IL-8 RECEPTOR ANTAGONISTS

Abstract: This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description: IL-8 RECEPTOR ANTAGONISTS FIELD OF THE INVENTION Thi.s invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8. GROα. GROβ. GROγand NAP-2 mediated diseases and pharmaceutical compositions lor use in such therapy BACKGROUND OF THE INVENTION Many different names have been applied to Interleukin-8 (IL-8). such as neutrophil attractant/activauon protein- 1 (NAP-1). monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF). and T-cell lymphocyte chemotactic factor. lnierleukin-8 i.s a chemoattractant for neutrophils. ba.sophil.s. and a sub.sct of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothehal and epithelial cells exposed to TNF, IL- l α, IL-lβ or LPS. and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al. J. Clin. Invest. 84, 1045 ( 1989): J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144. 2223 ( 1990) : Strieter. et al. Science 243. 1467 ( 1989) and J. Biol. Chem. 264. 10621 ( 1989); Cassatella et al, J. Immunol. 148. 3216 ( 1992). Groα, GROβ. GROγ and NAP-2 also belong to the chemokinc α family. Like IL-8 these chemokincs have also been referred lo by different names For instance GROα, β, γ havc been referred to as MGSAα. β and γ respectively (Melanoma Growth Stimulating Activity). see Richmond et al. J. Cell Phy.siologv 129. 375 ( 1 86) and Chang ei al. J. Immunol 148. 45 1 ( 1 92). All ot the chcmokines of the α-lamily which possess the ELR motif directly preceding the CXC motif bind to the 1L-8 B receptor IL-8. Groα. GROβ. GROγ and NAP-2 stimulate a number ol lunctions in vitro have all been shown to have chcmoattraciani properties lor neutrophils. while IL-8 and GROσ have demonstrated T-lymphocy.cs. and basophiles chemotactic activity In addition IL-fc can induce histamine release irom basophils Iron, both normal and atopic individuals GRO-α and IL-8 can in addition, induce lyso omal cn/yme release and respiratory burst from neutrophils IL-8 has also been shown to increase ihe surface expression of Mac- 1 (CD I l b/CD 1 ) on neutrophils without de protein synthesis This may contribute to increased adhesion oi the neutrophils to vascular cndothclial cells Many known diseases arc characterized b\ massive neutrophil infiltration As IL-8. Groα, GROβ. GROγ and NAP- 2 promote the accumulation and activation of neutrophils. these chcmokines have been implicated in a wide range ol acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggioiini et al. FEBS Lett 307. 97 ( 1992). Miller et al. Cπt. Rev. Immunol 12. 17 ( 1992): Oppcnheim ct al. Annu Rev Immunol 9. 617 (1991 ). Seit/ et al , J Clin. Invest 87 463 ( 1991 ). Miller et al Am Rev Respir Pis 146. 427 ( 1992). Donnplv PI al Lancet 341 . 643 ( 1993) In addition the ELR chcmokines ( those containing the ammo acids ELR motif j ust prior to the CXC motif) have also been implicated in angiostasis Stricter et al. Science 258, 1798 ( 1992) In vitro. IL-8, Groα, GROβ, GROγ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors ot the seven-transmembrane. G-protem-linked lamily, in particular by binding to IL-8 receptors, most notably the B-receptor Thomas et al , J. Biol. Chem. 26 14839 ( 1991). and Holmes et al . Science 253. 1278 ( 1991 ) The development of non-peptide small molecule antagonists tor members ol this receptor lamily has precedent. For a review see R Freidinger in Progress in Drug Research. Vol 40, pp 33-98, Birkhauser Verlag, Basel 1993 Hence, the IL-8 receptor represents a promising target for the development ol novel anti-inflammatory agents Two high aflinity human IL-8 receptors (77% homology) have been characteπzed IL- 8Rα, which binds only IL-8 with high affinity, and IL-8Rβ, which has high affinity tor IL-8 as well as lor GRO-α. GROβ, GROγ and NAP-2 See Holmes et al . supra: Murphy et al , Science 253. 1280 ( 19 1 ): Lee et al.. J Biol. Chem. 267. 16283 ( 199?) LaRosa et al , ! Biol Chem 267. 25402 ( 1992). and Gayle et al , J. Biol Chem 268. 7283 ( 1993) There remains a need tor treatment, in this field, tor compounds which are capable ol binding to the IL-8 α or β receptor Therefore, conditions associated with an increase in IL-8 production (which is responsible lor chemotaxis ot neutrophil and T-cclls subsets into the inflammatory site ) would benefit by compounds which arc inhibitors ol IL-8 receptor binding SUMMARY OF THE INVENTION This invention provides tor a method ot treating a chcmokinc mediated disease wherein the chcmokine is one which binds to an IL-8 α or β receptor and which method comprises administering an ctlcctivc amount ol a compound ol Formula (I) or a pharmaceuiicaJh acceptable salt thercol In particular the chcmokinc is IL-8 This invention also relates to a method ol inhibiting the binding ol IL-8 to Us icccpiors in a mammal in need thereol which comprises administering to said mammal an eltecuvc amount o! a compound ol Formula (I) Compounds ol Formula (1 ) usclul in the piescni iin cntion arc represented by the structure wherein X i.s oxygen or sulfur; R is any functional moiety having an ionizable hydrogen and a pKa of 1 or less; R] is independently selected from hydrogen: halogen; nitro: cyano; halosubstituted C j- io alkyl: C i- io alkyl: C2-1 alkenyl; Cj- io alkoxy; halosubstituted C i- io alkoxy: azide: S(O) t R4* hydroxy: hydroxy C i-4alkyl; aryl; aryl C i-4 alkyl: aryloxy: aryl C i -4 alkyloxy: heteroaryl: heteroarylalkyl; heterocyclic, heterocyclic C] -4alkyl: heteroaryl Ci -4 alkyloxy; aryl C2- 10 alkenyl; heteroaryl C2- 10 alkenyl; heterocyclic C2- 10 alkenyl; NR4R5: C2-10 alkenyl C(O)NR4Rs; C(O)NR4R5; C(O)NR4Rιo; S(O)3H; S(O)3Rs: Cj- K) alkyl C(O)R ] 1 ; C2- IO alkenyl C(O)R 1 1 ; C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12 : OC(O) R 1 1 ; NR4C(O)R 1 1 : or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; l is 0, or an integer having a value of I or 2; s is an integer having a value of 1 to 3; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C1.4a.kyl, heterocyclic. heterocyclic C | -4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member πng which may optionally comprise an additional hetcroatom selected lrom O/N/S: Y is independently selected Irom hydrogen; halogen: nitro: cyano: halosubstituted C \. \o alkyl. C 1.10 alkyl: C2- 10 alkenyl: C 1.10 alkoxy: halosubstituted C 1.10 alkoxy: azidc: S(O)|R4: hydroxy: hydroxyCi -4alkyl: aryl: aryl C |-4 alkyl: aryloxy: arylC i-4 alkyloxy: heteroaryl: heteroarylalkyl: heteroaryl C j-4 alkyloxy; heterocyclic, heterocyclic C 1.4a.kyl: aryl C2- |() alkenyl: heteroaryl C2- 10 alkenyl: heterocyclic C2- 10 alkenyl: NR4R5: C2- 10 alkenyl QO.NR4R5; C(O)NR4Rs; C(O)NR4R i(): S(O)3H: S(O)3Rg: C \ . \o alkyl C(O)R [ 1 . C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 : C(O)Rι 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R ι 1 : or two Y moieties together may lorm O-(CH2)sO- or a 5 to 6 membered unsaturated πng: n is an integer having a value ol 1 to 3: m is an integer having a value ol 1 to 3: Rx is hydrogen or C ] -4 alkyl: R |0 is C 1 - 10 alkyl C(O)2R8: R | 1 is hydrogen, C i -4 alkyl, optionally substituted aryl, optionally ubstituted aryl C j -4alkyl. optionally substituted heteroaryl. optionally subsututed heteroarylC ] -4alkyl. optionally substituted heterocyclic, or optionally substituted hetcrocyclιcC ] -4alkyl; R 12 is hydrogen, Ci- io alkyl, optionally substituted aryl or optionally subsututed arylalkyl. or a pharmaceutically acceptably salt thereof. Another aspect of the present invention is to a method of treating a chemokinc mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method compπses administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, as defined herein This invention also relates to a method of inhibiting the binding of IL-8 to us receptors in a mammal in need thereof which comprises administering to said mammal an effective amount ot a compound of Formula (II), as defined herein. This invention also relates to the novel compounds of Formula (II). or a pharmaceutically acceptable salt thereof, as defined herein. Another aspect of the present invention is to a method of treating a chemokjne mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method compπses administeπng an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof, as defined herein This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which compπses administering to said mammal an cflccuvc amount ol a compound of Formula (III), as defined herein This invention also relates to the novel compounds of Formula (III ), or a pharmaceutically acceptable salt thereol. as defined herein DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula (I) may also be used in association with the veterinary treatment ol mammals, other than humans, in need of inhibition of IL-S or othei chcmokines which bind to the IL-8 α and β receptors Chemokine mediated diseases lor treatment. thcrapcutically or prophylaciically, in animals include disease states such as those noted heiein in the Methods of Treatment section In compounds ol Formula (I). R is suitably any lunctional moietx which pπmdes an lonizablc hydrogen having a pKa ol 10 or less, preferably Irom about 3 to 9. more prclcrabh irom about 3 to 7 Such lunctional groups include, but are not limited to. . carhoxyl acid, thiol. -SR2 -OR2- -NH-C(O)R a , -C(O)NR6R7- a substituted sulfonamides ol the lormula -NHS(O)2Rb* -S(O)2NHR c , NHC(X2)NHRb. or a tetrazolyl. wherein X: is oxygen or sullur. preterably oxygen Preferably, the functional group is other than a sullonic acid. either directly or as a substituent group on the aryl. heteroaryl, or heterocyclic moiety πng, such as in SR2 or OR2- More preferably R is OH. SH. or NHS(O)2Rb Suitably. R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which πng has the lunctional moiety providing the ionizablc hydrogen having a pKa ol 10 or less. Suitably, R6 and R7 arc independently hydrogen or a C 1 -4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which πng may optionally contain an additional heteroatom which hetcroaiom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein Suitably R a is an alkyl, aryl, arylC i-4alkyl, heteroaryl. hcιeroarvlC | -4alkyl. heterocyclic, or a heterocyclic C | -4alkyl moiety, all of which may be optionally substituted, as defined herein below. Suitably, R is a NR R7, alkyl, aryl. arylC | -4alkyl. arylC2-4alkenyl. heierυaryl. heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic. or heterocyclic C] -4alkyl. or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be optional! * -, substituted one to three times independently by halogen; nitro: halosubstituted C ]-4 alkyl. such as CF3: C | -4 alkyl, such as methyl; C | .4 alkoxy. such as methoxy: NR9C(O)R a : C(O)NR6R7- S(O)3H. or C(O)OC 1 -4 alkyl. Rb is preferably an optionally subsututed phenyl. benzyl, or styryl When Rb is a heteroaryl preferably it is an opuonally subsututed thiazolc. optionally substituted thienyl, or optionally substituted quinolinyl πng Wherein R9 is hydrogen or a C | -4 alkyl. preferably hydrogen, and suitably when the substituent group is NR9C(O)R . then R a is preferably an alkyl group, such as methyl Suitably R is hydrogen, alkyl. aryl. arylC| -4alkyl. arylC i -4alkenyl. heteroaryl. heteroarylC 1 -4alkyl. hcteroarylCi-4alkenyl. heterocyclic. or heterocyclic C ] -4alkyl. or a heterocyclic C i-4alkenyl moiety, all ol which may be optionally substituted one to three times independently by halogen, nitro. halosubstituted C | .4 alkyl. C | .4 alk\ 1. C | .4 alkoxy. NR9C(O)R a , C(O)NR6R7- S(O)3H, or C(O)OC i -4 alkyl. wherein R9 is hydrogen or a C i -4 alkyl. Preferably, Rc is an optionally substituted phenyl When R is an OR2 or SR2 moiety 11 is lecognized by one ol skill 111 the art that the 1 πng must, theretore. contain the required ionizablc hydrogen The aryl πng may also be additionally substituted, independently, by one to three groups, which groups may al.so contain an additional lonizable group, and which include but arc not limited to. halogen, nitro. halosubstituted Ci -4 alkyl. C1 -4 alkyl. C i .4 alkoxy. hydroxy. SH. -C(0)NR6R7. -NH-C(O)R a , -NHS(O)2Rb- S(O)2NR R7- C(O)ORs. or a tetrazolyi ring In compounds of Formula (I), suitably R i is independently selected from hydrogen; halogen: nitro; cyano: halo.substituted C ] - |() alkyl. such as CF3: C i- 10 alkyl. such as methyl, ethyl, isopropyl. or n-propyl; C2- 10 alkenyl; C i - i o alkoxy, such as methoxy. or ethoxy: halosubstituted C ) . |0 alkoxy, such as irifluoromcihoxy; azide: S(O)(R4. wherein t is 0. I or 2: hydroxy; hydroxy C ]-4alkyl. such as methanol or ethanol; aryl, such as phenyl or naphthyl: aryl C i -4 alkyl, such as benzyl; aryloxy, uch as phenoxy; aryl C i -4 alkyloxy, such as benzyloxy; heteroaryl: heteroarylalkyl: heteroaryl C i -4 alkyloxy: aryl C2- K) alkenyl ; heteroaryl C2- 10 alkenyl: NR4R5. C2- 10 alkenyl-C(O)NR4R5; C(O)NR4R5: C(O)NR4R 1(): S(O)3H; S(O)3R8: C 1.10 alkyl C(O)R 1 1 : C2- 1 alkenyl C(O)R 1 1. C2- 1 alkenyl C(O)OR 1 1 : C(O)Rι 1 : C(O)OR 12- such as carboxy, methylcarboxylate or phenylbcnzoate: OC(O) R 1 1 : NR4C(O)Rι 1 ; azido: or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated πng; and s is an integer having a value of 1 to 3 The aryl, arylalkyl. arylalkenyl. heteroaryl, heteroarylalkyl. heteroarylalkenyl, heterocyclic. heterocyclicalkyl. and heterocyclicalkenyl moieties may all be optionally substituted as defined herein below. Preferably R i is other than azido or S(O)3Rg When R 1 forms a dioxybridge. s is preferably 1. When R | forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylenc ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other R 1 moieties as defined above. Suitably. R4 and R5 are independently hydrogen, optionally substituted C i -4 alkyl. optionally substituted aryl. optionally substituted aryl C ( -4alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C 1 -4alkyl. heterocyclic. heierocyclicC 1.4 alkyl. 01 R4 and R5 together with the nitrogen to which they are attached torn, a 5 to 7 member πng which may optionally comprise an additional hetcroatom selected from O/N/S. R lO is suitably C I - 10 alkyl C(O)2Rχ. such as CH2C(0)2H or CH2C(O)2CH3. R ] 1 is suitably hydrogen, C 1 -4 alkyl. aryl. aryl C i -4 alkyl. heteroaryl. heteroaryl C ]-4alkyl. heterocyclic. or heterocyclic C | -4alkyl R 12 is suitably hydrogen. C I - 10 alkyl. optionally substituted aryl or optionally substituted arylalkyl Preferably R \ is halogen, cyano. nu . CF3. C(O)NR4R . alkenyl C(O)NR4R . C(O ι R4RK). alkenyl C(0)OR i 2- heteroaryl. heteroarylalkyl . heteroaryl alkenyl. or S(O)NR4R . and prelerably R4 and R.s are both hydrogen or one is phenyl. A preferred ring substitution lor R ι is in the 4-posιiιon of the phenyl ring. When R is OH. SH or NSO2 b th n R j is preferably substituted in the 3-posιtιon. the 4- position or di substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably when R is OH, SH or NSO2Rb- than R i is nitro. halogen, cyano. trilluoromcthyl group. C(O)NR4R5. When R is carboxylic acid, than R | is preferably hydrogen, or R i is preferably substituted in the 4-posιtιon. more preferably substituted by trifluoromethyl or chloro. In compounds of Formula (I), suitably Y is independently selected from hydrogen: halogen; nitro: cyano: halosubstituted C|- io alkyl: Cμio alkyl: C2- 10 alkenyl; Ci-io alkoxy: halosubstituted C i - 1() alkoxy: azide: S(O)tR4: hydroxy: hydroxy C i -4alkyl: aryl: aryl C i -4 alkyl: aryloxy: arylC] -4 alkyloxy: aryl C2- 10 alkenyl; heteroaryl: heteroarylalkyl; heteroaryl C I -4 alkyloxy: heteroaryl C2- 10 alkenyl: heterocyclic, heterocyclic C i -4alkyl: heterocyc!icC2- 10 alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R5: C(O)NR4R5: C(O)NR4Rιo; S(O)3H: S(O)3R8: C 1.1 alkyl C(O)R 1 1 ; C2- 1 alkenyl C(O)R 1 1 ; C2- 1O alkenyl C(O)OR 1 1 ; C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R ] 1 : azido: or two Y moieties together may form O-(CH2).ςO- or a 5 to 6 membered unsaturated πng. When Y forms a dioxybridge, s is preferably 1 When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylcnc ring system T s naphthylene πng may be substituted 1 to 3 times by other Y moieties as defined above The aryl. heteroaryl and heterocyclic moieties noted above may all be optionally substituted as defined herein. Preferably R | is other than azido or S(O)3Rg Y is prclerably a halogen. C i -4 alkoxy. optionally substituted aryl. opuonally substituted aryloxy or arylalkoxy. methylcne dioxy. NR4R5. thio C i -4alkyl. thioaryl. halosubstituted alkoxy. opuonally substituted C i-4 alkyl. or hydroxy alky I Y is more prctcrabh mono-subsutuied halogen, disubstitutcd halogen, mono-substituted alkoxy. disubstuutcd alkox\ . methylenedioxy. aryl. or alkyl. more preferably these groups are mono 01 di-subsiuuted in the 2'- position or 2'-. 3 -positιon While Y may be substituted in any ol the 5 ring positions, prclerably when R is OH SH. or NSθ2Rb* is prelerably mono-substituted in the 2 -posιtιon or 3 - position, with the 4 - prelcrabh being unsubstituted It the ring i.s disubstituted. when R is OH. SH. or NSO2Rb* substuuents are preferably in the 2' or 3 position of a monocychc ring. While both R l and Y can both be hydrogen, it is prclered that at least one ot the rings be substituted, prelerably both rings arc substituted. In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen. While not explicitly covered by Formula (I), (Ia-c), (II), or (III), another aspect of this invention arc the symmetrical bis compounds which are included for each structure Compounds exemplified by this bis like structure include: N-(Bιs (2-hydroxy-4-nιtro phenyl) N'-(dianisdine) diurea 4-Methylene bis(N-(2-chloro phenyl) N'-(2-hydroxy 4-nιtro phenyl) urea) 2-Hydroxy-4-fluorophenyl)-N'-phenyl urea [(Phenylamino)carbonyl]amιno }thi phenol 2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea 2-Hydroxy-4-(trifluoromethyl)phenyI]-N'-phenyl urea 2-Hydroxy-4-nιtrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea 2-Hydroxy-4-nιtrophenyl)-N'-phenyl-thiourea 4-Nuro-2-(phenylsulfonylamιno)phenyl)-N'-phcnyl urea 2-Hydroxy-5-nιtrophenyl)-N ' -t ' 3-meιhoxy-2-thιenyl)urca 2-Hydroxy-4-nιtrophenyl)-N'-(3-methoxy-2-thιenyl)urea 2-H\ droxs -4-nιirophenyl)-N'-(3-mcthoxyphcnyl )urea 2-Hydroxy-4-mtrophenyl)-N'-(2-methoxyphenyl)urea 2-Hvdroxy-4-nιtrophenyl)-N'-(3-iπfluoromethyiphcnyl )urca 2-Hydroxy-4-nιtrophenyl)-N'-(2-tπtluoromethylphcnyl )urca 2-Hydroxy-4-nιtrophenyl)-N ' -(4-tπfluoromcthylphcnyl )urca 2-Hydroxy-4-nιtrophenyl)-N'-(2-bromophenyl )urca 2-Hydroxy-4-mtrophenyl)-N'-(3-bromophcnyl )urca 2-H\ drox\ -4-nιtrophenyl)-N ' -(4-bron.ophcnyl)urea -4-nιirophenyl)-N ' -(2-phenylphcnyl )ure»ι 2-Hydroxy-4-nitrophenyl)-N'-( l -naphthyl)urca: 2-Hydroxy-4-nιtrophenyl)-N'-(2-nιtrophenyl )urea 2-H\ droxy-4-nitrophenyl)-N'-(2-fiuorophenyl)urca 2-Hydroxv-4-nιirophenyl )-N ' -(2.6-dιfluorophenyl )urca N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifiuoromethoxyphenyl)urca N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea N-(2-Hydroxy-4-nilrophenyl) N'-(2-chloro 6-methyl phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-sulfoxymethyl phenyl) urea N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-bromo phenyl) urea N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-phenyl phenyl) urea N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2.4-dichloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2.4-dibromo phenyl) urea N-(2-Hydroxy- l-napthyl)-N'-(2-bromo phenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-methyl phenyl) urea N-[4-(Benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxy phenyl) urea N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea; N-(3.4-Difluoro 2-hydroxy phenyl) N'-(2-bromo phenyl) urea N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea N-(2-Hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea N-(2-Hvdroxy-4-niiro phenyl) N'-(2-phenylamino phenyl) urea N-(2-Hydroxy 3-carboxyphenyl) N'-(2-bromo phenyl) urea N-(2-Sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea N-(2-Hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea N-(2-Hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea N-|(2-Phenylsullamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amino sul onyl styryl) phenyl) N'-(2-bromo phenyl) urea 2-[ (3.4 Di-methoxyρhcnylsulfonyl )amino] phenyl) N'-(2-bromo phenyl ) urea N-(2-|(4-Acciamidopheny.sulfonyl)amino] phenyl) N'-(2-bromo phenyl ) urea N-(2-(Amιno sulfonyl (2-ιhiophenc) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amιno sulfonyl (3-tolyl) phenyl ) N'-(2-bromo phenyl) urea N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphcnyl )urea N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophcnyl| urea N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl ) urea N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3.4-diphenyl-phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophcnyl| urea N-|2-hHydroxy-3-glycincarbonylphenyl]-N'-f2-bromophenyl) urea N-[2-Hydroxy-3,5-dichloroρhenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea N-|2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl) urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoπ.methylphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromcthylphenyI] urea N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophcnyl) urea N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophcnyl | urea N-[2-Hydroxy-3-phcnylaminocarbonyl phenyl|-N'-[2-bromophcnyI | urea N-[2-Hydroxy-3-cyano-4-methylphenyl)-N'-[2-bromophcnyl | urea N-[2-Hydroxy-4-carbophcnyl phenyl]-N'-(2-bromophcnyl | urea N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophcnyl | urea N-[3-Benzyloxy-2-hydroxyρhenyl]-N'-[2-bromophcnyl | urea (E)-N-|4-[2-(Methoxycarbonyl) eiheny]]-2-hydroxyphcnyl l | urea (E ) -N-[3-[2-(Methoxycarbonyl ) cthenyll-2-hydroxyphcnyl |-N ' -[2-hromopheny! | urea- N"-| bromophenyl) urea (E)-N-[3-[2-(Amιnocarbonyl) cthenyl]-2-hydroxyphcnyl|-N'-|2-bromophenyl |urca-N ' -| 2- bromophcnyl] urea (E)-N-[4-|2-(Amιnocarbonyl) ethenyl]-2-hydroxyphcnyl|-N'-| 2-bromophenyl |urca-N'-| 2- bromophenyl] urea N-[2-Hydroxy-4-benzamidc phenyl]-N'-[2-bromophcnyl] urea N-[4-Amιnocarbonyl-2-hydroxyphenyl]-N'-f 2-bromophenyl] urea N-(2-Hydroxy-3.5.6-tπflLiorophenyl)-N'-(2-bromophcnyl )urea N- 2-Hydroxy-3-fluoro-4-trifiuoromethylphcnyl)-N'-(2-bromophcnyl)urea N- 2-Hydroxy-3-ιodophcnyl)-N'-(2-bromophcnyl)urca N- 2-[f[2-(Trifluoromethyl)phcnyl]sulfonyl|amino|phenyl)-N'-(2-bromophenyl)urea N- 2-Bromophenyl)-N'-f2-dimethylaminosulfonylamino]phcnyl|urca N- 2-(PhenethylsulfOnylamino)phenyl)-N'-(2-bromophenyl)urca N- 2-f(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino)phcnyl|-N'-(2-bromophenyl)urca N- 2-Hydroxy-4-cyanυphenyll-N'-[4-phcnylphcnyl| urea N- 2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea N- 2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea N- 2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl) urea N- 2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea N- 2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea N- 2-Hydroxyphenyl]-N'-f2-bromophenyl] urea N- Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl | urea N- 2-Hydroxy-3.4-dichlorophenyl]-N'-| 2-methoxyphenyl ] urea N- 2-Hydroxy-3.4-dichlorophenyl]-N'-[4-methoxyphenyl] urea N- 2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl) urea N- 2-Hydroxy-3.4-dichlorophenyI]-N'-[2-phcnylphcnyl] urea N- 2-Hydroxy-3,4-dichlorophenyl)-N'-[4-phcnylphcnyl] urea N- 2-Hydroxy-3.4-dichlorophenyl]-N'-[2.3-dichlorophcnyll urea N- 2-Hydroxy-4-isopropylphenyl]-N'-f 3-trifluoromethylphenyl] urea N- 2-Hydroxy-3-naphthy]]-N'-[2,3-dichlorophcnyl | urea N- 2-[(2.3-Dichloroihicn-5-yl)lsulfonylamιno]phcnyl|-N'-(2-bromoρhen\ l )urca N- 2-[(3.5-Bistrifluoromethylphenyl)sulfonylamino]phenyl |-N'-(2-bromophcnyl )urca N- 2-[(2-Benzyl)sulfonylamιno]-(5-trifluoromcthyl (phenyl )-N'-(2-bromophcnyl)urca N- 2-|2-(3-Nitrophcnyl)sulfonylamιno|phcnyl |-N'-(2-bromoρhcnyl )urea N- 2-[2-(4-Phenoxyphcnyl)sulfonylamino|phcnyl|-N'-(2-bromophenyl ) urea N- [2-( lS)- IO-Camphorsulfonylamino|phcnyl |-N'-(2-bromoρhenyl)urea N- f2-( lR)- 10-Camphorsulfonylamino|phenyll-N'-(2-bromoρhenyl )urea N- 2-[2-(2-Niiro-(4-trilluoromethyl)phcnyl)sulfonylamιnojphcnyl-N'-(2-bromophcnyl)urca N- 2-Hydroxy-4-azιdophenyl)-N'-(2-iodophcnyl )urca N- 2-Hydroxy-3-a/.ιdophcnyl)-N'-(2-bromophenyl )urea N- 2-Hydroxy-3-cyanophcnyl|-N'-[2-mcihoxyphenyl ] urea N- 2-Hydroxy-3-cyanophcnyl]-N'-[3-trifluoromcihylphenyl ] urea N- 2-Hydroxy-3-cyanophenyl)-N'-[2-phcnylphcnyll urea N- 2-Hydroxy-3-cyanophenyl]-N'-[2,3-dιchlorophenyl ) urea N- 2-Hydroxy-4-isopropylphenyl]-N'-[2.3-dichlorophenyl] urea N-[2-Hydroxy-4-ι.sopropylphenyl]-N -|2-chloro-5-trifluoromcthylphcnyl | urea N-|2-Hydroxy-3-phcnylphenyl|-N ' -[2.3-dichiorophenyl] urea N-f2-Hydroxy-5-nitrophcnyll-N'-[2-mcihoxyphcnyl] urea N-[2-Hydroxy-5-nιtrophcnyl |-N'-[3-irifluoromcthylphenyl] urea N-[2-Hydroxy-5-nitrophenyl|-N'-[2-phenylphcnyl) urea N-[2-Hydroxy-5-nilrophenyl|-N'-[2,3-dichlorophenyl] urea N-|2-Hydroxy-5-cthylsulfonylphenyl|-N'-[2.3-dichlorophenyl) urea N-f2-(2-4Amino-(4-trifluoromethyl) phenyl) sullonylamino] phenyl]- N'-(2- bromophenyDurea N-[2-( -vmιnosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea N-(2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea N-[2-Hydroxy-3.4-dichlorophenyl]-N ' -|2-chloro-5-trifluoromethylphenyl] urea N-[2-Hydroxy-3-naphthyI]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-5-naphthalenesulfomc acid]-N'-f2-bromophenyl] urea: N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-|2-bromophenyl] urea: 1.1 '-(4-Methyl-2-phenylene)bis[2-thio-3-3-tolylurea] N-(2-Carboxyphenyl)-N'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurca: l-(2-Carboxyphenyl)-3-(4-chlorophcnyl)urca : 2-(3,4-Dichlorophenylcarbonyldiimino)-5-trilluoromethylbenzoic acid: 2-(4-Chlorophenylcarbonyldiim_no)-5-irifluoromethylbenzoic acid: l -(p-Anιsyl)-3-(2-carboxyphcnyl)urca; l -(2-Carboxyphcnyl)-3-(3-fluorophcnyl)urca: l -(2-Carboxyphcnyl)-3-(3-chlorophcnyl)urca: l -(m-Anιsyl)-3-(2-carboxyphneyl)urca: l -(o-Anιsyl)-3-(2-carboxyphcnyl)urca : 1 -(2-Carboxyphenyl)-3-(3.4-dιchlorophcnyl )urca: 1 -(2-Carboxyphcnyl)-3-(2.4-dichlorophcnyl )urca; N-(5-Chlor - -hyd^oxy- -nUrophcnyl -N , -phenyl urea: -4-nιtrophcnyl)-N'-(4-nιtrophenyl)urca; Prclered compounds ol Formula (I ) include: N-(2-Hvdrox\ -4-nιlrophenyπ-N"-(2-n.eihuxyphenyl )urea N-(2-Hydrox\ -4-nιtrophen\ l )-N'-( 2-bromophenyl )urea -4-nιtrophenyl)-N ' -(2-phenylphcnyl )urea -4-nitrophcnyl)-N ' -(2-mcthylthιophenyl)urca N-(2-Hydrox\ -4-nιtrophenyl )-N'-(2.3-dιchlorophenyl)urea N-(2-hydroxy 4-nιiro phenyl ) N'-( 2-chloro phenyl) urea N ' -(2-Hydroxy-4-nιtrophenyl)-N'-(2,3-mcihylcnedιoxyphcnyl)urea N-(2-Hydroxy-4-nιirophcnyl)-N'-(2-mcthoxy-3-chlorophenyl)urea N-(2-hydroxy 4-nιtro phenyl) N'-(2-phcnyloxy phenyl) urea N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea N-(2-Hydroxy-3-glycιnemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea N-(3-Nιtro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3,4-dιchlorophenyl)-N ' -(2-bromophenyl)urea N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea N-(2-Hydorxy-4-cyanophenyl-N'-(2.3-dιchlorophenyl)urea N-(2-Hydrυxy-4-cyanophenyl)-N'-(2-methylphenyl)urea N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea N-(4-Cyano-2-hydroxyphenyl)-N , -(2-trifluoromethylphenyl)urea N-(3-Trinuoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(3-Phenylamιnocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea N-(2-phenylsulfonamιdo)-4-cyanophenyl-N'(2-bromo phenyDurea (E)-N-[3-|(2-Amιnocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N-(2-Hvdroxy.3.4-dιchlorophenyl)-N'-(2-methoxyphenyl)urca N-(2-Hydroxy.3.4-dichlorophenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-3.4-dιchlorophenyl)-N'-(2.3-dιchlorophcnyl)urca N-(2-Hydroxy-5-nιtrophenyl)-N'-(2.3-dichlorophenyl)urca N-(2-Hvdrox\ - ^-eyanopheny ] )-N'-(2.3 dichlorophenyburea As used herein, "opuonally substituted" unless specifically defined shall mean such groups as halogen, such as fluoπne. chlorine, bromine or iodine, hydroxy hydroxy substituted C j - 1 oalkyl: C | _ | o alkoxy. such as mcthoxy or cthoxy: S(O) n. ' C | . |() alkyl. wherein m' is 0. I or 2. such as methyl thio. methyl sulfmyl or methyl sulfonyl: amino. mono & di-substitutcd ammo, such as in the NR4R5 group: NHC(O)R4: C(O)NR4R5: C(O)OH: S(O)2NR4R5. »NHS(O)2R l 3 . C i - i o alkyl. such as methyl, ethyl, propyl. isopropyl. or t-butyl: halosubstituted C | . | () alkyl. such CF3: an opuonally substituted aryl. such as phenyl. or an optionally subsututed arylalkyl. such as benzyl or phenethyl. optionally substituted hciei ocylic. opuonally substituted heterocylicalkyl. optionally subsututed heteroaryl. optionally substituted heteroaryl alkyl. wherein these aryl . hetroarvl. or heterocyclic moieues may be substituted one to two times by halogen: hydroxy: hydroxy substituted alkyl. C i - io alkoxy: S(O)m'C l - K) alkyl; amino. mono & di-substituted amino, such as in the NR4R5 group: Ci - i alkyl. or halosubstituted C | . 10 alkyl, such as CF3. R 13 is suitably C | .4 alkyl. aryl. aryl C 1 -4alkyl, heteroaryl. hctcroarylC ] -4alkyl. heterocyclic, or heierocyclicC |-4alkyl. Another aspect of the present invention are the novel compounds of Formula (II). or a pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (II) are also useful tor treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method compπses administeπng an effective amount ol a compound of Formula (II) or a pharmaceutically acceptable salt thereof. Compounds of Formula (II) are represented by the structure: wherein X is oxygen or sulfur: R is any functional moiety having an lonizable hydrogen and a pKa of 10 or less: R 1 is independently selected from hydrogen: halogen; nitro: cyano: halosubstiiutcd C 1 - 1 alkyl: C l - io alkyl: C2- 10 alkenyl: C i- 10 alkoxy: halosubstiiuied C j . 