IL141121A - Process for preparing cyano-phenol derivatives - Google Patents

Abstract

A method for producing a cyano phenol derivative of the formula: wherein R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-C10 alkyl; halosubstituted C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; (CR8R8)q S(O)t R4; hydroxy; hydroxy substituted C1-4 alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy; heterocyclic, heterocylic C1-4 alkyl; heterocyclic C1-4 alkyloxy; heterocyclic C2-10 alkenyl; (CR8R8)q NR4R5; (CR8R8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; 2733 י" ב בתשרי התשס" ה - September 27, 2004 (CR8R8)q C(O)OR11; (CR8R8)q OC(O)R11; (CR8R8)q NR4C(O)R11; (CR8R8)q C(NR4) NR4R5; (CR8R8)q NR4C (NR5)R11, (CR8R8)q NHS(O)2R13; (CR8R8)q S(O)2 NR4R5, or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4 alkyl, heterocyclic, heterocylic C1-4 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; R8 is hydrogen or C1-4 alkyl; R10 is C1-10 alkyl C(O)2R8; R11 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4 alkyl, optionally substituted heteroayl, optionally substituted heteroaryl C1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4 alkyl; R13 is suitably C14 alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4 alkyl, heterocyclic, or heterocyclic C1-4 alkyl; t is an integer from 0 to 2; q is an integer from 0 to 10; and s is an integer from 1 to 3; which method comprises reacting a compound of the formula: wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine. בקשה הורה מס' 125717 לבקשה זו בוטלה The parent application No. 125717 from which this application has been divided has been abandoned

Description

"pijg-ii iTX 7Q] miTJ] Ji.Dn7 Τ7πη A PROCESS FOR PREPARING CYANO-PHENOL DERIVATIVES 141121/4 The present invention is a divisional patent application from the Israel .

Patent Application No. 125717 (hereafter "the parent application").

The parent application relates to phenyhirea compounds, process for their preparation and pharmaceutical compositions containing them.

The present invention relates to a process for producing a cyano phenol derivative of the formula: wherein Rj is indepeodently selected from hydrogen; halogen; nino; cyano; Ci-io alkyl; halosu sotutetfCl-lO alkyl; C2-10 alkenyl; Ci-10 alkoxy; halosubsriuned Ci-ioaikoxy; aaade; S(0)tR4; (CRnRg)q S(0)tR_i; hydroxy; hydroxy substituted Ci- alkyl; aryi; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryioxy; aryt C1-4 alkyloxy; heteroaryl; heteroarylalkyl: heteroaryl C2- 10 alkenyl; heteroaryl C l -4 alkyloxy; heterocyclic, heterocyclic Ci- alkyl; heterocyclicC 1 _4alkyloxy-, lteteocyclicC2-10 alkenyi; H.gR¾)q R4R5; (C eR8)q C(0)NR4R5; C2-10 *lkenyl C(0) R4 5; {.CRnRgJq QO)NR Rl0; S(0)3R8; (CR8Rg)q C(0)Rn; C2-10 alkenyl QO)Rl i; C2-10 alkenyf CfO)ORu; CCRgRgJq C(Q)OR l 1; (CRfiRgJq OCfOJRi 1; (C 8Rg)qN 4C(0) ii; (C g ^q C(NR4)N 4 5; (CRgR$)q NR4C( 5)RU , (CRgRg)q NHS(0>2Ri3 (CRgRg)q S(0)2N 4R5, or two Ri moieties together may form 0-(CH2)sO> or a 5 to 6 membered unsaturated ring, and wherein the alkyl. aryl ar lalkyl, heteroaryl. hetero yciic moities may be optionally substituted; R4 and R3 are indepcadeatly hydrogen, optionally substituted C 1.4 alkyl, optionally substituted aryi, opGoatliy substituted aryi C\^aJkyl opdoaiDy substi ted heteroaryi, optionally substituted heteroaryl Ci^alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and 5 together with the nitrogen to which they are attached form a 5 to 7 Twmhi-r rin which may optionally comprise as additional heteroatom selected from O N/S; R¾ is hydrogen or Cj_4 alkyl: RlO u Ci-io alkyl QO)2R«; Rl t is hydrogen, optioaally substituted Cl-4 alkyl, optionauy ¾tbstitntrd aryl. optionally mhttimeed aryl Ci^ lkyi, οφάοαύΐγ substi tsd heteroaryl optionally substituted heteroaryiCi-ial yi, optionally substituted heterocyclic or optionally ihstirnrrrl heimxryidicC 1 -4¾fl-yl; Rl3 is suitably Cl-4 alkyl, aryl, aryi C 1 -alkyl, flereroaryl heterocyclic, or acaerccvclicC j ^alryi; t is an integer from 0 to 2; q is an integer from 0 to 10: and s is an integer from 1 to 3; which method comprises a) reacting a compound of the formula: 141121/2 wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.

