example I .

HS-MS (M-M ): 385.

Example 26; Preparation of Compound 26: f -hexy!-3-ξ3-( _, S-phεny]penty!oxy)pheny!)- thiourea Compound 26 was prepared m a manner similar to that described in Example t .

Ei-MS (M-M ): 399.

Example 27: Preparation of Compound 27: ] -heptyi~3-( _. 3-(5~ pheny Ipentyloxyiphenyi Hhiourea

Compound 27 was prepared in a manner similar to that described in Example 1.

Ei-MS (M+! ): 413.

EMlOJβ.k.M: Preparation of Compound 28: l -octyl-3-(3-('5-phenylpentyloxy)pheny!)- tbiourøa

Compound 28 was prepared in a manner similar to that described in Example 1.

Ei-MS (M-H ): 427.

Example .29: Preparation of Compound 29: l-phe»ethyl-3-(3-{5-pheiiy!penty!oxvV pheny1)tbiourea

Compound 29 was prepared in a manner similar to that described in Example 1. 5 Ei-MS (VI-H ); 419.

Fxampie 30: Preparation of Compound 30: l -(3-(5-phenylpen{yloxy)phenyl)-3-{3- phetwlpropyl jthiourea

Compound 30 was prepared in a manner similar to that described in Hxampie 0 I .

HS-MS (M-M }: 433.

Example 3 1 ; Preparation of Compound 3 1 : l -(4-phεuy1butyl)-3-(3-(5- pheny!pentyioxy )-ρheny!khiourea 5 Compound 3 J was prepared in a manner similar to that described in Example t .

Ei-MS (M-M ): 447.

Example 33: Preparation of Compound 32: 5 -(7-bromo-9H~fluoren-2-yl}tntourea

! I Q Cortipousid 32

A solution of 7-bromo-9M-t ^' !iioren-2-yianiine (0.3 g, $ .0 mmol) and (hiocarbonyf diimidazoie (TCDf. 0.2 g, 12 mmol} in dichlorometbane ( 10 ml.,) was stirred at roorn temperature for 2 hours. After a 25% aqueous ammonia solution (2.0 mL, excess) was added, the reaction mixture was stirred at room temperature 5 overnight. The solvent was then removed and the residue thus obtained was purified by silica gel column chromatography elutmg with methanol-dicbioromethane to give (7-bromo-9If-fiuoren-2-yl)-thiourea (compound 32) (297 mg, 0. ^c) 3 mmoK yield 93%) as a white solid. fcl-MS (IVHl ): 320.

Example 33: Preparation of Compound 33: l~(9-ethyi-9H-carhazo)-3-yl)thiourea

Compound 33 was prepared in a manner similar Io thai described m Example 32. Ri-MS (VI-H ): 270.

Example 34: Preparation of Compound 34: l -(9-oxo-9H-fluoi'en-2-yi)thiourea

Compound 34 was prepared in a manner similar to that described in Example 32. Ei-MS (M-M ): 255.

Example 35: Preparation of Compound 35: l -(7-bromo-9-oxo-9H-ftuoren-2- yi)thiourea

Compound 35 was prepared in a manner similar to that described in Example 32.

Bi-MS (M-H ): 332, 334.

Preparation of Compound 36; l -(9-oxo-9H-f1uoren~3-yi)thiot«'ea

Compound 36 was prepared in a manner similar to that described in Example 32,

Ei-MS (M-H): 255.

Example 37: Preparation of Compound 37: l-(9H~fluorcn-2-yl)thioυrea

Compound 3? was prepared in a manner similar to ihai described in Example 32.

Ei-MS (MíJ ): 241.

Exanap.l.c.38: Preparation of Compound 38: l-(2-methoxydibenzo[b,d]fuκm-3- yijthtourea

Compound 38 was prepared in a manner similar to that described in Rxampie

32.

Ei-MS (M-H ): 273.

Example 39: Preparation of Compound 39: J ~(7-(dipropyiamino)~* ⁾ H-fluϋfen-2~ yi (thiourea

Compound 3 ¹ J

Sodium carbonate (1.06 g, 10.0 mmoi) was added to a solution of 9H- fluorene-2,7-diamine (1.0 g, 5,0 ranio!) and (BOChO ( 1 ,4 ml, 7.5 rnmol) in 1,4- dioxane (20 nil,) and HjO (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 mi, x 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-aπiino-9H-fiuoreπ-2-yl)-carbamic acid tert-bυtyl ester (640 rog, 2.16 mrnoK yield; 43%) as a yellow solid.

Potassium carbonate (120 mg, 0,87 mmol) was added to a stirred suspension of (7-ammo-9H-fUtoren-2-yl)-carbamic acid ten-butyl ester (200 nig. 0,67 mmol), n- propyl iodide { i J 4 mg, 0.67 ramoH in acetonitrile (20 mi..). The .reaction mixture was stirred at relluxmg 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. x 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 ((7-propylamino-9{-l-t]uoreiV-2-yi)-carbamic acid tert-bury! ester (9i nig. 0.27 mmoi, yield: 40%) as a light brown solid and (7- dipropyiamitto-9li-fl«oren-2-yl)-carbamic acid ten-butyl ester ( 1 14 mg, 0.30 mmoi. yield: 45%) as a Hghl brown solid.

Trifluoroaeetic acid (TFA, 2.0 ml.. 26,3 mmoi ) was added to a solution of (7- dipropylamiiH>9H~nuotx'n-2~yl)-carbamic acid tert-butyl ester (270 rag, 0.71 mraoi) in 20 mi., diehiorosnethane. The reaction mixture was stirred at room temperature for I hour, ft was then quenched with water < 30 ml), followed by extraction with ethyl acetate (30 mL x 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 io give N,N-dipropyl-9H~fluorerie-2J-diamine (220 rag, 0.78 mmoi. yield: 9t%) as a light brown solid. A solution of N.N-dipropyl~9}i~0«orene-2,7~dJamine (220 ing. 0.78 mmoi) and ihiocarbonyl diitmdazole (TCDi, 163 mg, 0.92 mmoi) in dichtorornethaoe (5 rnL) was stirred at room temperature for 2 hours, A Her 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 elutmg with methanol-diehloromethane to give C 7-dipropy lam ino-W-fluorcn-2-yll-thiourca (compound 39) (231 mg, 0.69 mmoi, yield: 88%) as a white solid. El-MS (M+! ): 340.

KxajJ}β.te..4Q. ^: Preparation of Compound 40; l -(7-{diethy!amino)-9H-fluoren-2- yOthiourea

Compound 40 was prepared in a manner similar to that described in Example

Ei-MS ClVHl ): 312.