10 alkoxy: a/.ide. S(O)tR4: hydroxy; hydroxyC i -4alkyl: aryl; aryl C ] -4 alkyl; aryloxy: arylC i .4 alkyloxy . heteroaryl: heteroarylalkyl: heterocyclic. heierocyclicC 1 -4alkyl: hcicroarylC | -4 alkyloxy . aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: heterocyclιcC2- K) alkenyl: NR4R5. C2 10 alkenyl C(O)NR4R5- C(O)NR4R5- C(O)NR4R l(): S(O ) 3H: S(O ) 3R«: C | .10 alkyl C(O)R 1 1 : C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 . C(O)R 1 1 ; C(O)OR 12 * OC(O) R 1 1 : NR4C(O)R 1 1 : or iwo R 1 moieties together may l rm 0-(CH2kO- 01 a 5 to ■ membered unsaturated πng: 1 is 0. or an integer having a value ot I or 2: s is an integer having a value ol I to 3: R4 and R5 are independently hydrogen, opuonally substituted C 1 -4 alkyl. optionally substituted aryl. optionally substituted aryl C i-4alkyl, optionally subsututed heteroar l. optionally substituted heteroaryl C i-4alkyl, heterocyclic. heierocyclicC 1.4 alkyl. or R4 and R5 together with the nitrogen to which they are attached torm a 5 to 7 member πng which may optionally comprise an additional heieroatom selected Irom O/N/S: Y is independently selected from hydrogen: halogen: nitro; cyano: halosubsuiuicd C i- ιo alkyl: C ι - 1 o alkyl: C2- 10 alkenyl; C i . ιo alkoxy: halosubstituted C i . ιo alkoxy: azide: S(O)(R4: hydroxy: hydroxy Ci-4alkyl; aryl; aryl C ] -4 alkyl: aryloxy; aryl C μ4 alkyloxy : heteroaryl heteroarylalkyl: heteroarylC ] -4 alkyloxy; heterocyclic, heterocyclic C ]-4alkyl: aryl C2- I0 alkenyl: heteroaryl C2- I0 alkenyl: heterocyclic C2- I0 alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R5 ' - C(O)NR4R5; C(O ) NR4Rl<). S(O)3H: S(O)3R8: C | - |() alkyl C ( O)R 1 1 : C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 ; C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1. NR4C(O)R ι 1 : or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 3: m is an integer having a value of 1 to 3: R8 is hydrogen or C 1.4 alkyl; RlO is C 1- 10 alkyl C(O)2R8: R l 1 is hydrogen. Ci-4 alkyl, optionally substituted aryl. optionally subsututed aryl C | -4alkyl optionally subsututed heteroaryl, optionally subsututed heteroarylC |-4alkyl. opuonally subsututed heterocyclic, or optionally substituted heierocyclicC 1 -4alkyl: Rl2 is hydrogen, Ci -io alkyl, optionally substituted aryl or optionally substituted arylalkyl: E is opuonally selected from asieπx * denoung point ol attachment of the ring, with at least one E being present. or a pharmaceutically acceptably salt thereof. Suitably, the variables for Formula (II). such as X. R. R j . R4 . Rs. R6 . R7. R«->- Y. R a . Rb. Rc* n * m. and s terms, etc. arc as defined in Formula (I) abov e The E ring denoted by its point ol attachment through the asicπx ( * > may opuonally be present II ll it is not present the πng is a phenyl moiety which is substituted by the R and R ] terms as shown At least one E πng is necessary. The E πng may be substituted by the R | moiety 111 any ring, saturated or unsaturated. and is shown for purposes herein substituted only in the 11 n sat it rated πng(s) Exemplified compounds of Formula (III) arc N-[2-hydroxy-5-ιndanonc]-N'-[2-bromophenyl | urea. N-| l -hydroxyfluorcne]-N'-[2-bromophenyl ] urea; N-[3-hydroxy-9, 10-anthraquιnon-2-yl |-N'-[2-bromophenyl | urea Another aspect of the present invention are the novel compounds ol Formula (III), or a pharmaceutically acceptable salt thereol. as described below, which arc al.so useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereol This invention al.so relates to the pharmaccuueal compositions comprising a compound of Formula (III) and a pharmaceutically acceptable diluent or earner Compounds of Formula (III > arc also uselul lot treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount ol a compound of Formula (III) or a pharmaceuucally acceptable salt thereol Compounds ol Formula (III ) are represented by the formula: wherein X is oxygen or sulfur; R is any functional moiety having an ionizable hydrogen and a pKa ol 10 or less. R ] is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C i- io alkyl: C i . i() alkyl; C2- 10 alkenyl: C\. \() alkoxy: haJosubstiiutcd C ι . ι alkoxy . a/idc. S(O)tR.4; hydroxy; hydroxyC ] -4alkyl: aryl: aryl C ι -4 alkyl: aryloxy . arylC ι .4 alkylox . heteroaryl: heteroarylalkyl: heterocyclic. heierocyclicC 1 -4alkyl. hcieioarvIC 1.4 aryl C2- 10 alkenyl: heicroaryl C2- 10 alkenyl: hctcrocyclιcC2- 10 alkeny l. NR4R . C2- I0 alkenyl C(O)NR4R5- C ( O)NR4R5: C(O ) NR4R 1 (j: S(O ) 3H. S ( O)3Rs C | - 10 alky 1 C(O)R 1 1 : C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1. C(O)R 1 1. C(O)OR 12» OC(O) Ri 1 : NR4C(O)R ι 1 : or two R i moieties together may form O-(CH2) O- 01 a 5 to 6 membered unsaturated πng: t is 0. or an integer having a value ol I or 2: s is an integer having a value of 1 to 3. R4 and R5 arc independently hydrogen, optionally .substituted C ) -4 alkyl. optionally subsututed aryl, optionally substituted aryl C | -4alkyl. optionally substituted heicroarvl. optionally substituted heteroaryl C 1 -4alkyl. heterocyclic, heterocvclicC | -4 alky 1 or R4 and R5 together with the nitrogen to which they are attached f orm a 5 to 7 member πng u lnd. may optionally comprise an additional hetcroaiom selected Irom O/N/S. Y is independently selected Irom hydrogen: halogen; nitro cyano; halosubstituted 1 - 10 alkyl. C i - i alkyl: C2- 10 alkenyl: C i - io alkoxy . halosubstiiuted C) .10 alkoxy . a/.ide S(O)tR4 hydroxy; hydroxyC | -4alkyl. aryl; aryl C j -4 alkyl: aryloxy: arylC |-4 alkyloxy: heteroaryl. heteroarylalkyl: heteroarylC 1.4 alkyloxy: heterocyclic, heterocyclicC i-4alkyl: aryl C2- 10 alkenyl; heteroaryl C2- 10 alkenyl: hetcrocyclicC2- |() alkenyl: NR4R5: C2- K) alkenyl C(O)NR4R5; C(O)NR4R5: C(O)NR4R ι»: SfOtøH: S(O)3R8- C | _ ιo alkyl C(O)R ι l ; C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R 1 1 : or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 3: m is an integer having a value of I to 3: R8 is hydrogen or C 1 -4 alkyl; R 10 is C 1- 10 alkyl C(O)2R8; Rl 1 is hydrogen, C ]-4 alkyl, optionally substituted aryl, opuonally subsututed aryl Ci-4alkyl. optionally substituted heteroaryl, optionally subsututed heteroarylC alky . opuonally subsututed heterocyclic, or opuonally substituted heterocyclicC 1 -4alkyl: R12 is hydrogen, C j - io alkyl, optionally substituted aryl or optionally substituted arylalkyl: or a pharmaceutically acceptably salt thereof. Suitably, the variables, etc. for Formula (II) arc the same as ihosc defined for Formula (I) above, such as for example the R variable Exemplified compounds of Formula (III ) are N-(2-Hydroxy-4-nιtrophenyl)-N'-(3- methoxy-2-thιenyl)urca : and N-(2-hydroxy-5-niirophcnyl)-N'-(3-methoxy-2-thicnyl)urca Another aspect ot the present invention is the novel compounds ol Formula (la), a subset of compounds of Formula (I) useful lor treating a chemokine mediated disease as defined herein This invenuon also relates to the phamiaccuucal compositions comprising a compound of Formula (la) and a pharmaceuucally acceptable diluent or carrier The compounds of Formula (la) arc represented by ihe sirucuiurc: wherein X is oxygen or sullur: Ra is an alkyl. aryl. arylC j -4alkyl. heteroaryl. heteroaryl C i-4alkyl. heterocyclic. or a heterocyclic C i -4alkyl moiety , all of which may be optionally subsututed. Rb is a NR R7, alkyl. aryl. arylC 1 -4alkyl, aryl C2-4alkenyl, heteroaryl. heteroarylC ]-4alkyl. heteroarylC2-4 alkenyl. heterocyclic, or heterocyclic Ci-4alkyl. or a heterocyclic C2-4alkcnyl moiety, camphor, all ol which may be optionally substituted one to three times independendy by halogen; nitro: halosubsututed C1-4 alkyl; Cj .4 alkyl: C1-4 alkoxy: NR9C(O)R a : C(O)NR6R7» S(O)3H. or C(O)OC 1.4 alkyl; R and R7 arc independently hydrogen or a C | .4 alkyl group, or R<s and R7 together with the nitrogen to which they arc attached torm a 5 to 7 member πng which ring may opuonally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sullur. which ring may be optionally substitued; R9 is hydrogen or a C | -4 alkyl. preferably hydrogen; Rl is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C\.10 alkyl: C 1-10 alkyl ; C2-K) alkenyl; Ci- 10 alkoxy: halosubstituted C\.10 alkoxy; azide: S(O)tR4; hydroxy: hydroxy Ci-4alkyl: aryl; aryl C] .4 alkyl; aryloxy: aryl C] .4 alkyloxy: heteroaryl: heteroarylalkyl: heterocyclic. heterocyclic C]-4alkyl: heteroaryl C]-4alkvloxy. aryl C2-10 alkenyl: heteroaryl C2- 1() alkenyl: heierocyclicC2-10 alkenyl: NR4R5; C2-10 alkenyl C ( O ) NR4R5* C ( O ) NR4R5» C ( O)NR4Ri(); S(O)3H; S(O)3R8- Ci-io alky) C(O)R 11; C2-IO alkenyl C(O)R 11 : C2-IO alkenyl C(O)OR 11 : C(O)R 11 ; C(O)OR 12: OC(O) Rl 1 : NR4C(O)R 11 ; or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; t is 0, or an integer having a value of 1 or 2. s is an integer having a value of 1 to 3: R4 and R5 are independently hydrogen, opuonally subsututed Ci-4 alkyl. optionally substituted aryl. optionally .substituted aryl C]-4alkyl, opuonally substituted heteroaryl. opuonally substituted heteroaryl C|-4alkyl. heterocyclic. heierocyclicC 1 -4 alkyl. or R4 and R5 together with die nitrogen to which they are attached lorm a 5 to 7 member πng which may optionally compπse an additional hcicroatom selected from ON/S. Y is independently selected Irom hydrogen: halogen: nitro: cyano: halosubstituted Ci- 10 alkyl. C l-io alkyl. C2- 10 alkenyl: Ci- 10 alkoxy: halosubstituted Ci- 10 alkoxy: azide: S(O)tR4. hydroxy: hydro\yC|-4alkyl: aryl; aryl C|-4 alkyl: aryloxy; arylCi-4 alkyloxy: heteroaryl. heteroarylalky 1: heteroarylC 1 -4 alkyloxy. heterocyclic. hetcrocyclicC 1 -4alkyl. aryl C2- 10 alkenyl: heteroaryl C2-10 alkenyl: hcicrocyclιcC2-]() alkenyl: NR4R5. C2-10 alkenyl C(O)NR4R5- C(0 ) NR4R5* C ( O ) NR4Rιo. S(O)3H: S(O)3Rχ. Ci-io alkyl C(O)R| ι» C2- 1 alkenyl C(O)R 11- C2-10 alkeny I C(0)OR 11 : C(O)R 11 : C(O)OR 1 Ύ. OC(0) R 11. NR4C(O)Ri 1. or two Y moieties logcthei may lorm 0-(CH2) . sO- 01.15 to 6 membered unsaturated ring. n is an integer having a value ol I to 3. m is an integer having a value ol 1 to 3. R8 is hydrogen or ]-4 alkyl. R 10 is C i - io alkyl C ( O)2R8; R 1 1 i.s hydrogen, C |-4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl. optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or opuonally substituted heierocyclicC i -4alkyl; R 12 is hydrogen, C i- io alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof. A preferred ring substitution for R i variable is monosubstituted in the 3-position. or the 4- position, or di-.substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably R j is nitro, halogen, cyano, trifluoromethyl group, or C ( O ) NR4R. While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstitutcd. If the ring is di-substituted. substituents are preferably in the 2'-, 3 - positions of a monocyclic ring. While both Rj and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more. Y i.s more preferably a mono-substituted halogen, disubstituted halogen, mono- substituted alkoxy. disubstituted alkoxy, methylenedioxy, aryl, or alkyl. preferably these groups arc substituted in the 2'- position or 2'-,3'-position. Exemplified compounds of Formula (la) are N-(4-Nuro 2-(phcnylsulfonylamino)phcnyl)-N'-phcnyl urea N-[(2-Phcnylsullamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea N-(2-(Amιno sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amιno sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea 2-[(3.4 Dι-mcihoxyphenylsulfonyI)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-[(4-Accιamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-(Amιno sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino sulfonyl (3-tolyl) phenyl) N'-(2-bromo phenyl ) urea N-(2-( Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea N-| 2-[| |2-(Trifluoromcthyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea N-(2- Bromophenyl )-N'-f2-dimethylamιnosuIfonylamino]phcnyl]urca N-[2-(Pheneιhylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea N-[2-f(2-Acetamido-4-mcthylthiazol-5-yl)sulfonylamino]phcnyl]-N'-(2-bromophenyl)urea N-[2-|(2.3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(3.5-Bιstrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-brυmophenyl)urca N-I2-[(2-Benzyl)sulfonylamino]-(5-trifluoromeihyl)phenyl |-N'-(2-bromophcnyl)urea N-[2-|2-(3-Nitrophenyl)sullonylamιno)phcnyl]-N'-(2-bromophenyl)urea N-[2-[2-(4-Phcnoxyphenyl)sulfonylamino]phenyl|-N'-(2-bromophenyl ) urea N-[[2-( I S)- l () -Camphorsulfonylamino]phenyl]-N'-(2-bromophcnyl)urea N-[[2-( lR)- 10-Camphorsulfonylamino]phenyl]-N'-(2-bromophcnyl)urca N-[2-[2-(2-Nitro- ( 4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl )urca N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenyl)urea N-[2-(amιnosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea Another aspect of the present invention is the novel compounds of Formula (lb), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (lb) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (lb) are represenied by the sirucuture: wherein X is oxygen or sulfur; X l i.s oxygen or sulfur; R l is independently selected Irom hydrogen: halogen; nuro: cyano: halosubstituted C ] - io alkyl: C i - io alkyl: C2- 10 alkenyl: C i- K) alkoxy: halosubsiiiuied C j - io alkoxy : azide: S(O)tR4; hydroxy: hydroxyC i -4alkyl: aryl; aryl C i-4 alkyl: aryloxy: arylC i -4 alkyloxy: heieroaryl heteroarylalkyl: heterocyclic, heterocyclic C ) -4alkyl: heteroaryl C i -4 alkyloxy: aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: heierocyclicC2- 10 alkenyl: NR4R5. C2- 10 alkenyl C(O)NR4R5: C(O)NR4R5: C(O)NR4R lo: S(O)3H: S(O)3R8: C | - i() alkyl C(O)R 1 1 : C2- 1 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 ; C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R 1 1 : or two R 1 moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; t is 0. or an integer having a value ol I or 2: s is an integer having a value of 1 to 3: R2 is a substituted aryl. heteroaryl, or heterocyclic ring which ring has a functional moiety providing the iomzable hydrogen having a pKa of 10 or less: R4 and R5 are independently hydrogen, optionally substituted C j -4 alkyl, optionally subsututed aryl, optionally substituted aryl C |-4alkyl, opuonally subsututed heteroaryl. optionally substituted heteroaryl C i -4alkyl, heterocyclic. heierocyclicC 1 -4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member πng which may opuonally comprise an additional heteroatom selected from O/N/S: Y is independently selected from hydrogen: halogen: nilro; cyano: halosubstituted C 1 - 10 alkyl: C 1.1 alkyl: C2- 1() alkenyl: C | . |() alkoxy: halosubstituted Cj - io alkoxy: azide: S(O)[R4: hydroxy; hydroxyCi-4alkyl: aryl; aryl C |-4 alkyl: aryloxy: arylC i-4 alkyloxy: heteroaryl; heteroarylalkyl: heteroarylC 1 -4 alkyloxy; heterocyclic. heterocyclicCi-4alkyl: aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: heterocyclicC2- 1 alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R5» C(O)NR4R5» C(O ) NR4Rlθ; S(O)3H; S ( O)3R8- Cj - io alkyl C(O)R j 1 : C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12 OC(O) R 1 1 : NR4C(O)R 1 1 ; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring: n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; R8 is hydrogen or C 1.4 alkyl; R lO is C 1- 10 alkyl C(O)2R8: R ] 1 is hydrogen, C ] -4 alkyl. optionally subsututed aryl, optionally substituted aryl Ci-4alkyl, opuonally substituted heteroaryl, optionally subsututed heteroarylC | -4alkyl, optionally subsututed heterocyclic. or opuonally substituted heierocyclicC i -4alkyl: R 12 is hydrogen. C i - 10 alkyl. optionally substituted aryl or optionally substituted arylalkyl: or a pharmaceutically acceptable salt thereof. Suitably, the variable, etc. for Formula (lb) are the same as those defined lor Formula (I ) above, such as for example the functional moieties on the R2 group having an ionizablc hydrogen with a pKa ol 10 or less. Suitably such functional groups include, but arc noi limited lo. hydroxy. carboxylic acid, ihiol. -NH-C(O)R a . -C(O)NR6R7. substituted sullonamidcs of the lormula -NHS(O)2Rb- -S(O)2NHR . NHC( X2)NHR n . or tcira/.oyl (as defined lor Formula (I) Suitably lor compounds of Formula (lb), a prclerrcd ring substitution lor R ] is in the 3-posιtιon. the 4- position 01 is prclerably di substituted in the 3.4- position The substituent group is suitably an electron withdrawing moiety Prclerably R 1 is nitro. halogen, cyano. tπfluoromethyl group, or C(O)NR.4R5 While Y may be substituted in any of the 5 ring posiuons. preferably the πng with the Y moiety is mono-substituted in the 2-posιtιon or 3- position, with the 4- preferably being unsubstitutcd If the ring is disubstituted. substitucnts arc prelerably in the 2' or 3' position ol a monocyclic πng While both R i and Y can both be hydrogen, it is prefered that at least one ol the rings be substituted, preferably both rings arc at least mono-substituted, l.c n amd m are each equal to 1 or more Suitably lor compounds of Formula (lb), Y is more preferably disubsututed halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy. methylencdioxy. aryl, or alkyl, preferably in the 2'posιtιon or 2'.3'-positιon Another aspect of the present invention is the novel compounds of Formula (Ic). a subset of compounds of Formula (I) useful for treating a chemokine mediated disease This invenuon also relates to the pharmaceutical compositions compπsing a compound ol Formula (Ic) and a pharmaceuucally acceptable diluent or carrier The compounds ol Formula (Ic ) are represented by the strucuture: wherein X is oxygen or sulfur; X ι is oxygen or sulfur: R l is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C μ io alkyl : C i - 1 () alkyl: C2- 10 alkenyl: C \ . \ alkoxy: halosubstituted C i . | o alkoxy: azide. S(O)tR4: hydroxy: hydroxyC | -4alkyl; aryl aryl C μ4 alkyl: aryloxy. aryl C | -4 alkyloxy heteroaryl: heteroarylalkyl: heterocyclic. heierocyclicC i-4alkyl: heteroarylC ] .4 alkyloxy aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: heterocyclic C2- 10 alkenyl. NR4R . C2- I 0 alkenyl C(O) R4R5: C(O)NR4R5; C(O)NR4R 1 (j: S(O)3H: S(O)3Rκ» C | . |(> alkvl C(O)R 1 1 : C2- 10 alkenyl C(O)R 1 1 ; C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 . C(O)OR 12 OC(O) Ri 1 : NR4C(O)R i | * . or two R j moieties logether may form O-(CH2)ςO- ot a 5 to ( * membered unsaturated πng: t is 0. or an integer having a value ol I or 2: s is an integer having a value ol I lo 3. R4 and Rs are independently hydrogen, optionally subsututed C i -4 alkyl. optionally substituted aryl. optionally substituted aryl C | -4alkyl. optionally subsututed heteroary l. opuonally substituted heteroaryl C 1.4 alkyl. heterocyclic. heterocyclic C | .4 alkyl. or R4 and R together with the nitrogen to which they arc attached lorm a 5 to 7 member ring which may optionally comprise an additional hctcioaiom selected Irom O/N/S. Y is independently selected irom halogen: nitro. cyano. halosubsututed C i- 10 alkyl: C μ io alkyl: C2- 10 alkenyl. C i- io alkoxy; halosubsututed C i- io alkoxy: azide: S(O)tR4. hydroxy: hydroxy C ] -4alkyl: aryl. aryl C ] -4 alkyl: aryloxy: arylC i -4 alkyloxy. heteroar l. hetcroarylalkyl: heteroarylC i .4 alkyloxy: heterocyclic, heterocyclic C i-4alkyl: aryl C2- 10 alkenyl; heteroaryl C2- I0 alkenyl; heterocyclic C2- 10 alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R.5: C(O ) NR4R5: C(O)NR4R |(): S(O)3H: S(O)3R8: C i - 10 alkyl C(O)R ι \ : C2- 10 alkenyl C(O)R 1 1 ; C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R 1 1 : or two Y moieties together may lorm O-(CH2)sO- or a 5 to 6 membered unsaturated πng: n is an integer having a value of I to 3; m is an integer having a value of 1 to 3: R8 is hydrogen or C 1.4 alkyl; R 10 is C 1 - 10 alkyl C(O ) 2R8: R l 1 is hydrogen. C j-4 alkyl, optionally substituted aryl, optionally subsututed aryl C |-4alkyl. optionally substituted heteroaryl, optionally subsututed heteroarylC i-4alkyl, opuonally subsututed heterocyclic, or opuonally subsututed heierocyclicC i-4alkyl; Rl2 is hydrogen. Cj-io alkyl, optionally substituted aryl or optionally substituted arylalkyl. provided that when n =1 than Y is subsututed in the 2- or 3- position; when n =2 than Y is di-subsiituted in the 2'- 3'- position, the 2'-5'- position, the 2'-6' position, the 3'-5' or the 3'-6' position; when b = 3 than Y is trisubsiitutcd in the 2'-3'-5' or the 2'-3'-6 - positions; further provided that when X ] is O. m=2. R i is 2-t-butyl. 4-methyl. and n=3 than Y is not 2 -OH.3'-t- butyl. 5 -mcthyl: when X i is O. m= l . R ] is 4-mcthyl. and n=2 than Y is not 2'-OH. 5 '-methyl: when X | is O. m=l . R ] is hydrogen, and n=2 than Y is noi 2'-6'-dιethyl: when X ) is O. m=l . R ] is 6-OH. and n=2 than Y is not 2'-5'-mcthyl: when X i is S. m= l . R | i 4-ethyl. and 11= I than Y is not 2-mcihoxy: or a pharmaceutically acceptably salt thereol Suitably , the variables, etc. lor Formula (Ic) arc the same as those defined lor Formula (I) above unless indicated Suitably lor compounds ol Formula (Ic). a preferred ring substitution lor R j is in the 3-posιtιon. the 4- position or di substituted in the 3.4- position Preferably R l is other than hydrogen The substituent group is suitably an electron withdrawing moiety Prclerably R I S nitro. halogen, cyano. iπfluoromeihyl group, or C(O)NR4R5. While Y may be subsututed in any ol the 5 ring positions, prelerably the πng with the Y moiety is mono-substituted in t e 2-posιtιon or 3- position, with the 4- preferably being unsubstituted. II the πng is disubstituted, substituents are preferably in the 2' or 3' position ol a monocyclic πng. While both R ] and Y can both be hydrogen, u is prclered that at least one ol the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to I or more. Suitably for compounds of Formula (Ic), Y is more preferably a mono-substituted halogen, disubsututed halogen, mono-substituted alkoxy, disubs tuted alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'posιtion or 2.3-positιon Exemplified compounds of Formula (Ic) are: N-|2-Hydroxy-4-(methoxycarbonyl)phcnyI)-N'-phenylurea; N-]2-Hydroxy-5-nιtro-phenyl]-N'-phenyl urea N-(2-Hydroxy-4-tluorophenyl)-N'-phenyl urea N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea N-(2-Hydroxy-4-nιu * ophenyl)-N'-(2-hydroxy-4-nιtrophenyl) urea N-(2-Hydroxy-4-nιtrophenyI)-N'-phenyl-thiourea N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea N-(2-Hydroxy-4-mtrophenyl)-N'-(3-methoxy-2-thιenyl)urea N-(2-Hydroxy-4-niιrophenyl)-N'-(3-methoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-nιirophenyl)-N'-(3-trifiuoromethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea N-(2-Hydroxy-4-nιirophenyl)-N'-(4-trifluoromethylphenyl)urea N-(2-Hydroxy-4-nιtrophenyl)-N'-(2-bromophcnyl)ι * rea N-(2-Hydroxy-4-nιtrophenyl)-N'-(3-bromophcnyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromophenyl)urea N-(2-Hydroxy-4-nιtrophcnyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-4-nιtrophcnyl)-N'-(2-nιtrophcnyl)urca N-(2-Hydroxy -4-nιirophenyl)-N'-(2-fluorophcnyl)urea N-(2-Hydroxv-4-nurophcny )-N'-(2.6-dιfluorophcnyl )urca N-(2-Hydroxy-4-nιirophcnyl)-N'-(2-cιhoxyphcnyl )urea N-(2-Hydroxy -4-nitrophenyl)-N'-(2-eihylphcnyl )urca N-(2-Hydroxy -4-nurophcnyl)-N'-(2-ιπfluoromcthoxyphenyl)urea N-(2-Hydroxy -4-nιtrophenyl) N'-(2-mcthylihιophenyl ) urea N-(2-Hydroxy-4-nιtro-phcnyl) N'-(2-chloro 6-mcthyl phenyl) urea N-(2-Hydroxy -4-nιtro-phenyl) N'-(2-sulloxymcthyl phenyl) urea N-(2-Hydroxy -4-ιrifluoromethyl phenyl)-N'-(2-bromo phenyl) urea N-(2-Hydroxy-4-tπfiuoromethyl phenyl)-N'-(2-phenyl phenyl) urea N-(2-Hydroxy-4-carbomelhoxy phenyl)-N'-( 2-phenyl phenyl) urea N-i2-Hydroxy-4-nιtrophcnyl)-N'-(2.3-dιchloro phenyl) urea - 25 N- Hydroxy-4-nitrophenyl)-N'-(2.4-dιchloro phenyl) urea N- Hydroxy-4-nitrophenyl)-N'-(2-chloro phenyl) urea N- Hydroxy-4-nitrophenyl)-N'-(2,4-dibromo phenyl) urea N- Hydroxy- l-napthyl)-N'-(2-bromo phenyl) urea N- Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea N- Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea N-; Hydroxy-4-(Benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)urea N- Hydroxy-4-nitro phenyl)-N'-(2-phenoxy phenyl) urea N- Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea N- Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea N- Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea N- Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea N- Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea N- Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea N- Sulfhydryl-4-bromo phenyl)-N'-(2-bromo phenyl) urea N- Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea N- Hydroxy 4-niiro phenyl)-N'-(2-bromo phenyl) thiourea N- Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea N- Hydroxy-5-cyanophenyl]-N'-[ 2-bromophenyl] urea N- Hydroxy-3-fluorophenyl]-N'-[2-bromophenyI] urea N-l Hydroxy-3-fiuoro-5-bromophenyl]-N'-f2-bromophenyl] urea N- Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea N- Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl | urea N- hydroxy-3.4-diphenyl phenyl]-N'-[2-bromophenyl] urea N-, Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea N- Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea N- Hydroxy-3.5-dichlorophenyl]-N'-|2-bromophenyl] urea N- Hydroxy-3-niιrophenyl]-N'-(2-bromophenyl] urea N- Hydroxy-3.4-dichlorophenyl]-N'-[2-bromophenyl] urea N- Hydroxy-3-cyanophenyl]-N'-(2-bromophenyl] urea N- Hydroxy-4-cyanophenyll-N'-f2-bromophenyl] urea N- Hydroxy-4-cyanophenyl]-N'-(4-methoxyphenyl] urea N- Hydroxy-4-cyanophenyl]-N'-[2-phcnylphenyl] urea N- Hydroxy-4-cyanophcnyl]-N'-[2-mcιhylphenyl] urea N- Hydroxy-4-cyanophenyl]-N'-[2-trifiuoromethylphenyl] urea N- Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N- Hydroxy-4-cyanophenyl]-N'-(4-irifluoromethylpheny]] urea N- Hydroxy-3-n-propylphenyl]-N'-|2-bromophenyl] urea N-(2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-|2-bromophenyl] urea N-[2-Hydroxy-3-cyano-4-methylphenyl|-N'-f2-bromophenyl ) urea N-[2-Hydroxy-4-carbophenyl phenyl ]-N'-(2-bromophenyl] urea N-(2-Hydroxy-3-carbophenyl phenyl )-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl|-N'-[2-bromophcnyl | urea (E)-N-[3-[2- ( Methoxycarbonyl)ethenyI]-2-hydroxyphenyl]-N'-[2-bromophenyl ]urea-.N - bromophenyl] urea (E)-N-[3-f2-(Aminocarbonyl)elhenyl]-2-hydroxyphenyl]-N'-[2-brυmophenyl |urea-N -[ 2- bromophenyl] urea (E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-f2-bromophenyl |urca-N -| 2- bromophenyl] urea N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-aminocarbonyl phenyl]-N'-[2-bromophenyl] urea N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea N-[2-Hvdroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl | urea N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl| urea N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3.4-dichlorophenyl]-N'-(2-methoxyphenyl ] urea N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|4-methoxyphcnyl | urea N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|2-phenylphenyl] urea N-f2-Hydroxy-3.4-dichlorophenyl]-N'-[4-phenylphenyl] urea N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[2.3-dichlorophcnyl ] urea N-[2-Hydroxy-4-ιsopropylphenyl]-N'-[3-irifluoromethylphcnyl| urea N-[2-Hydroxy-3-naphthyl|-N'-[2.3-dichlυrophenyl] urea N-(2-Hydroxy-4-azidophenyl)-N'-(2-ιodophenyl)urea N-(2-Hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea N-[2-Hydroxy-3-cyanophenyl]-N'-f2-methoxyphenyl] urea N-[2-Hvdroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-3-cyanophcnyl]-N'-[2-phcnylphenyl | urea N-|2-Hydroxy-3-cyanophcnyl]-N'-|2.3-dichlorophenyl| urea N-f2-Hydroxy-4-isopropylphenyl]-N'-f2,3-dichlorophcnyl) urea N-f2-Hydroxy-4-isopropylphenyl]-N'-(2-chloro-5-trifluoromcthylphcnyl | urea N-[2-Hydroxy-3-phenylphenyl ]-N'-f 2,3-dichlorophcnyl ] urea N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea N-[2-Hydroxy-5-nitrophenyl]-N ' -(3-trifiuoromethylphenyl| urea N-[2-Hydroxy-5-nitrophenyl)-N'-[2-phenylphenyl] urea N-f2-Hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophcnyl] urea N-[2-Hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl| urea N-[2-Hydroxy-3,4-dichlorophcnyl]-N'-[2,4 dimethoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-f2-chloro-5-trifluoromeihylphcnyl] urea N-[2-Hydroxy-3,4-dichlorophenyI]-N'-f benzyl] urea N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl| urea N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl| urea N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea N-[2-Hydroxy-3-naphthyl]-N'-[ benzyl] urea N-f2-hydroxy-3-(phenylaminocarbonyl) phenyl]-N'-[benzoyI] urea N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[benzoyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[benzoyl] urea N-f 2-Hydroxy-5-naphthalenesulfonic acιd]-N'-[2-bromophenyl ] urea: N-[2-Hydrox y-4-naphthalcnesullonic acid]-N'-f 2-bromophcnyl | urea; N-(2-Hydroxy 3-napihyl) N'-(2-bromo phenyl) urea: N-(2-Hydroxy- l -napthyl)-N'-(2-bromo phenyl) urea: N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyDurea: Suitable pharmaceutically acceptable salts are well known to those skilled in the an and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuπc acid, phosphoπc acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citπc acid, lacuc acid, oxalic acid, succimc acid, lumaπc acid. maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandchc acid. In addition, pharmaceuucally acceptable sails of compounds of Formula (I) may also be lormcd with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cauons are well known to those skilled in the an and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to. • "halo" - all halocens, that is chloro. Ωuoro. bromo and lodo • "C ]. |oalkyl" or "alkyl" - both straight and branched chain radicals ol I to 10 carbon atoms, unless the chain length is otherwise limned, including, but not limited to. methyl, ethyl, /.-propyl, /.sr.-propyl, n-bulyl, sec -butyl, ..w'-butyl. te/7-hutyl. /7-pentyl and the like • The term "cycloalkyl" is used herein to mean cyclic radicals, preferably ol 3 to 8 carbons, including but not limited to cyclopropyl. cyclopentyl. cyclohexyl. and the like • The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2- 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to cthenyl, 1 -propenyl. 2-propenyl. 2-mcihyl- l -propenyl. 