FIELD OF THE INVENTION This invention relates to a novel group of phenyl urea compounds, processes for their preparation and pharmaceutical compositions containing them for treating a chemokine mediated disease state wherein said chemokine binds to an IL-8 a or b receptor.

BACKGROUND OF THE INVENTION Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNGF). neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-la, IL-lb 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).

GROa, GROp, GROy and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GROa, β, γ have been referred to as MGSAa, b and g respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All of the chemokines of the a-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.

IL-8, GROa, GROP, GROy and NAP-2 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROa have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-a and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac- 1 (CD 1 lb/CD 18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive -1a- neutrophil infiltration. As IL-8, GROa, GROp, GROyand NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307.97 ( 1992); Miller et al, Crit. Rev. Immunol. 12. 17 (1992); Oppenheim et al. Annu. Rev. Immunol. 9. 617 (1991); Seitz et al., J. Clin. Invest. 87. 463 (1991); Miller et al.. Am. Rev. Resnir. Pis. 146 427 (1992); Donnely et al., Lancet 341. 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 (1992).

In vitro, IL-8, GROa, GROp, GROy and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al.. Science 253. 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drag Research. Vol. 40, pp.33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-Inflammatory agents.

Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and EL-8Rb, which has high affinity for IL-8 as well as for GRO-a, GROb, GROg and NAP-2. See Holmes et al.. supra; Murphy et al., Science ¾g3, 1280 (1991); Lee et al., J. Biol. Chem.267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267.25402 (1992); and Gayle et al., L Biol. Chem.268. 7283 (1993).

There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 a or b receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVFNTTON This invention provides a pharmaceutical composition comprises an effective amount of a compound of Fonnula (I) , (ID or (III) or a pharmaceutically acceptable salt thereof, for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor, in particular the chemokine is IL-8. 141121/2 This invention also relates to the compound of Formula (I) and its use in the preperation of a medicament for i-Aawring the binding of IL-8 to its receptors in a mammal in need thereof.

Compounds of Formula (I) useful in the present invention are represented by the structure: wherein X is oxygen or sulfur: R is any functional moiety having an iooizable hydrogen and a p a of 10 or less; R] is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; bakttubsatutedCi-iO alkyl; C2-10 alkenyl: CMO alkoxy halosubstituted Ci- loalkoxy; azide; S(0)tR4; (CRgRg)q S(0¼R ; hydroxy hydroxy substituted Ci-4alkyl; aryi; aryi M al yl; aryl C2-10 alkenyl; aryloxy, aryl C alkyloxy; heteroaryl; beteroarylalkyl; heteroaryl C2-IO alkenyl; beteroaryl C alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi- aikyloxv heterocyclicC2-10 alkenyl; (CRgRgjq R R5; (CRgRg q C(0) 4Rs; C2-10 alkenyl C(0)NR4R5; (CRsRg)q QO)NI RlO; S(0)3Rg; (CRgRg)q C(0)Rn; C2.10 alkenyl QO)Rn; C2.10 alkenyl C(0)ORu; (CRgRgJq C(OX3Ru; (CRgRgjq OC(0)Rii; (CR8 8 l 4C(0 Rii; (CRgRg)q CQiRAfi^R^ (CRgRs* ^Ci sJRn .

(CRgRgJq NHS(0)2Rl3 (CRgRg)q SCO^NR,^, or two K\ moieties together may form O(CH2)s0- or a 5 to 6 mexnbered nn«njratd. ting, and wherein the alkyl, aryl, arylalkyl, heteroaryl* heterocyclic moities may be optionally substituted; t is 0, or an integer having a value of 1 or ¾ s is an integer having a value of 1 to 3; R and Rs are independently hydrogen, optionally substituted CM alkyl, optionally substituted aryi, optionally substituted aryi i^taDcy opaomdty substituted heteroaryl, optionally substituted beteroaryl Ci-4alkyi, heterocyclic, heterocyclic C alkyl, or R4 and Rs 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 S; Y is independently selected from hydrogen; halogen; nitro; cyano; halowibvimted MO aifcyU C O alkyl; C2-10 alkenyl; C O alkoxy; halosubstituted C O alkoxy, azide; (CRg o qSCO^ * (C g gfeOR hydroxy; hydroxy substituted Ci^ lky aryl; aryl CM al yl; 141121/2 atyloxy; aiylCi-4 aikyloxy; aiyl C2-10 alkenyl; beteroetyl; heteroarylalkyl; heteroaryl C alkytoxy; heteroaryl C2-10 alkenyl; heteocydic, heterocyclic Cl^taltyl heterocvclicC2-lO aOoenyl; (CRgRg)qNR4RS; C2-10 alkenyl C{0)NR4R5; (C 8Rg q O) 4RS: (CRgRg)q C(O) R4Kl0: SCOfcRg; (CRgRg)qC(O)RH; CW0all-enyK¾^^ C2-10alkenylC(O)ORli; (CRgRg)qOC(0)Ru; (CRgRg)qNR4G(0)Rii; (CRgRg)qNHS(0)2R ; (CRgRg)qS(0)2 R4 5; (CR Rg)qC( R4) 4Rs; (CRgRs)q R C(NR5)Ri 1 or two Y moieties together may form 0- Another aspect of the present invention is to a pharmaceutical composition comprising an effective amount of a compound of Formula (Π or a phjcrmaceutically acceptable salt thereof, as defined herein, for treating a chernnkine mediated disease, wherein the chwnnkirm is one which binds to an IL-8 a or b receptor.