Example 41: Preparation of Compound 45 : l-(7~(dJmethyiamino)-9H~πuoren-2- ySjthioitrea

Compound 41 was prepared in a manner similar Io that described m Example 39. Ri-MS (VI-H ); 284.

Example 42: Preparation of Compound 42: l -(7-(ciibutySamino)-9H-!luoreii-2- yljthiourea

Compound 42 was prepared in a manner similar to that described in Example 39.

HS-MS (M-H }: 368.

Example 43: Preparation of Compound 43: l -(7-(prøpyiamino}-9H-fkioren-2- vi) thiourea

Compound 43

Tritluorøaeetie acid (TFA, 2,0 nil., 26.3 mπioi) was added to a solution of (7- propyiamino-θH-fluoren-2-yO-carbamic: acid tert-butyl ester (91 mg, 0.27 mmol) prepared in Example 39 in IO mL dichlorømethane. 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 x 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 ² -propy!-9H-f1uorene-2,7- dianiine (60 mg, 0.25 mmol, yield: 92%) as a light brown solid.

A solution of N"-propyl~9H-0uorene-2, /-dsasntne (60 sng. 0,25 tnmol) and tliiocarbonyi diirnidazole (53 mg« 0.30 mmol) m dichloromethane (5 ml,) was stirred at room temperature for 2 hours. After a 25'KJ 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 -dichioromeihane to give (7-propylamino- ^Q B- fUioren-2-yϊ )-thiourea (compound 43) (68 mg, 0.23 mmol, yield; 90%} as a white solid.

Ei-MS (M-H ): 298.

Example 4-1: Preparation of Compound 44; ] -(7-(etnyiamino)-9H-fluoren-2- yi)thiourea

Compound 44 was prepared in a manner similar to that described in Example 43. El-MS (M -H ): 284.

Example 45: Preparation of Compound 4S: M7-(methylamino)-9H-nuofen-2- yi)thio«rea

Compound 45 was prepared in a rnanner similar to that described in Example 43,

Ei-MS (M t I): 270.

Example 46: Preparation of Compound 46: l -(7-(buty{amim>-)-°H-fluoren-2- y!)thiourea Compound 46 was prepared in a manner ^■ similar to that described in Example

43.

Ei-MS ( M t { ): 312.

IiMiBβk.:'iI ^; Preparation of Compound 47: I -( 7~(3-prseny lpropy iammo)~9HM1tioren- 2-yl)thiυ«rea

Compound 47 was prepared ^" m a manner similar to that described in Kxample

43.

Ei-MS (M-M ): 37-

Example .4.8: Preparation of Compound 48: l -(7-(bis(3-pheny!propyl)aromo)-9H~ πυoren-2-yl thiourea

Compound 48 was prepared in a manner similar to that described in Example 43.

Ei-MS (M-H ): 492.

Example 49: Preparation of Compound 49: ] -(7-amtno-9Fi-f1uoren-2->i)thiourea

Compound 49

Sodium carbonate ( 1.06 g. 10.0 mmol) was added to a solution of 9H- f1uofene-2,7-dsamine (1.0 g. 5.0 iiiraolj and (BOC) _^ O ( 1.4 ml.., 7.5 mmol} in dioxane (20 mL) and H?.O (IO 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 x 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-aminϋ~9H~fluϋren-2~yi)-carbamic acid tert-butyl ester (640 rog, 2.16 trsrnoϊ, yield: 43%) as a yellow solid.

A solution of (7-amino-9Fl-fluoreri-2->i}-earbamic acid tert-butyl ester (1 16 mg. 0.39 mmol) and thiocarboπy! diimid&ϊole (B l rog, 0.45 mmol) in

dichlorøiriethane (5 nil.) 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 eiuting with methanol-djchloromeihane to give (7-thioureido~9H~fluoren-2-yl)-carbamic acid tert- butyl ester ( J 18 rng, 0.33 mrnoK yield: 85%) as a while solid,

Trifluoroaeetic acid (TFA, 2,0 oil... 26,3 mmol ) was added to a solution of ( 7- thioureido-9H-πuore»-2-yl)-earbaπiic acid tert-butyl ester {75 nig, 0.2 i mvπoi) in 2 ml., djchloromethane. The reaction mixture was stirred at room temperature for 1 hour. St was then quenched with water (30 niL), foHowed by extraction with ethyl acetate (30 mL x 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-aniino-9H-ωuoren-2-yl)-thiourea (compound 49) (51 mg, 0.20 mmo! _s yield: 95%) as a white solid, Ei-MS (M-H ): 256.

Example 50: Preparation of Compound 50: I J ^< -(9I l-lluoreiie-2 _! 7-diyl)drthωurea

Compound 50 was prepared in a manner similar to that described in Example

32. Oi-MS ( M t S ): 3 I S,

Example 5 J : Preparation of Compound s ! : i -(7-bromo-9M-f]uoren-2-yi}-3- methylthiourea

Compound 51 was prepared in a manner similar to that described in Example 32.

Ei-MS (Mí J ): 333, 335.

Example.52: Preparation of Compound 52: l-(7-bromα-9H-fluαren-2-yl)-3- ethylthiourea Compound 52 was prepared in a manner similar to that described in Example

32.

Ei-MS (M -f-1 ): 347. 349.

ExarnpM.5.3: Preparation of Compound S3: I -(7-bromo-9H-ωuoren-2-yl)-3- propy {thiourea

5 Compound 53 was prepared in a manner similar to ϊhaϊ described in Example

32,

FJ-MS (M+l ): 361 , 363.

Example 54: Preparation of Compound 54: l -(7~bronu>-9H-!iuoren-2-yl)-3- 10 buty (thiourea

Compound. 54 was prepared in a manner similar to that described in Example 32.

ES-MS ( M+ 0: 375, 377.

^5 Example 55: Preparation of Compound 55: l-(7-brøπio- ^<; H l-}]uoren-2-yl}~3-peoty]~ thiourea

Compound 55 was prepared in a manner similar to that described in Example 32.

Ei-MS (M+ ! ): 389, 391 . 20

Example 56: Preparation of Compound 56: i -(7-bromo-9H-f1uoiVn-2-yi)-3- hexyhhiourea

Compound 56 was prepared in a manner similar to that described in Example 32. 25 E S-MS (M -M ): 403, 405.

Example 57: Preparation of Compound 57: ] -(7-bromo-9H-Jlυoreπ-2-y|j-3-heptyi- ihiourea

Compound 57 was prepared in a manner similar to that described in Example 30 32.

Ei-MS (M-H ): 417. 419.