1 -buienyl, 2-buicnyl and the • "aryl" - phenyl and naphthyl; • "heteroaryl" (on us own or in any combination, such as "hetcroaryloxy". or "heteroaryl alkyl") - a 5- 10 membered aromatic πng system in which one or more rings contain one or more heteroatoms selected from the group consisting of N. O or S. such as. but not limited, to pyrrole, pyrazole. furan. thiophene. quinoline. lsoquinolmc. quinazolinyl. pyπdine. pyπmidme, oxazole, thiazolc, thiadiazole, tπazole, lmidazole, or benzimidazolc • "heterocyclic" (on its own or in any combination, such as "hctcrocyclicalkyl") - a saturated or partially unsaturated 4- 10 membered nng system in which one or more πngs contain one or more heteroatoms selected from the group consisting of N. O, or S. such as, but not limited to. pyrrohdine, piperidine, piperazme. morphohne, tetrahydropyran. or lmidazolidine. • The term "arylalkyl" or "heteroarylalkyl" or "hetcrocyclicalkyl" is used herein to mean C i - ιo alkyl. as defined above, attached to an aryl. heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated • "sultinyl" - the oxide S (O) ol the corresponding sullidc. ϋic term "thio' relcrs to the sullidc. and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety • The term "wherein two R \ moieties (or two Y moieties) may together lorm a 5 or 6 membered unsaturated πng" is used herein to mean the tormation ol a napthylcne ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a Ct, cycloalkcnyl. i.e hexenc. or a C5 cyloalkenyl moiety, cyclopcntene The compounds ol Formula (I). (la), (lb). ( Ic). ( II) and (III) may be obtained by apphing synthetic procedures, some ol which are illustrated in the Schemes below The synthesis prouded lor in these Schemes is applicable lor the producing compounds ol Formula (I), da). (II ) and (III) having a variety ol diltcrcni R. R |. and Ar groups which are icactcd. employing opuonal subsutucnts which arc suitably protected, to achieve compatibility with the reactions outlined herein Subsequent deprotection. in those cases, then aflords compounds ol the nature generally disclosed Once the urea nucleus has been established, lunher compounds of these formulas may be prepared by applying standard techniques for functional group interconversion. well known in the an. While the schemes arc shown with compounds only of Formula (I) this is merely for illustration purposes only. Scheme 1 R=NH 2 , OH, C0 2 H, SH a)PhNCO NHS0 2 R Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard conditions involving the condensation of commercially available ortho subsututed aniline(Aldrich Chemical Co.. Milwaukee, Wi) with the commercially available optionally substituted aryl isocyanaie (Aldrich Chemical Co., Milwaukee, Wi) in an aprotic solvent (DMF, toluene). When the l-(RSO2NH)2-(NH2)Ph is not commercially available it can be made by treating the commercially available RSO2CI with the cooresponding 2-phenylene diamine in the presence of an base like ethyl amine or NaH in an aprotic solvent (like methylene chloride or DMF). Scheme 2 R"=OH. NH 2 . NHS0 2 R a)HN0 3 . 23 °C b)SnCI 2 . EtOH If the desired 2-subsιuuιcd aniline 5-schemc 2. is noi commercially available the corresponding nitro compound can be prepared from 3-schemc 2. under standard nitration conditions (using HNO^ or BF4NO ) al 23 °C. The nitro compound is then reduced to the corresponding aniline using SnCb in EtOH(or alternately H2/Pd or LiAlFLj). Scheme 3 £ a)NH 4 SCN. Br 2 b)NaOH EtOH II the desired 2-amιno benzenethiol 8-schemc 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence ot an oxidantdike bromine) lo produce the 2-amιno benzthiazole 7-schemc 3 This thiazole can then be hydrolyzed to the desired 2-amιno benzenethiol 8 -scheme 3 with a strong base like NaOH in a protic solvent (I e . EtOH) Scheme 4 N N JO U2 x=s. o 11 a)TBSCl imid. DMF b)ι)CICXCI, NaHC0 3 ιι)PhNH 2 c)Et 3 N-HF CH 3 CN In the case where the thioisocyanate or phenyl isocyanate is not commercially a\aιlablc. the thiourea or urea 1 1 -scheme 4 may be prepared from the commercially a .ailable onho substituted aniline This compound is first protected with a protecting group (icn-buiyl dimethyl silyl or ben/yl ) by conditions well known in the arKsec Greene. T Protecting Groups in Organic Synthesis. Wiley&Sons. New York. 1981 ) This protected aniline is then reacted, in the presence ot a base(lιkc methyl amine or sodium bicarbonate), with either ihiophosgene or a solution ol phosgene in an aprotic solvent (ic DMF. toluene), followed by aniline lo produce the protected thiourea or urea respectively The corresponding urea or thiourea is then dcprotccicd. using condiuons standard in die art. to lorm the desired thiourea or urea 1 1 -scheme 4 Scheme 5 a)(PhO) 2 PON 3 ,Et 3 N b)PhXNH 2 X=OH, NHS0 2 R, SH Alternately the urea can be formed using a Curtius rearrangement from the corresponding aromauc or thiophene carboxylic acid 12-scheme 5 The carboxy c acid is submitted to standard Curuus condiuons ((PhO^PONi, Et N or C1COCOC1 followed by NaN ) and the intermediate isocyanate is trapped by an appropπately subsututed aniline. Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropπate amount of acid or base in the presence of a suitable solvent Another aspect of the present invention is the novel synthesis of cyano nitrophenol intermediates Numerous conversions of aryl halides to aryl cyano deπvatives with copper (I) cyanide have been published. However, no examples of an aryl ring with a hydroxy group present were mentioned Several attempts to obtain a cyano phenol moiety with published results tailed Using known conditions of elevated temperatures, greater than 170 ° C. uch as Irom 180 to 210 did not yield displacment of the halogen to a cyano moiety Standard bases such as DMF and pyπdine further provided no desired product Intermediates such as 2- amιno-5-.luorophenol. 2-nιtro-5-fluorophenol, 2-nιlro-5-meihyl-6-bromophenol were tπcd with a change ol halogens, from lluoπne to chloπne to bromine, and with use ol copper ( I ) cyanide The use ol a bromine derivative, such as 2-nιtro-5-methyl-6-bromophenol . with dimethyllormamide and using tπethylamine with a catalytic amount ol dimelhylamino pyπdine and copper (I) cyanide at reduced temperatures, i.e <100°C. prclerably 60 to about 80 C lor reduced times Irom strandaπzed procedures, i.e , < 18 hours, prclerably about 4 to 6 houi s yielded the desired products Thcrctore one aspect ol the invention is to a process lor producing a cyano phenol deπvatnc ol the lormula * wherein R i is as defined for Formula (I) above, which method comprises reacting a compound of the formula: R ' wherein X is halogen with copper (I) cyanide, dimethyllormamidc. triethylamine and a catalytic amount of dimethylamino pyridine. Preferably, the process is run at reduced temperatures of about 60 to about 80°C. Preferably X is bromine. In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. ■ H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively. Multiplicities indicated arc: s=singlet. d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, equiv. indicates the proportion of a molar equivalent of reagent relative to the principal reactant. Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh) SYNTHETIC EXAMPLES The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope ol the present invention. All temperatures are given in degrees centigrade, all solvents used herein are ol the highest available purity and all reactions are run under anhydrous conditions in an argon atmosphere unless otherwise indicated. General Method A: Synthesis of N, N'- phenyl urea To a solution ol substituted phenyl isocyanaie (l .O equiv.) in toluene (5 miliLitcrs (hereinafter "mL")) the coπesponding aniline ( 1.0 equiv.) was added. The reaction mixture was suncd al about 80°C until complete (24-48 hours (hereinafter "hrs" or "h"))» then cooled to room temperature The purifications, yields and spectral characteπstics for each individual compound are listed below General Method B: Synthesis of N, N'- phenyl urea To a solution ot phenyl isocyanaie ( 1.0 equiv.) in dimethyl formamide ( ImL) the coπesponding aniline ( I 0 equiv ) was added. The reaction mixture was stined at about 80°C until complete (24-48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics lor each individual compound are listed below General Method C:Synthesis of sulfonamide The ortho substituted aniline ( 1 equiv ). triethyl amine ( 1 equiv.) and the desired sulfonyl chloride ( 1 equiv ) were combined in methylene chloπde and allowed to stir at about 23 °C until complete ( 12-36 h) The reaction mixture was partitioned between water and methylene chloπde. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vac no The purifications of each compound are listed below Example 1 Preparation of N-f2-Hvdroxy-4-(methoxycarbonyl)phenyll-N'-phenyl urea N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from methyl-4-amιno-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanaie ( 1 19 mmol i according to the procedure noted above in General Method A The product was puπlicd by precipitation from toluene, and filteπng, to afford the titled compound (309 mg, 0^) mp 188.4- 188.8°C: - H NMR (CD3OD/CDCI3): 6 8.15 (d, 1 H. J = 8.25 Hz). 7.70 (s, 1 H), 7 51 (d, 1H, J = 8.25 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, J = 8.25 Hz), 7.01 (t, I H. J = 8.25 Hz), 3.87 (s, 3H): EI-MS m/z 286 (»M+H) + : Anal. C15H 14 N2O 4 ) C. H. N Example 2 Preparation of N-[5-nιtro-2-hvdroxyphenyll-N'-phenyl urea The N-[5-nιtro-2-hydroxyphenyl]-N'-phenyl urea was prepared Irom ihc 5-miro 2 hydroxy aniline and phenyl isocyanaie according to the procedure in General Method A The * ^ product was purified by precipitation Irom toluene and filtering to allord the titled compound ( 100 mg. 30*70 I H NMR (CD3OD): 6 9 48 (s. I H. NH). 9 07 (d. .1 = 1 56 Hz. NH ). 8 5*. (s. I H), 7 80 (dd. I H. .1 = 6.25 Hz and J = I 56 Hz). 7 50 (d. 2H. J = 6 25 Hz). 7 30 (t. 2H J = 6.25 Hz). 7 01 (m. 2H) EI-MS m/z 273 (M+H) + 0 Example 3 Preparation of 3-hydroxy-4-(f(phenylamino)carhonyllaminolhcn/amide a)Prcparatιon ol 0 67 Molar (hcreinalicr "M") Stock Solutions ol Aluminum Amide Reagents To a suspension ot die appropriate hydrochloπde (002 mole ( heieinaltci "mol" )) in dι \ toluene (20 mL) at about 0°C. was slowly added a solution ol (2M. 10 mL) ot tπmethyl ^ aluminum in toluene Alter the addition was complete, me reaction mi.xtuie was allowed lo warm to room temperature and was stirred lor about 1 -2 hours until gas olution has ceased b)Preparauon of 3-hydroxy-4-{[(phenylamιno)carbonyl]amιno }bcnzamιde To a solution of the N-[2-hydroxy-4- ( mcthoxycarbonyl)phcnyl |-N'-phenyl urea (60 miligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mL) was added aluminum amide reagent (0.9 mL, 0.67M) The reaction mixture was stirred al reflux for about 12 hours. The reaction mixture was cooled to room temperature and was carefully quenched with 5% HC1. The organic layer was separated and the aqueous layer was extracted three limes with ethyl acetate The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (ethyl acetate) gave the desired amide (28 mg. 49%). mp: 106.8- 107.1 °C: *H NMR (CD3OD/CDCI 3 ): 6 7.98 (d, I H. J = 8.25 Hz), 7.35 (d, 2H, J = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7 17 (1, 2H. J = 8.25 Hz). 6.91 (t, I H, J = 8.25 Hz): EI-MS m/z 271 (M+H) + : Anal (C uH πN^Oi) C. H. N Example 4 Preparation of N-(2-hvdroxv-4-Ωuorophenvl)-N'-nhenvl ure.a a)Preparation of 2-amιno-5-fluoro phenol A mixture of 5-fluoro-2-nιtrophenol (500 mg, 3. 18 mmol) and tin (II) chloπde ( 1.76 g, 9.2 mmol) in ethanol ( 10 mL) was heated at 80°C under argon. After 30 min. the starting material had disappeared and the solution was allowed to cool down and then poured into ice The pH was made slightly basic (pH 7-8), by addition of 5% aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered. Evaporation of the solvent gave the title compound(335 mg, 83 ). Η NMR (CDnOD/CDC ): 6 6.6 (m. I H), 6.38 (dd. I H, J = 8.3 H/ and J = 2.8 Hz). 6.29 (m. I H). b)Preparatιon of N-(2-hydroxy-4-fluorophenyl)-N'-phcnyl urea N-(2-Hydroxy-4-fiuorophcnyl )-N'-phcnyl urea was prepared I ron. 2-amino-5-fluoro phenol (2(X) mg. 1.57 mmol ) and phenyl isocyanaie according to the procedure in General Method A. The product was purified by precipiiation Irom toluene and filtering to allord the titled compound (352 mg. 91 9? ) mp: 195.5- I95.7°C: - H NMR (CD^OD/CDCh): δ 7 70 <m. I H). 7.3 (d. 2H. J = 8.25 Hz). 7. 15 ( l. 2H. J = 8.25 Hz). 6.89 α. I H. J = 8.25 Hz). 6 50 - 6.38 (m. 2H): EI-MS m/z 246 (M+H) + . Anal (C πH n ^O: F) C. H. N Example 5 2-{ |(Phenylamιno)carbony l|amιno }thιophcnol was prepared Irom 2-amιnoιhιophcnol (200 mg. 1 6 mmol ) and phenyl isocyanaie according to the pioccdurc in General Method A The product was purified by precipitation Irom toluene and filtering lo allord the titled compound (330 mg. 85 7c) mp: 194.5°C; -H NMR (CD^OD/CDCh): δ 7 48 - 7.26 <m. 4H). 7.25 - 7 10 (m. 3H). 7 04 - 6 79 ιm. 2H); EI-MS m/z 244 (M+H r. Anal C. H. N Example 6 Preparation of N-(2-Carhoxy-4-hydroxyphenyl)-N"-phcnyl urea N-(2-Carboxy-4-hydroxyphenyl)-N'-ρhcnyl urea was prepared Irom 2-amιno-5- hydroxy benzoic acid ( I g, 6.53 mmol) according to the procedure in General Method B. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with bπne, dried over MgSO4 and filtered. Removal of solvent under reduced pressure and chromatυgraphy of the resulting solid on silica gel (hexane : ethyl acetaie, 1 : 1 to 100% ethyl acetate) gave the titled compound ( 1.5 g. 84% ). Η NMR (CD3OD/CDCI 3 ): 6 8.36 (d, I H, J = 8.25 Hz), 7.63 (m. 4H), 7.48 (t, 2H. J = 8.25 Hz). 7.20 (m, I H): EI-MS m/z 272 (M+H) + : Anal. (C 1 4H12N2O4) C H, N. Example 7 Preparation of N - 12 - hvdroxy - 4- (trifluoromethyl) phenyll - N' - phcnyl urea a)Preparatιon of 2-nιtro-5-trifluoromethylphenol 2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 mL) drop-wise to α.α,oc-trifluoro-m-cresol (5g, 30.8 mmol) at room temperature. After the addition was complete the reaction was quenched with saturated ammonium acetate and extracted with EtOAc. The organic was separated, dried over sodium sulfaic and filtered. Concentration of the solution in vacua afforded an oil which was purified by column chromatography (gradient 100% hexane 10 50% EtOAc/hexanes) to allord the tilled compound as an oil( 1.7 g. 21 < 7< ). I H NMR (CDC ): 10 6 (s. I H. OH). 8.26(d. I H. J = 7 8 Hz). 7 45(s. I H. arom ). 7.26(d. I H. J= 7.8 Hz) b)Prcparaiιon of 2-amιno-5-trifluoromcihylpheno! 2-4Amιno-5-tπfluoromcihylphenol was prepared by treating 2-nιiro-5- tπlluoromcihylphenol (5(K) mg. 2.41 mmol ) with a solution ol SnCb(3.5g. mmol ) in EiOH at 23 °C tor 12h The mixture was concentrated to 50 mL and adiustcd 10 pH 7 using saturated sodium bicarbonate The reaction mixture was pariiuoncd between H2O and EtOAc The aqueous layer was separated and extracted with ElOAc The combined organic extracts were dπed over sodium sullatc. filtered and concentrated //; vacua The resulting colorless oιl(370 mg. 87% ) was used without lurthcr purification I H NMR (CDCh) 7 6 (.s. I H). 7.39(d. I H. .1 = X 5 H/). 7 08(d. I H. J= 8.5 H/) c)Prcparatιon ol N - |2 - hydroxy - 4- (iπlluoiomethyl ) phenyl] - N" - phenyl urea N - [2 - Hydroxy - 4- (trilluoromcthyl) phenyl ] - N" - phenyl urea was prepared troni 2-amιno-5-iπfluoromcihylphenol ( 150 mg. 1.09 mmol ) and phenyl ιsocyanatc( 1.09 mmol) according to the procedure in General method A The product was purified by precipitation from methylene chloπde and filteπng to allord the titled compound ( 230 mg. 87% ) mp: °C: I H NMR (DMSO-d ). δ 9 45 (s. I H. NH). 8 50 (s. I H. NH). 8.31 (d. I H. J = 10 0 Hz). 7 45 (d, 2H. J = 10.0 Hz). 7 29 (t, 2H. J = 6 67 Hz). 7 10 (m. 2H). 6 99 (t. I H, J = 6.67 H/) EI-MS m/z 296 (M + ) Anal (C 14 H 1 1 N2O2F .C, H, N Example 8 5 Preparation ol N- ( 2-hvdroxy-4-nιtrophenyl ) -N'- (' 2-hydroxy-4-nιtrophenyl) urea a)Preparatιon ol 2-(/--rt-butyldιmeihylsilyloxy)-4-nιiroanilιne To a solution of 2-amιno-5-mtrophenol ( 1 g, 6.49 mmol) and lmidazole (0 88 g. 12 3 mmol) in DMF ( 15 mL), ten -butyldimethylsilyl chloride ( 1 1.2 mL, 64 9 mmol) was added o The resulting mixture was allowed to sur at 23°C for 48 hours The reacuon mixture was partiuoned beiween 0 1 % HC1 and ethyl acetate. The combined organic phase was washed with brine, dπed over MgSO4 and filtered Removal of solvent at reduced pressure and chromatography of the resulung oil on silica gjel (hexane : ethyl acetate: 5: 1 ) gave the titled compound ( 1.7 g, 98 % ) Η NMR (CDCI3): 6 7.78 (dd, IH, J = 6 7 Hz and J = 2 7 Hz). 5 7 61 (d, I H, J = 2.7 Hz), 6.7 (d, I H, J = 8.8 Hz), 1.0 (s, 9H). 0.28 (s. 6H) b)Preparation of N-[(2-t -butyldιmethylsilyloxy)-4-nitrophenyl]-N'-|(2-tert- buiyldιmethylsiloxy)-4- nitrophenyl] urea To a solution of 2-(ieri-butyldιmethylsilyloxy)-4-niiroanιlιne(200 mg, 0.75 mmol) in toluene ( 10 mL) tπcthylamine (0.13 mL, 1 64 mmol) and triphosgene (88 4 mg, 0.3 mmol) 0 were added. The reaction mixture was surred at 70°C for 2 hours, then cooled to room temperature. Then more 2-(tert -buιyldιmethylsilyloxy)-4-nιtroanιlιnc (2(X) mg, 0.75 mmol) was added The resulting mixture was allowed to sur at 70°C for 48 hours then cooled to room lemperaiurc The reaction mixture was partitioned beiween waicr and cthvl acetate The combined organic phase was washed with brine, dried over MgSOa and filtered Removal ol * > solvent al reduced pressure and chromatography of the resulting oil on silica gel (hexane cthy 1 acetate. 10.1 ) e the tilled compounds 30 mg. 31 % ) Η NMR (CDCh) 6 8 36 (d. 2H. J = 8 3 Hz). 7 90 (dd. 2H. J = 8 3 Hz and J = 2 8 Hz). 7 71 (d. 2H. J = 2 S Hz). 7 22 (s. 2H ) 1 02 (s. 18H). 0 35 (s. 12H) αPreparauon ol N-(2-Hydroxy-4-niirophcnyl)-N'-(2-hydroxy-4-nitrophenyl) urea 0 To a solution ol N-|(2-teri-buiyldιmeihyl.sιlyloxy)-4-nιirophcnyl]-N'-](2-ieπ- buiyldimethylsily loxv - nitrophenyl | urca(50 mg. 0 089 mmol ) in THF (2 mL). letrabuty lammonium fluoride ( 1 M. 0 09 L. 0 089 mmol ) was added at <)°C The reaction mixture w s surred al 2^°C Alter I houi . the starling material had disappeared The reaction mixture w as partitioned between water and ethyl acetate The combined otganic phase was ^ dπed over MgSO 4 and filtered Removal ol solvent al reduced pre.ssuie and chromatography ol the resulung oil on silica gel (hexane ethyl acetate. 1 : 1 to 100%- ethyl acetate) gave the titled compound(24 mg. 8 1 % ) -H NMR (CDiOD/CDC V δ 8.32 (d. 2H. J = 8 25 Hz). 7 80 ( dd. 2H. J = 8.25 Hz and J = 2.06 Hz). 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H ) + . Anal. (C nH |()N 4 O 7 ) C, H, N. Example 9 Preparation of N-(2-hvdroxy-4-nitrophenyl ) -N'-phenyl-thiourea a)Prcparauon of N-(2-tcrt-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-lhιourea N-(2-tcrt-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourca was prepared by treating a biphasic solution of 2-teπ-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO^ in CHClvH 2 O(2.5: 1 , 7mL) with thiophosgene at 0°C. The solution was allowed to warm to 23°C and the reaction was continued overnight. The CHCI3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacua and the residue was dissolved in toluene and treated with aniline (100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography ( 10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145 0 C: *H NMR (CD3OD/CDCI3): 6 8.65 (d, IH, J = 10.0 Hz), 7.58 (d, IH, J = 10.0 Hz), 7.47 (d, IH, J = 1.25 Hz), 7.26 (m, 4H), 7. 10 (m, IH). b)Prcparaiion of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-lhiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 L) with E^N'HF (lOOuL, 0.62 mmol) in acetonitrile for 10 minutes at 23°C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%). mp: |44- 145°C:-H NMR (CD3OD/CDCI3): 6 8.65 (d, IH, J = 10.0 Hz). 7.58 (d. I H. J = 10 0 Hz). 7.47 (d. I H. J = 1.25 Hz), 7.26 (m. 4H). 7. 10 (m. I H). Example 10 Preparation of N- ( 4- nitro 2- ( phcnylsulfonylamino ) phcnyl ) -N'-phenyl urea a ) Preparation of 4-nιiro 2-(phcnylsulfonylamιno) aniline A solution ol 4-nιtro 1.2-phcnylcne dιamιnc( 1.53 g. 10.0 mmol) in DMF was treated with phenyl sulfonyl chloπde( 1.76 g. 10.0 mmol) and tπethyl amιne( 1.01 g ) in DMF lor 12 h at 23 "C The reaction mixture was partitioned between saturated NH 4 C1 and methylene chloπde The organic layer was dried over sodium sullate. filtered and concentrated //; vacua The lesulting solid was recrystallized (EtOH) to allord desired (0.275 g. 9% ). Η NMR(DMSO) 9.5(s. I H. hi ). 7.83 (dd. IH. J= l () Hz. 2 Hz). 7.74(d. 2H. J=8 Hz). 7.76(1. I H. .1=8 Hz). 7.56(1. 2H. .1=8 Hz). 7.55(d. l H. J=2Hz). 6.79 (d. I H. J=8Hz). 6.5(s. 2H. br) b)Preparauon of N-(4- nitio 2-(phenylsulfonylamιno)phenyl)-N'-phenyl urea N-(4-Nnro 2-(phenylsulfonylamιno)phenyl)-N'-phenyl urea was prepared Irom 4- nitro 2-(phenylsulfonylamιno) anιlιne(82 mg) and phenyl ιsocyanaie(33 mg) by method A The reacuon was cooled and then partitioned between saturated ammonium chloride and 9. 1 methylene chloπde and methanol The organic phase was dπed over magnesium sultatc. 5 filtered and concentrated in vacua. The residue was purified by column chromaiographv (ethyl acetaie/hexanes) to allord desιred(30.8 mg, 26% ). EI-MS m/z 4 I 3(M+H) + Example 1 1 Preparation of N- ( 2-hvdroxy-5-nιtrophenyl)-N'-(3-methoxy-2-thιenvnurea 0 a)Preparauon of 3-methoxy-2-lhιenylcarboxlιc acιd To a solution of 3-methoxythιophene (4.81 g, 42 1 mmol) in ether (20 mL) at -78T butyllithium ( 17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78°C lor 1 hour, then it was warmed to 0 °C for 3 hours After to recooling -78°C the reaction mixture was poured into a beaker filled with crushed dry ice ( 14 5 g) and allowed to stand until the 5 excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture ol ice ( 10 g) to which cone. HC1 (24 L) had been added. The product was purified by precipitation from ether and filteπng (6.42 g, 96 %) EI-MS m/z 159 (M+H) * b)Preparauon of N-(2-hydroxy-5-nιtrophenyl)-N'-(3-methoxy-2-thιcnyl)urea To a solution of 3-methoxy-2-thιophene carboxylic acid (200 mg. 1.27 mmol) in 0 benzene, (PhO)2PON3 (0.33 mL), 2-ammo-4-nitrophenol (195 7 mg. 1 27 mmol) and tπethylamine ( 1 1 equiv .. 0.25 mL) were added. The reaction mixture was siined at reflux overnight The reaction mixture was partitioned between 5% curie acid and ethyl acetate The organic layer was separated and the aqueous layer was extracted direc times with ethyl acctaie The organic extracts were combined, dπed over MgSU 4 . filtered and concentrated under 5 reduced pressure Chromatography of the resulung solid on silica gel (hexane ethyl aceιate: l I ) gave a solid product ( 160 mg. 41 %-) mp 172 6- 173 () C C. ' H NMR (CD^OD/CDC ): δ 8 96 (d. I H, J = 2.5 Hz). 7 74 (dd. IH. J =5 0 Hz and J = 1 25 H/, 6 82 (d. I H. J =7 5 Hz). 6 76 (s. 2H), 3 80 (s. 3H). EI-MS m// 309 ( M+H ) + Anal (C i2H n N-*OsS) C. H. N ) Example 12 To a solution ol 3-methoxy-2-thιophene carboxylic acid (example 1 l . 200 mg 1 2 " mmol) in toluene. (PhO)2PON3 (0.33 mL) and tπcthylamine ( 1 1 . 0 25 mL ) were 35 added The reaction mixture was suned at 70°C lor 2 hours and cooled down to room temperature then 2-amιno-5-nιtrophenol was added The reaction mixture was suned at 70°C overnight The reaction mixture was paruuoned between 5%- citπc acid and ethyl acetate The organic layer was separated and die aqueous layer was extracted three times with ethvl acetate The organic extracts were combined, dπed over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane.ethyl acetate: ! : I ) gave the product ( 190 mg, 48%). -H NMR (CD3OD/CDCI3): 6 8.38 (d. I H, J = 5.0 Hz). 7.85 (dd. I H, J = 5.0 Hz and J = 1.25 Hz), 7.76 (d. I H, J = 2.5 Hz), 6.9 <s, 2H). 3.95 (s, 3H): EI-MS m/z 309 (M+H) + : Anal. (C12H 1 1 N 3 O5S) C, H, N. Example 13 Preparation of N-(2-hvdroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2- hydroxy 4-nιtro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filteπng afforded the title compound ( 140 mg, 46%). EI-MS m/z 302(M-H) * Example 14 Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-methoxvphenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2- hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate( l mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg. 27% ). EI-MS m/z 302(M-H) * Examnle 15 Preparation of N-(2-hvdroxy-4-nitrophenyl)-N'-(3-trifiuoromcthylphcnyl )urca N-(2-Hydroxy-4-nιtrophenyl)-N'-(3-methoxyphenyl)urea was prepared Irom 2- hydroxy 4-nιiro aniline (154 mg. 1.0 mmol) and 3-trifluoromethyl phenyl isocyanaie ( I mmol according to the procedure in General Method B. The product was puπfied by dilution with methylene chloπde and precipiiauon with hexanes. Filtcπng afforded the title compound ( 1 0 mg. 52% ). EI-MS m/z 342(M+H) + Example 16 Preparation ol N-f2-hvdroxy-4-nιtrophenyl)-N'-(2-trifluoromeihylphenyl)urea N-(2-Hydroxy-4-nιtrophenyl)-N'-(2-trifluoromemylphenyl)urca was prepared Irom 2- hydroxy 4-nιiro aniline ( 154 mg. 1.0 mmol) and 2-trifiuoromcthyl phenyl isocyanaie ( 1 0 mmol) according 10 die procedure in General Method B. The product was purified by dilution with methylene chloride and precipiiauon with hexanes. Filteπng afforded ihc title compound ( 180 mg. 52% ). EI-MS m/z 342(M+H) + Example 17 Preparation of N-(2-hvdroxy-4-nurophenyl)-N"-(4-tπfiuoromeihylphenyl )urea N-(2-Hydroxy-4-nιtrophenyl)-N'-(4-trifiuoromethylphenyl)urca was prepared Irom 2- hydroxy 4-nιiro aniline ( 154 mg, 1.0 mmol) and 4-trifiuoromcthyl phenyl isocyanaie ( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 1 1 1 mg, 32%). EI-MS m/z 340(M-H) * Example 18 Preparation of N-(2-hvdroxv-4-nilrophenyl)-N'-(2-hromophenyl)urea N-(2-Hydruxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared Irom 2-hydroxy 4-nιtro aniline (5 ( X ) mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol ) according lo the procedure in General Method B. The product was puπfied by dilution with methylene chloride and precipitation with hexanes. Filteπng afforded the title compound(530 mg. 47% ) EI-MS m/z 350(M-H) - Example 1 Preparation of N-(2-hvdroxy-4-nitrophenyl)-N'-(3-hromophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl )urea was prepared from 2-hydroxy 4-nιtro aniline (500 mg. 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmoDaccording to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipiiauon with hexanes. Filtering afforded the uϋe compound(0.96g. 87% ) EI-MS m/z 350(M-H) * Example 20 Preparation of N-(2-hvdroxy-4-nιtrophenyl)-N'-(4-hromophcnyl)urea N-(2-Hydroxy-4-nitrophcnyl)-N'-(4-bromo phenyDurca was prepared Irom 2-hydro\y 4-nιtro aniline (5(X) mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution with mcihylcne chloπde and precipitation with hexanes. Filtering afforded the title compound^) 41 g. 37% ) EI-MS m/z 352(M+H) + Example 21 Preparation ol N-(2-hvdroxy-4-nιirophenyl)-N'-(2-phenylphcnyl)urca N-(2-Hydroxy-4-nitrophcnyl)-N'-(2-phenylphenyl )urea was prepared i rom 2-hydι 4-nιtιo aniline (5(X) mg. 3.24 mmol) and 2-phenyl phenyl isocyanaie (3 24 mmol ) according to the procedure in General Method B. The product was purified by dilution with mcihylcne chloride and precipiiauon with hexanes. Filtering allordcd the title compound(0.22 g. 19% ) EI-MS m/z 350(M+H) + Example 22 Preparation of N-(2-hvdroxy-4-nitrophenyl)-N'-( l -naphthyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-( l -naphthyl)urea was prepared Irom 2-hydroxy 4- nitro aniline (500 mg, 3.24 mmol) and 1 -naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was litruated with 1 :3 uiethyl amine:methylene chloride. The filteraie was concentrated in vacua. The resulting residue was dissolved in methylene chloride and treated with IN HC1 in water. The desired product precipitated from solution and was collected by filtration(0.1 l g, 10%). EI-MS m/z 324(M+H) + Example 23 Preparation of N-(2-hydroxy-4-nitrophenyl .-N'-(2-niirophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-nιtro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g. 44%-). EI-MS /z 319(M+H) + E-sample 24 Preparation of N-f2-hvdroxv-4-nitrophenvl .-N'-(2-fluorophenvl)urea N-(2-Hydroxy-4-nitrophenyI)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fiuoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.59 g. 31 % ) EI-MS m/z 292(M+H) + Example 25 Preparation of N-(2-hvdroxy-4-nitrophenyl)-N'-(2.6-difluorophenyl )urea N-(2-Hydroxy-4-niirophenyl)-N'-(2.6-dilluorophenyl)urea was prepared Irom 2- hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 2.6-difluoro phenyl ιsocy anaie(3.24 mmol , according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded ihc title compound^).9 1 g. 91 ). EI-MS m/z 308(M-H) - Example 26 Preparation of N-(2-hvdroxy-4-niιrophenyl )-N'-(2-ethoxyphcnyl Uirca N-(2-Hydroxy-4-niιrophenyl)-N'-(2-cihoxyphcnyl)urca w as prcp.ircd trom 2-hydroxy 4-nιirυ aniline (5(X) mg. 3.24 mmol) and 2-cihoxy phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution wiih methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.84 g. 1 % i EI-MS m/ 318(M+H) + Example 27 Prcparaiion of N- ( 2-hvdroxy-4-nιtrophenyl)-N'-(2-ethylphenyl)urca N-(2-Hydroxy-4-nitrophenyl)-N'- ( 2-cthylphcnyl)urca was prepared from 2-hydroxy 4- nitro aniline (5 ( X ) mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by diluuon with methylene chloπde and precipitation wilh hexanes. Filtering afforded the title compound(044 g, 43%). EI-MS m// 302(M+H) + Example 28 Preparation of N-(2-hvdroxy-4-nιtro phenyl)-N'-(2-trifiuoromethoxyphcnyl)urea N-(2-Hydroxy-4-nιtrophenyl)-N'-(2-iπfiuoromeihyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromeιhoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was puπfied by dilution with methylene chloride and precipitation with hexanes Filtcπng afforded the title compound(0.69 g. 60%). EI-MS m/z 358(M+H) + Example 29 Synthesis of N-(2-hvdroxy-4-nitro phenyl) N'-(2-meihylιhιo phenyl) urea The urea was prepared from 2-hydroxy 4-nιiro aniline (5(X) mg . 3.24 mmol) and 2- methylthio phenyl ksocyanate(3.24 mmol) by general Method B The product was purified by dilution with methylene chloride and precipitation wilh hexanes Filtering afforded the title compound(0.63 g. 61 -). EI-MS m/z 320(M+H) + Example 30 The urea was prepared from 2-hydroxy 4-nιiro aniline (500 mg. 3.24 mmol ) and 2- chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipiiauon wilh hexane. Filtering al lorded the desired compound(0.31 g. 29% ). EI-MS m/z 322(M+H! + Example 31 The urea was synthesized by trcaimcni ol N-( 2-hydro\y 4-nιiro phenyl) N'-(2-mcih\ 1 thio phenyl) urca(cxample 28. 