This invention also relates to the compound of Formula (II) and its use for preparing a medicament for inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.

This invention also relates to the novel compounds of Formula (Π), or a pharmaceutically acceptable salt thereof, as defined herein.

Another aspect of the present invention is to a pharmaceutical composition comprising an effective amount of a compound of Formula (ΠΓ) or a pharmaceutically acceptable salt thereof, for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor.

This invention also relates to the compound of Formula (ΠΙ) and its use for preparing a medicament for inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.

This invention also relates to the novel compounds of Formula (ΙΠ). or a pharmaceutically acceptable salt.thereof, as defined herein.

DETAILED PESCRJPTIQN QF THE I E TIO The compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of Π.-8 or other chemokines which bind to the IL-8 a and b receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.

In compounds of Formula (I), R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to 7. Such functional groups include, but are not limited to, hydroxy, carboxylic acid, thiol, -SR2 -OR2, -NH-C(0)Ra, -C(0) R6R7. a substituted sulfonamides of the formula -NHS(0)2Rb, -S(0)2NHRc. NHC(X2)NHRt>, or a tetrazolyl; wherein X2 is oxygen or sulfur, preferably oxygen. Preferably, the functional group is other than a sulfonic acid, either directly or as a substituent group o the aryl, heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2. More preferably R is OH, SH, or HS(0)2Rb» Suitably, R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.

Suitably, R6 and R7 are independently hydrogen or a C alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.

Suitably Ra is an alkyl, aryl, arylCi-4alkyi, heteroaryl, heteroarylCi;4aIkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted, as defined herein below.

Suitably, RD is a NR5R7, alkyl, aryl. aryl Ci_4 alkyl, aryl C .4 alkenyl, heteroaryl, heteroaryl alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci_4 alkyl, a heterocyclic C2-4 alkenyl moiety, or camphor, all of which groups may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C i_4 alkyl, such as CF3; C1 alkyl, such as methyl; Cj^ alkoxy, such as methoxy; aryl; heteroaryl; heterocyclic; NRo<:(0)Ra; C(0)NR$R7, S(0)3H, S(0)m'Ra (wherein m' is 0, 1 or 2), or QOOC^ alkyl. When Rb is an aryl or arylalkyl, preferably it is an optionally substituted phenyl, benzyl, or styryl. When R0 is a heteroaryl preferably it is an optionally substituted thiazole, optionally substituted thienyl, optionally substituted quinolinyl or isoquinolyi ring, or pyridyl ring.

R9 is hydrogen or a C1 alkyl, preferably hydrogen. Suitably, when the substituent group on the R¾ moiety is NR9C(0)Ra, then Ra is preferably an alkyl group, such as methyl.

Suitably Rc is hydrogen, alkyl, aryl, arylCi^alkyl, arylCi-4alkenyl, heteroaryl, heteroarylCi-4alkyl, heteroarylCi^alkenyl, heterocyclic, or heterocyclic Ci^alkyl, or a heterocyclic Ci- alkenyl moiety, all of which groups may be optionally substituted one to three times independently by halogen, nitro, halosubstituted CM alkyl, Ci-4 alkyl, C alkoxy, NRaQC R* C(0)NR6R7, S(0)3R or C(0)OCM alkyl, wherein R9 is hydrogen or a C alkyl. Preferably, Rc is an optionally substituted phenyl.