Example 58: Preparation of Compound 58: t -(7~bromo~9i l-fluoren~2~y!}~3- αcfykhiourea

Compound 58 was prepared in a manner similar to that described m Example 32.

Rl-MS <M+ J ): 431 , 433.

Example 59; Preparation of Compound 59; l -(7-bromo-9H-$luoren~2-y!V3-{3- methoxy-ρropyl)thjourea Compound 59 was prepared in a manner similar io (hat described m Example

32.

Ei-MS (M-M): 3 ^Q l , 393.

Example 60: Preparation of Compound 60: l -(7-brorøα-9l l-fluαren-2-yiV3-isobwyi- thiourea

Compound 60 was prepared in a manner similar to that described in Example 32.

Ei-MS (M-M ): 375, 377.

Preparation of Compound 6i : l -(7-faromo-91T-tluoren-2-yl)-3-(2- (dime thy lamino)c{hyi)thiøurca

Compound 61 was prepared in a manner similar to that described in Example 32.

EI-MS (M-H i: 390, 302.

Example 62: Preparation of Compound 62: 1 -(7-bromo-9H-il«oren-2-yl)-3-( ^' 2~ (diethylamino)elhyDthiourea

Compound 62 was prepared in a manner similar to that described hi Example 32. * ^■ !-MS (M-H ): 418, 420.

Example 63; Preparation of Compound 63: l-(7-bromo-9H-f]»oren~2-y!V3-(3- (diniethylaminojpropyl thiourea

Compound 63 was prepared in a manner similar to thai described in Example 32. Ei-MS (VI-H ); 404, 406.

Example 64: Preparation of Compound 64: l -(7-broroo-9H-ftυoren-2-yiV3-phene{hyi thiourea

Compound 64 was prepared in a manner similar to that described in Example 32.

HS-MS (M-H ): 423, 425.

Example 63; Preparation of Compound 65: l -(7-bromo-9H-fktoren-2-yϋ-3-(3- phenylpropyl (thiourea Compound 65 was prepared in a manner similar to that described in Example

32.

Ei-MS (M-M ): 437, 439.

Example 66: Preparation of Compound 66: ] -(7-bromo-9H-rluoren-2-y!)-3-f4~ phenylbutyi)thiourea

Compound 66 was prepared in a manner similar to that described in Example 32.

Ei-MS (M+! ): 45 L 453.

.fiM!KOj?.k.f>Z ^: Preparation of Compound 67: l -benzyl-3-(7-bromo-9H-fluoren-2-yl)- tbiourea

Compound 67 was prepared in a manner similar to that described in Example 32,

Ei-MS (IVHl ): 430. 432.

Example 68; Preparation of Compound 68: l-(7-bromo- ^c >H-fiuυren~2-yiV3-phenyi- thioυrεa

Compound 68 was prepared in a manner similar to thai described in Example 32. Ei-MS (VI-H ); 304, 396.

Example 6ψ, Preparation of Compound 69: l -(7-broroo-9H-ftυoren-2-yiV3-(pyridJn- 3-yl}thiøurea

Compound 69 was prepared in a manner similar to that described in Example 32.

HS-MS (M-M ): 395, 397.

Example 70: Preparation of Compound 70: f -(7-bromo-9H-fktoren-2-yii-3-(4- mαrphoimophenyOihiourea Compound 70 was prepared in a manner similar to that described in Example

32.

Ei-MS (M-M ): 480, 482.

Example 71 : Preparation of Compound 71 : 1 -(7-brotno-9H-!iuoren-2-yl}-3- ( naph tha len - 1 -y 1 }ιhi ourea

Compound 71 was prepared in a manner similar to that described in Example 32.

Ei-MS (M+! ): 445. 447.

.liMlQlR.k.Z— Preparation of Compound 72: N-(7-thioureido-9H-n«oren-2- yObiuyramide

Compound 72

Triethylamine (37 mg, 0.37 mnioi) was added to a solution of ( 7-amino-9H- {]uoreπ-2-yl)-carbarnie acid terf-butyl ester { 100 mg, 0.34 mmαl) and o-hutyryl chloride (36 mg, 0,34 rnmol) in diehloroniethane (5 niL), The reaction mixture was stirred at room temperature for 4 hours, H was then quenched with excess saturated ammonium chloride aqueous solution (30 mi,), followed by extraction with dichkiromethane (30 mL x 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-buiyryiaπiino-9H-flιtoren-2-yl)-carbamic acid test-butyl ester (99 mg, 0.27 romoi, yield: 80%) as a white solid.

Trifluoroacefie acid (TFA, 2.0 mL, 26.3 mraoi) was added to a solution of (7- butyrylamino-9H-fiuoren-2-yi)-carbaniie acid tert-buty! ester (99 mg, 0.27 mrnol) in 2 oil, dichloromethane. T he reaction mixture was stirred at room temperature for J hour, U was then quenched with water (30 ml.), foliowed by extraction with ethyl acetate (30 mL s. 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-ammo-9H-llικ>ren-2-yl)-butyramkie (69 mg, 0,26 mmoi, yield: 95%) as a yellow solid, A solution of N-(?-amino-9H-fluoren-2-yi)~bυtyrarnide (69 mg, 0.26 mrnoi) and thioearboπyl diimidazoie (55 mg, 0.30 mmoi) 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 solveiU was removed and then the residue thus obtained was purified by silica gel column chromatography eluiing with methanol-dichiororaethane to give

N-{7~thiourekio-9H-fluoren-2-y3)~butyrarciide (compound 72) (75 mg, 0,23 lamoi, yield: ⁽⁾ 0%) as a white solid, Ei-MS (M-M ): 326.

Example 73: Preparation of Compound 73: N~(7-thioureido~9}i~fluoren-2~yl)- cyclohexanecarbmamide

Compound 73 was prepared in a manner similar to that described in Example 72.

Ei-MS (M-H ): 366.

Example 7-1; Preparation of Compound 74: N-(7-thbureido-9H-fluoren-2- yi)isoxazoie-5-carboxamide

Compound 74 was prepared in a manner similar to that described in Example 72. Ei-MS (M-H ): 3SJ .

Example 75: Preparation of Compound 75: tert-butyi ?-tbioureido-9H-fluoreu-2- yicarbamafe

Compound 75 was prepared in a manner similar to that described in Example 72,

Hi-MS (M t !): 356.