100 mg ) with sodium pcπodaie( 100 mg ) in t-butanol/watci loi 12 hours al 23 "C. The product precipitated Irom the reaction mιxιuι e(30 mg. 29% ) EI-MS m/z 336(M+H) + Example 32 Synthesis of N-(2-hvdroxy 4-trιnuoromcthyl phenyl) N'-(2-hromo phenyl) urea The urea was prepared from 2-hydroxy 4-trifluoromethyl anilineiexamplc 7a. 0. 17 l g, 1 mmol) and 2-bromo phenyl lsocyanated mmol) by general Method B. It was purified by diluuon with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54% ). EI-MS m/z 375(M+H) + Example 33 Synthesis of N-(2-hvdroxy 4-carhomcihoxy phenyl) N'-(2-hromo phenyl) urea The urea was prepared from 2-hydroxy 4-carbomeihoxy anilιne(0.167 g. 1 mmol) and 2-bromo phenyl lsocyanatef 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g. 33%). EI-MS m/z 363(M-H) - Example 34 Synthesis of N-(2-hvdroxy 4-trifiuoromethyl phenyl) N'-(2-phenyl phenyl) urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. Ii was purified by dilution with methylene chloride and precipitation with hexane. Filieπng afforded the desired compound(0.24 g, 64*). EI-MS m/z 373(M+H) + Example 35 Synthesis of N-(2-hydroxy 4-carbomcthoxy phenyl) N'-(2-phcnyl phenyl) urea The urea was prepared from 2-hydroxy 4-carbomcthoxy ani ncH) 167 g. 1 mmol ) and 2-phenyl phenyl isocyanaicd mmol) by general Method B It was purif ied by dilution with methylene chloride and precipitation with hexane Filtering allorded the desired compound(0.185 g. 50% ). EI-MS m// 363(M-H) ' Example 36 Synthesis of N-(2-hvdroxy 4-nιtro phenyl) N'-(2.3-dιchloro phenyl ) urea The urea was prepared Irom 2-hydroxy 4-nιιro anιlιnc(3()8 mg. 2 mmol ) and 2.3-dιchloro phenyl ιsocyanate(2 mmol) by general Method B It was purified by dilution with mcihylcne chloride and precipiiauon with hexane. Filtering allorded the title compound(0.5 g. 73% ) EI-MS ml/ 342(M+H ) + Example 37 Synthesis of N-(2-hvdroxy 4-nιtrp phenyl) N'-(2.4-dιchloro phenyl ) urea Thc urea was prepared from 2-hydroxy 4-nιiro anιhne(308 mg. 2 mmol) and 2,4- dichloro phenyl ιsocyanate(2 mmol) by general Method B. It was purified by dilution with mcihylcne chlonde and precipiiauon wilh hexane Filtering afforded the title compound(0.26 g. 38% ). EI-MS m/z 342 (M+H) + Example 38 Synthesis of N-(2-hvdroxy-4-nιtro phenyl) N'-(2-chloro phenyl) urea The urea was prepared from 4-nιtro 2-hydroxy anιlιne(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloπde and precipiiauon with hexane. Filteπng afforded the title compound(0.29 g. 47% ). EI-MS m/z 308(M+H) + Example 39 Synthesis of N-(2-hvdroxy-4-nitrophenyl) N'-(2.4-dibromo phenyl) urea The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg. 2 mmol) and 2,4- dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g. 39%). EI-MS m/z 430(M+H) + Example 40 Synthesis of N-(2-hvdroxynapthyl) N'-(2-hromo phenyl) urea The urea was prepared from 1 -amino 2-hydroxy napthalenc( 195 mg. 1 mmol) and 2- bromo phenyl ιsocyanaic( 1 mmol) by general Method B. It was puπficd by dilution with methylene chloride and precipitation with hexane Filieπng afforded the uile compound(0.03() g. 8% ) EI-MS m/z 357(M+H) + Example 41 Synthesis of N-(2-hvdroxy-4-niirophcnyl )-N'-(2.3-mcihylcnedioxyphcnyl)urca a Preparation of 2.3-mcihylcncdιoxyphcnylcarboxylιc acid A solution ol 1 .3-benzodιoxole (3 09 g. 32 mmol ) in dry ether (50 mL) w as treated dropwise al - 1()"C with 2 5 M n-butyllilhium ( 15 mL. 35 mmol) in hexane When ihe addition w as complete, the mixture was simed under reflux lor one hour Alici cooling to room temperature, it w as added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq NaHCO, and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HC1. and extracted with chlorolorm The combined organic layers were dried over MgSO . filtered and concentrated under reduced pressure ( 1.1 g. 20 % ). EI-MS m/z 167 (M+H) ' b)Preparatιon of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methylencdioxyphenyl)urea To a solution of the 2,3-methylenedioxyphenylcarbiM.ylic acid in toluene, triethylamine (0.27 mL. 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL. 1.5 mmol) were added. The reaction mixture was stined at 60°C for 2 hours, then 2-amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred at 100°C for 18 hours. After the reaction mixture was cooled to room temperature, it was partitioned between 5 % citπc acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three limes with ethyl acetate. The organic extracts were combined, dried over MgSO 4 , filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5: 1 ) gave product (200 mg, 42 %). EI-MS m/z 318 (M+H) * Example 42 Synthesis of N-(2-hvdroxv 4-nitro phenvl) N'-(2-methoxy 3-chloro phenyl) urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48 g, 63% ). EI-MS m/z 338(M+H) + Example 43 Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-methyl phenyl) urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol) and 2-meihyl phenyl isocyanatc(2 mmol) by general Method B. Ii was purified by dilution with methylene chloride and precipitation with hexane. Filieπng afforded the title compound(0.38 g. 53% ) Example 44 Synthesis of N(bis (2-hvdroxy 4-niiro phenyl) N'-(dianisdinc) diurea The urea was prepared from 2-hydrυxy 4-nitro anilιnc(61 mg. 4 mmol) and dianidisdinc diisocyanatc(2 mmol ) by general Method B(cxccpi 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of 1 equiv.). The product was purified by diluuon wilh methylene chloride and precipitation with hexane. Filtering afforded the title eυmpoundf 0.08 g. 6% ). EI- Example 45 Thc urea was prepared from 2-hydroxy 4-nitro anilιne(616 mg. 4 mmol) and 4- methylcnc bιs(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(excepi 2 equiv of 4-nιtro 2-hydroxy aniline was used instead of lequiv.). The product was purified by diluuon with me ylene chloride and precipitation with hexane. Filieπng afforded the tide compound(0. 10 g, 8%). EI-MS m/z 627(M+H) + Example 46 Synthesis of N-I2-hvdroxy 4-(benzylamino)carhonyl phenyll-N'-(2-hromophenyl)urea a)Synthesιs of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 3-hydroxy 4-amιno benzoic acid (3.69 g, 24 mmol) and 2- bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%>). EI-MS m/z 351 (M+H) + b)Preparauon of N-[4-(benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.58 mmol) in DMF ( 15 mL), EDC ( 121.9 mg, 0.58 mmol), HOBT ( 156.6 mg. 1 1.6 mmol) were added . The reaction mixture was stined al room temperature for 16 hours. Then the benzyl amine (123 mg, 1 1.6 mmol) was added. The reaction mixture was stined at same temperature for 24 hours. Then the reaction mixture was partitioned between water and ethyl acctaic. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO . filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane * ethyl acetaic; 1 : 1 ) gave benzylamino product (5(X) mg. 65 %). EI-MS m/z 441 (M+HV Example 47 Synthesis ol N-(2-hvdroxy 4-nιtro phenyl) N'-(2-phenoxy phenyl) urea The urea was synthesized by the ireatment of 2-phenoxyphenyl carboxylic acιd(2 mmol.) with diphenyl phosphoryl azide(0.475 mL) and tπethyl amine(. 14 mL) in DMF at 80 °C after 24 hours ihc 2- amino 5-nιiro phenol ( 1 equiv.) was added. The reaction was heated for 24 hours at 80°C The reacuon product was oiled out with hexane. The residue was dissolved in methanol and the solid was precipitated out with waicr.( l 0 mg. 24% ) EI-MS m/z 364(M-H) Example 48 Synthesis ol N-(2-hvdroxy-4-fluoro phenyl) N'-(2-hromo phenyl) urea a)Svnthesιs of 2-hydroxv 4-fluoro aniline 3-fluoro 6-nιtro phenol (2 g. 1 1 mmol) was treated with 10%Pd/C( I g) al 23 °C The reaction mixture was Hushed with hydrogen gas and the reaction was allowed lo stir 12 h bclorc it was filtered through cclitc. The filtrate was concentrated in vacua to allord ihe title compound ( 1.4 g, 77% ) EI-MS m/z 169(M+H) + b)Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg. 2 mmol) and 2- bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipiiauon with hexane( 173 mg. 26% ). EI-MS m/z 325 (M+H) Example 49 Synthesis of N-( 2-hydroxy 3.4-difluoro phenyl) N'-(2-hromo phenyl) urea a)Synthesιs of 2-hydroxy 3,4-difluoro aniline 2,3 difluoro 6-nιtro phenol (2 g, 1 1 mmol) was treated with 10%*Pd/C( l g) at 23 U C The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacua to afforded the utle compound ( 1.6 g. 97%). EI-MS m/z 146(M+H) + b)Synthesιs of N-(2-hydroxy 3,4-difiuoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 3.4-difluoro anilιne(0.290 g. 2 mmol) and 2- bromo phenyl ιsocyanate(0.4 g) by general Method B. It was puπfied by diluuon with methylene chloride and precipitation with hcxane(0.254 g, 37%) EI-MS m/z 343(M+H) Example 50 Synthesis of N-(2-hvdroxy 3-napthyl) N'-(2-bromo phenyl) urea The urea was prepared from 3-amιno 2-hydroxy napthalenc(0 320 g. 2 mmol) and 2- bromo phenyl ιsocyanate( 40 g) by general Method B It was purified by dilution of the with methylene chloπde and precipitation with hcxane(0.339. 47%-). EI-MS m// 357(M+H) Example 51 Synthesis ot N-(2-hvdroxy 4-phcnyl phenyl) N'-(2-hromo phenyl) urea a)Synthesιs ol 2-mtro 5-phenyl phenol A solution ol 3-phenyl phenol(2 g. 1 1 mmol ) in acetic acid was treated with concentrated nitric acid drop-wise until all starling mateπal was consumed The solution was partitioned bet een water and methylene chloride The organic phase w as separated and the aqueous phase s extracted once more with methylene chloride The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacua The residue was purified by silica gel chromatography(ethyl acetate/hexanes) to afford desired ( 1.2 g. 50% ) - H NMR (CDC ): δ 10.65(s, I H), 8.18 (d, I H. J = 10.0 Hz). 7.65 (d. 2H. .1 = 6.0 Hz). 7 49 (m. 3H). 7.34 (s. IH), 7.10 (d, I H, J=10.0Hz) b)Synthesis of 2-amιno 5-phenyl phenol A solution of 2-nitro 5-phenyI phenol( l .2 g, 5.5 mmol) in methanol was treated with 10% Pd/C( 1.2g). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reacuon mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired ( 1.01 g, 98%).EI-MS m/z 186(M+H) + c)Synthesis of N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g. 1 mmol) and 2- bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56%r) EI-MS m/z 383(M+H) + Example 52 Synthesis of N-(2-hvdroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-melhyl aniline(.274g. 2 mmol) and 2-bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39% ). EI-MS m/z 319(M-H) " Example 53 Synthesis ol N(2-hydroxy 4-nitro phenyl) N'-(2-phenylamιno phenyl) urea The urea was synthesized by the ireatmeni of 2-tertbutyldιmcihylsιlyloxy 4-nιiro phen \ I ιsocyanate(example 9a. 0.419g, 1.5 equiv.) with 2-anilιno anilιnc(0 184 g. 1 equiv. ) in TH1 overnight at 40 °C. The desired product precipitated out of ihe reaction mιxturc(30 mg. 8% ) EI-MS m/z 365(M+H) + Example 54 Synthesis of N-(2-hydroxy 3-carhoxylate phenyl) N'-(2-bromo phenyl ) urea The urea was prepared from 2-hydroxy 3-amιno benzoic acιd(3(X) mg. 2 mmol) and 2- bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with mcihylcne chloride and precipiiauon with hexane(.2S7 g. 41 % ) EI-MS ml/ 35 I (M+H) + Example 55 Synthesis of N(2-sulfhvdryl 4-bromo phenyl) N"-(2-bromo phenyl ) urea a)Svnthesιs ol 2-amιno 6-bromo thiazole 4-Bromo anιlιne(4.3 g, 25 mmol, 1 equiv.) and ammonium thιocyanatc(5 7 g. 3equιv ) was dissolved in aceuc acid and treated with bromme(4 g, 1 equiv ) at room temperature After complete disappearance ol starting mateπal the reacuon mixture was poured into water and the solid was collected. The solid was used in the next step without any puπficatιon(3 6 g. 46% ) EI-MS m/z 229(M+H) + b)Synthesιs of bis (3-bromo 6-amιno phenyl) disulfide The 2-amιno 6-bromo thiazole hydrobromide (500 mg, 1 6 mmol) in watcr(5mL) was treated with KOH (2.5 g) was heated at reflux for 8 h at reflux The reaction mixture was then acidified to ph 4 with acetic acid and extracted with methylene chloπde The methylene chloπde mixture was concentrated in vacua The residue was dissolved in DMSO and treated with 1 2 After stirπng overnight at room temperature me reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate The methylene chloπdc layer was dried with magnesium sulfate and concentrated in vacua. The resulung solid was purified by flash chromatography(ethyl acetate/hexane) to afford the utle compound (230 mg. 34%) EI-MS m/z 405(M+H) + c)Synthesιs of N(2-sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea A solution of (3-bromo 6-amιno phenyl) disulfide(201 mg, .5 mmol) in DMF was treated with 2-bromo phenyl ιsocyanate( 1 mmol) at 80 °C overnight The reacuon mixture was diluted with methylene chloπde and a solid was precipitated out with hexanes The soluuon was dissolved in MeOH and treated with NaBH 4 After gas evolution ceased the reaction mixture was carefully acidified with I N HC1 and the resulting solid was lιltered(52 mg. 13%) EI-MS m/z 399 (M-H) ' Example 56 Synthesis of N-(2-hvdroxy 4-πιtro phenyl) N'-(2-ιodo phenyl) urea The urea was synthesized by the treatment ol 2-ιodo ben/oic acιd(5 g. 20 mmol) with diphenyl phosphoryl azιdc( 1 equiv.) and tπcthyl ammc ( 1 equiv ) in DMF at 80 °C alter gas evolution ceased the 5-nιlro 2-amιno phenol (3 g. 1 ) was added The reacuon was heated overnight at 80°C The reaction mixture was purified by filtering through a plug ol silica with methylene chloπde The desired product was then precipitated out ith hexane Filteπng aftorded the desired compound( 1.08 g. 13% ) EI-MS m// 398(M-H) Example 57 Synthesis ol N-(2-hvdroxy 4-nιiro phenyl) N'-(2-bromo phenyl) thiourea The thiourea was synthesized by treatment ot the 2-tfrt-butyldιmeιhylsιlyloxy 4-nιtro phenyl thιoιsocyanate(see example 9a , 3 73 mmol) with 2-bromo aniline in toluene at 88°C over 36 h The solution was concentrated and the residue was puπfied by flash chromaiography(EtOAc/Hexanes) The traction slightly lower rl than starting matcπal contained the desired compound This traction was concentrated and then treated with trie thy I amine hydrofluoπde in acetonilnle for 15 minutes al 23 °C The reaction mixture was then concentrated in vacua and the residue was punficd by flash chromaiography(cιhyl actate/hexanes) to give N-(2-hydroxy 4-nιtro phenyl) N'-(2-bromo phenyl) ihιoureaι52 mg. 4%) EI-MS m/z 369(M+H) + Example 58 Synthesis of N-(2-phenvlsulfamιdo) 4-cvanonhenvl N -(2-bromo phenyl) urea a)Synthesis of 3-(phenylsulfamιdo) benzonitπle The of 3-(phenylsulfamιdo) benzonitrile was synthesized from the 3-cyano aniline (23.9 g, .2 mol) by Method C It was puπfied by recrystalizauon from EtOH( 15 8 g. 31 ). *H NMR (CDCI3). 6 7.95(s, IH), 7 84 (d, 2H, J = 8.0 Hz), 7.59 (1. I H. J = 8 0 Hz). 7 45 (m, 2H), 7.35 (m, 4H). b)Synthesιs of 3-(phenylsulfamιdo) 4-nιtro benzonitπle The 3-(phenylsulfamιdo) benzonιtπle(IO g, 39 mmol) was dissolved in acetic anhydride and treated with concentrated mine acid dropwise at room temperature until all the starting mateπal had been consumed. The reacuon mixture was then quenched by carefully pouπng it into sodium bicarbonate and left to sit until all gas evoluuon had subsided It was ϋien paruuoned between methylene chloπde and water The organic layer was dπed over sodium sulfate and filtered The reaction mixture was concentrated in vacua, absorbed onto silica gel and puπfied by column chromatography ( methylene chloπdc/hcxane) to allord the title compound ( 1 7g, 15%) EI-MS m/z 302(M+H) + c)Synthesιs ol 3-(phcnylsuliamιdo) 4-ammo benzonitrile The 3-(phenylsultamιdo) 4-nιtro ben/onιtπle( l 5 g. 4 9 mmol ) w as treated with tin chloride dihydrate in EtOH at 80 °C lor 12h It was then concentrated and Hushed through a plug of silica gel with 5% mcthanol/methylcnc chloride The filteraie was absorbed onto silica gel and puπfied by Hash chromaiography(ethyl acci tc/hcxanc) to allord ihe title compound (0 9 g. 60%r) EI-MS m/z 274 (M+H) + d)Synthesιs ol N-(2-phenylsultamιdo) 4-cyanophenyl N'-(2-bromo phern 1 ) urea The urea was synthesized Irom 2-(phcnylsullamιdo) 4-amιno bcn/onιiπle(77 mg. 0 2S mmol) and 2-bromo phenyl isocyanate by general Method C It was puπlied b\ column chromaiography(eihyl aceiatc/hexanc) to allord ihe title compound (30 mg. 22% ) EI-MS ml/ 469(M-H) ~ Example 59 Synthesis ot N-(2-(phenyl sullamido) phenyl) N'-(2-bromo phenyl) urea a)Syndιesιs of 2-( phenyl sullamido) aniline The sulfonamide was synthesized irom phenyl sulfonyl chlorιdc(001 mmol) and o- phenylenc dιamιnc( 1.08 g, 0.01 mmol) by general Method C Ii was purified by recrystalhzation from EtOH( 1.0 g, 40%).EI-MS m/z 249(M+H) + b)Synthesιs of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl ) urea The urea was synthesized 2-(phenyl sullamido) anilincf I mmol ) and 2-bromo phenyl isocyanate by general Method B Ii was purified by dilution with methylene chloπde and precipitation with hexane. Filtering allorded the desired compound(0.234 g, 52%).EI-MS m/z 446(M+H) * Example 60 Synthesis of N-(2-( styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea a)Synthesιs of 2-( styryl sulfamido) aniline The sulfonamide was synthesized from styryl sullonyl chloπde(001 mol) and o- phenylene diamine(0.01 mol) by general Meϋiod C. It was purified by rccrystallizaiion from EtOH(1.2 g, 60%)EI-MS m/z 199(M+H) + . b)Synthesis of N-(2-(styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-(styryl sulfamido) anilincf I mmol) and 2-bromo phenyl isocyanate(I mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane Filtering afforded the desired compound(0.309 g. 65%*) EI-MS m/z 472(M+H) + Example 61 Synthesis of 2-1(3.4 dimethoxyphenyl lsulfonyl amιno| phenyl) N"-(2-bromo phenyl ) urea a)Synthesιs of 2-[(3.4-dιmethoxyphcnyl)sulfonyl amιno|phcnyl aniline The sulfonamide was synthesized Irom 3.4-dιmcthoxy phenyl sullon l chloπde(0 01 mol) and o-phenylenc diamine by general Method C It was purified by recrystallization irom EtOH(0.65 g. 21 ) EI-MS m/z 309(M+H ) + b)Synthesιs ol 2-|(3.4-dιmcthoxyphenyl)sullonylamιno] phenyl ) N"-( 2-bromo phenyl) urea The urea was synthesized from 2-|(3.4-dιmcthoxyphcny I jsullony I aminojpheny I ani ned mmol) and 2-bromo phenyl isocyanaie by general Method B It was purified by diluuon with methylene chloπdc and precipitation with hexane Filtering allorded the desired compounds 062 g. 12% ) EI-MS ml/ 504(M-H ) " Example 62 Synthesis of N-f2-l(4-acetamιdophenyl)sullonylamιnol phenyl ) \"-(2-hromo phenyl ) urea a)Synthesιs ol 2-|(4-aceiamιdophenyl)sullonylamιno]phcnyl aniline The sultonamide was synthesized irom 4-acctamιdophcnyl sulfonyl chloπdc.0.01 mol ) and o-phcnylcnc dιamιne(0.01 mol) by general Method C. It was purified by recrystallization from EtOH( 1.27 g.40%)EI-MS m/z 304(M-H) b)Synthesιs of N-(2-|(4-acetamidophcnylsulfonyl)amιno] phenyl) N'-(2-bromo phenyl) urea The urea was synthesized Irom 2-|(4-acetamidophenyl)sulfonylamino]phenyl anilιne( 1 mmol) and 2-bromo phenyl ιsocyanatc( l mmol) by general Method B. It was purified by- dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compounds. 12 g. 24%). EI-MS m/z 50KM-H) " Example 63 Synthesis of N-(2-(2-thιophene sulfamido phenyl) N'-(2-bromo phenyl) urea a)Synthesιs of 2-(2-thiophene sulfamido) aniline The sulfonamide was synthesized from 2-ihιophene sulfonyl chloride(0.01 mol) and o- phenylene dιamιne(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.77 g, 30% ). EI-MS m/z 255 (M+H) + b)Synthesιs of N-(2-(2-thiophenc sulfonyl amino phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-( 2-thiophene sulfonyl amino) anilined mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with methylene chloride and precipiiauon with hexane. Filteπng afforded ihe desired compound(0.29 g. 64% ). EI-MS m/z 450(M-H ) ' Example 64 Synthesis of N-(2-( 3-tolyl sullonyl amino phenyl) N"-(2-bromo phenyl ) urea a)Syndιesιs of 2-( 3-lolyl sullonyl am o I aniline The sultonamide was synthesized Irom 3-iolyl sullonyl chloπde(0.01 mol ) and o- phenylcne dιamιnc(0.0 l mol) by general Method C It was purified by recrystallization Irom EtOH(0 73g. 28% ). EI-MS m/z 263 (M+H ) + b)Synihesιs ol N-(2-(( -tolyl sullonyl amino) phenyl ) N'-(2-bromo phenyl) urea The urea was synthesized Irom 2-ι 3-iolyl sullonyl amino) anihnef 1 mmol ) and 2- bromo phenyl ιsocyanate( 1 mmol ) by general Meihod B It was puπlied by dilution with methylene chloπde and precipitation with hexanes It was rccrysallized two times with EtOH(25 mg. 5% ) EI-MS ml/. 458(M-H) " Example 65 Synthesis of N-(2-(8-quιnolιnyl sullonyl ammo) phenyl) N'-(2-bromo phenyl) urea a)Synlhcsιs ol 2-(8-quιnolιnyl sullonyl amino) aniline The sullonamidc was syn esized from 8-quιnolιnyl sullonyl chloπdc(0 01 mol) and o- phenylcnc dιamιnc(0 1 mol) by general Method C It was puπfied by recrystallization Irom ElOH(0 82 g. 27% ).EI-MS m/z 300 (M+H) * b)Synthesιs ol N-(2-( (8-quιnolιnyI) sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-((8-quιnolιnyl) sulfonyl ammo) anilined mmol) and 2-bromo phenyl isocyanatcd mmol) by general Method B It was purified by dilution with methylene chlonde and precipitation with hexane Filteπng afforded ihe desired compound^) 23 g. 46% ) EI-MS m/z 495(M-H) " Example 66 Synthesis of N-(2-( hcn/yl sulfonyl amino) phenyl) N"-(2-bromo phenyl) urea a)Synthesιs of 2-(bcnzyl sulfonyl ammo) aniline The sultonamide was synthesized Irom benzyl sulfonyl chloπde(0 1 mol) and o- phenylene dιamιne(001 mol) by general Method C It was purified by recrystallization from EtOH(0.87g, 33%) EI-MS m/z 263(M+H)+. b)Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-( benzyl sulfonyl amino) anilined mmol) and 2-bromo phenyl ιsocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloπde and precipitauon with hexane Filteπng afforded the desired compound(C).1 1 g. 23% ) EI-MS m/z 460 (M+H ) + Example 67 Synthesis ol N-(2-hvdroxy-4-azιdophcnyl)-N , -(2-methoxyphenyl)urea a)Synthesιs ol N-(2-hydro.\y -4-amιnophcnyl)-N'-(2-mcthoxyphcnyl)urca To a solution ol N-(2-hydroxy-4-nιtro phenyl )-N'-(2-methoxyphenyl )urca( 1.0 g. example 15) in methanol. palladium (on activated carbon. 10% ) ( 100 mg ) was added Then the reaction mixture was hydrogenated under a hydrogen balloon lor 18 hours The solid was filtered oil by celite and washed three Umcs by methanol The filtrate was concentrated undci reduced pressure to giv e amine compound (0 8 g. 89% ) EI-MS m/z 274 ( M+H) * b)Synthcsis ol N-(2-hydroxy-4-azιdophcnyl)-N'-(2-meιhoxyphenyI)urca The N-(2-hydιoxy -4-amιnophenyl)-N'-(2-mcthoxyphenyl)urea (300 mg. 1.17 mmol ) was added lo HC1/H-.C) ( 1 17 mL/2.34 mL). cooled lo ()°C Sodium mime (80 7 mg. 1 17 mmol ) w s added to the reaction mixture The reacuon mixture was stined at 0°C tor 30 minutes The sodium azide (76 mg. 1 17 mmol ) was added to reaction mixture and it was warmed to room lempcraiurc The reaction mixture was stirred at room temperature lor 18 hours Then it was extracted with three umes by ethyl acetaie The organic extracts were combined, dπed over MgSO 4 . filtered and concentrated under reduced pressure and chromaiography ol t e resulting solid on silica gel (hexane : ethyl acetaie: 5: 1 ) gave product ( 125 mg. 38% ) EI-MS m/z 300 (M+H) * Example 68 Preparation ol N-l 2-hvdroxy-5-cvanophenyll-N'-12-hromophenvH urea a)Pιeparatιon ol 2-amιno-4-cyanophenol To a soluuon ol 2-nιtro-4-cyanophenol( 10g, 61 mmol) in mcihanol(250mL was added 10% Pd/C ( l gj The mixture was Hushed with argon, ihen hydrogen was bubbled through ihe solution lor 10 m and a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite and the celite was washed with methanol The solvent was evaporated and chromatography of the resulting solid on silica gel (5%cMeOH/ CH-jC gave the desired product(8.0 g, 97%*). Η NMR (CD--OD): 6 6 96 (d. I H), 6 90 (dd. I H). 6 77 (d, I H) b)Preparatιon ol N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea N-|2-hydroxy-5-cyanophenyl]-N'-]2-bromophenyl] urea was prepared from 2-amιno- 4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitauon from methylene chloride/ hexane( 1/20) and filtering (540mg.8 l% ) Η NMR (CD 3 OD): 6 8.10 (d, I H), 7 87 (d, IH). 7 43 (d. IH), 7.20 (t. IH). 7 09 (d. I H). 6 86 (t. I H). 6 77 (d, IH). Example 69 Preparation ol N-12-hvdroxy-3-Ωuorophenyll-N'-12-bromophenyl l urea a (Preparation o! 2-amιno-3-fluorophenol To a solution ol 2-niiro-3-lluorophenol( lg. 6 4mmol) in mcthanol(250mL) was added 10% Pd/C g) The mixture was flushed with argon, then hydrogen w as bubbled through the solution lor 10 nun and a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite and the celite was washed with cdianol The son c was c\aporaied and chromatography of the resulung solid on silica gel (5%MeOH CH->Cl ) the desired product(650 mg, 80 2 % ) Η NMR (CD,OD) 6 6 41 -6 17 (m. 3H) b)Preparalιon ol N-| 2-hydroxy-3-fluorophcnyl ]-N'-|2-bromophenyl | urea N-|2-Hvdιoxy-3-fluorophenyl]-N'-| 2-bromo phenyl] urea was prepared from 2- amιnυ-3-fluorophcnol (254mg. 2.00 mmol ) according to the procedure in General Method B The product was purified by precipiiauon Irom mcihylcne chloride/ hexanc( 1/20) and tillering ( 500 mg. 77% ) Η NMR (CD--OD) 6 8 05 (d. I H). 7 50 (d. I H). 7 26 (i. I H). 7 18 (d I H ). 6 92 (l. I H). 6 86-6 68 (m, 2H) Example 70 Preparation ol N-2-1 1 -hvdroxyfluorencl-N -(2-bromophenyl l urea a)Preparatιon of 2-amιno- 1 -hydroxytluorenc To a soluuon of l -hydroxy-2-nitrolluorenc(250 mg, 1.23mmol) in methanol(250mL) was added 10% Pd/C ( I g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 mm. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the desired produci( l 71 mg, 81.2 %). Η NMR (CD.OD): δ 7.60 (d, I H), 7.47 (d. I H), 7.28 (t. IH), 7. 18 (m, 2H), 6.82 (d. IH), 3.76 (s. 2H). b)Preparation of N-2-[ l-hydroxyfluorene]-N'-(2-bromophenyl] urea N-2-[ l-hydroxyfiuorene]-N'-[2-bromo phenyl] urea was prepared Irom 2- amino- 1 - hydroxyfluorene ( 170mg, 0.86 mmol) according to die procedure in General Method B. The product was purified by chromatography of the resulung solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). Η NMR (CD,C1): 6 8.04 (d, IH), 7.66 (d, IH), 7.49 (t. 2H), 7.35-7.20 (m, 4H). 7.09 (d. IH). 6.90 (t. I H). Example 71 Preparation of N-3-I2-hvdroxv-9.10-anihraquinonvll-N'-f2-hromonhenvll urea N-3-[2-Hydroxy-9,10-anthraquinonyl]-N'-[2-bromophenyl| urea was prepared from 2-hydroxy-3-aminoanthraquinone(480mg, 2.(X) mmol) according to the procedure in General Method B. The product was purified by precipiiauon from methylene chloride/ hexane( 1/20) and filtering. (610mg, 70%). Η NMR (CD-iOD): 6 8.93 (s.lH). 8.12 (m. 2H). 8.02 (d. I H). 7.77 (m. 2H). 7.61 (d. I H), 7.52 (s. I H), 7.38 (l. I H). 7.05 (I. I H) Example 72 Preparation of N-f2-hvdroxy-3-fluoro-5-bromophcnyl l-N"-12-bromophcnyl l urea a)Preparation of 2-amιno-6-fiuoro-4-bromophcnol A mixture of 4-bromo-2-fiuoro 6-nιtrophcnol( l g, 4.2mmol) and tin (II) chloride (4 78 g. 21.2mmol) in ethanol(50mL) was heated at 80°C under argon. Alter 2 hours, die starling mateπal had disappeared and the soluuon was allowed to cool down and ihcn poured into ice The pH was made slighdy basic (pH7-8). by addition ol solid NaOH. bclore being extracted with ethyl aceiate. The organic phase was washed with bπnc. dried over MgSO and filtered The solvent was evaporated and chromaiograpny of the resulung solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired product(710 mg. 82 % ) Η NMR (CD--OD): δ 6.51 -6 40 < m. 2H ) b)Preparauon ol N-[2-hvdroxy-3-lluoro-5-bromophcnyl]-N'-[2-biOmophenyl] urea N-[2-hydroxy-3-fiuoro-5-bromophcny]]-N'-[2-bromophenyl | urea was prepared Irom 2-amino-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipiiauon from methylene chloride/ hexanc( 1/20) and tillering. (500 mg, 77%;). Η NMR (CD.OD): 6 7.98 (s, I H). 7 91 (d, I H), 7.60 (d. I H). 7.33 (l, I H), 7.00 (t, I H), 6.94 (d. I H ) Example 73 Preparation of N-12-hvdroxy-3-chlorophenyll-N'-[2-bromophenyll urea a)Preparatιon of 2-amino-3-chlorophenol A mixture of 3-chloro-2-nιtrophcnol(250 mg, I 4mmol) and tin (II) chloride ( 1.2 g. 5.3mmol) in elhanol(50mL) was heated at 80°C under argon Alter 2 hours, the starting mateπal has disappeared and the solution was allowed lo cool down and then poured into ice The pH was made slightly basic (pH7-8). by addition ol solid NaOH. before being extracted with ethyl acetate The organic phase was washed with bπne. dried over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulung solid on silica gel (4%-MeOH/ CH 2 C1 2 ) gave the desired product( l43 mg. 69 %) Η NMR (CD,OD): 6 6.75 (t. l H), 6 70 (d. I H), 6.65 (d, IH) b)Preparatιon of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl ] urea N-[2-hydroxy-3-chlorophenyl]-N'-(2-bromophenyl] urea was prepared from 2-amιno- 3-chlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulung solid on silica gel (30%EtOAc/ Hexane) to give the desired product( 195mg. 57%). Η NMR (CD-.OD): 6 7 81 (d, I H). 7 68 (d. IH). 7.47 (d, I H). 7.20 (t, I H). 6 90 (m. 2H), 6 70 (l. I H) Example 74 Preparation ol N-[2-hydroxy-3-iπfiuoromcihylphcnyl l-N'-| 2-hron.ophcny l urea a)Preparaιιon ol 2-nιiro-6-tnfluoromcιhylphenol 2-tπlluoromcthylphenol (3 OOg. 18 5mmol) was dissolved in methylene chloπdc(40mL) lollowed by the addition ol sodium nitrate ( 1 73g. 20 4mmol) The addition of sulfuπc acid (23 mlJ 3M) was then made, lollowed by addition ol a catalytic amount ol sodium nitrite The mixture was allowed to sur Altei 24 hours, the reaction mixture wa.s diluted with methylene chloπdc and extracted with water The organic layer was dried ovei MgSO 4 and filtered The solvent was ev aporated and chromaiogiaphy ol the resulting solid on silica gel (4% MeOH/ CH-*C] 2 ) gave the desired productd 84 g 47 % ) Η NMR (CD-.COCD 6 8 35 (d. l H). 7 95 ( d. I H). 7 1 3 u. I H ) b)Preparatιon ol 2-amιno-6- iπlluoromeihylphenol A mixture ol 6-tπfiuoromethy l-2-nιtrophenol( l 84 g. 8 67mmol ) and tin (II ) chloride (6.0 g. 26.2 mmol) in cthanol( 150mL) was healed at 80°C undei argon Alter 2 hours, the starting material has disappeared and the soluuon was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8). by addition ol solid NaOH. bctorc being extracted with ethyl acetate. The organic phase was washed with bπnc. dπcd over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulung solid on silica gel (4%MeOH/ CH.Cl-.) gave the desired producK 1.35 g. 88 % ). Η NMR (CD 3 OD): 6 6.93 (d. I H), 6.82 (1, I H), 6.78 (d, I H). c)Preparation of N-f2-hydroxy-3- trifluoromethylphenyl]-N'-]2-bromophenyl] urea N-[2-hydroxy-3-trifiuoromethylphenyl]-N'-[2-bromophcnyl) urea was prepared from 2-amino-6-trifluoromethylphenol (280mg. 1.60 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( l/20) and filtering. (390mg, 65%). Η NMR (CD 3 OD): 6 7.99 (d. I H). 