When R is an OR2 or SR2 moiety it is recognized by one of skill in the art that the aryl ring must, therefore, contain the required ionizable hydrogen. The aryl ring may also be additionally substituted, independently, by one to three groups, which groups may also contain an additional ionizable group, and which include but are not limited to, halogen, nitro, halosubstituted CM alkyl, CM alkyl, CM alkoxy, hydroxy, SH, -C(0) R6R7, -NH-C(0)Ra, - HS(0)2Rb, S(0)2NR6R7, C(0)OR8, or a tetrazolyl ring.

In compounds of Formula (I), suitably Ri is suitably an electron withdrawing moiety. R\ may be independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl such as CF3; Ci-io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trirluoromethoxy; azide; S(0)tR4, wherein t is 0, 1 or 2; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted Ci-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C1-4 alkyl, such as benzyl; aryl C2-10 alkenyl ; aryloxy, such as phenoxy; aryl Ci-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; (CRgRg)qNR4Rs; C2-10 alkenyl-C(0)NR4R5; (CRgRg)qC(0) R4R5 (CRgRg)qC(O)NR Rl0; S(0)3H; S(0)3Rg; (CRgRg)q C(0)Ri 1, such as trifluromethyl ketone ; C2-10 alkenyl C(0)Ri 1, C2-10 alkenylC(0)ORi 1; (CRgRg)qC(0)ORi 1, such as carboxy, methylcarboxylate or phenylbenzoate; (CRgRg)qC(0)ORi2; (CRgRg)qOC(0)Ri 1; (CRgRg)q NR4QO)Ri 1; (CRgRg)qNHS(0)2Ri3. (CR R )qS(0)2 4R5; or two K\ moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; and s is an integer having a value of 1 to 3. The alkyl, aryl, arylalkyl, arykdkenyl, heteroaryl, heteroarylalkyl, heteroaiylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties may all be optionally substituted as defined herein below. Preferably Ri is other than azido or S(0)3Rg. Rg is independently hydrogen or C «4 alkyl, which may be branched or straight When Ri forms a dioxybridge, s is preferably 1. When Rl forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other Ri moieties as defined above.

Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C l-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C i-4alkyl, heterocyclic, heterocyclicCi-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. The optionally substituted moieties are as defined herein below.

RlO is suitably Ci-io alkyl C(0)2R8, such as Cr¾C(0)2H or CH2C(0)2CH3.

Rl i is suitably hydrogen, optionally substituted CM alkyl, optionally substituted aryl. optionally substituted aryl C alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic Ci- alkyl. The optionally substituted moieties are as defined herein below.

Rl2 is suitably hydrogen, optionally substituted CJ.JO alkyl, optionally substituted aryl or optionally substituted arylalkyl. The optionally substituted moieties are as defmed herein below.

Preferably Rl is halogen, cyano, nitro, CF3, C(0)NR4R5. alkenyl C(0)NR4R5, C(O) R4R10. alkenyl C(0)ORl2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(0)NR4R5, and preferably R4 and R5 are both hydrogen or one is phenyl. A preferred ring substitution for Rl is in die 4-position of the phenyl ring.

When R is OH, SH or S02 b than Rl is preferably substituted in the 3-position, 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 NS02Rb» than Ri is nitro, halogen, cyano, trifluoromethyl group, C(0) R4Rs.

When R is carboxylic acid, than Rl is preferably hydrogen, or Rl is preferably substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro.

In compounds of Formula (I), suitably Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; C O alkyl; C2-10 alkenyl; CMO alkoxy; halosubstituted C O alkoxy; azido; (CRgR^qSiO)^, wherein q is 0 or an integer having a value of 1 to 10; (CRgRg)qOR4*, hydroxy; hydroxy Ci-4alkyl; aryl; aryl C alkyl; aryloxy; arylCi-4 alkyloxy; aryl C2-IO alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic Ci^alkyl; heterocyclicC2-10 alkenyl; (CRgRg)q R4R5; C2-10 alkenyl C(0) R4R5; (CR8Rg)qC(0)NR4R5; (CR8R8)qC(O)NR4Rl0; S(0)3R8; (CR8R8)qC(0)Rii; C2-10 alkenyl C(0)Rn; C2-IO alkenyl C(0)ORn; (CR8R8)q C(0)0Ri2; (CR8R8)qOC(0)Rn; (CR8R8)qNR4C(0)Rii; (CR8R8)q NHS(0)2Rb, (CR8Re)qS(0)2 4R5; CR8R8) ( R4) 4R5 (CR8R8)q NR4C(NR5)Rn, or two Y moieties together may form 0-(CH2)s0- or a S to 6 membered unsaturated ring. When Y forms a dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring . may be substituted 1 to 3 times by another Y moiety, such as defined above.