Example 76: Preparation of Compound 76: l-(3-(benzyloxy)pbeny!}tmtdazo1idine-2~ thϊone

Hf ₃ N. π iF it; Hu λ ntfXr

Cotnpoum) ?t>

2-Ohtøroethyl isothiocyanate (293 ing, 2.4 mroot) was added io a solution of 3~bεnzy)oxy~pheny)amine (398 mg, 2,0 mmoi) in dicMoromethane (4 mL), The reaction mixture was stirred at room temperature overnight It was quenched with water (30 mL), followed by extraction with diehloromethane OO mL x 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 l -(3-benϊλ'ioxy-plienyl)-3-{2-chloro-ethyl)-{hioufea (627 mg, 1.96 mmoi. yield; 98%) as colorless oil.

Tricihylarmne (2.0 mL, excess) was added to a solution of i ~(3-be«zyloxy- phctty!)-3-(2-chloro-ethyl)-mionrea ( S 87 mg, 0.58 mmol} in dry THF (3 mL). The reaction mixture was stirred at refluxiog temperature for 6 hours. It was then quenched with a saturated ammonium chloride aqueous solution {30 niL), followed by extraction with ethyl acetate (30 mL x 3), The organic layers were combined, washed with brine, and concentrated under vacuum. The residue thus obtained was subjected Jo column chromatography on silica gei to give l-(3-benz.yloxy~phenyl>- imidazoiidine-2-thione (compound 76) as a white solid (150 mg. 0.52 mmoi, yield: 90%).

Fi-MS (M-M ): 285.

iiM _ϊ Uβ!*LZZ ^: Preparation of Compound 77: l -(3-(benzyloxy)phenyl>-3-buiyi- πτύdazoSidioe-2-thione

Compound 7fι

A suspension of Compound 76, i.e., i ~(3-be«zyk>xy-phenyl)-im!daiOlkiine-2- thione (71 mg, 0.25 mmol) and potassium tert-buioxide (56 mg, 0.50 mmol) in acetortitrile ( 1 mL ^' s wa.s cooled in art ice bath and stirred at.0 ^υ C for 30 minutes, followed by addition of a solution of n-butyl bromide (41 mg, 0.30 mmol) in acetonitrile ( i 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 mi, x 3 ), The organic layers

were combined and washed with brine, dried anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude mixture thus obtained was purified with silica gel column chromatography to yield H3-benzy!oxy-phenyS)-3-bulyI- imidazolidine-2-thione (compound 7? ) as yellow oil (59 mg. 0.18 mmoi, yield: 72%). Ei-MS (M+ J ): 341.

Example 78: Preparation of Compound 78: l -(3-ben2yloxy-phenyiV3-(3-phenyi- propyi)-imidazoiidi«e-2-thJo«e

Compound 78 was prepared in a manner similar io that described in Example 77.

Hi-MS (M-H }: 403.

Example ?* ^■) : Preparation of Compound 79: l -{3-(5-phenyl-pentyioxyϊ-phenyij- iraidazolidine-2-thione t.'ompound 79 was prepared in a manner similar to that described in Example

76.

Ei-MS (M-M ): 341 .

Example 80: Preparation of Compound 80: l -bu{yl-3-[3-(5-phenyl~pcmyioxyj- phenyl]-imidazoiidine-2-thion<;

Compound 80 was prepared in a manner similar to that described in Example 77.

El-MS (M-H ): 397.

iMOlSklJj Preparation of Compound 81 ; l -(3-C5-pheny{-pentyki.\y)-phtfnyi]-3-f 3~ phenyl-propylVirnidazolidine-2-thione

Compound 81 was prepared in a manner similar to that described in Example 77, fci-MS (M-H ): 459.

Example 82; Preparation of Compound 82: {3~j5-C2.6-dicblυro-phenoxy)~pemyioxyj- phenyl [-thiourea

Compound 82 was prepared in a manner similar to that described in Example

Ei-MS (VI-H ); 400.

Example 83: Preparation of Compound 83: ' _t 3-[5-{4-πuoro-phenoxy)-pentyioxyj- pheiw!} -thiourea

Compound 83 was prepared in a manner similar to that described in Example 7.

HS-MS (M-M }: 349.

Example 84; Preparation of Compound 84: U-|5-(2-chioro-4-meιhoxy-phenoxy)- penty foxy]- phenyl I -thiourea Compound HA was prepared in a manner similar to that described in Kxanipie

7.

Ei-MS (M-M ): 395.

Example 85: Preparation of Compound 85: U-|5-{4-cbloro-phenoxy}-pentyioxy]- phenyl ¹ , -thiourea

Compound 85 was prepared in a manner similar to that described in Example 7.

El-MS (M+! ): 365.

.fiMlQ}j?.kJif> ^: Preparation of Compound 86; |3-|5-(2,4-dif]υoro-phenoxy)-pentyloxy]- pheny U -thiourea

Compound 86 was prepared in a manner similar to that described in Example 7. fci-MS (IVHl ): 367.

Example 87; Preparation of Compound S?: ',3~f 5-(2,6-dich]oro-4-f]uoro-piienoxyJ- pentyloxyj-phenyl) -thiourea

Compound 8? was prepared in a manner similar to thai described m Example

Ei-MS (VI-H ); 4? 8.

Example 88: Preparation of Compound 88: (3-j5-(pyridin-4-yloxy)-pentyios.yj- phetw!} -thiourea

Compound 88 was prepared in a manner similar to that described in Example 7.

HS-MS (M-H }: 332.

Example 8*- ⁾ ; Preparation of Compound 89: }3-[5-(pyridtn-3-y1oxy)-penfyioxyl- phenyl] -thiourea Compound K9 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 332.

Example 90: Preparation of Compound 90: {3-[5-(pyrimkiin-4-yloxy)-peπ{yloxy]- phenyl ¹ , -thiourea

Compound ^Q 0 was prepared in a manner similar to that described in Example 7.

Ei-MS (M+! ): 333.

KM. ^J J]β.te..?.l ^: Preparation of Compound 9 J : 4-{ 5-C 3-th iouretdo-pharøxy )-pemyJoxy j- benzoic acid

Compound ⁽⁾ ! was prepared in a manner similar to that described in Example

7.

Ei-MS (M-H ): 375.

Example 92; Preparation of Compound 92: {3~j5-(4-dimethvlaminυ-phenα\y)- penty!oxy)~pheny!) -thiourea

Compound 92 was prepared in a manner similar to thai described in Example

Ei-MS (VI-H ); 374.

Example 93: Preparation of Compound 93: ' _t 345-{4-diethyiamino-phenoxy)- penty loxy ^' }-ρheny 1 } -thiourea

Compound 93 was prepared in a manner similar to that described in Hxampie 7.

HS-MS (M-H }: 402.

Example 94; Preparation of Compound 94: U-!5-(4-morphoiin-4-y!-phenoxy)- penfy foxy]- phenyl I -thiourea Compound 94 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 416.