7.60 (d, I H). 7.58 (d, I H). 7.34 (t, I H). 7.30 (d. I H), 7.00 (t, I H). 6.96 (d. I H) Example 75 Preparation of N-f3.4 diphenvl-2-hvdroxvphenvll-N'-f2-hromophenyll urea N-[3.4 diphenyl-2-hydroxyphenyl]-N'-|2-bromophcnyl| urea was prepared from 2- amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering (61mg. 69%). Η NMR (CD 3 OD): δ 7.97 (d. I H). 7.66 (d, I H), 7.58 (d. IH). 7.31 (l, I H), 7.25-7.00 (m, 1 I H), 6.91 (d, I H). Example 76 Preparation of N-f2-hvdroxy-3-glvcinemethylestercarhonylphenylI-N'-f2-hromophcnyll urea N-[2-hydroxy-3-glycincmethylesιcrcarbonylphcnyl]-N'-|2-bromophenyl] urea was prepared from 6-glycinemcthylestcrcarbonyl-2-amιnophcnol (50mg. 0.22 mmol). purchased from the University of New Hampshire, according lo ihe procedure in General Method B The product was puπfied by precipitation from methylene chloride/ hexancf 1/20) and filtering (65mg. 69% ) Η NMR (CD DD): 6 8.14 (d. I H). 7.96 <d. I H ). 7 49 (d. I H ). 7 24 ( t. 2H). 6.89 (dd. I H). 6.81 (t. I H). 4 10 (s.2H). 3.74 (s.3H ) Example 77 N-(2-Hydroxy-3-glycιnecarbonylphenyl ]-N'-|2-bromophcnyl| urea was prepared from N-[2-hydroxy-3-glycιncmcihylcsιcrcarbonylphcnyl ]-N"-[ 2-bromophcnyl | urca(50mg. 0 12 mmol) by stining in a 3/1 ratio ol mcihanol waicr ( 10 mL) Addition of 1 ol luhium hydroxide was added and stirring continued until the starting material had disappeared (45mg. 92% ) The product was purified by chromatography ot ihe resulung solid on silica gel (9/1/0. 1 CH 2 C1 2 / MeOH AcOH) to give ihe desired producK I95mg. 57% ) Η NMR (CD.OD): δ 8.14 (d. I H). 7.92 (d. I H). 7.60 (d. I H ). 7 46 (d. I H). 7 4 α. I H). 7 04 (t. I H). 6 82 (l. I H ). 3.96 (2H). Exa ple 78 Preparation ol N-f2-hvdroxy-3.5-dichlorophenyll-N'-12-bromophenylI urea a)Prcparatιon of 2-amιno-4,6-dιchlorophenol A mixture ol 4,6-dιchloro-2-nιtrophenol( 1 g, 4.8mmol) and tin (II) chloπde (3.2 g, 14 4mmol) in ethanol(50mL) was heated at 80°C under argon After 2 hours, die starting material had disappeared and the soluuon was allowed to cool down and ϋien poured into ice The pH was made slighdy basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate The organic phase was washed with bπne, dπed over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulung solid on silica gel (4%MeOH/ CH 2 C1 : ) gave the desired product(685 mg, 80 % ) Η NMR (CD 3 OD) 6 6 75 (s. l H), 6 61 (s, I H) b)Preparatιon of N-[2-hydroxy-3,5-dιchlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,5-dιchlorophenyl]-N'-[2-bromophenyI] urea was prepared from 2- amιno-4,6-dιchlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B The product was puπfied by precipitauon from methylene chloπde/ hexane( 1/20) and filtering (660mg, 88% ) Η NMR (CD-,00): 6 7.96 (s. IH), 7 89 (d, IH). 7 60 (d, IH), 7 35 (I. I H). 7 00 (t, I H). 6.95 (dd, I H). Example 79 Preparation ol N-l2-hvdroxy-3-nitrophenyll-N'-12-bromophenyll urea N-|2-Hydroxy-3-nιirophcnyl |-N , -]2-bromophcnyl] urea was prepared trom 2-hydroxy-3- nitroanilinc ( l .25g. 8 I mmol) according to the procedure in General Method B The product was purified by precipiiauon Irom methylene chloride/ hexane( l/20) and tiltcπng (2 4g. 84% ) Η NMR (CD.OD) 6 8 45 (d. I H). 7 94 (d. I H). 7 78 (d. I H ). 7 60 (d. I H). 7 35 ( t I H ). 7 () l (m, 2H) Example 80 Preparation ol N-I2-hvdrox\ -4-naphthalencsullonιc acιdl-N'-[2-bromophenyll urea N-[2-hydroxy-4-naphlhalcncsullonιc acιd|-N'-]2-bromophenyl | urea was prepared irom l -amιno-2-hydroxy-4-naphthalcnsullonιc acid (048g. 2 0 mmol) according to the procedure in General Method B and the addition ot I mL ot tπethylamine The product was puπlied by precipiiauon Irom mcihylcne chloride/ hcxane( l/20) and filtering (690 mg. 79% ) Η NMR (CD A OD ) 6 8 14 I S 1 H ). 8 04 (d. I H ). 7 98 ( m. 2H). 7 61 -7 55 (m 3H). 7 43 (l. I H ). 6 98 (l. I H) Example 81 Preparation ol N-12-hvdro\\ -5-naphihalencsullonιc acιdl-N'-12-bromophcnyll urea N-3-|2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromophenyl] urea was prepared Irom 2-amino-3-hydroxy-6-naphdιalensulfonic acid (0.48g, 2.0 mmol ) according to the procedure in General Method B and the addition of I mL of triethylamine The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (715 mg. 82% ). Η NMR (CD-iOD): 6 8.09 (s, I H), 7.96 (d, I H), 7.65-7.48 (m, 3H), 7.36 (t, I H), 7.25 (s, I H), 7.04 (m. 2H). Example 82 Preparation of N-[2-hvdroxy-3.4-dichlorophenyll-N'-f2-bromophenyll urea a)Preparation of 2-nilro-5.6 dichlorophenol 2.3-dichlorophenol (3.26g, 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol). The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted widi memylene chloride and extracted with water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH 2 Cl->) gave the desired product( 1.8 g, 44 %). Η NMR (CD3COCD ): 5 8.04 (d. l H). 7. 15 (d. IH). b)Preparaιion of 2-amino-5.6 dichlorophenol A mixture of 5.6-dichloro-2-nitrophenol( 1.8 g. 8.7mmoI) and tin (II) chloride (5.8 g. 26. 1 mmol) in eιhanol(50nιL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH 2 CI 2 ) gave the desired producK 1 .4 mg, 90 % ). Η NMR (CD,OD): 6 6.71 (d. I H ). 6.45 (d. I H). c)Preparaiion of N-[2-hydroxy-3.4-dichlorophenyl]-N'-[2-bromophcnyl] urea N-12-Hydroxy-3.4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2- amino-5.6-dichlorophenol (350mg. 2.(X) mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( l/20) and filteπng (670mg. 89% ). Η NMR (CD,OD): 6 7.90 (d. I H). 7.85 (d. I H). 7.59 (d. I H ). 7.3 1 (l. I H ). 6.99 ( t. I H ). 6.96 td. ( I H). Example 83 Preparation oi N-l 2-hvdroxy-3-cvanophenyll-N'-f2-hromophenyll urea a)Preparauon of 2-nιtro-6-cyanophenol 2-cyanophenol (2.38g. 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol). The addition ol sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalyuc amount of sodium nitπte. The mixture was allowed to stir. After 24 hours, the reacuon mixture was diluted with me ylene chloride and extracted with water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH CH 2 C1 2 ) gave the desired product( 1.4 g. 42 % ). Η NMR (CD3COCD,): 6 8.47 (d. l H). 8. 15 (d. I H), 7.30 (t, I H). b)Preparatιon of 2-amino-6-cyanophenol A mixture of 6-cyano-2-niirophenol(600 mg. l .Ommol) and tin (II) chloride (3.2 g. 14.4mmol) in acetic acid(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slighdy basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulung solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product(365 mg. 75 %). 1H NMR (CD--OD): 6 6.92 (d, I H). 6.85- 6.69 (m,2H). c)Preparatιon of N-[2-hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino- 6-cyanophenol ( 134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipiiauon from methylene chloride/ hexane( l/20) and filtering. (260mg. 78% ). Η NMR (CD.OD): 6 7.98 (d. IH). 7.74 (d. I H). 7.57 (d. I H). 7.30 (1. I H J. 7.22 (d. I H). 6.98 (l. IH), 6.94 (t, ( I H). Example 84 Preparation of N-12-hvdroxy-4-cvanophenvn-N'-f2-hromophenyll urea a)Prcparatιon of 2-nitro-5-cyanophenol 3-cyanophenol (2.38g. 20mmol) was dissolved in methylene chloπde(40mL) lollowed by the addiuon of sodium nitrate ( l .88g. 22mmol). The addition ol sulfuric acid (20mL/ 3M) was ihcn made, followed by addition ol a caialyuc amount of sodium nitπie The mixture was allowed to sur. After 24 hours, the reacuon mixture was diluted with methylene chloride and cxiractcd with water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of ihe resulting solid on silica gel (4%-MeOH CH 2 C1 2 ) gave the desired produci(910 mg. 28 % ) Η NMR (CD3COCD,): 6 8 30 (d. l H). 7 67 (s. I H). 7.49 (d. I H). b)Preparauon of 2-amino-5-cyanophenol A mixture of 5-cyano-2-nιtrophenol(250 mg. 1.5mmol) and tin (II) chloride (3.2 g. 14.4mmol) in elhanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and ihen poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracied with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%. MeOH/ CH 2 C1 2 ) gave the desired producK 175 mg, 86 %•). Η NMR (CD--OD): 6 7.00 (d, I H). 6.88 (S, 1 H), 6.69 (d, IH). c)Preparation of N-[2-hydroxy-4-cyanophenyl|-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino- 5-cyanophenol ( 170mg, 1.27 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (310mg, 74%). Η NMR (CD,OD): 6 8.25 (d, IH). 7.91 (d. I H). 7.59 (d. I H), 7.33 (t. I H). 7.17 (d, IH), 7.07 (s, IH). 7.01 (t, ( I H). Example 85 Preparation of N-f2-hvdroxv-4-cvanophenvll-N'-l4-methoxvphenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-f4-methoxyphenyl] urea was prepared from 2- amino-5-cyanophenol (60mg r 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. ( 1 10mg,86%). Η NMR (CD--OD): 6 8.23 (d, I H), 7.61 -7.51 (m. 2H). 7.32 (d, I H). 7.20 (d. IH), 7.15 (d. IH), 7.03 (s, IH). Example 86 Preparation of N-f2-hvdroxy-4-cyanophcnyll-N'-l2-phenylphcnyll urea N-[2-Hydroxy -4 cyanophenyl |-N'-[2-phcnylphenyl] urea was prepared from 2-amιno-5-cyanophenol ( 170 mg. 1.27 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hcxane( 1/20) and filtering. ( 150mg, 85% ), Η NMR (CD-.OD): 6 8.20 (d. I H), 7.73 (d. I H), 7.51 -7.20 (m. 8H). 7. 13 (d. I H), 7.01 (s. ( I H ) Example 87 Preparation ol " N'-l2-hvdroχy-4-cvanophenyl l-N'-I2-methylphenyll urea N-[2-Hydroxy-4-cyanophenyl|-N'-|2-mcthylphenyl| urea was prepared from 2-amιno- 5-cyanophcnol (60mg. 0.45 mmol) according to the procedure in General Method B. The product was purified by precipiiauon from mcihylcne chloride/ hexanc( 1/20) and filtering (90mg, 75% ). Η NMR (CD--OD): 6 8.25 (d. I H). 7.59 (d. I H ). 7.26-7.00 (m. 5H). 2.30 (s. 3H). Example 88 Preparation of N-[2-hvdroxy-4-cvanophenyll-N'-[2-trifluoromethylnhenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-ιrifluoromeihylphenyl| urea was prepared Irom 2-amιno-5-cyanophcnol (60mg, 0.45 mmol) according lo ie procedure in General Method B. The product was purified by precipitauon from methylene chloride/ hcxane(l/20) and filtering ( 1 lOmg, 76% ). Η NMR (CD--OD): 6 8.25 (d, I H), 7.81 (d, I H). 7.68 (d, I H), 7.61 (t. IH). 7.32 (l. IH), 7.15 (dd, I H), 7.09 (s, ( IH). Example 89 Preparation of N-12-hvdroxy-4-cvanophenyll-N'-f3-trifluoromethylphcnyll urea N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amιno-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B The product was purified by precipitauon from methylene chloride/ hexane(l/20) and filtering ( 1 14mg, 79%). Η NMR (CD 3 OD): 6 8.30 (d, IH), 7.92 (s, I H). 7.60 (d, IH). 7.47 (t. I H ). 7.29 (d, IH), 7. 18 (dd, IH), 7.06 (s, IH). Example 90 Preparation of N-^-hvdroxv^-cvanophenvll-N'- -triπiioromethylphenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. ( 108mg, 75%r). Η NMR (CD--OD): 6 8.31 (d. IH), 7.68 (d. 2H). 7.59 (d, 2H). 7.20 (dd. I H). 7.07 (s. I H). Example 91 Preparation of N-l2-hvdroxy-3-n-propylphenyll-N'-l2-hromophenyll urea a)Preparatιon ol 2-nitro-6-n-propylphenol 2-n-ρropylphenol (5.00g, 36.8mmol) was dissolved in methylene chloπde(4()mL) followed by the addition of sodium nitrate (3.43g, 40.5mmol). The addiuon of suliuπc acid (45mL/ 3M) was then made, followed by addition of a catalyuc amount o\ ~ sodium niiπie The mixture was allowed to stir. After 24 hours, die reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulung solid on silica gel (4% MeOH CH : C1 ) gave the desired product(3.2 mg, 48 % ). Η NMR (CD3COCD,): δ 7.W (d. l H i. 7.46 dd. I H ). 6.90 (l. IH). 2.70 (I. 2H). 1.70 ( m. 2H). 1.00 (l. 3H). b)Preparauon of 2-amino-6-n-propylphenol To a solution of 2-nitro-6-n-propylphenol(2g, I l .Ommol ) in methanoK lOOmL) was added 10%* Pd/C (200 mg). The mixture was Hushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnighi. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of ihe resulting solid on silica gel (5%?MeOH/ CH 2 C1 2 ) gave the desired producK 1.50 g. 80.2 %-). Η NMR (CD.OD): 6 6.65 (m. 2H), 6.55 (t, I H), 2.58 (t. 2H), 1.61 (m, 2H), 0.96 (t, 3H). c)Preparation of N-[2-hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl | urea N-[2-Hydroxy-3-n-propyl phenyl ]-N'-[2-bromo phenyl] urea was prepared from 2- amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hcxanc( 1/20) and filtering. (640mg,92%). Η NMR (CD 3 OD): 6 8.00 (d, I H), 7.58 (d. I H). 7.32 (t. I H). 7.26 (t, IH), 6.96 (dd, IH), 6.89 (t, IH), 6.78 (d. IH). Example 92 Preparation of N-I2-hvdroxv-4-ethylphenyll-N'-f2-hromophenyll urea a)Preparation of 2-nitro-5-ethylphenol 3-ethylphenoI (5.00g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric acid (50mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired producK 1.7 g, 25 %). Η NMR (CD3COCD ): 6 8.02 (d. l H). 6.99 (s.l H). 6.85 (d, I H), 2.69 (q. 2H), 1.30 (t, 3H). b)Preparation of 2-amino-5-ethyllphenol To a solution of 2-nitro-5-ethylphenol( lg. 6.4mmol) in methanol(250mL) was added 10% * Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and die celite was washed with methanol. The solvent was evaporated and chromatography of ihe resulting solid on silica gel (5%cMeOH/ CH 2 CI 2 ) gave the desired producι(750 mg. 91 % ). Η NMR (CD,OD): 6 6 41 - 6. 17 (m, 3H). c)Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl| urea N-f2-Hydroxy-4-ethylphenyl]-N'-(2-bromo phenyl] urea was prepared from 2- amino- 5-cihylphenol (274mg. 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitauon from mcihylcne chloride/ hcxanc( 1/20) and filtering. (520 mg. 77%). Η NMR (CD--OD): δ 7.96 (d. I H). 7.62 (s. I H). 7.56 (d. I H ). 7.30 ( l. I H). 6.96 (t, I H). 6.82 (d. IH). 6.76 (d, IH). Example 93 Preparation of N-(2-hvdroxy 3-phenylamιnocarhonvI phenyll-N'-l2-bromophcnyl l urea a)Prcparaiion of 2-nιtro-6-phcnylamιnocarbonylphcnol 2-Phenylamιnocarbonylphenol (5.00g. 23 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrale (2.20g. 25.5 mmol). The addition of sulfuric acid (30mIJ 3M) was then made, followed by addition of a catalytic amount ol sodium nitrite. The mixture was allowed to stir After 24 hours, the reaction mixture was diluted with me ylene chloride and extracted with water The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of die resulung solid o silica gel (4%MeOH CH 2 C1 2 ) gave the desired product(2.50 g. 42 % ). Η NMR (CD3COCD-*): 6 8. 15 (d. l H), 8.09 (d, l H). 7.51 (d. I H). 7.30 (d. I H). 7 10 (I. IH). 7.01 (I I H). b)Preparation of 2-amιno-6-phenylaminocarbonylphenol To a soluuon of 2-nitro-6-phenylamιnocarbonylphenol ( lg. 4.0 mmol) in methanol(250mL) was added 10%.Pd/C ( 100 mg). The mixture was Hushed widi argon, then hydrogen was bubbled through the solution for 10 mm. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celit was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the desired producl(800 mg, 91 %). Η NMR (CD 3 OD): δ 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m. I H). 6.94 (t. IH). 6.74 (l, IH). c)Preparation of N-[2-hydroxy 3-phenylamιnocarbonyl phenyl]-N'-]2-bromophenyl] urea N-[2-hydroxy 3-Phenylamιnocarbonyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amιno-6-phenylaminocarbonylphcnoI (456mg. 200 mmol) according to the procedure in General Method B. The product was purified by precipiiauon Irom methylene chloride/ hexane( 1/20) and filteπng. (800mg.94% ) ' H NMR (CD ,OD ) ' H NMR (CD-.OD ι δ 25 (d, IH), 7.94 (d. I H). 7.75-7.57 ( . 4H). 7 48-7.30 (m. 3H). 7. 1 (l. I H). 7.02 (dd. I H), 6.92 (I, I H). Example 94 Preparation of N-12-hvdroxy-3-cvano-4-mcthylphenyll-N'-12-hromopheι.yl l urea a) Preparauon ot the 2-nιιro 5-methyl 6-bromo phenol A solution of t-butyl amιne(6.88 mL. 4 79 g. 2 equι\ .) in methylene chloride was ircated with bromine ( 1 67 L. 5.2 g. 1 equiv ) al -20 "C The flask w as then cooled to -78 °C and the the 2-nιlro 5-methyl 6-bromo phenol (5 g. 1 equiv.. m meihylenc chloride) was added drop-wise with vigrous stirπng. The reacuon mixture was slowly warmed to -30 "C lo 1 h. then to - 10 "C for 2 hours. The reaction mixture was then partitioned beiween methylene chloride and 5% aqueous acetic acid. The organic " layer was dried over magnesium sultaic. filtered and concentrated in vacua. The reaction mixture was puπlicd by flash chromatography(Ethyl acetate/ hexanes) to remove dibrominated species The 2-nιtro 4-bromo 5-methyl phenol was then selectively crystallized out of methylene chloride. A final silica gel column(5%5Cthyl acetate/ hexanes) yielded desired isomer in 90% puπty.( 1.05 g. 14% ) -H NMR (CDCI3): 6 7.95 (d, I H. J = 10.0 Hz), 6.91 (d, I H. J = 10.0 Hz). 2.52 (s, 3H). b) Preparation of 2-nitro-5-methyl-6-cyanophenol 2-Nιtro-5-meihyl-6-bromophenol ( 100 mg, 0.433 mmol) was dissolved in dimethyl formamidc (2mL) followed by ihe addition of triethylamine (0.175g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridinc was then made, followed by addition of copper (I) cyanide (155mg, 1.73mmoI). The mixture was allowed to stir at 80°C for 4 hours. The solvent was evaporated and chromatography ol " ihe resulting solid on silica gel (2%MeOH/ CH 2 C1 2 ) gave the desired product (70 mg. 91 %). Η NMR (CD3COCD,): 6 8.30 (d. l H). 7. 15 (d, l H), 2.61 (s, 3H). c) Preparation of 2-amino-5-meιhyl 6-cyanophenol A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmol) and tin (II) chloride (265 mg. 1.18mmol) in ethanol(20mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slighdy basic (pH7-8), by addition ol " solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH 2 CI 2 ) gave the desired producK 175 mg, 86 %). l H NMR (CD--OD): δ 6.87 (d, IH), 6.75 (d. l H). 6.32 (s. 3H). d) Preparation of N-[2-hydroxy 3-cyano 4-methyl phcnyl|-N'-[2-bromophenyl] urea N-[2-hydroxy 3-cyano 4-methyl phenyl|-N'-|2-bromophcnyl] urea was prepared from 2-amιno-5-mcihy]-6-cyano phenol (50mg, 0.34 mmol) according to the procedure in General Method B. The product was purified by precipitauon from methylene chloride/ hcxane( 1/20) and filtcπng (70mg. 60% ) Η NMR (CD--OD): 6 7.92 (d. I H). 7.68 (d. I H). 7.59 (d. I H). 7.31 (t. I H). 7.00 (l. I H). 6.62 (t. I H). 2.49 (s. (3H) Example 95 Preparation of N-12-hvdroxy 4-Carboxyphenyl phenyl l-N"-[2-hromophenyl I urea a)Preparatιon oi 4-niuo-3-hydroxybcnzophenonc 3-Hydroxybenzophenonc (3.00g, 15. 1 mmol) was dissolved in mediylene chloπdc(40mL) followed by ihe addition ol sodium nitrate ( I .42g. I 6.7mmol) The addition ol sulfuric acid (25mU 3M) was then made, followed by addition ol a catalytic amount ol sodium nitrite. The mixture was allowed to stir. Alter 24 hours, the reaction mixture was diluted with methylene chloπdc and extracted with water. The organic layer was dried over MgSO and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH C1 2 ) gave the desired producK 1.10 g. 30 % ). Η NMR (CD3COCD,): 6 8.25 (d. l H). 7.86 (d.l H), 7.71 (m. I H), 7.59 (d. I H). 7 48 (s, I H), 7.39 (dd, I H). b)Prcparation of 4-amino-3-hydroxybenzophenone A mixture of 4-nιtro-3-hydroxybenzophenone (900 mg, 3.7mmol) and ϋn (II) chloride (2.5 g. I l l mmol) in ethanol(50mL) was heated at 80°C under argon After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed widi bπne, dried over MgSO and filtered. The solveni was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired product(685 mg, 87 %-). Η NMR (CD^OD): δ 7.65 (d, 2H), 7.55 (d,lH), 7.49 (t, 2H). 7.26 (s, I H), 7.16 (dd, IH), 6.68 (d, IH). c)Preparation of N-f4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N-[4-Carboxyphenyl-2-hydroxypheny]l-N'-[2-bromophenyl] urea was prepared from 4-amιno-3-hydroxybenzophenone (330mg, 1.5 mmol) according to the procedure in General Mediod B. The product was purified by precipitauon from methylene chloride/ hexaned/20) and filtering. (490mg, 79%). Η NMR (CD--OD): 6 8.40 (d, IH), 8.09 (d, I H), 7.83 (d. 2H), 7.65-7.60 (m, 4H), 7.48 (s, IH), 7.43 (d, IH), 7.35 (d, (I H), 7. 10 (1.1H). Example 96 Preparation of N-12-hvdroxy 3-carhoxyphenyl phenyl]-N'-[2-hromophenyll urea a)Prcparatιon of 3-mtro-2-hydroxybenzophenone 2-Hydroxybcnzophenonc (3.00g, 15. l mmol) was dissolved in mediylene chloπde(40mL) followed by die addition of sodium nitrate ( 1.42g. 16 7mmol) The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition ol a catalyuc amount ol sodium niiπtc The mixiurc was allowed to stir Alicr 24 hours, the reaction mixture was diluted widi mcihylcne chloride and extracted with waier The organic layer was dried ovci MgSO 4 and filtered The solvent was evaporated and chromatography ol the resulung solid on silica gel (4%*MeOH CH C1 : ) gave the desired producK 1 60 g. 44 % ) Η NMR (CD3COCD,): δ 8.30 (d. l H ). 7.86 (m.3H), 7 7 1 ( m. I H). 7.78 (d. I H). 7 56 (dd 2H ). 7 24 (i. I H) b)Preparaiιon of 3-amιno-2-hydroxybenzophenonc A mixture of 3-nιiro-2-hydroxybenzophcnone (600 mg. 2.5mmol ) and tin (II) chloride ( 1 7 g. 7.5mmol) in cihanol(50mL) was heated at 80°C under argon Alter 2 hours, die starting mateπal had disappeared and the soluuon was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted with eihyl acetate The organic phase was washed with bπnc. dned over MgSO 4 and filiered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH.C ) gave the desired product(490 mg, 92 % ). Η NMR (CD 3 OD): δ 7.65- 7.40 (m, 5H), 6.98 (d, lH), 6.86 (d, I H), 6.67 (t, IH). c)Preparaiιon of N-[2-hydroxy 3-carbυxyphcnyl phenyI]-N'-[2-bromophenyl] urea N-[2-hydroxy 3-carboxyphenyl phenyl ]-N'-[2-bromophenyl] urea was prepared from 3-amιno-2-hydroxybcnzophenone (250mg, 1.20 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexanc( 1/20) and filtering. (200mg, 78% ). Η NMR (CD 3 OD): δ 8.35 (d, I H), 7.96 (d, I H). 7.72 (d. 2H), 7.65-7.50 (m, 4H), 7.35 (d. I H). 7.30 (d, IH). 7.01 (dd. ( I H). 6.92 (t. I H) Example 97 Preparation of N-12-hvdroxv 3-benzvloxv phenvIl-N'-r2-hromophenyll urea a)Preparatιon of 2-nitro-6-benzyloxy phenol 2-Benzyloxyphenol (5.00g. 25.0mmol) was dissolved in methylene chloride(40mL) followed by the addiuon of sodium nitrate (2.30g, 27.5mmol). The addiuon of sulfuπc acid (3 lmlJ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted wilh water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH 2 C1 : ) gave the desired product(2.6 g. 43 %). Η NMR (CD3COCD,): δ 7.70 (d, I H). 7.50-7.28 (m. 5H), 7. 14 (d. I H). 6.92 (t. IH), 5.21 (s, 2H). b)Preparauon of 2-amιno-6-benzyloxy phenol A mixture of 2-nιιro-6-bcnzyloxy phenol (1.00 g, 4. lOmmoD and tin (II) chloride (2.75 g. 12.2 mmol) in ethanol( 150mL) was heated at 80°C under argon Alter 2 hours, the starting material had disappeared and ihe soluuon was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8). by addition of solid NaOH. betore being extracted with ethyl acetate. The organic pha.se was washed wilh bπne. dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%-MeOH/ CH 2 C1 2 ) gave the desired producK 1.35 g. 88 % ). Η NMR (CD-.OD): δ7.46 (d. 2H). 7 40-7.35 (m. 5H). 6.55 (d. I H), 6.40 (d. I H). 5. 10 (s. 2H) b)Preparatιon ot N-[2-hydroxy3-bcnzyloxy phenyl]-N'-]2-bromophenyl] urea N-[3-bcnzyloxy-2-hydroxyphenyl]-N'-[2-bromophcnyl] urea was prepared Irom 2- nιiro-6-benzyloxy phenol (430mg. 2. ( X) mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane( l/20) and tillering (630mg. 76% ). Η NMR (CD-,OD): 6 7.93 (d, I H), 7.58 (d. I H). 7.54-7.42 (m. 3H). 7.40-7.25 (m. 4H). 7.00 (l. I H ). 6 69 (d. 2H). 5. 16 (s. 2H). Example 98 Prcparation of N-3-I2-hvdroxy-5-ιndanonel-N'-f2-hromophenvπ urea a)Prcparatιon of 2-hydroxy-3-nιtro-5-indanone 2-Hydroxy-5-indanone(3.00g, 20.0mmol) was dissolved in methylene chloride(40mL) followed by the addiuon of sodium nitrate ( 1.95g, 21.0mmol). The addiuon of sulfuric acid (25mLJ 3M) was then made, followed by addiuon of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted widi water. The organic layer was dried over MgSO 4 and filtered The solvent was evaporated and chromatography ol " the resulting solid on silica gel (4% MeOH/ CH 2 CI2) gave the desired producK 1.5 g, 39 %). Η NMR (CD 3 COCD : δ 7.70 (d. l H), 7.04 (d. I H), 3.04 (d, 2H). 2.74 (d, 2H). b)Preparauon ol " 3-amιno-2-hydroxy-5-indanone A mixture of 2-hydroxy-3-nitro-5-indanone ( 1.50 g, 7.80mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol( 150mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH7 CH 2 C1 2 ) gave the desired product(1.00 g, 79 %). Η NMR (CD 3 OD): δ 6.85 (d. l H), 6.45 (d, IH), 2.95 (d, 2H), 2.60 (d, 2H). c)Prcparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea N-(2-Hydroxy-5-ιndanone]-N'-[2-bromophenyl] urea was prepared from 3-amιno-2- hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in General Method B The product was purified by precipiiauon from methylene chloride/ hexane( l/20) and filtering (610mg. 85% ) Η NMR (CD--OD): 6 7.92 (d. I H). 7.65 (m. 2H). 7 45 (t. I H). 7 09 ( t. I H ). 7 00 (d. IH), 2.90 (d. 2H). 2.66 (d. 2H) Example 99 Preparation of (E)-N-l4-f 2-(Methoxycarbonyl) ethenyll-2-hydroxyphenyll-N'-l2- bromophenyll urea a)Prcparatιon of 4-nιlro-3-hydroxycιnnamιc acid 3-Hvdroxycιnnamιc acid (3.00g, 18.3 mmol) was dissolved in methylene chloπde(40mL) followed by the addition ol " sodium nitrate ( 1.70 g. 26.1 mmol). The addition ol suit uric acid (25 mL/ 3M) was then made, followed by addition of a catalytic amount ol sodium nitπie. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated and chromatography ot the resulting solid on si ca gel (4%MeOH/ CH 2 C1 2 ) gave the desired producK 1.0 g, 26 % ) Η NMR (CD^COCD 6 8.07 (d, IH), 7.69 (d, IH), 7.51 (s, IH), 7.46 (d, 2H), 6.75 (d. l H) b) Preparation of 4-nιtro-3-hydroxymethylcmnamate 4-Nιtro-3-hydroxycinnamιc acid was stined in excess methanol with a catalyuc amouni of sulfuric acid. The solvent was evaporated and chromatography of ihe resulung solid on silica gel (4%rMeOH/ CH 2 C1 2 ) gave the desired producK 1.0 g, 94 %) Η NMR (CD*,COCD,r δ 8.17 (d, IH), 7.69 (d, IH), 7.52 (s, IH). 7.45 (d, 2H), 6.75 (d. l H). 3 80 (s. 3H) c)Preparauon of 4-amιno-3-hydroxymethylcιnnamate A mixture of 4-nitro-3-hydroxymethylcinnamate ( 1.0 g, 4.50mmol) and un (II) chloπde (3.0 g. 13.4 mmol) in ethanol(50mL) was heated at 80°C under argon Alici 2 houis. the starting matenal had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slighdy basic (pH7-8), by addition of solid NaOH. beiorc being extracted with eϋiyl acetate. The organic phase was washed with bπne, dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product (650 mg, 75 % ) Η NMR (CD ,OD): 67.50 (d,lH), 6.94 (s, IH), 6.89 (d, IH), 6.68 (d, IH), 6.18 (d, IH). 3.74 (s, 3H). d)Preparation (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2- bromophenyl] urea (E)-N-|4-[2-(Methoxycarbonyl) ethenyI]-2-hydroxyphenyl]-N'-[2-bromophcnyl | urea was prepared from 4-amino-3-hydroxymethylcinnamate (250mg, 1 3 mmol) according to the procedure in General Mediod B. The product was puπfied by precipitation from methylene chloride/ hexane(l/20) and filteπng (300mg. 59% ) Η NMR (CD--OD): δ 8.24 (d. lH). 8 05 (d. IH), 7 69 (d. I H), 7.65 (d. IH), 7 42 (t. I H). 7.21 (s. I H). 7 19 (d. I H). 7. 10 ( t. I H ) 6.45 (d. l H) 3 81 (s. 3H) Example 100 Preparation of (E)-N-f.3-l2-(Methoxycarhonyl) ethenyll-2-hvdro\vphenyll-N'-f2- bromophenyll urea N'-f2-hromophenyl l urea a)Preparaiιon ol 3-nιtro-2-hydroxycιnnamιc acid 2-Hydroxycιnnamιc acid (3.00g, 18.3 mmol) was dissolved in methylene chloπde(40mL) lollowed by the addiuon of sodium nitrate (2.21 g. 26 l mmol) The addition ol sulfunc acid (30 mlJ 3M) was then made, followed by addition ol a catalytic amouni ol sodium nitrite The mixture was allowed to sur Alter 24 hours, the reaction mixture was diluted with mcihylcne chloπde and extracted with water The organic layer was dπcd ovci MgSO 4 and filtered. The solvent was evaporated and chromaiographv of the resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave die desired product(2.0 g. 52 % ) Η NMR (CD,COCD* ) δ 8.21 (d. IH). 8 16 (d. IH). 8.05 (d. IH), 7 19 (I, IH). 6.72 (d. I H ) b) Preparation of 3-nιtro-2-hydroxymethylcιnnamate 3-nuro-2-hydroxycιnnamιc acid was stined in excess mcdianol with a catalytic amount ol sulf uric acid The solvent was evaporated and chromatography ot ihe resulung solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired producK 1 0 g. 94 % ) Η NMR (CD,COCD 6 8.25 (d, I H), 7 8 15 (d, I H), 8 06 (s, I H). 7.20 (t, 2H), 6 76 (d. l H). 3 80 (s. 3H) c)Preparatιon ot 3-amιno-2-hydroxymelhylcιnnamate A mixture of 3-nιtro-2-hydroxymethylcιnnamate ( 1 0 g, 4 5 mmol) and un (II) chloride (3.0 g. 13 4 mmol) in ethanol(50mL) was heated at 80°C under argon After 2 hours, the starting mateπal had disappeared and the soluuon was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8). by addition ol solid NaOH. bclore being extracted with ethyl acetate. The organic phase was washed with bπne. dπed ovei MgSO 4 and filtered The solvent was evaporated and chromatography ol the resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product (700 mg, 81 % ) Η NMR (CD-.OD) δ 8 04 (d. IH), 6 93 (d, 1H),6.79 (d, IH), 6.71 (t, IH), 6 43 (d, I H), 3 72 (s. 3H) d)Preparatιon(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-12- bromophenyl I urea (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-f 2-bromophenyl ] urea was prepared from 3-amιno-2-hydroxymethylcιnnamate (100 mg, 0.52 mmol) according to ihe procedure in General Method B. The product was puπfied by precipitauon from methylene chloride/ hcxane(l/20) and filtering ( 150mg, 74% ) Η NMR (CD-,OD) 6 8.10 (d. l H). 8 00 (d. I H). 7 69 (d, IH), 7.65 (d, I H), 7 42 (t, IH), 7 38 (l. I H). 7 32 (d. I H) 7 O (t. I H ) 6 55 (d. l H) 3 81 (s, 3H) Example 101 urea N'-I2-bromophenvn urea a)Preparatιon of 2-hydroxycιnnamιde 2-Hydroxycιnnamιc acid (2 OOg, 12 3 mmol) was dissolved in dimethyl lormamιde( lOmL) followed by the addition of benzoιπazol- 1 -yloxy- tπs(dιmethylamιno)phosphonιum hexatluorophosphaic (5 4g. 12 3 mmol) and lamme ( 1.7mL. 12 3mmol) Ammonia gas was bubbled into the reaction mixture lor 30 minutes The mixture was allowed to sur for 24 hours, the reaction mixture was diluted wilh mcihvlene chloride and extracted with water The organic layer was dπcd over MgSO., and tikeied The solvent was evaporated and chromaiographv ol the resulting solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired producK 1 5 g, 75 %-) b)Preparatιon of 3-nιtro-2-hydroxycιnnamιde 2-Hydroxycmnamιde (750 mg. 4 6 mmol) was dissolved in methylene chloπdc(40mL) lollowed by the addition of sodium nitrate (430 mg, 5 lmmol) The addition ol sultuiic acid (7 mlJ 3M) was then made, followed by addition of a catalytic amouni of sodium nitπic The mixture was allowed lo sur. Alter 24 hours, the reacuon mixture was diluted with methylene chloride and extracted with waicr. The organic layer was dπed over MgSO and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product(350 mg, 36 %*). Η NMR (CD3COCD-*): 6 8.19 (d, I H ). 