Additionally all of the various aryl, heteroaryl and heterocyclic groups noted above, as well as the R4, R5 and Ri 1 substituent groups, may be optionally substituted as defined herein in the specification below. Preferably Y is other than azido or S(0)3Rg. Rg is independently hydrogen or Q-4 alkyl.

Y is preferably a halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5, thioCi- alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2- position or 2-, 3'-position.

While Y may be substituted in any of the 5 ring positions, preferably when R is OH, SH, or NHS02Rb> Y & preferably mono-substituted in the 2'-position or 3'-position, with the 4 - preferably being unsubstituted. If the ring is disubstituted, when R is OH, SH, or NHS02Rb» substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.

In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen.

While not explicitly covered by Formula (I), (Ia-c), (Π), (Ila-c), or (ΙΠ), another aspect of this invention are the symmetrical bis compounds which are included for each structure.

Compounds exemplified by this bis like structure include: N-(Bis (2-hydroxy-4-nitro phenyl-N'-(dianisdine)diurea 4-Methylene bis(N-(2-cbJoro phenyl N'-(2-hydroxy 4-nitrophenyl)urea) Exemplified compounds of Formula (I) include: N-P-Hydroxy^memoxycarbonylJphenyll-N-phenylure^ N-[5- itro-2-hydroxyphenyl]-N,-phenyl urea 3-Hydroxy-4-{ [(phenylanimo)carbonyl]arnmo}benzamide N^-Hydroxy-^fluorophenyl '-phenyl urea 2- { [(Phenylamino)carbonyl]amino Jthiophenol N-i -Carboxy^-hydroxyphenyl N'-phenyl urea N-[2-Hydroxy-^(txifluoromethyl)phenyl]-N'-phenyl urea N-(2-Hydroxy-4-nitrophenyi)-N'-(2-hydroxy-4-nitrophenyl) urea N-i -Hydroxy^nitrophenylJ-N'-phenyl-thiourea N^4-NiU -2^phenylsulfonylamino)phenyl)- '-phenyl urea N-(2-Hydroxy-5-nitrophenyl)-IT-(3-methoxy-2-thienyl)urea N-(2-HydrOxy^niLrophenyl)-- T-(3-methoxy-2-thienyl)urea N-(2-Hydroxy^idtrophenyl)-NM3-methoxyphenyl)urea N-(2-Hydroxy^rdtrophenyl)-NX2-methoxyphenyl)urea N-(2-Hydroxy-4-rritrophenyi)- r-(3-a^ N-(2-Hydroxy^nitrophenyl)- '-(2-trifiuoromethylphenyl)urea N-(2-Hydroxy-4-mtiophenyl)-^^ N-(2-Hydroxy^iutiophenyl)-N, 2-bromophenyi)urea N-(2-Hydroxy^mtrophenyl)-^^3-bromophenyl)iirea N-(2-Hydroxy^nitrop enyl)-l -(4-bromopheayl)urea N 2-Hydroxy^rdtic^lienyI)-l^-(2-phenylphenyl)urea N-(2-Hydroxy-4-nittophenyl) - -(l-naphthyl)urea; N-(2-Hydroxy^iutrophenyI)- ^2-rutiOphenyl)urea N-(2-Hydroxy^nitrophenyl)-N'-<2-rluorophenyl)urea N-(2-Hyciroxy-4-nitrophenyl)-Ir-(½^ N-(2-Hydroxy^nitrophenyl)-N,-(2-ethoxyphenyl)urea N-(2-Hyd-foxy^nitrophenyl)-N,-<2-ethylphenyl)urea N-(2-Hydroxy-4-mtrophenyl)-^-@^^ N-(2-Hydroxy-4-rritrophenyl) *-(2-metiiylthiophenyl) urea N-(2-Hydroxy-4-nitrophenyl) 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-Carbornethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea N -Trifluorornethyl-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'-(2t4-dibromophenyl) urea N-(2-Hydroxy-l-napthyl)-N,-(2-broniophenyl) urea N-(2-Hyromophenyl) urea