Example 95: Preparation of Compound 95: >3-[5-(4-pjperidiπ-l-y{-phenoxy}- pemyio,xy]-phefvy ! f -thiourea

Compound 95 was prepared in a manner similar to that described in Example 7.

Ei-MS (M+! ): 414.

.liM!π)β.k.?i> ^: Preparation of Compound 96 ^; (3- [5-[4-(4-nie ^{ hy!-pipera?Jn-l -yO- phenoxy|-penfylo.s.y}~phetiyl)-thiourea

Compound 96 was prepared in a manner similar to that described in Example 7.

Ei-MS (M-H ): 429.

Example .97: Preparation of Compound ^c >7: ',3~f 5-(2-methox\-piienoxy)-peotyloxyj- phenyl [-thiourea

Compound 97 was prepared in a manner similar to thai described in Example

EJ-MS (M-H ); 361.

Example 98: Preparation of Compound 98: ' _t 3-[5-{3-methoxy-phenoxy )-penty}oxyJ- phetw!} -thiourea

Compound 98 was prepared in a manner similar to that described in Example 7.

HS-MS (M-H ): 36 i .

Example 9*- ⁾ ; Preparation of Compound 99: U-S5-<3,4.S-triuietlioxy-phenoxy)- penty foxy]- phenyl I -thiourea Compound 99 was prepared m a manner similar to that described in Example

7.

Ei-MS (M-M ): 42 S .

Example 100: Preparation of Compound J00: { 3-[5-(4-pyrrolidin-l~yl-phenoxy)- penty!o,xy)-pheny ! f -thiourea

Compound 100 was- prepared in a manner similar to that dc&cribed in Example 7.

EI-MS (M-H ): 400.

Exa.πjβM.IOJJ Preparation of Compound JOl : (3-[5-(4'-mtfihoxy-bipheny]-4-yloxyV pentyioxyl-phenyi} -thiourea

Compound 1 Oi was prepared in a manner similar to that described in Example 7.

Ei-MS (M-H ): 437.

Example J 02: Preparation of Compound 102: {3-f5-H'~methyi-bJphenyl-4-yloxy)- penty!oxy)~phersy!) -thiourea

Compound 102 was prepared in a manner similar to that described in Example

Ei-MS (VHJ ): 421.

Hxampie 103: Preparation of Compound 103: ^-(S-W-chloro-biphenyM-yloxyV penty loxy ]-ρheny 1 ) -thiourea

Compound 103 was prepared in a manner similar to that described In Hxample 7.

Hi-MS (M-H ): 44 i .

Example 104: Preparation of Compound !04; U-(5-(4'-bromo-hipherιyM-yloxy)~ penfy loxy]- phenyl I -thiourea C.'onφo«nd 104 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 485, 487.

Example 105: Preparation of Compound 105: { 3-[5-(naph-haien-i -y1oxy)-ρentyloxyj~ phenyl ¹ , -thiourea

Compound 105 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 3Si .

Exaθ)βMJM ^: Preparation of Compound 506: [3-[S-(naphthaien-2-yloxy)-penlyIoxy ^' j- phcny U -thiourea

Compound 106 was prepared in a manner similar to that described in Example 7. fci-MS (IVHl ): 381 .

Example .10?: Preparation of Compound 107: {3-f5-(4~thiophen~3-yi~phenoxy}- pentyloxyj-phenyl} -thiourea

Compound 107 was prepared in a manner similar to (hat described in Exampie

Ei-MS (VI-H ); 413.

Example 308: Preparation of Compound 108: ^ 3-[5-{4~eyaffθ-phenøxyVpen{yioxy]- phetw!} -thiourea

Compound 108 was prepared in a manner similar to that described In Exampie 7.

Hi-MS (M-M ): 356.

Example 109: Preparation of Compound I O ^Q ; U-(5-{3-eyano-phenoxy )-pesUyioxy]- phenyl] -thiourea Compound 109 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 356.

Example 1 10: Preparation of Compound i 10: ^H5~(2-eyamvphenoxy)-pentyioxy|- phenyl ¹ , -thiourea

Compound 1 10 was- prepared in a manner similar to that des-eribeci in Example 7.

El-MS (M+! ): 356.

.liMlOJβMJJJj Preparation of Compound i l l : (3-[5-(2,ό-dichioro-4-røethyi-phenoxy )- pemyioxyl-phenyi } -thiourea

Compound ! ! 1 was prepared in a manner similar to that described in Exampie 7. fci-MS (IVHl ): 414.

Example.11.2: Preparation of Compound 1 12: {3-f5-{4~triπuoromethyl-pheooxy)- pentyloxyj-phenyl} -thiourea

Compound ! 12 was prepared in a manner similar to thai described in Bxampie

Ei-MS (VI-H ); 309.

Example 3 13: Preparation of Compound 1 13: [3-(3-ph<;noxy-ρropoxy}--ρhenylj- thiourea

Compound 1 13 was prepared in a manner similar to that described in Hxampie 7.

Hi-MS (M-H }: 303.

Example 1 14: Preparation of Compound i 14; [3-(4-phenoxy-butoxy)-pheriyi{- Ihiourea Compound I i 4 was prepared in a manner similar to that described in Kxampie

7.

Ei-MS (M-M ): 317.

Example i 15: Preparation of Compound i 15: [3-{6~phenoxy-hexyfoxy)-phenyf j- thiourea

Compound 1 15 was- prepared in a manner similar to that dc&cribed in Example 7.

El-MS (M+! ): 345.

KM. ^J J]βM..U.δ ^: Preparation of Compound 5 16: [3-(7-phenoxy-heptyio\y)-phen>'ij- thiourea

Compound ! 16 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-H ): 359.

Example .11 ?: Preparation of Compound 1 17: {3-P-{bipbenyi~4~yioxy)-ptOpoχy|- phenyl [-thiourea

Compound ! 17 was prepared in a manner similar to {hat described in Example

Ei-MS (VI-H ); J?9.

F-xampk i 18: Preparation of Compound 1 18: ^-[4-{biphenyi-4-yioxy)-buioxy]- phetwl} -thiourea

Compound 1 18 was prepared in a manner similar to that described In Hxample 7.

HS-MS (M-M ): 393.

Example 1 19: Preparation of Compound ! I ^Q ; { 3-(6-{biplienyi-4-y!oxy)-hexyioxy]- phatyP, -thiourea C.'onφo«nd ! i 9 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 42 S .

Example 120: Preparation of Compound 120: { 3-[7-(bipherjy!-4-yio\y)-hepty{oxyj~ phenyl ¹ , -thiourea

Compound 120 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 435.