8.02 (d. I H). 7.88 (d. I H), 7. 15 (t, I H), 6 84 (d, I H) c)Preparatιon ol 3-amιno-2-hydroxycιnnamidc A mixture ol 3-nιiro-2-hydroxymcthylcinnamaie (350 mg. 1 7 mmol) and tin (II) chloπde (3.0 g. 13.4 mmol) in edιanol(50mL) was heated at 80°C under argon. After 2 hours. die starting matcπal had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slighdy basic (pH7-8). by addition of solid NaOH. before being extracted widi ethyl acetate. The organic phase was washed with brine, dried over . MgSO 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on " silica gel (4% * MeOH/ CH 2 C1 2 ) gave the desired product(244 mg.807r) d)Preparauon of (E)-N-[3-[2-(Aminocarbonyl) eιhenyl]-2-hydroxyphenyl]-N'-[2- bromophcnyl] urea (E)-N-[3-[2-(Aminocarbonyl) ethcnyl]-2-hydroxyphenyl]-N'-f2-bromophenyl] urea was prepared from 3-amιno-2-hydroxycιnnamιde (100 mg, 0.56 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexanc( l/20) and filtering. ( 1 10 mg, 52%).Η NMR (CD--OD): δ 8.00 (d. l H), 7.90 (d. I H). 7.63 (d. I H). 7.55 (d. I H). 7 35 (m. 2H), 7.05 (t. I H). 6.95 (t. I H). 6 70 (d. l H ) Example 102 urea N'-f 2-hromophenyl l urea a)Preparatιon ol 3-hydroxycιnnamιdc 3-Hydroxvcιnnamιc acid (2 OO g. 12 3 mmol ) was dissolved in dimethyl lorn.anudel l o mL) followed by the addition ol bcn/oiπa/ol- l -yloxy-tns(dimclhylamino)phosphoniuni hexalluorophosphate (5 4g. 12 3 mmol ) and tπcihylaminc ( 1 7 mL. 12 3mmol) Ammonia gas was bubbled inio ihe reaction mixture lor 30 minutes The mixture was allowed to sin loi 24 hours, ihe reaction mixture was diluted wuh mcihylcne chloride and extracted with watei The organic layer was dried over MgSO 4 and filtered. The soh ent was evaporated and chromatography ol the resulting solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired producK 1 3 g. 65 % ) b)Preparalιon ol 4-nιtro-3-hydroxycιnnamιde 3-Hydroxycιnnamide (750 mg. 4 6 mmol) was dissolved in methylene chloπde(40 mL ) followed by die addition ol sodium nitrate (430 mg. 5 I mmol ) The addition ot sulluπc acid (7 mlJ 3M) was then made, followed by addition ol a catalytic amouni ot sodium niiπie The mixiurc was allowed to sur. Alter 24 hours, ihe reaction mixture was diluted with mcthvlene chloride and extracted with water. The organic layer was dπcd over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulung solid on silica gel (4% MeOH CH 2 CI 2 ) gave the desired produci(240 mg, 25 %.). Η NMR (CD--COCD-*): δ 8.09 (d. I H). 7.49 (d, I H). 7.26 (s, IH). 7. 16 (d, I H), 6.71 (d, I H) c)Prcparation of 4-aminυ-2-hydroxycιnnamide A mixture of 4-nιtro-3-hydroxymemylcιnnamate (300 mg. I 40 mmol) and tin (II) chloride (980 mg, 4.30 mmol) in ethanol(50 mL) was heated at 80°C under argon After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8). by addition ol solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered. The solvent was evaporated and chromatography of ihe resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product (200 mg. 74 %*). d ) Prcparation ( E)-N-[3-[2-(Aminocarbonyl) ed enyl]-2-hydroxyphenyl]-N'-]2-bromophenyl] urea (E)-N-[3-[2-(Aminocarbonyl) elhenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl ] urea was prepared from 4-amino-2-hydroxycinnamide (lOOmg. 0.56 mmol) according to die procedure in General Method B. The product was purified by precipitauon from mcihylene chloride/ hexane( l/20) and filteπng. ( 125mg, 54% ). Η NMR (CDiOD): δ 8.05 (d. lH). 7.92 (d, I H ). 7.60 (d, I H), 7.4 5 (d. I H), 7.35 (t, I H), 7.05 (m. 2H). 6.50 (d. l H) Example 103 Preparation of N-12-hvdroxy 4-(phenyl amino carhoxy) phenyl l-N'-l 2-hromophcnyll urea N-|2-hydroxy 4-(phcnyl amino carboxy) phenyl |-N'-|2-bromophenyl | urea was prepared Irom 5-(phcnyl amino carboxy) 2-amιno phenol (0.50 mmol ) according to ihe procedure in General Method B. The product was puπficd by precipitation from methylene chloride/ hcxanc( l/20) and filtering ( 150 mg, 70% ). Η NMR (CD^OD): 6 8.25 (d. I H ) 8 00 (d. I H). 7.75 (d. 2H). 7.64 (d. I H). 7.50 (d. 2H), 7 41 (m. 3H). 7. 16 u. I H ). 7 05 ( l. I H ) Example 104 Preparation ol N-l4-amιnocarhonyl-2-hvdroxyphenyl l-N"-[2-hromophcnyl l urea N-|4-Amιnocarbonyl -2-hydroxyphcnyl]-N'-|2-bromophcnyl | urea was prepared Irom 5-anunυcarbonyl-2-amιno phenol (304 mg. 0.50 mmol ) according lo ihe procedure in General Method B The product was purified by precipitation Irom methylene chloπdc/ hcxanef 1/20) and filtering (440 mg. 62% ). Η NMR (CD--OD): 6 8.09 (d. IH). 7.91 (d. I H). "7 60 (d. I H ). 7 45 tm. 3H). 7.00 (d. I H) Example 105 Preparation ol N-(2-Hvdroxy-3.5.6-trifluorophcnyl)-N'-(2-bromophcnyl)urca N-(2-Hydroxy-3.5,6-trinuorophenyl)-N'-(2-bromophenyl)urea was prepared from 3.5.6-trifiuoro-2-hydroxyaniline (83 mg, 0.51 mmol) and 2-(bromophenyl)ιsocyanatc ( 100 mg, 0.53 mmol) according to the procedure in General Method B. The product was purified by preparation thin layer chromaiography. EI-MS m/z 359 (M-H) " . Example 106 Preparation of N-(2-Hvdroxy-3-fluoro-4-tritluoromethylphenyl)-N'-(2-bromophenyl )urea N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea was prepared from 4-trifluoromethyl-3-fluoro-2-hydroxyanilιne (239 mg. 1.2 mmol) and 2- (bromophenyl)ιsocyanate (243 mg, 1.2 mmol) according to the procedure in General Method B. Removal of solvent under reduced pressure and chromatography of the resulung solid on silica gel (hexane:ethyl acetate) gave the tide compound (20 mg, 4%). EI-MS m/z 391 (M-H) Example 107 Preparation of N-(2-Hvdroxy-3-iodophenyl)-N'-('2-bromophenyl)urea N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-ιodo-2- hydroxyaniline (200 mg. 0.85 mmol) and 2-(bromophenyl)isocyanaie ( 169 mg, 0.85 mmol) according to the procedure in General Mediod B. Removal of solvent under reduced pressure and chromaiography of the resulting solid on silica gel (hexane:ether) gave die tide compound (40 mg. 1 1 % ). Η NMR (DMSO): 6 9.45 (s, I H). 9. 15 (s. I H). 8.8 (s. I H). 7.95 (d. I H ). 7.8 (ύ. 1 H).7.65 (d. IH). 7 4 (d. I H), 7.3 (t. I H). 7.0 (l, I H). 6.65(1. I H) Example 108 Preparation ot N-[2-l fI2-(trinuoromethyl)phenyllsullonyllamιnolphenyl l-N'-(2- bromophcnvDurea a)Prcρaratιon of |2-[2-(tπnuoromethyl)phenyl](sulIonamιdo)anιlιne] The title compound was prepared according to General Method C using 2- (tππuoromcthyl)bcnzenesull nyl chloride 1 1 equiv ) The product was purified by chromatography on silica gel (methylene chloπdc:mcthanol) ( 1.04 g. 33% ) EI-MS m/z 3 17 (M+H)' b)Prcparaiιon ol .\-|2-[]| 2-(trιfiuoromethyl (phenyl )sultonyl |amιno|phenyϊ |-N'-(2- bromophcnvDurea The ti e compound was prepared usιng|2-|2(tritluoromeihyl)phenyl] (sulfonamιdυ)anιlιne ( 1 04 g. 3.2 mmol) and 2-(bromophenyl)ιsocyanaic (652 mg. 3 2 mmol ι according lo General Mediod B. The solvent was evaporated to give the desired urea ( 1.03 g. 61 % ). EI-MS m/z 5 14 (M+H) * Examplc 109 Preparation of N- ( 2-Bromophenyl ) -N'-f2-dimethylamιnosulfonylamιn lphcnyllurea a)Preparauon of [2-[ l , l-(dimcthylamino)]sullonamιdoaniline] The title compound was prepared according to General Method C using dimediylsulfamoyl chloride ( 1 equiv.). The product was purified by chromaiography on silica gel (methylene chloride:methanol). ES-MS m/z 216 (M+H) + . b)Preparation of N-(2-Bromophenyl)-N'-[2-(dimethylamιnosulfonylamιno|phcnyl]urca The ύde compound was prepared from [2-[ l ,l-(dιmethlyamιno)sulfonamιdo- aniline ( 137 mg. 0.6 mmol) and 2-(bromophenyl)ιsocyanate ( 126 mg, 0 6 mmol) according to General Mediod B. The solvent was evaporated and chromaiography on silica gel (ethyl acetate :hexane) gave die desired urea. EI-MS m/z 413 (M+H) * Example 1 10 Preparation of N-12-(Phenethylsulfonylamino) phenvπ-N'-(2-bromophcnyl)urea [2-(Pheneϋιylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a Pan shaker bottle containing palladium ( 180 mg) under an argon stream. Methanol ( 150 mL) was added and die container placed on a Parr shaker (55 psi) for several hours. The reaction mixture was filtered through Celite and d e filtrate was evaporated to give die desired aniline (269 mg. 90%r). EI-MS m/z 277 (M+H) + . b)Preparauon of N-[2-(Pheneihylsulfonylamιno)phenyl]-N'-(2-bromophcnyl)urca The title compound was prepared Irom [2-(phcnethylsullonamιdo) aniline] (269 mg. 0.97 mmol) and 2-(bromophenyl)isocyanaic ( 193 mg. 0 97 mmol) according to General Method B. The desired urea was precipitated oui of toluenc hcxanc (384 g. 78% ). EI-MS m/z 472 (M-H) Example 1 1 1 Preparation of N-l2-l(2-aceiamido-4-methylthιazol-5-yl)sulfonylamιnolphcnyll.N'-(2- bromophenvDurea a)Prcparatιon of [ 2-[(2-acetamido-4-mcihyl-5-ιhιazole)sulfonamιdo]anιlιne| The title compound was prepared using 2-acciamido-4-methy l- i s-ιhιa/olesullonyl chloπde ( 1 . ) according to General Method C A solid precipataied irom the lcaction mixture and was filtered to give ihe desired aniline ( 1 68 g. 52% ) ES-MS ml/ 327 (M+H ) " b)Prcparatιon ol N-[2-[(2-acciamιdo-4-meihylιhιazol-5-yl)sullonylamιι.()|phenyl ]-N'-(2- bromophenyDurea The title compound was prepared Irom [ 2-[(2-acetamιdo-4-mcihyl-5- thιazole)sultonamιdo]anilιne] ( 1.68 g.5. 14 mmol ) and 2-(bromophenyl)ιsocyanate (1.02 g, 5.14 mmol) according to General Method B The product was precipitated Irom ethyl acetate/hexanc (220 mg, 8%). EI-MS m/z 524 (M+H) * . Example 112 Preparation of N-l2-hydroxy-4-cyanophenyll-N-l4-phenylphenyll urea N-(2-Hydroxy-4- cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-amιno-5-cyanophenol (60mg. 0.45 mmol) according to the procedure in General Method B. The product was puπficd by precipitation from methylene chloride/ hcxanc(l/20) and filtering. (135 mg.75% ) Η NMR (CD--OD): 68.33 (d, IH), 7.71-7.29 ιm.9H), 7.25 (d. IH).7.12 (s. IH). Example 113 Preparation of N-f2-hvdroxy-4-cyanophenvH-N'-[2.3-dιchlorophenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3 dichlorophenyl) urea was prepared from 2- amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B The product was purified by precipiiauon from methylene chloride/ hcxaned/20) and filtering (125mg, 86%). Η NMR (CD 3 OD): 68.27 (d, IH), 8.15 (m, IH).739-7.20 (m.2H), 7.16 (d. IH), 7.06 (s. IH). Example 114 Preparauon of N-12-hvdroxv-4-cvanophenvll-N'-f2-methoxvphenvll urea N-[2-Hydroxy-4-cyanophenyl]-N'-f2-meihoxyphenyl) urea was prepared Irom 2- amιno-5-cyanophenoI (60mg, 0.45 mmol) according lo the procedure in General Method B The product was purified by precipitation Irom methylene chloride/ hexane( 1/20) and filtering (105mg, 83%) 'H NMR (CD„OD): 68.26 (d. IH).8.02 (d. IH).714 <d. IH).705 <s. IH).7.00-6.83 (m.3H), 3.84 (s, 3H) Example 115 Preparation of N-12-hvdroxy-4-cvanophcnyll-N'-[3-mcihoχyphen\ll urea N-|2-Hydroxy-4-cyanophenyl|-N'-[3-mcthoxyphcnyl| urea was prepared Irom 2- amιno-5-cyanophenol (60mg.0.45 mmol) according to the procedure in General Method B The product was purified by precipitation Irom methylene chloride/ iιexane( 1/20 • and filtering (102mg.80% ). Η NMR (CD,OD): 68.25 (d. IH).7.25-708 <m.3H).704 <s. IH).690 tl. IH).6.58 (d. IH) Example 116 Preparation ol N-[2-hvdroxy-5-fluorophenyll-N'-f2-hromophcnyll urea a)Preparatιon of 2-amιno-4-Huorophcnol A mixture ol 4-lluoro-2-mirophcnol( lg. 4 64mmol ) and tin (II) chloride (5 4 g, 24.2mmol) in cihanol(5 () mL) was healed at 80°C under argon Alici 2 hours, die starting material had disappeared and the solution was allowed to cool down and then poured into ice The pH is made slightly basic (pH7-8), by addition ot solid NaOH, bclore being extracted with ethyl acetate The organic phase was washed with brine, dπed over MgSO 4 and filtered The solvent was evaporated and chromaiography of ihe resulting solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired producl(622 mg. 85 % ) Η NMR (CD,OD) 6 6 51 (dd. I H). 6 32 (dd, I H), 6 17 (ddd. IH) b)Preparatιon ol N-[2-hydroxy-5-fluorophenyl|-N'-[2-bromophenyl] urea N-f2-Hydroxy-5-fiuorophenyl |-N'-f2-bromophenyl | urea was prepared Irom 2-amιno- 6-lluoro phenol (254mg, 2 (X ) mmol) according to the procedure in General Method B The product was puπfied by precipitauon from methylene chloride/ hexane( 1/20) and fdieπng (520mg,80%). Η NMR (CD,OD): 6 7.88 (d, IH), 7 79 (dd. IH). 7 57 (d, IH), 7 31 (t. I H). 7 00 (i. I H). 6 76 (dd. I H). 6 57 (ddd. l H) Example 1 17 Preparation of N-f2-hvdroxy-5-iπfiuoromcthv]phenyll-N'-[2-hromophenyll urea a)Prcparatιon ol 2-amιno-4- iπlluoromethylphenol A mixiure ol 4-tnHuoromcthyI-2-nitrophcnol( I 0 g. 4 8mmol) and tin (II) chloπde (5 4 g, 24.2 mmol) in ethanol( 150mL) was healed at 80°C under argon After 2 hours, the starting mateπal had disappeared and the solution was allowed to cool down and dien poured into ice The pH was made slightly basic (pH7-8) by addi on ol solid NaOH. belore being extracted with ethyl acetate The organic phase was washed with brine, dried over MgSO 4 and filtered The solvent was evaporated and chromaiography ol ihe resulung solid on silica gel (4% MeOH/ * ^ CH 2 C1 2 ) gave the desired produci(708 mg. 83 % ) 'H NMR (CD,OD) 6 6 87 (s. I H ) 6 80 (d. I H ). 6 69 (d, I H) b)Prcparatιon ol N-[2-hydro\\ -vιπHuoromcιhylphcnvl |-N'-|2-bromophcnyl| urea N-| 2-hydroxy-5-iπtluoromcthylphcnyl |-N'-| 2-bιomoplιcnyl] urea was prepared Irom 2-amιno-4-ιπfiuoromelhylphenol ( 354mg. 2 00 mmol ) according to the procedure in General 0 Method B The product was purified by precipitauon Horn nicthvlcne chloride/ hexancd equn /20cquι\ l and filtering (490mg. 65% ) Η NMR (CD-.OD) 5 8 40 ( s I H ) 7 94 (d I H ) 7 60 (d. I H ) 7 3 ( t I H ) 7 18 (d 111 ) 7 03 ( l I H) 6 95 (d. I H ' Example 1 I S 5 N-]2-hydroxypheny l]-N'-|2-bromo phenyl] urea was prepared Irom 2- ammo-phenol ( 141 mg. 1 30 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hcxanc( 1/20) and filtering (3(X)mg.75% ) Η NMR (CD--OD) δ 8 05 (d. I H ). 7 49 (d. I H), 7 25 it. 2H), 6 96 (i. I H). 6 90 ( t, 2H ). 6 68 (l I H ) Example 1 19 Preparation ol N-lirans-3-styrl 2-hydroxy phenyl]-N'-f2-hromophenyll urea a)Prcparatιon ot irans-6-styrl-2-nιtrophenol Trans-2-styrlphcnol (5(X ) mg, 2 55 mmol) was dissolved in methylene chloπde(40mL) lollowed by the addition ol sodium nitrate (240 mg, 2 81 mmol) The addition ol sultuπc acid (3 mL ol 3M) was then made, followed by addiuon ol a catalytic amount ol sodium nitπte The mixture was allowed to stir After 24 hours, ihe reaction mixture was diluted with methylene chloπde and extracted widi water The organic layer was dπcd over MgSO 4 and tillered The solvent was evaporated and chromatography of the resulting solid on silica gel (4%-MeOH/ CH ; CI 2 ) gave the desired product (200 mg, 36 %) Η NMR (CD3COCD " 6 8 05 (d. I H). 7 90 (d. 2H).7 65-7.20 (m.7H),7 00 (t, lH) b)Prcparaiιon of trans-6-styrl-2-amιnophenol A mixture ol trans-6-styrI-2-nιtrophenol (200 mg, 0 83 mmol) and un (II) chloride (560 mg. 2 60 mmol) in cdιanoI(50mL) was heated at 80°C under argon After 2 hours, the starling material has disappeared and the solution was allowed to cool down and dien poured into ice The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate The organic phase was washed wiϋi bπne, dπed over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH 2 CI 2 ) gave the desired product (50 mg. 29 % ) Η NMR (CD,OD) 6 7 51 (m 3H ). 7 29 ( m. 3H).7 1 I d. I H). 7 00 (m, 2H). 6 69 (m. 2H) c (Preparation ol N-|irans-3-siyrl-2-hydroxyphcnyl]-N'-[2-bromophenyI| urea N-| ιrans-3-st\ rl-2-hydroxyphenyl]-N'-f2-bromophenyl] urea was prepared Irom irans- 6-siyrl-2-amιnophenol (35mg. 0 17 mmol) according to the procedure in General Method B The product was purified by precipiiauon Irom mcihylcne chloride/ hcxanc( 1/20) and filtering ( 36mg. 53% ) Η NMR (CD-OD) δ7 97 (d. I H). 7 62-7 48 (m, 4H). 7 45-7 26 i . 5H). 7 25 ( i I H) 7 15 (d I H). 7 01 (t. IH). 6 88 (1 2H) Example 120 N-|2-h\ dro\\ -3 4-d]chlorophenyl|-N'-[2-mcthoxy phenyl] urea was prepared Irom 2- amino 5 6-dιchlorophenol (80mg 0 50 mmol. example 82b) according to ihe procedure in General Method B The product was puπlied by precipiiauon Irom methylene chloride/ hexane( 1/20) and filtering ( 125mg.77% ) Η NMR (CD,OD) 6 8 ()2 (d. I H) ^ 79 (d. I H ) 7 05-6 86 t 4H ) 2 , s . 3H) Example 121 Preparation of N-12-hvdroxy-3.4-dichlorophenyll-N'-14-methoxyphenyll urea N-f2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl | urea was prepared from 2- amιno-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hcxane( l equιv./20equιv.) and filtering. ( 120mg, 74%). Η NMR (CD-.OD): δ 7.89 (d. I H). 7.35 (d. 2H), 6.99 (d, I H), 6.90 (dd, 2H), 3.80 (s, 3H). Example 122 Preparation of N-[2-hvdroxv-3.4-dichlorophenvll-N'-l3-triπuoromeιhvlphenyll urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitauon from methylene chloπde/ hexane(lequiv./20equiv.) and filtering. (130mg, 71%). l H NMR (CD-«OD): 6 7.96 (d, 2H). 7.60 (d, IH), 7.48 (t, I H), 7.30 (d, I H), 7.00 (d, I H). E-Sarηple 123 Preparation of N-I2-hvdroxy-3.4-dichlorophenyll-N'-12-phenylphenvI l urea N-(2-hydroxy-3.4-dichlorophenyl]-N'-[2-phenylphenyl] urea was prepared from 2- amιno-5.6-dichlorophenoI (80mg. 0.50 mmol. example 82b) according to the procedure in General Meϋiod B. The product was purified by precipitation from methylene chloride/ hcxane( lequιv./20equiv ) and filtering. ( l lOmg, 59% ) Η NMR (CD,OD): δ 7 77 (d. I H ). 7 73 i d. I H). 7.53-7 14 (m. 8H). 6.95 (d. I H) Example 124 Preparation of N-[2-hvdroχy-3.4-dιchlorophcnyll-N'-12.3-dichlorophenyl l urea N-|2-Hydroxy-3.4-dichlorophenyl]-N'-[2.3-dιchlorophenyl] urea was prepared Irom 2-amιno-5.6-dichlorophcnol (80mg. 0.50 mmol. example 82b) according to the procedure in General Method B The product was purified by precipitauon from mcihylcne chloride/ hexaned equn /20eqιnv ) and filtering ( 1 30mg. 71 % ) Η NMR (CD.OD ): δ 8 06 (dd. I H ) 7 9 1 i d. I H). 7.25 ( m. 2H ). 7.00 (d. I H) Example 125 a)Preparation ol " 2-mtro-5-ιsopropylphenol 3-ιsopropylphenol (3.00g. 22 mmol ) was dissolved in methylene chloπde(40ml ) lollowed by the addition of sodium nitrate (2 06g. 24mmol) The addition ol sulluπc acid (25mL/ 3M) is ϋien made, followed by addition ol a catalytic amount ol sodium nitπte The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloπde and extracted with water. The organic layer is dried over MgSO 4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH 2 CI 2 ) gave the desired producK 1.09g, 27 %). Η NMR (CD3COCD-,): 6 7.95 (d. l H), 7.62 (d. l H). 7 1 1 (d, I H), 2.95 (m, I H), 1.24 (d, 6H) b) Preparation oI " 2-amιno-5-ιsopropylphenol To a solution of 2-nιtro-5-ιsopropylphenol( lg. 6.4 mmol) in mcdιanol(50 mL) was added 10% Pd/C ( 100 mg). The mixture was Hushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen aimosphere was maintained at balloon pressure overnight The mixture was filtered dirough celite and die celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the desired product(775 mg, 93 % ) Η NMR (CDiOD): 6 6 71 - 6 44 (m, 3H). 2.73 (m, IH), 1.20 (d, 6H). c) Preparation of N-[2-hydroxy-4-ιsopropylphenyl]-N'-[3-triHuoromcihylphenyl] urea N-[2-hydroxy-4-ιsopropylphenyl]-N'-[3-trifiuoromethylphenyl] urea was prepared from 2-amino-5-ιsopropylphenol (75mg, 0.50 mmol) according to die procedure in General Mediod B. The product was purified by precipitation from meϋiylenc chloπde/ hexane(lequιv./20equιv.) and filtering. ( 140mg. 83%-). Η NMR (CD--OD): δ 7.91 (d. 2H). 7.62 (d, IH). 7 47 (t, I H), 7.39 (d, IH), 6.75 (s. IH), 6.72 (d, IH). 2 80 (m, I H). 1 21 (d. 6H) Example 126 Preparation ol N-[2-hvdroxy-3-naphthyll-N'-[2.3-dιchlorophenyl l urea N-|2-hydroxy-3-naphthyl]-N'-|2.3-dιchlorophenyl] urea was prepared Irom 3-amιιm 2-naphthol ( I60mg. 1 00 mmol) according to ihe procedure in General Method B The product was purified by precipitauon Irom methylene chloride/ hexaned equn » and tillering (285mg. 82% ) Η NMR (CD,OD): δ 8 48 (s. I H). 8 10 (d. I H). 7 68 td. I H ) 7 57 (d. I H). 7 40-7 23 ( m. 4H), 7 18 (d. I H ) Example 127 a)Preparatιon ol |2-|(2.3-Dιchlorothιen-5-yl)|sultonylamιnoanιlιnc| The title compound was prepared according to General Method C using 2.3- dιchloroihιophcnc-5-sullonyl chloride (( I cq) The product was purified by Hash chromatography on silica gel (ethyl acetatc/hcxanc 20/80-methylenc chloπdc-methano! 90/10 ) ( 1.25 c. 39 % ) EI-MS m/z 321 (M-H) b)Preparaiιon o[ ' N-|2-](2.3-Dichloroιhιcn-5-yl)]sulfonylamιno|phenyl |-N'-(2- bromophenyDurea The tide compound was prepared Irom [2-[(2.3-dιchlorothιcn-5- yDjsulfonylaminoanihne ( 1.25 g,3.9 mmol) and 2-(bromophcnyI)ιsocyanatc (768 mg, 3.9 mmol) according to General Mclhod B. The product was purified by Hash chromaiography on silica gel (ethyl ace tale: hexane 30/70) (272 mg. 13 % ) EI-MS ml/ 520 (M-H) Example 128 Preparauon of N-f 2-l(3.5-Bistrifluoromethylphenyl)sullonylaminolphenyl l-N'-(2- bromophenyPurea a)Preparaiιon of [2-(3,5-Bιstπlluoromethylphenyl)sullonylamιnoanιlιnc| The tide compound was prepared according to General Method C using 3,5- (bistrifluoromethyl)phenylsulfonyl chloride ( 1.28 g, 4.1 mmol) and o-phenylenediamme (441 mg, 4.1 mmol). The product was purified by flash chromaiography on silica gel (methylene chloπde:methanol 95/5) (61 1 mg, 39 %). EI-MS m/z 383 (M-H) b)Preparation of N-[2-[(3,5-Bιstrifluoromethylphenyl)sulfonylamιno|phenyl]-N'-(2- bromophenyDurea The tide compound was prepared from [2-(3,5-bιsιriHuoromeιhylphenyl) sulfonylaminoanihne (591 mg, 1.5 mmol) and 2-bromophenylιsocyanatc (305 mg. 1 5 mmol) according to General Method B. The product was purified by Hash chromatography on silica gel (ethyl acetate: hexane 30/70) ( 10 mg. 1 %-).EI-MS m/z 580 (M-H) Example 129 Preparation ol N-l2-l(2-Benzyl)sullonylamιnol-(5-ιrιfiuoromcihyl )phcnyl l-N'-(2- bromophenyPurea a)Preparatιon of |(4-Benzylsulfonylanuno)-(3 -nιtro)-benzoiπnuoπde | 4-Amino-3-niiro-bcnzotrilluondc ( 1 0 g. 4 85 mmol ) w as in DMF and ihe reaction mixture was cooled lo 0"C Sodium hydπdc ( 175 mg. 7 28 mmol ) was added to the cold mixture and allowed to mix lor ten minutes ( a deep red color w as noicd) Toluencsultonyl chloπdc (925 mg. 4 85 mmol ) was added t reaction color changed to y ellow ) and the reaction was mixed lor sixteen hours ai room icmperauiie The reacuon w as quenched in NR-Cl and extracted with ethyl aceiaic: hexane ( 1 1 ) The pmdiiei as purified by Hash chromaiography on silica gel ( ethyl aceiaιc:hexanc 30/70) (878 mg. 52 % ) EI-MS ml/ 359 (M- H) b)Preparauon ol [(4-Bcnzylsullonylamιno)-(3-amιno)-benzoirιHuoπde | [(4-Benzylsulfonylamιno)-(3-nιtro)-benzotπHuoπde (230 mg. 0 64 mmoh was mixed in medianol and poured into a Pan bottle Palladium on carbon ( 15 g > was added under an argon stream The reaction mixture was placed on a Parr shaker ( 55 psi. H 2 ) tor several hours. The reaction mixture was filtered through Celite lo give the title compound. (210 mg. 99% ) EI-MS m/z 329 (M-H) . c)Prcparaύon ol ' N-f2-[(2-BcnzyI)sulfonylamino]-(5--rifiuoromcthyl)phenyl|-N'-(2- bromophenyDurea The tide compound was prepared from I(4-benzylsulfonylamino)-(3-amino)- benzotritluoride (210 mg, 0.64 mmol) and 2-bromophcnylisocyanate ( 126 mg. 0.64 mmol) according to ihe procedure in General Method B. The product was purified by Hash chromaiography on silica gel (c yl acetate: hexane 30/70) (70 mg, 21% ) EI-MS m/z 526 (M- H) Example 130 Preparation of N-r2-f2- ( 3-Nitrophenyl ) sulfonylaminolphenyll-N'-(2-bromophenyl)urea a)Preparauon of [2-((3-Nitrophenyl)sulfonylamino)aniline] The title compound was prepared according to General Method C using 3- nitrobenzenesulfonyl chloride ( I eq). The product was purified by Hash chromatogrphy on silica gel (methylene chloride:methanol 96/4).( 1.07 g, 37 %) EI-MS m/z 294 (M+H) * b)Preparaιion of N-[2-[(3-Nitrophcnyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea The utle compound was prepared from [2-(3-nitroρhenyl)sulfonylaminoanilinc] (590 mg, 2.0 mmol) and 2-(bromophenyl)isocyanate (398 mg. 2.0 mmol) according to the procedure in General Mediod B. The product was purified by Hash chromatography on silica gel (ethyl acetate:hexanc 30/70) (4(K) mg. 40% ). EI-MS m/z 489 (M-H) Example 131 Preparation of N ' -f2-l2-(4-Phcnoxyphenyl)sulfonylaminolphcnyl l-N'-(2-hromophcnyl ) urea a)Prcparaιion of [2-((4-Phcnoxyρhenyl)sulfonylamιno)anilinc| The title compound was prepared according lo General Method C using 4- phcnoxyphcnylsulfonyl chloride (969 mg, 3.6 mmol) and o-phcnylenediaminc (300 mg. 2 77 mmol). The reacuon mixture was partitioned between water (200 ml) and ιoluenc:methyIcne chloride ( 1 :3). The organic phase collected and the mcihylcne chloride evaporated leaving the toluene. Hexane added and the product prccipatated from solution. (317 mg. 34 % ) EI-MS m/z 341 (M+H ) " b)Preparaiιon ol N-|2-|(4-Phcnoxyphcnyl )sullonylamιno|ρhcnyl]-N'-(2-bromophenyl )urca The title compound was prepared from [2-(4-phcnoxyphenyl)sullonyl aminoaniline (276 mg. 0.8 mmol) and 2-(bromophcnyl)i.socyanaie ( 161 mg. 0.8 mmol) according lo ihe proccdurcd in General Method B. The product was purified by flash chromatograph on silica gel (ethyl acetaιc:hexanc 30/70) (240 mg. 55 %) EI-MS m/z 536 ( M- H) " Example 132 Preparation ol N-fl2-d S ) - 10-Camphorsulfonylamιnolphenyll-N'-(2-bromophenyl)urea a)Prcparatιon of 2-(( l S)- 10-Camphorsulfonylamιno)anihne The udc compound was prepared according to General Method C using (l S)(+)- 10- Camphorsulfonyl chloπdc ( 1.16 g, 4.6 mmol) and o-phenylenedιamιnc (500 mg. 4.6 mmol) The reaction mixture was partitioned between water (200 ml) and toluenc:methylene chloride ( 1 :3) The organic phase was separated and the methylene chloπde evaporated leaving the toluene Hexane was added and solid precipitated from solution ( 130 mg. 9% ) EI-MS m/z 323 (M+H) * b)Prcparaiιon of N-[[2-( l S)- 10-Camphorsulfonylamιno]phenyl]-N'-(2-bromophenyl )urea The title compound was prepared from [2-(lS)- 10-camphorsulfonylamιno]anιhne ( 130 mg. 0.4 mmol) and 2-(bromophenyl)ιsocyanate (80 mg, 0.4 mmol) according to the procedure in General Method B. The solvent was evaporated and product was precipitated from methylene chloπde:hexane. (200 mg. 95 %). EI-MS m/z 518 (M-HV Example 133 Preparation of N-ll2-d R)- 10-Camphorsulfonylamιnolphenyll-N'-(2-bromophcnyl)urea a)Prcparaiιon of 2-(( lR)- IO-Camphorsulfonylamino)anιhne The tide compound was prepared according to General Method C using ( I R)(-)- 10- camphorsullonyl chloride ( 1. 16 g. 4.6 mmol) and o-phenylenediaminc (5(X) mg. 4 6 mmol) The reaction mixture was paruuoned between water (2(X) mL) and toluenc:mcιhylenc chloπdc( 1 .3) The organic phase was separated and the methylene chloride evaporated leaving the lolucne Hexane was added and the product precipitated from solution (563 g. 38% ) EI-MS m/z 323 (M+H) * b)Preparaiιon ot N-| | 2-d R)- 1 -Camphorsullonylamιno]phenyl]-N'-(2-bromophcnyl )urca The dc compound was prepared Irom [ l-( lR)- 10-camphorsullonylamιnoanιlιne| (563 mg. 1 75 mmol) and 2-(bromophenyl )ιsocyanaιe (346 mg. 1 75 mmol ) according to the procedure in General Method B The product was puπfied by Hash chromaiography on silica gel (cihy I acetatc:hexane 30/70) (263 mg, 29 % ) EI-MS m/z 51 (M-H) Example 134 biomophcnvPurca a Preparation ol |2-|(2-Nιiroι-(4-tπlluoromcthyl (phenyl |sullonylamιno|anιhne The utle compound was prepared according lo General Mediod C using 2-mtro-4- (tπfiuoromethyl)benzenesullony chloride ( 1 eq) The product was punficd by Hash chromaiography on silica gel i mcihylcne chloπdcmcthanol 96/4) (875 mg. 25 % ) EI-MS b).Prcparation of N-|2-|2-(2-Nιlro-(4-iriπuoromethyl)phenyl)sulfonylamιno|phenyl-N'-(2- bromophcny urea The tide compound was prepared from [2-[(2-nitro)-(4-tritluoromethyl) phenyl ]sulfonylamino|aniline (740 mg. 2. 1 mmol) and 2-(bromophenyl)ιsocyanate (406 mg. 2. 1 mmol) according to General Mediod B. The product was purified by Hash chromaiography on silica gel (ethyl acetate:hcxane 30/70). The product was further purified by recrystallization in ethyl acetate:hexane. (320 mg, 28 %*) EI-MS m/z 557 (M-H) Example 135 Preparation of N-(2-hvdroxy-4-azidophenyl)-N'-(2-iodophenyl)urea a)Preparatιon of N-(2-hydroxy-4-aminophenyl)-N'-(2-ιodophenyl)urea To a solution of N-(2-hydroxy-4-nitrophenyl)-N'-(2-ιodophenyl)urea (220 mg. 0.55 mmol) in eihanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reacuon mixture was suned at reflux for 16 hours then cooled to room temperature. The reacuon mixture was basified to pH 8 wiϋi aq. NaHCO-. ϋ en extracted wiϋi ethyl acetate (3x). The organic extracts were combined, dried over MgSO 4 , filtered and concentrated under reduced pressure to give product (180 mg, 89%). EI-MS m/z 370 (M+H) * b)Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-ιodophenyI)urea The N-(2-hydroxy-4-amιnophenyl)-N'-(2-ιodophenyl)urea(77 mg. 0.21 mmol) was added to HCl/H 2 O (0.21 mL/0.42 L), and cooled to 0°C. Sodium nitrate ( 14.5 mg. 0.21 mmol) was added to the reaction mixture. The reaction mixture was stmed at 0°C for 30 minutes. Sodium azide ( 14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room tempcraiurc. The reaction mixture was stined ai room temperature lor 18 hours. Then it was extracted with three limes by ethyl acetate. The organic extracts were combined, dried over MgSO . filtered and concentrated under reduced pressure and chromaiography of the resulting solid on silica gel (hexane : ethyl acciatc: 5: 1 ) gave product (20 mg. 24% ) EI-MS ml/ 396 ( M+H) * Example 136 Preparation ol N-(2-hydroxy-3-azιdophcnvP-N'-(2-hromophenyl)urea a) Preparation of N-(2-hydroxy-3-amιnophcnyl )-N"-(2-bromophcnyl)urca To a solution of N-(2-hydroxy-3-nιtrophcny!)