N-(2-Hydroxy^nitrophenyl)-N,-(2-iodophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl) thiourea N-[(2-Phenylsulfamido yanophenyl]-N'-(2-bromophenyl) urea N^2^Aminosulfonamidophenyl)phenyl)-l^-(2-bromophenyl) urea N-(2-(AminosulfonyIstyryl) phenyl)-N'-{2-biOmophenyl) urea 2-[(3A-Di-memoxyphenylsulfonyl)an^ N-(2-[( -Acetamidophenylsulfonyl)amino]phenyl)-N,-(2-bromophenyl) urea N-(2-( Aminosulfonyl (2-thiophene)phenyl)-N'-(2-bromophenyl) urea N-(2-(Ammosulfonyl (3-tolyl) phenyl)- -(2-bromophenyl) urea N-(2-( Aminosulfonyl (S^umoliny^^henyl^^-bromophenyl) urea N-(2-( Aminosulfonyl benzyl) phenyl)- r-(2-broniophenyl) urea N^2-Hydroxy^azidophenyl>N,-(2-methoxyphenyl)urea N-[2-Hydroxy-5-cyanophenyi]-N,-[2-bromophenyl]urea N-[2-Hydroxy-3-fluorophenyl]-N,-[2-bromophenylurea N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-chloropheflyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-trifluoromethylphenyl]- T-[2-bromophenyl]urea N-[2-Hydroxy ,4-dphenyl-phenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-glycmememylestercarbo¾ N-[2-Hyclroxy-3-glycincarbonylphenyl]- ,-[2-bromophenyl] urea N-P-Hydroxy-S.S-dichlorophenyll-N'-P-bromophenyl] urea N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N,-[2-broniophenyl] urea N-P-Hydroxy-S-cyanophenylJ- '-P-bromophenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-cyanopfaenyi]- '-[4-methoxyphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea N-[2-Hy<-xoxy-4-cyanopheayl]-N'-[2-methylphenyl] urea N-[2-Hydroxy-4n:yanophenyl]-N'-[2-triiluoromethylphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-l>r-[3-tr^^ urea N-P-Hydroxy-^yanophenyn- -^trifluoromethylphenyl] urea N-P-Hydroxy-S-n-propylphenyll-N'-P-bromophenyl] urea N-P-Hydroxy-^thylphenyll- -P-bromophenyl] urea N-[2-Hya^xy-3^henylaminocarbonyl phenyl]-N'-{2-bromophenyI] urea N-[2-Hydroxy-3^yano^methylptenyl]-I^-[2-bromophenyl] urea N-[2-Hydroxy-4-carbophenyl phenyl]-^-[2-bromophenyl] urea N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-P-Benj^loxy^-hydroxypteny^ T-P-bromophenyl] urea (E)-N-[4-[2-(Methoxycarbonyl)etheny^^ (E)-N-[3-[2-(Methoxycarbonyl)etheny^ urea- tf-[2-bromophenyl]urea (E N-[3-[2-(Aniinocarbonyl)ethenyl]-2-hydroxyphenyl] [2-bromophenyl]urea (E)-N-[4-[2-(Aniinocarbonyl)ethenyl]-2-hydroxyphen^ [2-bromophenyl]urea N-P-Hyd^oxy^benzarnide henyll- '-P-bromophenyllurea N-[4-Ajninocarbonyl-2-hydroxy^^ N-(2-Hyd^xy-3^,6-trifluorophenyl)-NH2-bromophenyl)urea N-(2-Hydfoxy-3-fluoro-4-trifluoro^ N-(2-Hydroxy-3-iodophenyI)-N,-{2-bromophenyl)urea N-[2-[[[2-(Trifluoromethyl)phenyl]si^ N-(2-Bromophenyl)-N'-[2-diiriethylanunosulfonylamino]phenyl]ui^ N-[2-(Pheaethylsulfonylammo^ N-[2-[(2-Acetamido-4-niethyltMazol-5-yl)si^ bromophenyl)urea N-[2-Hydroxy- oxyphenyl)-W-phenyliirea N-(2-Hydroxy-4-nitrophenyl)-N,-phenylurea 1 -(2-Carboxyphenyl)-3-(4-chloropheny l)urea 2-{3,4-Dichiorophenylcarbonyldiin-ino)-5-trifluorom 2 4-CMorophenylcarbonyldiimmo) Hp-Anisyl)-3-(2-carboxyphenyl)urea H2-Carboxyphenyl)-3-(3-fluorophenyl)urea H2-Carboxyphenyl)-3-(3-chlorophenyl)urea Hm-Anisyl)-3-(2-carboxyphneyl)urea