.liMlOJβM.Ill; Preparation of Compound 521 : l , l -dimethyl-3-(3-C5-phenoxy- pemyioxy)-phenyi]~dikHirca

Compound 121 was prepared in a manner similar to that described in Example 1. fci-MS (IVHl ): 359.

Example J 2.2: Preparation of Compound 122: ! . l-Dte{Jiyi-3~[3-(5-phem>xy~ pentylϋxyVphenylj-fMøurea

Compound ! 22 was prepared in a manner similar to ύmi described in Bxampie 1. Ei-MS (VI-H ); 387.

Example 123: Preparation of Compound 123: ptperidirte-l -carbothioic acid [3-(5- phetioxy~pi'ntyioxy)~phe«yi ^' j~amide

Compound 123 was prepared in a manner similar to that described In Example I .

Hi-MS (M-M ): 399.

Example 124: Preparation of Compound ϊ24; morphoHiie-4-tarbotliioic acid j3-{5- phenoxy-peiiryioxy )-pne«yJ ^" j-amide Compound !24 was prepared in a manner similar to that described in Example t .

Ei-MS (M-M ): 40 S .

Example 125: Preparation of Compound i25: 4-mefhyi-piperaxine- 1 -carbolhioic acid p-(5-phenoxy-pemyIoxy)-pheny!]-amide

Compound 125 was- prepared in a manner similar to that des-eribed in Example 1.

El-MS (M+! ): 414.

.liM!π}βMJ2.6: Preparation of Compound 126: [3-[5-(quiiωim-6-yki.\y)-pai!yloxyJ- pheny U -thiourea

Compound ! 26 was prepared in a manner similar to that described in Example 1. fci-MS (IVHl ): 382.

Example J 21: Preparation of Compound 127: {3-f5-<quinolJn-5-yioxy)-pentyloxyJ- phenyl [-thiourea

Compound ! 27 was prepared in a manner similar to (hat described in Bxampie 1. Ei-MS (VI-H ); 382.

Example 128: Preparation ofCompound 128: ^-f 5-{quinolin-4-yioxy)-pent>ioxy]~ phenyl} -thiourea

Compound 128 was prepared in a manner similar to that described In Example I .

HS-MS (M-H ): 382.

Example 129: Preparation of Compound !2 ^Q ; { 5-(5-{isoquinolin-5-yloxy)-penty!oxy|- phenyϊ] -thiourea Compound 129 was prepared in a manner similar to that described in Example t .

Ei-MS (M-M ): 382.

Example 130: Preparation of Compound 130: { 3-[5-(quinoiin-8-yJoxy)-pentyloxy|~ phenyl ¹ , -thiourea

Compound 130 was- prepared in a manner similar to that des-eribed in Example

1.

El-MS (M+! ): 3S2.

.liMlOJβMJiJJ Preparation of Compound 13 ! : [3-[S-(isoquino!in-1 -yloxyVρentyioxy|- pheny U -thiourea

Compound 131 was prepared in a manner similar to that described in Example 1. fci-MS (IVHl ): 382.

Example.13.2: Preparation of Compound 132: {3-[5-{1 H~indoM-y]oxy)-pentyk>xy ^" j~ phenyl [-thiourea

Compound ! 32 was prepared in a manner similar io fhat described in BxampSe 1. Ri-MS (VI-H ); 370.

Example 133: Preparation of Compound 133: {3-[5-(4~furati-2-yi-phenoxy)~ penty loxy ]-ρheny I ) -thiourea

Compound 133 was prepared in a manner similar to that described In Example I .

Hi-MS (M-H ): 397.

Example 134: Preparation of Compound ϊ 34; {3-(5-(4-furan-3-y!-ρhenoxy)- penfy foxy]- phenyl I -thiourea Compound I 34 was prepared in a manner similar to that described in Example t .

Ei-MS (M-M ): 397.

Example 135: Preparation of Compound J 35: {3-[5-(4-thiσpben-2-yl-ρhenoxy)- pemylox>φpheny 1 } -thiourea

Compound 135 was- prepared in a manner similar to that described in Example

L

El-MS (M+! ): 413.

KM.mβA§J..M ^: Preparation of Compound 136: (3- |S-J4-(5-chloro-thiophen-2-yi)- phe«oxy|-penf,yloxy}~phetiyl)-{hiourea

Compound 136 was prepared in a manner similar to that described in Example 1.

El-MS (M-H ): 447.

Example.13?: Preparation of Compound 137: {3-[5-{4~phenoxy-pbeπoxy)~ pentyloxyj-phenyl} -thiourea

Compound ! 37 was prepared in a manner similar io that described in Example 1. Ri-MS (VI-H ); 423.

Example 138: Preparation of Compound 138: {3-[5-(3~phenoxy~phenoxy)- penty løxy ]-ρheny 1 } -thiourea

Compound 138 was prepared in a manner similar to that described in Example I .

Hi-MS (M-H ): 423.

Example 139: Preparation of Compound ! 39; {3-[5-(biphenyi-3-ySoxy)-pentyloxyj- phetiyϊ ¹ , -thiourea Compound I 39 was prepared in a manner similar to that described in Example t .

Ei-MS (M-M ): 407.

Example 140: Preparation of Compound 140: {3-[5-(biphenyi-2-yioxy)-pentyloxy ^' |- phenyl ¹ , -thiourea

Compound 140 was- prepared in a manner similar to that des-cribeci in Example L

El-MS (M+! ): 407.

.liMlOJβM.IiJj Preparation of Compound 541 : (7-DifaenzyJamino-9H-f1uoren-2-yl)- thiourea

Compound 141 was prepared in a manner similar to that described in Example 39,

El-MS (M-H ): 436.

Example.142: Preparation of Compound 142: (?-Beozy]arairu>-9H~iluoren-2-yl}- thioυrεa

Compound ! 42 was prepared in a manner similar io {hat described in Example 39. Ri-MS (VI-H ); 346.

Example 143: Preparation of Compound 143: {3-[5-f4~Methoxy-phenoxyV pentyloxy j-phenyl} -thiourea Compound 143 was prepared in a manner similar to that described in Example

Ei-MS (M-M): 361.

Example j 44: Preparation of Compound ϊ 44: {3-{5-(3.4-Dimetboxy-phenoxy)- pentyloxy ]~phenyl} -thiourea

Compound !44 was prepared in a manner similar to that described in Rxampie

Fi-MS (M-M ): 391 .

MxiLOlβisJA?.: Preparation of Compound ϊ4S: { 3-f5-{Pyridiτι-2-yløxy)-penty!oxy]- phenyl' -thiourea

Compound 145 was prepared in a manner similar to that described in Example 7.