-N'-(2-bromophcnyl )urea (300 mg. 0 S mmol ) in eihanol (20 mL). Tin chloπde (958 mg. 4.25 mmol ) was added The reaction mixiuie w as stined al rcllux loi 1 hours then cooled lo room temperature. The reaction mixiure was basified to pH 8 with aq. NaHCO-, ϋien extracted with ethyl acetate (3x) The organic extracts were combined, dried over MgSO . filtered and concentrated under reduced pressure to give product (274 mg. 99% ). EI-MS m/z 323 (M+H) * b) Prcparauon of N(2-hydroxy-3-azιdophenyl)-N'-(2-bromophenyl)urca The N-(2-hydroxy-3-amιnophcnyl)-N'-(2-bromophenyl)urea(274 mg. 0 85 mmol ) was added to HCl/H 2 O (0.85 mL/1 7 mL). cooled to 0°C. Sodium nitrate (58 6 mg. 0 85 mmol ) was added to ie reaction mixture. The reacuon mixture was stined at ()"C lor 30 minutes Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature The reaction mixture was suned at room temperature lor 1 hours then n was extracted with three umes with ethyl acetaie The organic extracts were combined, dπcd ovci MgSO , filtered and concentrated under reduced pressure and chromaiography of ihe resulung solid on silica gel (hexane : ethyl acetate: 5: 1 ) gave product (210 mg. 71 ) EI-MS m/z 349 ( M+H) * Example 137 Preparauon of N-r2-hvdroxy-3-cvanophenyll-N'-l2-methoxyphenyll urea N-[2-hydroxy-3-cyanophenyl]-N'-[2-meihoxyphenyl] urea was prepared from 2- amιno-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General Method B The product was puπfied by precipitation from methylene chloπde/ hcxane( lequιv./20cquιv ) and filtering (230 mg, 81%). Η NMR (CD 3 OD): 6 8.06 (d. I H). 7 79 (d. I H), 7 49-7 35 (m. 2H), 7.05-6,87 (m. 3H), 3.95 (s, 3H). Example 138 Preparation of N-f2-hvdroxy-3-cvanophenyll-N'-13-trifluoromethylphcnyll urea N-[2-hydroxy-3-cyanophenyl]-N'-|3-ιπfluoromethylphcnyl] urea was prepared Irom 2-amιno-6-cyanophcnol ( 134mg, 1.00 mmol. example 83a) according to ihe procedure in General Method B The product was puπfied by precipitation Irom methvlenc chloride' hexanedequn /2()equιv ( and filtering (280mg. 87% ) Η NMR (CD .OD) 6 8 10 . d I H ) 7 96 (s. I H). 7 54 (d. I H). 7 55-7 25 (m. 3H ). 7 01 (l. I H) Example 139 Preparation ol N-l2-hvdroxy-3-cvanophenyll-N'-l2-phenylphcnyll urea N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea w as prepared Irom 2-amιno 6-cvanophcnol ( I 34mg. 1 00 mmol. example 83a) according to the proccduic in Gcncial Method B The product was purified by precipitation trom methylene chloride/ hexaned equ /20equn ( and filtering (270mg, 82% ) Η NMR (CD .OD) 6 7 81 i d l H i 7 75 (d. I H). 7 56-7 15 (m. 9H). 6 91 ( t I H) Example 140 N-(2-hydroxy-3-cyanophenyl|-N"-|2.3 dιchlorophcnyl| urea was prepared Irom 2- amιno-6-cyanophenυl ( I 34mg, l.(X) mmol. example 83a( according to the procedure in General Method B. The product was purified by precipitation Irom methylene chloride/ hcxane( lequiv./20equiv.) and filtering. (300mg. 93% ). Η NMR (CD,OD): 6 8. 1 1 (d. I H). 8.01 (d, I H). 7.33-7.25 (m, 3H), 7.00 (t, I H). Example 141 Preparation ol " N-l2-hvdroxy-4-isopropylphenyll-N'-l2.3-dιchlorophcnyl l urea N-|2- hydroxy-4-ιsopropylphenyl]-N'-[2,3-dιchloropnenyl] urea was prepared from 2-amιno-5- isopropylphenol ( 150 mg, 1.00 mmol, example 128a) according lo ihe procedure in General Mediod B The product was purified by precipitation from methylene chloπdc/ hexane(lequiv./20equiv.) and filtering (285mg, 84%). l H NMR (CD.OD): δ 8.05 (d. 2H). 7.77 (s, I H), 7.26 (m, 2H), 6.88 (m. 2H), 2.82 ( . IH). 1.25 (d. 6H) Example 142 Preparation of N-l2-hvdroxy-4-isopropylphenyll-N'-f2-chloro-5-irifiuoromethylphenyll urea N-[2-hydroxy-4-isopropylphenyll-N'-[2-chloro-5-iriπuoromcihylphenyl] urea was prepared from 2-amino-5-isopropylphenol ( 150mg, 1.00 mmol. example 128a) according lo ϋie procedure in General Method B. The product was purified by precipitauon from mcihylcne chloπde/ hexane( lequiv./20equiv.) and filtering. (275mg. 82% ). Η NMR (CD--OD): 6 8.50 (s. I H). 7.70 (s. I H), 7.51 (d. IH). 7.22 (d. I H). 6.70 (m. 2H). 6 62 (dd. I H). 2 76 <m. ( I H). 1. 16 (d. 6H). Example 143 Preparation of N ' -12-hydroxy-3-phenylphcnv]l-N'-l2.3-dιchlorophcnγl l urea a)Prcparatιon ol 2-nιtro-6-phcnylphenoI 2-phenylphenol (3.00g. 17.6mmoI) was dissolved in mcihylcne chloπde(40ml i followed by the addiuon of sodium nitrate ( 1.65g. 19 4mmol ) The addition ol sull uπc acid (25ml 3M ) was then made, followed by addition ol a cataly tic amount ol sodium nitrite The mixture was allowed to stir Alter 24 hr . ihe reaction mixture w as diluted with methylene chloride and extracted with water The organic layer w as dried eι MgSO and lilicicd The solvent was evaporated and chromatography ol the resulting solid on silica gel (4% MeOH/ CH 2 C1 2 ) gave the desired product(900 mg. 24 % ). Η NMR (CD3COCD- ): 6 8 19 (d. l I P. 7.79 (d. l H). 7.64 (d. 2H). 7.50 (I. 2H). 7.45 (t. I H). 7.22 i t. I H ) b)Prcparatιon ol 2-amino-6-phenylphenol To a soluuon of 2-nitro-6-phenylphenυl(900 mg. 4.2mmoP in mcihanol(50ml) was added 10%r Pd/C ( 100 mg) The mixture was Hushed wun argon, ihcn hydrogen was bubbled through the solution lor 10 mm and a hydrogen atmosphere s maintained at balloon pressure overnight. The mixture was filtered through celite and the cchtc was washed with methanol The solvent was evaporated and chromatography of the resulung solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the desired product(7 ( )() mg. 90 % ). Η NMR (CD OD). δ 7.55- 7.27 (m. 5H), 6.77-6.61 (m, 3H) c)Preparauon of N-[2-hydroxy-3-phcnylphcnyl]-N'-[2,3-dιchlorophenyl] urea N-[2-hydroxy-3-phenylphenyl ]-N'-[2.3-dιchlorophenyl ] urea was prepared Irom 2- amιno-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B The product was purified by precipitation from mcihylcne chloride/ hcxanc( lequιv./20cquιv ) and filteπng. ( 150mg,81 % ). Η NMR (CD 3 OD): 6 8.06 (d. I H).7.65 (d. I H). 7.54 (d, 2H),7.40 (I. 2H), 7.32 (d, I H) 7.22 (m, 2H), 7.04-6.88 Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2.3-dιchlorophenyl] urea b)N-[2-hydroxy-3-phenylphenyl]-N'-(2,3-dichlorophenyl] urea was prepared from 2- amino- 6-phenylphenol (92.5mg, 0.50 mmol) according to ihe procedure in General Method B. The product was purified by precipitation from methylene chloride hexane( lequιv./20equιv.) and filtering. (150 mg, 81%). Η NMR (CD--OD): 6 8.06 (d, 1 H),7.65 (d. I H). 7.54 (d, 2H).7.40 (t, 2H), 7.32 (d, I H) 7.22 (m. 2H), 7.04-6.88 (m. 2H) Example 144 Preparauon of N-[2-hvdroxy-5-nιirophenyll-N'-f2-methoxyphenyl l urea N-[2-hydroxy-5-nιtrophcnyl]-N'-[2-methoxyphenyl] urea was prepared Irom 2-amιno- 4-nιtrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B The product was purified by precipitauon Irom methylene chloride/ hcxane( lequιv./20equιv.) and filtering (270 mg. 89% ) Η NMR (CD,OD): δ 9 10 (s. I H). 8 10 (d. I H). 7.85 (d. I H). 7 08-6 88 tm. 4H). 3 96 (s. 3H) Example 145 N-[2-hydroxy-5-niirophcnyl |-N'-[3-influoromeihylphcnyl] urea was prepared Irom 2- amιno-4-nιtrophenol ( 154 mg. I 00 mmol ) according to ihe procedure in General Method B The product was purified by precipitation Irom methylene chloride/ hcxanc( lequn ) and filtering (290 mg. 85% ) 'H NMR (CD.OD ): 6 9 12 ( s. I H). 7 89 (d. I H). 7 68 (d. I H). 7 55 ( m. 2H). 7 45 (d. I H ). 7 00 (d. I H ) Example 146 N-|2-hvdroxy-5-mirophcnyl ]-N'-[2-phcnylphcnyl| urea was prepared Irom 2-amιno-4- nitrophenol ( 154 mg. 1.00 mmol ) according 10 me procedure in General Method B The product w s purified by precipitauon Irom methylene chloride/ hexaned equn ) and filieπng. (285 mg. 81 % ). Η NMR (CD 3 OD): 6 8.09 (s. I H), 7.86 (d. I H), 7.58-7.20 (m. 9H). 6.95 (d. I H). Example 147 Preparation of N-[2-hydroxy-5-nitrophenyll-N'-f2.3-dichlorophenyl] urea N-|2-hydroxy-5-nitrophenyI]-N'-[2,3-dichlorophenyl] urea was prepared from 2- amιno-4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (290 mg, 85% ). Η NMR (CD 3 OD): 6 9.1 1 (s. IH), 8.17 (d. I H). 7.89 (d, I H), 7.34 (m. 2H). 6.95 (d. I H). Example 148 Preparation of N-I2-hvdroxv-5-ethvlsulfonylphenyl]-N'-f2.3-dichlorophenyl l urea N-]2-hydroxy-5-ethylsulfonylphenyl]-N'-[2.3-dichlorophenyl] urea was prepared Irom 2-amino-4-(ethylsulfonyl)phenol (185 mg. 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hcxane( lequiv./20cquiv.) and filtering. (310 mg, 84%). Η NMR (CD 3 OD): δ 8.65 (s, IH), 8. 18 (d. IH), 7.45 (d, I H), 7.26 (m, 2H). 7.00 (d. IH), 3.33 (q, 2H). 1.24 (t. 3H). The following compounds ol " Formula (I) may be prepared in accordance with the examples and schemes as described above: Example 149 : N-[2-(2-Amino-(4-trilluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenypurca EI-MS m/z 527 (M-H) . Example 150 : N-(2-(ammosullonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl ) urcaEI-MS m/z 426 (M+H)\ The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above, or may also be purchased commercially Irom well recognized sources. For instance. Irom Aldrich Chemical Company: N-(2-Hvdroxv-4-nitrophcnyl)-N'-phcnylurca For instance, from the Alfred Badcr Collection ol Aldrich Chemical: l -(2-Carboxyphcnyl)-3-(3-l.ιιorophcnyl)urca l -(2-Carhoxypheny!)-3-(3-chlorophcnyl)urca Available Irom Gallard Schlcsingcr Company and/or the Sigma Aldrich Library of Rare Compounds: l-(2-Carboxyphenyl)-3-(4-chlorophenyl)urca l -(p-Anιsyl)-3-(2-carboxyphcnyl)urea Available from Gallard Schlisingcr Company : 2-(3.4-Dιchlorophenylcarbonyldiιmιno)-5-trinuoromethylbenzoιc acid 2-(4-Chlorophenylcarbonyldiιmιno)-5-trifluoromethylbenzoιc acid N-Phenyl-N'-(2-carboxyphenyl)urea From Maybπdge Chemical Company, Cambridge England: 1.1 '-(4-Methyl-2-phenylene)bis(3-ιolyl)]thiourea N-(5-Chloro-2-hydroxy-4-nιtrophenyl)-N'-phenylurea The following compounds of Formula (I) may be prepared in accordance with die examples and schemes as described above, or as indicated by their respective citations in Chemical Abstracts: 1 -(m-Anisyl)-3-(2-carboxyphneyl)urea; 1 -(o-Anιsyl)-3-(2-carboxyphenyl)urea ; l -(2-Carboxyphenyl)-3-(3.4-dichlorophenyl)urea; l -(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea; METHOD OF TREATMENT The compounds of Formula (I), (la), (II) and (III), or a pharmaceutically acceptable salt thereol can be used in the manufacture of a medicament for the prophylactic or ihcrapeuuc treatment of any disease stale in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, uch as but not limited lo monocyies and/or macrophages. or other chcmokines which bind to the IL-8 α or β receptor, also rclcncd lo as the type I or type II receptor For purposes herein, the compounds of Formula (I), (la). (lb). ( Ic). (II) and (III) all have ihe same dosages, and dosage formulations as that of Formula (I ) are used interchangeably Accordingly, the present invention provides a method ot treating a chemokine mediated disease, wherein the chcmokinc is one which binds to an IL-8 or β recepior and which method comprises administering an ctteciivc amouni ol a compound ol Formula (I) or a pharmaceutically acceptable sail thereol In particular, the chcmokines ai s IL-X. GROα. GROβ. GROγ or NAP-2 The compounds of Formula (p are administered in an amouni sufficient to inhibit cyiokinc tunction. in particular IL-8.GROα. GROβ. GROγ or NAP-2 . such that they are ologically regulated down to normal levels ol physiological tunction. or in some case lo subnormal levels, so as to ameliorate the disease siatc Abnormal levels of IL-8. GROα. GROβ, GROγ or NAP-2 tor instance in the context of the present invention, consuiute: (ι) levels of free IL-8 greater than or equal to I picogram per mL: (ii) any cell associated IL-8. GROα, GROβ, GROγ or NAP-2 above normal physiological levels: or (iii)ιhe presence of IL- 8, GROα, GROβ. GROγ or NAP-2 above basal levels in cells or tissues which IL-8, GROα, GROβ. GROγ or NAP-2respectively, is produced. There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbaύng and/or causing the disease. Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerativc colitis. stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis. thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaπa. restinosis, angiogenesis or undesired hematopoietic stem cells release. These diseases are primarily characterized by massive neutrophil infiltration, T-ccll infiltration, or neovascular growth, and are associated with increased IL-8, GROα, GROβ, GROγ or NAP-2 production which is responsible for the chemotaxis of neutrophils into ihe inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL- 1, TNF. and IL-6), IL-8. GROα, GROβ. GROγ or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation The α-chcmokines but particularly. GROα. GROβ. GROγ or NAP-2. working through the IL-8 type 1 or II receptor can promote the neovascularizaiion of tumors by promoting ihe directional growth ol endothelial cells. Thcrelorc. die inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration. The compounds of Formula (I) arc administered in an amount sufficient to inhibit IL- binding to ihe IL-8 alpha or beta receptors, from binding lo these receptors, such as cvidencetl by a reduction in neutrophil chemotaxis and activation. The discovery thai the compounds ol Formula (I) are inhibitors of IL-8 binding is based upon the cllccis ol the compounds ol Formulas (I) in the in vitro receptor binding assays which are described herein. The compounds of Formula (I) have been shown to be dual inhibitors ot both recombinant type I and type II IL-8 receptors. Preferably the compounds are inhibitors of only one receptor, preferably Type II As used herein, the term "IL-8 mediated disease or disease state" relers to any and all disease states in which IL-8. GROα. GROβ, GROγ or NAP-2 plays a role, cither by production of IL-8, GROα, GROβ, GROγ or NAP-2 themselves, or by IL-8. GROα, GROβ, GROγ or NAP-2 causing another monokine to be released, such as bui not limited to IL- 1. IL- 6 or TNF. A disease state in which, for instance, IL- 1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8. would theref re be considered a disease stated mediated by IL-8 As used herein, the term "chemokine mediated disease or disease stale" relers to any and all disease states in which a chemokine which binds to an IL-8 α or β receptor plays a role such as but not limited to IL-8, GRO-α, GRO-β, GRO-γ, or NAP-2 This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself , or by IL-8 causing another monokine to be released, such as but not limited to IL- 1. IL-6 or TNF A disease stale in which, for instance, IL- 1 is a maior component, and whose producuon or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease staled mediated by IL-8. As used herein, the term "cytokine" refers to any secreted polypcptidc d al all ecus the funcuons of cells and is a molecule which modulates interactions between cells in ihe immune. inflammatory or hematopoietic response. A cytokine includes, bui is not limned to. monokincs and lymphokines, regardless of which cells produce them For instance, a monokine is generally referred to as being produced and secreted by a mononuclcar cell, such as a macrophage and/or monocytc. Many other cells however also produce monokincs. such as natural killer cells, fibroblasts. basophils, neutrophils. endothelial cells, brain astrocyies. bone marrow siromal cells, epideral keratinocytes and B-lymphocyics Lymphokines are general! \ rclerrcd to as being produced by lymphocyte cells Examples ot cyiokincs include, but aie not limited to. Inicrleukιn- 1 (IL- 1 ). Intcrlcukm-6 (IL-6), Inicrlcukιn-8 (1L-8). Tumoi Neciosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF- 1..) As used herein, ϋie term "chemokine" relers to any secreted polypcptidc thai al lecis die tuncuons ol cells and is a molecule which modulates interactions beiween cells in the immune inflammatory or hematopoieuc response, similar to the term cyiokine" A chcmokinc is pπmaπly secreted through cell iransmcmbrancs and causes chemotaxis and activation ol specific while blood cells and leukocytes, neutrophils. monocyics. macrophages. T-cells. B- cells, endothelial cells and smooth muscle cells Examples ol chcmokines include, but aic not limited to. IL-8. GRO-α, GRO-β. GRO-γ. NAP-2. IP- 10. MlP- l α. MlP-β. PF4 and MCP 1. 2. and 3 In order to use a compound ol Formula (I) or a pharmaceutically acceptable sail thereol in therapy, ii will normally be lormulated into a pharmaccuiical composition in accordance with standard pharmaceuueal practice This invention, ihcrclorc. also relates to a pharmaceutical composiuon compπsing an eflective. non-toxic amount ol a compound of Formula (I) and a pharmaceutically acceptable earner or diluent Compounds of Formula (I), pharmaceutically acceptable salts thereol and pharmaceuueal compositions incorporating such may conveniently be administered by any ol the routes conventionally used for drug administration, lor instance, orally, topically, parenterally or by inhalauon The compounds of Formula (I ) may be administered in conventional dosage forms prepared by combining a compound ol Formula (I) wiϋi standard pharmaceuueal carriers according to convenuonal procedures The compounds ol Formula (I) may also be administered in conventional dosages in combination wiϋi a known, second therapeutically acuve compound These procedures may involve mixing, granulaung and compressing or dissolving the ingredients as appropriate to the desired preparation It will be appreciated that ϋie form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of acuve ingredient with which it is lo be combined, the route ol administrauon and other well-known vaπables The camcπs) must be ' acceptable" m the sense of being compatible wiϋi the oϋier ingredients ol the lormulation and not deleterious to the recipient ϋiereof The pharmaceutical earner employed may be. lor example, either a solid oi liquid Exemplary ol solid earners are lactose, lena alba, sucrose, talc, gelatin, agar. pectin, acacia. magnesium stearate, steaπc acid and the like Exemplar, ol liquid carriers are svπip peanut oil. olive oil, water and the like Similarly, the camci or diluent may include time delay maieπal well known to the art. such as glyccryl mono-siearaie or l distearaie alone oi with a wax A wide vaπety ol pharmaceuueal lorms can be employed Thus, il a solid earner is used, the preparauon can be tablcicd. placed in a hard gelatin capsule in powder or pellet lorm or in the form ot a troche or lozenge The amount ol solid earner will w ideh but prclerably will be Irom about 25mg to about l When a liquid earner is used, the picpaiation will be in the lorm ol a syrup, emulsion, soli gclaiin capsule stei ile inicctable liquid such as an ampule or nonaqucous liquid suspension Compounds of Formula (I) may be administered topically, that is b\ non-sysiemic administrauon This includes the application ol a compound ol Formula (I ) eucmalh to the epidermis or the buccal cavity and the insullaiion ot such a compound into the car. eye and nosc, such that the compound docs noi significantly enter the blood stream. In contrast, systemic administration relers 10 oral, intravenous, lntrapeπioneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable lor penetration through ihe skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye. car or nose. The active ingredient may compπse, tor topical administrauon, Irom 0.001 % to 10% w/w, for instance Irom 1 % lo 2% by weight of the Formulation. It may however comprise as much as 10% w/w but prelerably will compπse less than 5%- w/w, more preferably from 0. 1 % to I %- w/w ol ihe Formulation. Lotions according to die present invenuon include ϋ ose suitable for app cauon to the skin or eye. An eye lotion may compπse a sterile aqueous solution optionally containing a bacteπcide and may be prepared by mcϋiods similar to those for the preparauon of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil Creams, ointments or pastes according to the present invention arc semi-solid lormulaiions ol the acuve ingredient lor external application They may be made by mixing the active ingredient in finely-divided or powdered lorm. alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid ol suitable machinery, wilh a greasy or non-greasy base The base may comprise hydrocarbons such as hard, solt or liquid para! fin. glycerol. beeswax, a metallic soap, a mucilage: an oil ol natural oπgin such as almond, corn, arachis. castor or olive oil: wool lat or us dcπvativcs oi a laity acid such as stcπc or oleic acid together with an alcohol such as propylenc glycol or a macrogel The lormulation may incorporate any suitable surlace acuve ageni such as an anionic. canonic or non-ionic surlactant such as a sorbitan ester or a polyoxycihylcnc derivative thereol Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaccous silicas, and other ingredients uch as lanolin, may al.so be included Drops according to die present invention ma\ comprise sterile aqueous oi oily solutions or suspensions and may be prepared by dissolving ihe active ingredieni in a suitable aqueous soluuon ol a bactericidal and/or lungicidal agent and/or any other suitable preservative, and prclerably including a surlace acuve ageni The resulting solution may then be clarified by filtration, translerred to a suitable container which is then sealed and sicπlizcd by autoclaving or maintaining at 98- l(X)°C tor hall an houi Alicrnaiively. the soluuon may be sterilized by filiration and translencd to the conuuner by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in ihe drops are phcnylmercuric nitrate or acetale (0.(X)2%r), benzalkomum chloπde (0.01 %) and chlorhexidine acetate (0.01 %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylenc * ϊ glycol Compounds of formula (I) may be administered parenterally. that is by intravenous, intramuscular, subcutaneous intranasal, mtrarectal, intravaginal or inirapcπtoneal administration. The subcutaneous and intramuscular forms of parenteral administrauon are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by- conventional techniques. 5 For all methods of use disclosed herein for die compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg kg of total body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, 0 administered one lo lour, preferably two or three times daily. The daily inhalation dosage regimen will prelerably be from about 0.01 mg kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that die optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable sail thereof will be determined by the nature and extent of the condition being treated, ihe lorm. route and site of 5 administration, and the particular patient being treated, and diat such optimums can be determined by conventional techniques. Il will al.so be appreciated by one of skill in the art thai the optimal course ol treatment, i.e.. the number ol doses ol a compound of Formula (I ) or a pharmaceuucally acceptable salt thereof given per day lor a defined number of days, can be ascertained by those skilled in the art using conventional course of treatmcni determination 0 tests The invention will now be described by rclcrcncc lo ihe following biological examples which arc merely illustrative and arc not to be construed as a limitation ol ihe scope ol the present invenuon S BIOLOGICAL EXAMPLES The IL-8. and Gro-α chemokine inhibition' effects ot compounds of the present invention were determined bv the following m vitro assa\ ■ Receptor Binding Assays: [ 125 I] IL-8 (human recombinant) was obtained Irom Amcrsham Corp , Arlington Heights. IL, with specific acUvity 2000 Ci/mmol Gro-α was obtained Irom NEN- New England Nuclear. All other chemicals were of analytical grade. High levels ol recombinant human IL-8 type α and β receptors were individually expressed in Chinese hamster ovary cells as descπbed previously (Holmes, et al.. Science, 1991, 253, 1278) The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour. et a!., J Biol Chem., 249 pp 2195-2205 ( 1974)). Except that the homogcnization bufter was changed to lOmM Tπs-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diammeteira-aceuc acid). 1 mMPMSF (α-toluenesulphonyl fluoπde), 0.5 mg/L Leupepun, pH 7 5 Membrane protein concentration was determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays were performed in a 96-well micro plate format Each reaction mixture contained 125 I IL-8 (0.25 nM) or 125 I Gro-α and 0.5 μg/mL of IL-8Rα or 1.0 μg/mL of IL- 8Rβ membranes in 20 M Bis-Tπspropane and 0.4 mM Tπs HC1 buflers, pH 8.0. containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.01 nM and 100 uM. The assay was miuated by addiuon ol -2 i- IL-8 Alter 1 hour at room temperature die plate was harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenιmιne/0.5% BSA and washed 3 times with 25 mM NaCl. 10 M TπsHCl, 1 mM MgSO4, 0.5 mM EDTA. 003 % CHAPS. pH 7 4 The filter was then dried and counted on d e Betaplate liquid scintillation counter The recombinant IL-8 Rα, or Type 1, receptor is al.so referred to herein as the non-pernussivc receptor and the recombinant IL-8 Rβ, or Type II, receptor is refencd to as the permissive receptor All ol the exemplified compounds ol " Formulas (I) lo (IIP noted herein in the S\ nthetκ Chemistry Section, of Examples 1 to 150 plus the additional purchased compounds demonstrated an IC50 Irom about 45 to about < 1 μg/mL in ihe permissive models lor IL- receptor inhibition All of these compounds were also lound to be inhibitors ol Gio-a binding at aboul the same level The compound l -(2-Carboxyphenyl)-3-(4-chloro-2- methylphenyPurca was lound to be active ai about 75 μg/mL The lollowing compounds, generally tested at levels ol up to 45 μg/mL were lound to noi demonstrate levels of IL-8 receptor antagonism within the criteria set lorth at ihe dosage levels tested These compounds arc l -(4-Chloro-alpha.alpha,alpha-trιfluoro-3-iolyl)-3-[2-(4-chlorophenyl)ιhιo]-5- chlorophenyl urea l-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyI)-3-[2-(4-chlorophenoxy)-5- chlorophenyljurea l-(2-Mercaptophenyl)-3-phenyl-2-thiourea l-(2-Hydroxyphenyl)-3-phenyl-2-thiourea 3,3'-(Carbonothioyldiimino)bis[4-hydroxybenzoic acid] m,m'-(l ,3-thioureylene)di(4-hydroxybenzoic acid) l-(2-Tolyl)-3-(3-chloro-6-hydroxyphenyl)-2-thiourea l-[(2-Hydroxy-4-aminophenyI)]-(3-phenyl)-urea N-(2-Carboxy-4-trifluromethylphenyl)-N'-(3-chlorophenyl)urea N-(2-Carboxyphenyl)-N'-(2,5-dichlorophenyl)urea l-(2-Carboxyphenyl)-3-(2-Chloro-5-trifluoromethylphenyl)urea 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid; 2-[2-[3-(4-Chlorophenyl)ureido]phenoxy]benozic acid 2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid N- (2-Hydroxyphenyl) -N'-phenyl urea N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N'-phenylurea N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyI)urea; l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea l-(6-Carboxy-2,4-dichlorophenyl)-3-(2,4,6-trichlorophenyl)urea l-(2-Carboxyphenyl)-3-(2,5-dimethoxyphenyl)urea l-(2-Carboxyphenyl)-3-(2-meϋιylphenyI)urea l-[(2-Hydroxyphenyl)-3-(2-methyl)-5-nitrophenyl]urea l-(2,5-Dichlorophenyl)-3-(2-hydroxy-4-nitrophenyI)urea l-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea N-(2-phcnylsulfonylaminophenyl-N'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-ethoxycarbonylphcnyl)urca N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxycarbonylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-ethoxycarbonylphenyl)urca N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-propylphenyl)urea N-(4-Tritluromethyl-2-(4-nitrobenzenesulfonyl)amino]-N'-phenylurca N-(3-Carboxyphenyl)-N'-2-hydroxy-4-nitrophenyl)urea N-(4-Trilluromethyl-2-(methylsulfonyl)amino]-N'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-f2-(isopropyl)phenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-dimethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluoro-5-nitrophenyl)urea N-(2-Hydroxy-4-nιtrophenyl)-N'-(2-chloro-5-tπfluromcthylphcnyPurca N-(2-Hydroxy-4-nιtrophenyl)-N'-(2-mcthoxy-4-nιtrophcnyl)urca N-(2-Hydroxy- l-napthyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-5-ethylsull ' onylphenyl)-N'-(2-bromophenyl)urca N-(2-hydroxy 3,4 dichlorophenyl )-N'-(4-phenylphenyl)urca N-(2-hydroxy-3-naphthyl)-N'-(2-mcιhoxyphenyl)urea N-(2-hydroxy-3-naphϋιyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(4-methoxyphenyl)urea N-(2-Hydroxy-3-naphthy])-N'-(3-trifluoromethylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(4-phenylphenyl)urea N-[2-(2-Carboxyphenylsullonylamιno)phenyl]-N'-(2-bromophcnyl )urea N-(2-Hydroxy-3-phenylphenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(4-meϋ oxyphenyl)urea N-(2-Hydroxy-3-phenyiphenyl)-N'-(3-triflouromethylphenyl)urca N-(2-Hydroxy-3-phenylphenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(4-phenylphenyl)urea N-f2-[(2,5-Dichlorothien3-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urca N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2,4 dimethoxyphenyPurea N-(2-Hydroxy,3.4-dichlorophenyl)-N ' -(2-chloro-5-trifloromethylphcnyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(2,4 dimethoxyphenyPurea N-(2-Hydroχy-3-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)urca N-(2-Hydroxy-3 phcnylphenyl)-N'-(2.4-dιmethoxyphcnyl)urca N-(2-Hydroxy-4-ιsopropylphcnyl)-N'-(2,4-dιmeihoxyphcnyl )urca N-(2-Hydroxy-3-phcnylphenyl)-N'-(2-chloro-5-trιfluoromcihylphenyPuιca N-(2-Hydroxy-5-nιtrophenyP-N'-(2.4-dιmeihoxyphenyl)urca N-(2-Hydroxy-5-nιlrophenyl)-N'-(2-chloro-5-lπtluoromeihylphenyPurea N-(2-Hydroxy -3-cyanophenyP-N'-(4-mcthoxyphcnyPurea N-(2-Hydroxy-3-cyanophenyl)-N'-(4-phcnylphenyl)urca N-(2-Hydroxy -3-cyanophenyl)-N'-(2.4 dimcihoxyphenyl lurca N-(2-Hydroxy-3-cyanophenyl)-N'-(2-chloro-5-lπlluoromeihylphenyPurea N-(2-Hydroxy - 5-phenylphenyl)-N"-(2-meιhoxyphenyl)urca N-(2-Hydroxy - 5-phenylphenyl)-N -(4-methoxyphenyl)urca N-(2-Hydroxy - 5-phenylphenyP-N , -( 3-iriHuoromethylphcnyPurca N-(2-Hydroxy - 5-phcnylphcnyl)-N -(2-phenylphcnyl )urca N-(2-Hydroxy -5-pheny]phenyl)-N'-(4-phenylphenyl)urea N-(2-Hydroxy-5-phenylphenyl)-N'-(2.3-dichlorophenyl(urca N-(2-Hydroxy -5-phenylphenyP-N'-(2,4-dimeihoxyphcnyPurea N-(2-Hvdroxy -5-phcnylphenyl )-N'-(2-chloro-5-iπnuoromethylphenyl )urea N-(2-Hydroxy-5-cthylsullonylphcnyp-N'-(4-mcihoxyphenyPurea N-(2-Hydroxy-5-edιylsulfonylphcnyl)-N'-(3-trifluoromcihylphcnyl)urca N-(2-Hydroxy-5-ethylsulfonylphcnyl)-N'-(2-phcnylphcnyl)urca N-(2-Hydroxy-5-eihylsulfonylphenyl)-N'-(4-phenylphcnyl)urea N-(2-Hydroxy-5-eϋιylsull " onylphenyl)-N'-(2,4-dιmethoxyphenypurea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N ' -(2-chloro-5-iriHuoromethylphenyl)urea N-f 2-Hydroxy-3.4-dιchlorophenyI |-N'-f 2,4 dimeihoxyphcnyl | urea N-(2-Hydroxy-3,4-dιchlorophcnyl ]-N'-[2-chloro-5-trifluoromcthylphenyl ] urea N-[2-Hydroxy-3-naphihyl |-N'-|3-trifluoromeihylphcnyl| urea Chemotaxis Assay : The in vitro inhibitory properties of these compounds were determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I. Suppl 1. Unit 6.12.3.. whose disclosure is incorporated herein by reference in us entirety. Neutrophils where isolated from human blood as described in Cuσcnt Protocols in Immunology Vol I. Suppl 1 Unit 7.23. 1 , whose disclosure is incorporated herein by reference in its enurety. The chemoattractants IL-8, GRO-α. GRO-β. GRO-γ and NAP-2 where placed in die bottom chamber of a 48 multiwell chamber (Neuro Probe. Cabin John, MD) at a concentration beiween 0.1 and 100 nM. The two chambers where separated by a 5um polycarbonate filler. When compounds of this invention were tested, they where mixed with die cells (0.001 - I (MX ) nM) |usi prior to the addition of the cells to the upper chamber Incubation was allowed to proceed for between about 45 and 90 min at about 37°C in a humidified incubator with 5% CO2 At the end of the incubation period, the polycarbonate membrane was removed and the lop side washed, the membrane was then stained using the Dill Quick sunning protocol (Baxter Products. .McGaw Park. IL. USA) Cell which had chemotaxed 10 the chemokine were visually counted using a microscope Generally, lour fields where counted lor each sample, these number where averaged to give ihe average number ol cells which had migrated. Each sample was icsicd 111 triplicate and each compound repeated at least four times To certain cells (positive control cells) no compound was added. these cells represent ihe maximum chemotactic response ol the cells In the case where a negative control (unsiimulatcd) was desired, no chcmokinc was added to the boiiom chambei The difference between the positive control and the ncgamc control represents the chemotactic activity of the cells Elastase Release Assa\ : The compounds ol this invention where tested lor their ability to prevent Elastase release Irom human neutrophils. Neutrophils where isolated Irom human blood as described in Current Protocols in Immunology Vol I. Suppl I Unit 7.23 I PMN 0 88 x \ cells suspended in Ringer's Solution (NaCl 1 18. KC1 4.56, NaHCO3 25. KH2PO4 1 03. Glucose 1 1 1 . HEPES 5 mM. pH 7 4) where placed in each well ol a 96 well plate in a volume ol 50 ul To this plate was added the test compound (0.001 - KXK) nM) in a volume ot 50 ul, Cylochalasin B in a volume ol 50 ul (20ug/ml) and Ringers buffer in a volume ol 50 ul These cells where allowed lo warm (37 °C, 5% CO2, 95% RH) for 5 mm before IL-8, GROα. GROβ. GROγ or NAP-2 at a final concentration of 0.01 - 1000 nM was added The reaction was allowed to proceed for 45 min bclore the 96 well plate was ccntπluged (8(X) xg 5 mm) and 1(X) ul ot ihe supernatant removed. This suppernatant was added to a second 96 well plate lollowed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC. Nova Biochem. La Jolla. CA) to a final concentration ol 6 ug/ml dissolved in pho.sphate buffered saline Immediately, the plate was placed in a fluorescent 96 well plate reader (Cyiofluor 2350. Millipore. Bedford. MA) and data collected at 3 min intervals according to die method of Nakaμma et al J. Biol Chem 254 4027 ( 1979). The amount of Elastase released from the PMNs was calculated by measunng the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation The above descπption fully discloses the invention including prclerred embodiments ϋiercof. Modifications and improvements ol " the embodiments specifically disclosed herein arc within the scope of the following claims. Without further elaboration, n is believed ϋiat one skilled in the are can, using ϋie preceding descπption, utilize the present invention to its fullest extent Therclorc the Examples herein arc lo be construed as merely illustrative and not a limitation of the scope ol ihe present invention in any way The embodiments ol the invenuon in which an exclusive property or privilege is claimed arc defined as lollows