Ho-Anisyl)-3-(2-carboxyphenyl)urea H2-C^rboxyphenyl)-3-(3,4-dichloropbenyl)urea l-(2 ¾rboxyphenyl)-3 2,4-dichlorophenyl)urea N-(5-CUoro-2-hydroxy-4-riitrophenyl)-N'-phenylurea N-(2-Hy4-cyano phen^ N-(2-(Phenykulfonylamino)-4-cyan^ N-[2-(Phenylsulfonylamino)-4-< a∞ N-[2-(Phenyisulfonylamino)-4-cyano phenyy-N'-^-methoxy 3-chloro phenyl) urea N-[2-(4-cyanophenyl NX3-fluoro phenyl) urea N 2-Thiophenesulfonylamko-4-cy^ N-[(2-Pyrid-2-yl)tMophene-5-siilfonyto N-[(2-AcetanuncH4-methyl-5-tM^ dichlorophenyDurea N-((2-Aminosulfonylphenyl) 4-cyano phenyl) N"-(2-methyl 3-chloro phenyl) urea N-(2-Benzenesulfonylamino-3-cyanophenyl)-N'-(2,3dichlorophenyl)urea N-[(Benzylsulfonylarnino)-5-cyanophenyl]-NX2 -NH2-beiizyto ^-[2^2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy^nitrophenyl)u^ N-[2-(2-Memoxycarbonylbenzyloxyphenyl]-^^ N-[2-(2 aj*oxybenzyloxy)phenyl)-N,-(2-hydroxy^mtrophen^ N-[2-(Benzoylamino)phenyl]-N,-(2-hyT-(2-methylthiophenyl)urea N-(2-Hydroxy^mtrophenyl '-(2^-dichlorophenyl)urea N-(2-hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea N-(2-Hydroxy^rdtrophenyl> -(2i3-methylenedioxyphenyl)urea N-(2-Hydroxy^nitrophenyl)-N,-{2-methoxy-3-chlorophenyl)urea N-(2-hydroxy 4-nitro phenyl) N^-phenyloxy phenyl) urea N-(3-CWoro-2-hydroxyphenyl)-N,-(bromophenyl)urea N-(2-Hydroxy-3-glyckememylestercarbonyl^^ N-(3-Nitro-2-hydroxyphenyl)-N,-(2-bromophenyl)urea N-(2-Hyr 2-methoxyphenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N,-(2i)henylphenyl)urea N-(2-Hyd¾rxy-4-cyanophenyl-N'-(2 -dichlorophenyl)urea N-(2-Hydroxy-4-cyanophenyl I^-(2-rnethylphenyi)urea N-(2-Hydroxy-3-cyano-4-rnethylphenyl)-N'-(2-broniophenyl)urea N-(4-Cyano-2-hydroxyphenyl)-^-(2-trifluoromemylphenyl)urea N-(3-Trifluoromemyl-2-hydroxyphenyl)-N,-(2-bromophenyl)urea N-(3-Phenylainmocarbonyl-2-hyaroxypheny N-(2-hydroxy 4-nitro phenyl) N*-(2-iodo phenyl) urea N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea N 2-phenylsulfonarnido)-4-cyanophenyl-N,(2-bromo phenyl)urea (E)-N-[3-[(2-Aimnocarbonyl)eraeny^2-hydro^ N-(2-Hyciroxy,3.4-dichlorophenyI)-N,-(2-niethoxyphenyl)urea N^2-Hydroxy ,4^ichlorophenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-3,4Huchlorophenyl)- 2 ^chlorophenyl)urea N-(2-Hydroxy-5-nitrophenyl)- ,-(2 3-dichlorophenyl)urea N-(2-Hydroxy-3-cyanophenyl)- ,-(2,3 dichlorophenyl)urea As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as cyano, nitro, fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-ioalkyl; Ci-io alkoxy, such as methoxy or ethoxy; S(0)m' C i . io alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the R4R5 group; NHC(0)R4; C(0)NR4R5; C(0)ORn; S(0)2NR4R5 HS(0)2Rl3, Ci-io alkyl, such as methyl, ethyl, propyl, isopropyi, or t-butyl; halosubstituted Ci-io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl, hetroaryl, or heterocyclic moieties may themselves be optionally substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O)m'Ci-l0 alkyl; amino, mono & di-substituted amino, such as in die NR4R5 group; Ci-io alkyl, or halosubstituted Ci-io alkyl, such as CF3.