El-MS (M-H :>: 382.

Example 146: Preparation of Compound 546: {3-[5-(4-Pyrrol- i -yl-phenoxy)- peotyloxyl-pheny I } -thiourea

Compound 146 was prepared in a manner similar to that described in Example 7, El-MS (M-H ): 382.

Example .14?: Preparation of Compound 147: {3-f5-{4~lmidaz:αl-J ~yl-pheriθ}sy)~ penty!oxy)~phersy!) -thiourea

Compound ! 47 was prepared in a manner similar to (hat described in Exampie

Ei-MS (M+J ): 307.

Hxampie 148: Preparation of Compound 148: { 3-(5-{4-Thiomorpholm-4-yi-pheno5-y)- penty loxy ]-ρhe»y 1 ) -thiourea

Compound 148 was prepared in a manner similar to that described in Hxampie 7.

Hi-MS (M-H }: 432.

Example 149: Preparation of Compound i40; i 3-(7-{Naphtha!en-l -y!oxy)- hepfy foxy]- phenyl I -thiourea Compound 149 was prepared in a manner similar to that described in Exampie

7.

Ei-MS (M-M ): 409.

Example 150: Preparation of Compound 150: { 3-[8-(Naρbthalen~] -y!oxy,)-σctylox;y]- phenyl ¹ , -thiourea

Compound 150 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 423.

EMIOJβMJiJJ Preparation of Compound ! 51 : 4-|5-(3-Thtoureido~phenoxy.)- pemyioxyl-benzoie acid phenyi ester

Compound 151 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-H ): 451 .

Example J 5.2: Preparation of Compound 152: [4-(5-Phetiyi-pentytoxy}~phenylj- thioυrεa

Compound ! 52 was prepared in a manner similar to (hat described in Exampie

Ei-MS (VI-H ); 315.

Example 1 S3: Preparation of Compound 553: 2-[5-{3-Thiotireidcι-phenoxy)- pentyloxy ^' j-benzoie acid phenyl ester

Compound 153 was prepared in a manner similar to that described in Example 7.

Hi-MS (M-M ): 45 i .

Example 154: Preparation of Compound ϊ 54; }2-{5-Phεuy!-pe«iy!oxy )-pheny1 |- ihiourea Compound 154 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 315.

Example 155: Preparation of Compound 155: { 3-[5-(3-Phenylamino-phenoxyV pemyio,xy)-pheny ! f -thiourea

Compound 155 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 422.

KM. ^J J}βMJ.5.δ ^: Preparation of Compound 556: [3-[5-(3-Benzoyl-phenoxyVpentyloxy|- pheny U -thiourea

Compound 156 was prepared in a manner similar to that described in Example 7. fci-MS (IVHl ): 435.

Example.15?: Preparation of Compound 157: (3-{5-[3~(i-iydroxv-pJie»yl-meth%-l)- phenoxy j-persty loxy ' -phenyl)- thiourea

Compound ! 57 was prepared in a manner similar to (hat described in Exampie

Ei-MS (VI-H ); 437.

Example 158: Preparation of Compound 158: ^ 3-[5-{4~Ben7.yi-phenoxy)~penty!oxy|- phetw!} -thiourea

Compound 158 was prepared in a manner similar to that described in Example 7.

Ei-MS (M-H ): 42 i .

Example 159: Preparation of Compound 159; ] 3-(3-(Naphtha!en-! -y!oxy}-propoxy |- phenyl] -thiourea Compound 159 was prepared in a manner similar to that described in Exampie

7.

Ei-MS (M-M ): 353.

Example 160: Preparation of Compound J 60: { 3-[4-(Naρhmalen~l-yloxy;-buk>xyj- phenyl ¹ , -thiourea

Compound 160 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 367.

KMϊOPM Ji>A ^: Preparation of Compound 16 ! : [4-(5-Phtfnoxy-pentyioxy)-phenyi]- thiourea

Compound 161 was prepared in a manner similar to that described in Example

7.

Bl-MS (M*! ): 381 .

Example.162: Preparation of Compound 162: {3-[5-{4~Methoxy-ιiaphthaien-l-yioxy)~ pentyloxyj-phenyl} -thiourea

Compound 162 was prepared in a manner similar io {hat described in Exampie

Ei-MS (VHJ ): 41 1.

Example 163: Preparation of Compound 163: {3-[6-(Naphthaieii-l -yloxy)-hexykixy ^' |- pheny!} -thiourea

Compound 163 was prepared in a manner similar to that described in Example 7.

HS-MS (M-M ): 395.

Example i 64: Preparation of Compound 164; [3-(5-Naphtha!en-! ->'i-pentyloxy)- phenylj-thtoυrea Compound 164 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 365.

Example 165: Preparation of Compound 165: {3-[5~(4-Chioro-nap!ifha1eπ-l~ytoxy}~ pemylox>φpheny 1 } -thiourea

Compound 165 was- prepared in a manner similar to that des-cribeci in Example 7.

El-MS (M+! ): 415.

Kxaθ)βMJM ^: Preparation of Compound 166: {3-[5-{2-Methy!-naphthaien-l -yloxy)- pemyioxyj-phenyi} -thiourea

Compound 166 was prepared in a manner similar to that described in Example 7.

El-MS (M-H ): 395.

Example J 67: Preparation of Compound 167: {3-f5-{ 343eozyi~phenoχy)-perityloxyj- phenyl [-thiourea

Compound 167 was prepared in a manner similar to (hat described in BxampSe

Ei-MS (VHJ ): 421.

F-xampk 168: Preparation of Compound 168: { 3-(5-{4'-ChlotO-biphenyi-2-yloxy)- penty loxy ]-ρhe»y 1 ) -thiourea

Compound 168 was prepared in a manner similar to that described in Example 7.

HS-MS (M-H ): 44 i .

Example 169: Preparation of Compound 169; U-(3-(Biphenyl-2-ykiχy)-propoxy]- phenyϊ] -thiourea Compound 169 was prepared in a manner similar to that described in Exampie

7.

Ei-MS (M-M ): 379.

Example 170: Preparation of Compound 170: { 3-[4-(Biphenyl-2-yioxy)-butoxy]- phenyl ¹ , -thiourea

Compound 170 was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 393.

EMIOJPM.IUJ Preparation of Compound J 71 : (3-(6-iS ^r aph{halen-i phenylj-lhiourea

Compound 171 was prepared in a manner similar to that described in Example 7.

El-MS (IVHl ): 379.

Example J 7.2: Preparation of Compound 172: {4-f5-{2,4-Diebloro-phenoxy)~ pentyloxyj-phenyl) -thiourea

Compound ! ?2 was prepared in a manner similar to (hat described in BxampSe

Ei-MS (VI-H ); 340.