Claims: 1. A method of treating a chemokine mediated disease stale wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amouni of a compound of ihe formula: wherein X is oxygen or sulfur; R is any functional moiety having an ionizable hydrogen and a p a of 10 or less; Rj is independendy selected from hydrogen; halogen; nitro: cyano: halosubstituted C|.|() alkyl; C i-io alkyl; C2- 10 alkenyl; C i _ | () alkoxy: halosubstituted Cj-io alkoxy; azide: S(O)tR4- hydroxy; hydroxy C]-4alkyl; aryl; aryl Ci-4 alkyl: aryloxy: aryl Ci-4 alkyloxy ; heteroaryl; heteroarylalkyl; heterocyclic. heterocyclic Ci-4alkyl: heteroaryl C|-4 alkyloxy: aryl C2- 10 alkenyl; heteroaryl C2- 10 alkenyl; heterocyclicC2- 1() alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R5;C(O)NR-4R5;C(O)NR4Ri(); S(O)3H; S(O)3Rg: C\. \{) alkyl C(O)Rι 1: C2-10 alkenyl C(O)Rj 1; C2-10 alkenyl C(O)OR] \: C(O)Rj 1: C(O)OR|2: OC(O) Rj 1 : NR4C(O)R 11 : or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; 1 is 0. or an integer having a value of I or 2: s is an integer having a value of 1 to 3: R4 and R5 are independently hydrogen, optionally substituted C1.4 alkyl. optionally substituted aryl, optionally substituted aryl C|-4alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C)-4alkyl. heterocyclic. heterocyclic C|-4 alk l.01 R4 and R5 together with the mirogen to which they arc attached lorm a 5 to 7 member ring which may optionally comprise an additional heteroatom selected Irom O/N/S: Y is independently selected from hydrogen: halogen: nitro: cyano: halosubstituied \. \o alkyl. C i-]() alkyl: C2-10 alkenyl: C|-io alkoxy: halosubstituied C|_|o alkoxy: a/.ide: S(())|R4. hydroxy: hydroxyC]-4alkyl: aryl: aryl C)-4 alkyl: aryloxy: arylC|_4 alkyloxy: heieioaryl. heteroarylalkyl: heteroarylC 1.4 alkyloxy: heterocyclic. heierocyclicC |-4alkyl: aryl 2- 10 alkenyl: heicroaryl C2-10 alkenyl: hcierocyclic * C2- 10 alkenyl: NR4R5: 2-|o alkenyl C(O)NR4R : C(O)NR4R5: C(O)NR4R 10: S(O)3H: S(O) Rs: C 1.10 alkyl C(0)R 11 : C2-l()alkenylC(O)Ri|:C2-|0alkcnylC(O)0Rii:C(O)R]|:C(O)ORi2:OO())R|i: NR4C(O)R 11 : or two Y moieiics together may form O-(CH2).sO- or a 5 to 6 membered unsaiuraied ring: n is an ιnte_:er havinn a value of 1 to 3: rn is an integer having a value ol I to 3. R is hydrogen or C ] -4 alkyl: RlO is Ci-io alkyl C(O)2R8: Rl 1 is hydrogen, C 1-4 alkyl, optionally subsuiuicd aryl, optionally subsututed aryl C]-4alkyl, optionally subsututed heteroaryl, optionally subsututed heteroaryl C l -4alkyl, opuonally subsututed heterocyclic, or optionally subsututed heterocyclic Ci-4alkyl: R |2 is hydrogen, C l-K) alkyl. optionally substituted aryl or optionally subsututed arylalkyl. or a pharmaceutically acceptably sail thereol 2 The method according to Claim 1 wherein ihe lonizable hydrogen has a pKa ot 3 to 10 3 The method according to Claim 2 wherein R is hydroxy, carboxylic acid, ϋuol. -SR2 -OR2, -NH-C(O)R a , -C(O ) NR6R7- -NHS(O)2Rb» -S(O)2NHR c . NHC(X)NHRb. or letrazolyl; wherein R2 is a substituted aryl, heteroaryl. or heterocyclic moiety which ring has the functional moiety providing the lonizable hydrogen having a pKa ol " 10 or less: R6 and R7 are independendy hydrogen or a Ci-4 alkyl group, or R and R7 together wiϋi ϋie nitrogen to which ihey are attached lorm a 5 to 7 member ring which πng may optionally contain an addiuonal heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur; Ra is an alkyl, aryl. aryl Ci-4alkyl, heteroaryl. heteroaryl C|-4alkyl, heterocyclic, or a heterocyclic C]-4alkyl moiety, all ol which may be optionally substituted; Rb is a NR6R7, alkyl. aryl. arylC i-4alkyl. arylC2-4alkeny . heteroaryl. hcicroarylCi-4alkyl, heieroarylC2-4 alkenyl. hcicrocyclic. hcicrocyclic j-4alkyl. hcierocyclic C2-4alkenyl moiety, camphor, all ol which may be optionally subsututed one to three times independently by halogen, nuro. halosubslilutcd C)-4 alkyl. Cj-4 alkyl. C|-4 alkoxy. NR C(O)R a . C(O)NR6R7- S(0)3H. or C(O)OC | ,4 alkyl. Ry is hydrogen or a C 1-4 alkyl. R is alkyl, aryl. arylC|-4alkyl. arylC2-4alkcnyl. heteroaryl. heteroarylC |-4alkyl. hctcroarylC2-4alkenyl. hctcroe\clιc. heterocyclic C | _4alky I. or a hcicrocyclic C2-4alkcny I moiety, all of which may be optionally subsututed one 10 three limes independently by halogen nitro. halosubsututed Ci-4 l. C|-4 alkyl. C 1.4 alkoxy NR*-)C ( 0 ) R a . C(O ) NRfiR7 S(O)3H.01 C(O)OC 1-4 alkyl 4 The method according 10 Claim 3 whciein ihe R2 is optionally subsuiuicd one to ihree times by halogen, nitro. halosubs tuted Ci- 10 alkyl. C].10 alkyl C ] - ] 0 alkox\. hydroxy. SH. -C(O)NR6R7- -NH-C(O)R . -NHS(O)Rb- S(O ) NRfiR7. C ( 0 ) ORs. or a icira/olvl ring 5. The method according to Claim 3 wherein R is OH. -NHS(O)2Rb or C(O)OH. 6 The method according to Claim I wherein R ] is halogen, cyano. nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R 10. alkenyl C(O)OR i 2, heteroaryl, heicroarylalkyl . heteroaryl alkenyl, or S(O)NR4R5. 7 The method according to Claim I wherein Y is halogen, Ci -4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy. methylene dioxy. NR4R5. ϋιioCi -4alkyl, thioaryl, halosubstituted alkoxy, optionally subsututed C] -4aIkyl, hydroxy alkyl. 8. The method according to Claim 1 wherein R is OH, SH, or NHS(O) s Rb and R| is substituted in the 3-posiϋon, the 4- position or di substituted in ϋie 3,4- position by an electron wididrawing moiety. 9. The compound according to Claims 1 or 8 wherein Y is mono-substituted in the 2'- position or 3'- position, or is disubstituted in the 2'- or 3'- position of a monocyclic ring. 10. The compound according to Claims 1 , 8 or 9 wherein n amd m are each equal to I or more. 1 1. The method according to Claim 1 wherein R is a carboxylic acid, and R ] is hydrogen, or R ] i.s substituted in the 4-position. 12 The method according to Claim 1 wherein the mammal i.s afflicted wilh a chemokine mediated disease selected Irom psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease Crohn's disease ulceraiive colitis, septic shock, cndoioxic shock, gram negative sepsis, toxic- shock syndrome stroke cardiac and renal rcperlusion injury, glomcπilo-nephriiis. or thrombosis, alzhcimers di.sca.sc. graft vs. host reaction, or allograft rejections. 1 The method according to Claim 1 wherein the compound, or a pharmaceuucally acccpatablc sail is: -4-niirophenyP-N'-(2-mcihoxyphenyl)urca N- (2- Hydroxy -4-nιirophcnyl)-N'-(2-bromophcnyPurca N-(2-Hydroxy-4-nιiiOphcnyP-N'-(2-phenylphenvl)urca N-(2-Hydroxy-4-nitroρhenyl)-N'-(2-mcthylmiophcnyl)urca N-(2-Hydroxy-4-nιirophcnyl)-N'-(2.3-dιchlorophcnyl)urea N-(2-Hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea N- 2-Hydroxy-4-niirophcnyl)-N'-(2.3-meihylcncdioxyphenyl)urca N- 2-Hydroxy-4-nitrophcnyl)-N'-(2-mcthoxy-3-chlorophenyl)urea N- 2-hydroxy 4-nitro phenyl) N'-(2-phenyloxy phenyl) urea N- 3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea N- 2-Hydroxy-3-glycincmethylestercarbonylphenyl)-N'-(2-bromophcnyPurea N- i 3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N- 2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea N- 2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea N- 3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N- 2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N- 2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea N- 2-Hydorxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea N- 2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea N- 2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea N- 4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea N- 3-Trifluoromelhyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N- 3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N- 2-hydroxy 4-niιro phenyl) N'-(2-iodo phenyl) urea N- 2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea N- 2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyPurea (E -N-[3-](2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N- 2-Hydroxy.3.4-dichlorophenyl)-N'-(2-methoxyphcnyl)urea N- 2-Hydroxy.3.4-dichlorophenyl)-N'-(2-phenylphenyl)urea N- 2-Hydroxy-3.4-dichlorophenyl)-N'-(2.3-dichlorophenyl)urea N- 2-Hydroxy -5-nιirophenyl)-N'-(2,3-dichlorophenyl)urea; or N- 2-Hydroxy -3-cyanophenyl)-N'-(2.3 dichlorophcnyPurea. 14. A compound of the formula: E is optionally selected from or the asieπx * denoting point of attachment of the ring; wherein at least one E ring is present: or a pharmaceutically acceptably salt thereof. 15. A pharmaceutical composition compπsing a compound according to Claim 14 and a pharmaceuucally acceptable carrier or diluent. 16 A meϋiod of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administeπng lo said mammal an effective amount of a compound of die formula according to Claim 14. 17. A compound of the formula: wherein X is oxygen or sulfur: R is any functional moiety having an ionizablc hydrogen and a pKa ol 10 or less: R | is independently selected from hydrogen: halogen: nitro: cyano halosubsututed C j - i o alkyl: C j - ιo alkyl: C2- 10 alkenyl: C μ i o alkoxy: haJosubstiiutcd C ] - ιo alkoxy : azide. S(O)tR4: hydroxy: hydroxyC | -4alkyl: aryl: aryl C | -4 alkyl: aryloxy: arylC | -4 alkyloxy . heieroaryl: heteroarylalkyl: heterocyclic. heierocyclicC l -4alkyl: heteroarylC | -4 alkyloxy . aryl C2- 10 alkenyl: heieroaryl C2- 1<) alkenyl: heterocyclιcC2- 10 alkenyl: NR4R5: C - 10 alkenyl C(O)NR4R5: C(O)NR4R : C(O)NR4R 1(): S(O)3H: S(O)3Rs: C | - 10 alkyl C(O)R 1 1 : C2- IO alkenyl C(O)R 1 1 : C2- I0 alkenyl C(O)OR 1 ] : C(O)R 1 ] . C(0)OR 12. OC(O) R 1 1 : NR4C(O)R 1 ] : or two R | moieties together may lorm 0-(CH2kO- or .1 5 u, membered unsaturated πng: 1 is 0. or an lniegcr having a value ol 1 or 2. s is an integer having a value of I to 3: R4 and R5 arc independently hydrogen, optionally subsututed C ] -4 alkyl. opuonally substituted aryl. optionally substituted aryl C i -4alkyl, optionally substituted heteroary l. optionally substituted heteroaryl C | -4alkyl, heterocyclic. heierocyclicC ] -4 alkyl. oi R4 and R5 together widi the nitrogen lo which ihey are attached lorm a 5 to 7 member ring which may opuonally compπse an additional heteroatom selected Irom O/N/S; Y is independently selected from hydrogen; halogen; nitro; cyano: halosubstiiuted C μ 1 alkyl. C i- io alkyl; C2- 10 alkenyl; Cμ 10 alkoxy: halosubsututed C i - i alkoxy: azide S(O) t R4. hydroxy; hydroxyCl -4alkyl; aryl; aryl C | -4 alkyl. aryloxy. arylC ] -4 alkyloxy. heteroaryl heteroarylalkyl; heteroarylC 1 -4 alkyloxy: heterocyclic, heierocyclicC 4alkyl. aryl C2- 1 0 alkenyl; heieroaryl C2- 10 alkenyl. heierocyclιcC2- 10 alkenyl. NR4R5: C2- 10 alkenyl C(O)NR4R5; C(O)NR4R5» C(O ) NR4R 1(). S(O)3H: S(O)3R8* C 1 - 1 alkyl C(O)R 1 1 C2- 10 alkenyl C(O)R 1 1 ; C2- 10 lkenyl C(O)OR ] μ C(O)R ι μ C(O)OR [ 2» OC(O) R ) 1 NR4C(O)Rι 1 ; or two Y moieties togeϋier may form O-(CH2)sO- or a 5 to 6 membered unsaturated πng; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3: R8 is hydrogen or C 1-4 alkyl; RlO is C 1- 10 alkyl C(O)2R8i Rl 1 is hydrogen, C μ4 alkyl, optionally subsututed aryl, optionally subsututed aryl C μ4alkyl. optionally subsututed heteroaryl, optionally subsututed heteroarylC μ4alkyl, optionally subsututed heterocyclic, or optionally subsututed heterocyclιcC i -4alkyl. R12 is hydrogen, Cμ 10 alkyl, optionally substituted aryl or opuonally subs iuied arylalkyl. or a pharmaceuucally acceptable salt ϋiereof 18 A pharmaceutical composiuon compπsing a compound according 10 Claim 17 and a pharmaceutically acceptable earner or diluent 19 A mediod ol treating a chemokine mediated disease siaie. wherein the chemokine bind* , to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal Λn cllecuve amount ol a compound ol the tormula according to Claim 17 20 A compound ol the tormula. wherein X is oxygen or sullur. R a is an alkyl, aryl, arylC 1.4a.kyl. heteroaryl. heteroarylC | -4alkyl. hcicrocyclic. or a heterocyclic C i -4alkyl moiety, all ol which may be optionally substituted: Rb is a NR6R7. alkyl, aryl. arylC | -4alkyl, arylC2-4alkcnyl, heteroaryl. heteroarylC ] -4alkyl. hetcroarylC2-4 alkenyl, heterocyclic. or heterocyclic C | -4alkyl. or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independendy by halogen: nitro: halosubstituted C ] -4 alkyl: C μ4 alkyl: C μ4 alkoxy: NR9C(O)R a ; C(O)NR6R7» S(O)3H. or C(O)OC μ4 alkyl; R6 and R7 are independently hydrogen or a C μ4 alkyl group, or R and R7 togedicr wuh the nitrogen to which they are attached form a 5 to 7 member πng which πng may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substitued; R9 is hydrogen or a C1-4 alkyl; R | is independendy selected from hydrogen: halogen: nitro: cyano: halosubsututed C μ 10 alkyl: Cμ io alkyl: C2- |() alkenyl: C μ io alkoxy; halosubstituted C μ 1 alkoxy: azide: S(O)tR4* hydroxy; hydroxyC μ4alkyl; aryl; aryl C μ4 alkyl: aryloxy: arylC μ4 alkyloxy; heteroaryl: heteroarylalkyl: heterocyclic, heterocyclicC μ4alkyl; heteroarylC 1-4 alkyloxy; aryl C2- 10 alkenyl; heteroaryl C2- 10 alkenyl; heterocydicC2- 10 alkenyl: NR4R5: C2- 10 alkenyl C(O ) NR4R5» C(O)NR4Rs; C(O)NR4R l(): S(O)3H: S(O)3R : C μ 10 alkyl C(O)R 1 1 ; C2- 10 alkenyl C(O)R 1 1 : C2- ] 0 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R 1 1 : or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; t is 0. or an integer having a value of I or 2; s is an integer having a value of 1 to 3: R4 and R5 are independently hydrogen, opuonally subsuiuicd C 1-4 alky I. opuonally substituted aryl. optionally substituted aryl C μ4alkyl. optionally substituted heieroaryl. opuonally substituted heteroaryl C μ4alkyl, heterocyclic. heierocyclic |-4 alky l. or R4 and R5 together wi i die nitrogen to which they arc attached form a 5 to 7 member πng which may opuonally comprise an additional heieroatom selected Irom O/N/S: Y is independently selected from hydrogen: halogen: nitro: cyano: halosubsututed μ 10 alkyl C i- io alkyl: C2- 10 alkenyl: C μ 10 alkoxy: halosiibsutiued Cμ i alkoxy: a/ide. (OnR4. hydroxy: hydroxyC 4alkyl: aryl: aryl C μ4 alkyl: aryloxy: arylC |-4 alkyloxy : heieroaryl: heteroarylalkyl: heteroarylC | -4 alkyloxy: heterocyclic. heierocyclic | -4alkyl: aryl C2- K) alkenyl: heieroaryl C2- K) alkenyl: heterocyclic C2- lo alkenyl: NR4R5: C2- 10 alkenyl C(O)NR4R5» C(O ) NR4R5: C(O ) NR4R |o: S(O)3H: S(0 ) 3Rχ. C | . |o alkyl C ( O ) R | μ C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 μ C(O)OR 12: OC(O) R | μ NR4C(O)R 1 1 : or two Y moieties together may l rm O-(CH2).sO- or a 5 to 6 membered unsaturated πng: n is an integer havinc a value ol 1 10 3. m is an integer having a value of I to 3; RX is hydrogen or C ] -4 alkyl; R 10 is C μ io alkyl C ( O ) 2R8: R l 1 is hydrogen, C μ4 alkyl, optionally substituted aryl, optionally substituted aryl C μ4alkyl. optionally substituted heteroaryl, optionally substituted heteroaryl C μ4alkyl, optionally subsututed heterocyclic, or optionally substituted heterocyclic C μ4alkyl: R 12 i hydrogen, C μ io alkyl, optionally substituted aryl or optionally subsututed arylalkyl: or a pharmaceutically acceptably salt ϋiereof. 2 1 The compound according to Claim 20 wherein R l is subsututed in the 3-posιtιon, the 4- posiuon or di substituted in the 3,4- posiύon by an electron wid drawing moiety. 22. The compound according to Claim 20 or 21 wherein Y is mono-substituted in the 2'- position or 3'- position, or is disubstituted in the 2 - or 3 - position of a monocyclic ring. 23. The compound according to Claim 20 or 21 wherein n amd m are each equal to 1 or more. 24. The compound according to Claim 20 which is N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phcnyl urea N-](2-Phenylsulfamιdo) 4-cyanophenyl]- N'-(2-bromo phenyl) urea N-(2-( Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amιno sullonyl styryl) phenyl) N'-(2-bromo phenyl) urea 2-| (3.4 Dι-meihoxyphcnylsullonyl )amιno| phenyl) N'-(2-bromo phenyl ) urea N-(2-[(4-Aceiamιdophcnylsullonyl)amιno] phenyl) N'-(2-bromo phenyl ) urea N-(2-( Amino sullonyl (2-ihιophenc) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amιno sulfonyl (3-lolyl) phenyl) N'-(2-bromo phenyl) urea i N'-(2-( Amino sulfonyl (8-quιnolinyP) phenyl) N"-(2-bromo phenyl ) urea N-(2-(Amιno sultonyl benzyl) phenyl) N'-(2-bromo phenyl) urea N-| 2-[[ |2-(Tritluoromcthypphcnyl]sulfonyl ]amιno|phcnyl|-N'-(2-bromophcnyl)urea N-(2-BromophcnyP-N'-|2-dimcthylamιnosulfonylamιno|phcnyl|urca N-| 2-(Phencthylsullonylamιno)phcnyl]-N'-(2-bronιophenyl)urca N-| 2-| (2-Acciamιdo-4-melhylthιazol-5-yl)sullonylamιno|phcnyl ]-N'-(2-bι omophcnyl )urea N-| 2-( (2.3-Dιchlorolhιen-5-yl) |sullonylamιno]phenyl]-N'-(2-bromophenyl )urca N-|2-| (3.5-Bιsirilluoromcihylphenypsullonylamιno|phenyl]-N'-(2-bromophcnypurea N-|2-l(2-Benzyl)sullonylamιno]-(5-trilluoromeihyl)phenyl]-N'-(2-bromophcnyl)urea N-| 2-[2-(3-Nιtrophenyl)sulfonylamιno]phcnyll-N , -(2-bromophcnyl)urca N-[2-|2-(4-PhenoxyphcnyPsultonylamιno]phenyl|-N'-(2-bromophenyl ) urea N-|[2-( l S)- IO-Camphorsulfonylamino]phcnyl ]-N'-(2-bromophenyl)urca N-||2-( IR)- 10-Camphorsulfonylamιno]phenyl]-N'-(2-bromophcnyl)urca N-|2-[2-(2-Nιtro-(4-irifluoromethyl)phenyl)sulfonylaminυJphenyl-N ' -(2-bromophenyl)urca N-f2-(2-Amιno-(4-trifluoromeϋιyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenypurea : or N-[2-(amιnosullonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea. 27 A pharmaceuueal composiuon compπsing a compound according to any of Claims 22 to 27 and a pharmaceutically acceptable carrier or diluent. 28 A compound of ϋie formula: wherein X is oxygen or sulfur; X i is oxygen or sulfur; R l is independently selected from hydrogen; halogen: nitro; cyano halosubstituted Cμ |() alkyl: Cμ io alkyl: C2- I0 alkenyl: Cμ io alkoxy: halosubstituted C μ io lkoxy: azide: S(O)tR4: hydroxy; hydroxyC ] -4alkyl: aryl; aryl C μ4 alkyl: aryloxy: aryl C μ4 alkyloxy: heteroaryl: heteroarylalkyl: heterocyclic. heierocyclicC ι -4alkyl: heteroarylC \ .4 alkyloxy: aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: heterocyclic C2- 10 alkenyl: NR4R5: C2- |0 alkenyl C(O)NR4R5: C(O)NR4R5: C(O)NR4R 10: S(O)3H: S(O)3R8: C 1 - 10 alkyl C(O)R 1 1 : C2- 10 alkenyl C(O)R 1 1 : C2- 10 alkenyl C(O)OR 1 1 : C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 : NR4C(O)R 1 1 ; or two R 1 moieties together may form O-(CH2)sO- or a 5 to membered unsaturated ring; 1 is 0. or an integer having a value ol 1 or 2: s is an integer having a value of 1 to 3: R4 and R5 arc independently hydrogen, opuonally subsututed C] -4 alkyl. optionally subsuiuicd ary 1. optionally subsuiuicd aryl C μ4alkyl. optionally sub ututed heteroaryl. optionally substituted heieroaryl C | -4 alkyl. hcicrocyclic. hcicrocyclic Cμ4 alkyl. or R4 and R together with the nitrogen to which they arc attached lorm a 5 to 7 member πng which may optionally compπse an additional hctcroaiom selected Irom O/N/S: Y is independently selected trom halogen: nitro; cyano; halosubsututed C μ io alkyl: Cμ i o alkyl: C2- 10 alkenyl: C μ ]() alkoxy: halosubsututed C μ io alkoxy: azide: S(O)tR4: hydroxy: hydroxy C ]-4alkyl: aryl: aryl C | - alkyl: aryloxy: arylC | .4 alkyloxy: heteroaryl. heteroarylalkyl: heteroarylC ] -4 alkyloxy: heterocyclic, heterocyclic C μ4alkyl: aryl C2- 10 alkenyl: heteroaryl C2- 10 alkenyl: hcicrocyclic C2- 10 alkenyl: NR4R5; C2- K) alkeny I C(O)NR4R5; C(O)NR4R5; C ( O ) NR4R |(): S(O)3H; S(O)3R8: μ i o alkyl C(O)R 1 ] . C2- 10 alkenyl C(O)R 1 1 ; C2- 10 alkenyl C(O)OR 1 1 ; C(O)R 1 1 : C(O)OR 12: OC(O) R 1 1 . NR4C(O)R 1 1 : or iwo Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated πng; n is an integer having a value of 1 10 2: m is an integer having a value of 1 to 3; R# is hydrogen or C 1.4 alkyl; R io is C 1- 10 alkyl C(O)2R8i Rl 1 is hydrogen, C 1 -4 alkyl, optionally subsututed aryl, optionally subsututed aryl C μ4alkyl. optionally subsututed heteroaryl, optionally subsututed heteroaryl C μ4alkyl, optionally subsututed heterocyclic, or opuonally subsututed heterocyclic C μ4alkyl; Rl2 is hydrogen, C μ io alkyl, optionally substituted aryl or opuonally substituted arylalkyl. provided ϋiat: when n =1 than Y is substituted in the 2'- or 3'- position; when n =2 than Y is di-substituted in the 2'- 3'- posiuon; furϋier provided ϋ at when X i is S, m= l , R i is 4-elhyl, and n= l than Y is not 2-methoxy: or a pharmaceutically acceptably salt thereof. 27 The compound according to Claim 26 wherein R | is subsututed in die 3-posιιιon. the 4- posiuon or di-substituted in the 3.4- position by an electron wididrawing moiety 28 The compound according to Claim 26 or 27 wherein Y is mono-subsuiutcd in ihe 2 - position or 3'- position, or is disubstuulcd in ihe 2' or 3' position ol a monocyclic ring 29 The compound according to Claim 26 or 27 wherein n amd m are each equal to I 01 more 30 A pharmaceutical composition comprising a compound according to anv ol Claims 2(* to 29 and a pharmaceutically acceptable earner or diluent 31 A process lor producing a cy ano phenol derivative ol the lom ula. wherein R | is as defined for Formula (I) above, which method comprises a) reacting a compound of ϋie formula: wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount oi dimeϋiylamino pyridine. 32. The process according to Claim 31 wherein ϋie temperature i.s about 60 to about 80 C. and X is bromine. /AMENDED CLAIMS [recei ved by the International Bureau on 16 Ouly 1996 ( 16.07.96 ) ; or iginal claims 1 -32 replaced by amended claims 1 -32 (3 pages ) ] N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea N-[2-[(2-Acetamido-4-methyIUιiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)ur N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(3,5-Bistrifluoromeϋιylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea N-[[2-(lS)-10-Camphorsulfonylamino]phenyI]-N'-(2-bromophenyl)urea N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(2-Niu-o-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)u N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenyl)urea ; or N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea. 25. A pharmaceutical composition comprising a compound according to any of Clai 20 to 24 and a pharmaceutically acceptable carrier or diluent. 26. A compound of the formula: wherein X is oxygen or sulfur; X ι is oxygen or sulfur; Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubsututed C μi alkyl; Cμio alkyl; C2-10 alkenyl; Cμio lkoxy; halosubstituted C μ io alkoxy; azid S(O)tR-4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Cμ4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC μ4alkyl; heteroarylC 1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-IO alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R5. C(O)NR4R5; C(O)NR4Rlθ; S(O)3H; S(O)3R8ϊ Ci- 10 alkyl C(O)Rι 1; C2-10 alkenyl C(O)Rι 1; C2- 10 alkenyl C(O)ORι 1 ; C(O)Ri 1 ; C(O)OR 12; OC(O) R 11 ; NR_4C(O)R 11 ; or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R4 and R5 are independently hydrogen, optionally substituted C μ4 alkyl, optionally substituted aryl, optionally substituted aryl C 4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic Cj .4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; Y is independently selected from halogen; nitro; cyano; halosubstituted C μio alkyl; -io alkyl; C2- 10 aUcen y 1 ". Cl-lO alkoxy; halosubstituted C μ 10 alkoxy; azide; S(O)tR4; hydroxy; hydroxy Ci-4alkyl; aryl; aryl Cj-4 alkyl; aryloxy; arylCμ4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC 1 -4 alkyloxy; heterocyclic, heterocyclic Cμ 4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-IO alkenyl; NR4R5; C2-10 alkenyl C(O)NR R5; C(O)NR 4 R5; C(O)NR Rlo: S(O)3H; S(O) 3 R 8 ; Cμ 10 alkyl C(O)Rj 1; C2-IO lkenyl C(O)Rj 1; C2-10 alkenyl C(O)ORι 1; C(O)Rι 1; C(O)ORi2; OC(O) Ri 1 ; NR4C(O)R 1 1 ; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 2; m is an integer having a value of 1 to 3; R8 is hydrogen or Cj .4 alkyl; R lO is C 1-10 alkyl C(O)2R8; Rj 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cμ 4-dkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C 1. 4alkyl; Rl2 is hydrogen, Cμio alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that: when n =1 ϋ an Y is substituted in the 2'- or 3'- position; when n =2 than Y is di-substituted in die 2'- 3'- position; further provided that when X 1 is S, m=l, Rj is 4-ethyl, and n=l than Y is not 2-meϋιoxy; or a pharmaceutically acceptably salt thereof. 27. The compound according to Claim 26 wherein R\ is substituted in the 3-position, the 4- position or di-substituted in the 3,4- position by an electron withdrawing moiety. 28. The compound according to Claim 26 or 27 wherein Y is mono-substituted in die 2'- position or 3'- position, or is disubstituted in die 2' or 3' position of a monocyclic ring. 29. The compound according to Claim 26 or 27 wherein n amd are each equal to 1 or more. AMENDED SHEET {ARTICLE 19) 30. A pharmaceutical composition comprising a compound according to any of Clai 26 to 29 and a pharmaceutically acceptable carrier or diluent. 31. A process for producing a cyano phenol derivative of the formula: wherein R] is as defined for Formula (I) above, which mediod comprises a) reacting a compound of the formula: wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine. 32. The process according to Claim 31 wherein the temperature is about 60 to about 80 * C, and X is bromine.

Inventors: HERTZBERG ROBERT PHILIP, JUREWICZ ANTHONY JOSEPH, RUTLEDGE MELVIN CLARENCE JR, VEBER DANIEL FRANK, WIDDOWSON KATHERINE LOUISA, HERTZBERG, ROBERT, PHILIP, JUREWICZ, ANTHONY, JOSEPH, RUTLEDGE, MELVIN, CLARENCE, JR., VEBER, DANIEL, FRANK, WIDDOWSON, KATHERINE, LOUISA
Applicants: HERTZBERG ROBERT PHILIP, JUREWICZ ANTHONY JOSEPH, RUTLEDGE MELVIN CLARENCE JR, SMITHKLINE BEECHAM CORP, VEBER DANIEL FRANK, WIDDOWSON KATHERINE LOUISA, HERTZBERG, ROBERT, PHILIP, JUREWICZ, ANTHONY, JOSEPH, RUTLEDGE, MELVIN, CLARENCE, JR., SMITHKLINE BEECHAM CORPORATION, VEBER, DANIEL, FRANK, WIDDOWSON, KATHERINE, LOUISA
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P29, A61P37, C07C253, C07C255, C07C275, C07C307, C07C309, C07C311, C07C317, C07C323, C07C335, C07D213, C07D215, C07D217, C07D277, C07D317, C07D333, C07D409