Example 173: Preparation of Compound 173: f4-[5-{2,4-Di!luora-pheftoxy}- penty loxy ]-ρheny 1 ) -thiourea

Compound 173 was prepared in a manner similar to that described in Example 7.

HS-MS (M-H ): 367.

Example 174: Preparation of Compound ϊ 74; U-(5-(4'-F!uoro-biplienyl-2-yioxy)- penfy foxy]- phenyl I -thiourea Compound ! 74 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 425.

Example 175: Preparation of Compound 175: { 3-[5-(4'-Trifl«oromethyi-biphenyi-2~ y loxy}-pemy loxyj-pheny i } -thiourea

Compound 175 was- prepared in a manner similar to that dc&eribed in Example 7.

El-MS (M+! ): 475.

.fiMlQ}j?MJ2f> ^: Preparation of Compound 176: [3-[S-(4'-Methoxy-biphenyl-2-y!oxyj- pentyloxyl-phenyl} -thiourea

Compound 176 was prepared in a manner similar to that described in Example 7. fci-MS (IVHl ): 437.

Example. I??: Preparation of Compound 177: {3-f5-(4'~Methγl-biphenyl-2~yU>xyV pentyloxyj-phenyl) -thiourea

Compound 177 was prepared in a manner similar to (hat described in Exampie

Ei-MS (VKi ); 421.

Hxampie 178: Preparation of Compound 178: i 3-|5-O'-lVkthyM>iphenγl-2-yloxyV penty loxy ]-ρhe»y 1 ) -thiourea

Compound 178 was prepared in a manner similar to that described in Hxampie 7.

Hi-MS (M-H ): 42 i .

Example 179: Preparation of Compound 179; U-(5-{3\5'-Dif!uoro-biphen>'l-2- Compound 179 was prepared in a manner similar to that described in Example

7.

Ei-MS (M-M ): 443.

Example hSfl: Preparation of Compound 180: { 3-[5-(N-ipbmalen~] -ySamino)- pemyloxy^-pheny 1 f -thiourea

Compound I SO was- prepared in a manner similar to that des-eribed in Example 7.

El-MS (M+! ): 3S0.

.liMlOJβM JJJJ Preparation of Compound 181 : [3-[S-(2-Cyciohexyi-phenoxy)- pemyioxyl-phenyi} -thiourea

Compound 181 was prepared in a manner similar to that described in Example 7. fci-MS (IVHl ): 413.

Example J 8.2: Preparation of Compound 182: {3~f5-(4~Cyciohexyi-pherioxy)- pentyloxyj-phenyl} -thiourea

Compound ! B2 was prepared in a manner similar to (hat described in Exampie

Ei-MS (VI-H ); 413.

Example 183: Preparation of Compound 183: { 3-(5-{2-Fιiπ-n-2-γl-ρhenoxy)- penty loxy ]-ρheny 1 } -thiourea

Compound 183 was prepared in a manner similar to that described In Example 7.

Hi-MS (M-H ): 397.

Example 184: Assay for inhibition of HCV replication

Dulbeceo's modified Eagle's medium (DMEM) high glucose, fetal bovine serum (PBS ), (34 KS (geneύcin), and blasticidin were purchased from Invitrogen

(Carlsbad, Cλ). λ reporter cell line, Ava5-EG(δ4AB)SEλP, for UCW drug screening was derived from HCV repUcon eelis (Ava5). See, e.g.. Lee e{ ah, λtwL Biochvnu 3 ) 6: 162-70 and ϊ.ee et a?,, </. Virol. Methods 1 16:27-33. FG(A4AB)SFAP is a reporter gene consisting of enhanced green fluorescent protein (EG), art NS3-NS4A protease decapeptide recognition sequence (λ4AB), and secreted aikahne phosphatase { S RA P). See, e.g.. Lee et ai.. Anal. Bioclwm. 316: 162-70. A reporter gene, EG(λ4A B)SEAF, was stably integrated in the Ava5 cells to generate Ava5- ECI(MAB)SEA P cells. The cells were cultured in a medium containing 500 μg/rni G418 (genetiein) and 10 μg/mi blasUcidin in a 5% CO? incubator. Ava5~EG(δ4ABjSL AP eelis were seeded in %~weil plates px 10 ^:i cells/

100 μi'vvell). After iπcubaϋoo for i 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 ceils were then incubated for another 24 hours. The culture medium was collected and subjected to SKAP activity assays. The SEAP activities were measured using the Phospha-Light assay kit

(Tropix, Foster. CA, USA} according to manufacturer's instructions. Of note, SEAP activity in the culture medium can be used to reflect arsti-HCV activity. See, e.g. _* Lee ei al., λ Virol. Methods 1 16:27-33.

Compounds 1 -42, 45-62, 64-9 ! , 93- 135, and 1 37- 583 were tested for {.heir efficacy in inhibiting HCV replication. Unexpectedly, i 19 teat compounds showed low EC-50 values ( i.e., the concentration of a test compound at which 50% MCV replication is inhibited) between 0,001 μ!Vl and 1 μM. Among them, 63 test compounds showed EQo values as low as between 0,001 μM and 0.1 μM.

ExamglgJ_85: Cytotoxicity assay

Cell viability was determined by the MTS assay similar to that described in Cory et a!,. Cancer Cammim. 3:207- 12. In short, Ava5-EG(λ4AB)SEAP cells were seeded in %-well plates (5* 10 ^J cells/ 100 μS/weli). 100 μL/weli solution containing phenol red-free DMBM, MTS (tetrazoiium compound [3-(4,5-dimethylthiozoS-2-yl)- 5-(3-caf'boxymefhoxyphenyi}~2~(4-su!fophenyt)-2H4etrazoiium. inner salt]: Prømega, Madison, Wi) and phenazine roethosulfate (PMS; Sigma, St. Louis, MG) at a ratio of 80:20; 1 to each well. The cells were incubated with test compounds for 1 -4 hours at 37 ¹¹ C in a humidified, 5% CCb incubator and the absorbance was then measured at 490 nm. Compounds I -42, 45-62, 64-9 i , 93-135, and 137- 1 S3 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 kiiled _. ) above i μM. Specifically. 67 of the tested compounds showed CC _> o values above 50 μM. 88 of the tested compounds showed CC ₅₀ values between H) μJVf and 50 μM, and 23 of the test compounds showed CC50 values between 1 μM and 10 μM. Most of the effective compounds exerted little cytotoxicity.

OTHER EMBODIMENTS

AlS 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.

From the above description, one skilled in the an 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.