Rl3 is suitably Ci-4 alkyl, halosubstituted C1-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi^alkyl, heterocyclic, or heterocyclicCi-4alkyl.

Another aspect of the present invention are the novel compounds of Formula -(Π), 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 (Π) and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (Π) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (Π ΟΓ a pharmaceutically acceptable salt thereof.

Compounds of Formula (Π) are represented by the structure: wherein X is oxygen or sulfur, R is any functional moiety having an ionizabie hydrogen and a p a of 10 or less; Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted C O alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(0)tR4; (CR8Rg)q S(0)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl CM alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Q-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi^alkyloxy; heterocyclicC2-10 alkenyl; (CRgRg)^ R4R5; (CRgRg)q C(0)NR4Rs; C2-10 alkenyl C(0) R4Rs; (CRgRg)q C(0) R4RlO; S(0)3R8; (CRgRg)q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1; C2-10 alkenyl C(0)ORi 1; (CRgRg)q C(0)ORi 1; (CRgRg q OC(0)Ri i; (CRgRg)qNR4C(0)Rl li (CR8R8 q C( R4) R4R5; (CR8Rg)q R4C( R5)Ri lt (CRgRg)q NHS(0)2Ri3i (CRgRg)q S(0>2 R4R5, or two Rl moieties together may form 0-(CH2)sO- or a S to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; 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 1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclicCi-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 hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C alkyl; aryloxy; arylQ-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic Ci-4alkyl; heterocycUcC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl C(0)NR4R5; (CRgRg)qC(0) R4R5; (CR8Rs)q C(0) R4RlO; S(0)3R8; (CR8R8)qC(0)Ri i; C2-10 alkenylC(0)Ri i; (CR8R8)qC(0)ORl i; C2-10alkenyiC(O)ORl i; (CR8R8)qOC(0) Rn; (CR8R8)qNR4C(0)Rn; (CR8R8)q NHS(0)2Rb; RlO is Ci-10 alkyl C(0)2R8; Rl 1 is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heteroaryi, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic i-4alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 is suitably C1-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryi, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC i-4alkyl; RD is R5R7, alkyl, aryl, aryl Cj^ alkyl, aryl C2.4 alkenyl, heteroaryi, heteroaryi Ci_4 alkyl, heteroarylC2^ alkenyl, heterocyclic, heterocyclic C1.4 alkyl, heterocyclic C2_4 alkenyl, or camphor, all of which groups may be optionally substituted; E is optionally selected from the asterix * denoting point of attachment of the ring, with at least one E being present; or a pharmaceutically acceptably salt thereof.

Suitably, the variables for Formula (Π), such as X, R, Ri, R4 , R5, R6, R7. R8. R9, Y, Ra, Rb, Rc» n, m, and s terms, etc. are as defined in Formula (I) above. The E ring denoted by its point of attachment through the asterix (*) may optionally be present. If if it is not present the ring is a phenyl moiety which is substituted by the R and Ri terms as shown. At least one E ring is necessary. The E ring may be substituted by the Ri or Y moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).

Another aspect of the present invention are the novel compounds of Formula (Ha), (lib) and (lie) which are similar to those described herein for Formulas (la), (lb) and (Ic) but which require one of the two phenyl rings to posses an E ring.

Suitably, for compounds of Formula (Ila-c), the variables are as defined herein for Formulas (I) and (Π).

Compounds of Formula (Ha) are represented by the structure: wherein X is oxygen or sulfur; R is -NHS(0)2Rb Ra is an alkyl, aryl, arylCi-4alkyl, heteroaryi, heteroaryl Ci-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted; Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, aryl C2-4alkenyl, heteroaryl, heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic Ci-4alkyl, or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted CM alkyl; CM alkyl; C alkoxy; NRoC(0)Ra; S(0)m«Ra, C(0)NR6R7, S(0)3H, or C(0)OCi-4 alkyl; R6 and R7 are independently hydrogen or a C alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring 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 CM alkyl, preferably hydrogen; Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci-10 alkyl; C2-10 alkenyl; Q-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(0)tR4; (CR8Rg)q S(0)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl CM alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl CM alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocychcCi-4alkyloxy; heterocyclicC2-l0 alkenyl; (CRgR^q R4R5; (CRg ^q C(0)NR4R5; C2-10 alkenyl C(0)NR4Rs; (CR8R8)q C(0)NR4RlO; S(0)3R8; (CRgRg)q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1; C2-10 alkenyl C(0)ORn; (CRgRg)q C(0)ORn; (CRgR8)q OC(0)Rn; (CR8R8)qNR4C(0)Ri 1 ; (CR8Rg)q C(NR4) R4R5; (CR8R8)q R4C(NR5)Ri lt (CR8R8)q HS(0)2Ri3; (CR8R8)q S(0)2NR4Rs, or two Ri moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; 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 Rs are independently hydrogen, optionally substituted C alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclicC 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 hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR8R8)qS(0)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C alkyl; aryloxy; arylCM alkyloxy; aryl C2- 10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl CM alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic Ci-4alkyl; heterocyclic.10 alkenyl; (CR8R )q R4R5; C2-10 alkenyl C(0)NR4R5; (CR8R8)qC(0)NR4R5; (CR8R8)q C(O)NR4Rl0; S(0)3R8; (CR8R¾)qC(0)Rn; C2-10 alkenylC(0)Rn; (CR8R8)qC(0)ORu; C2-10alkenylC(O)ORii; (CR8Rg)qOC(0) Rn; (CR8R8)qNR4C(0)Rii; (CRgRg q NHS(0)2 b; ( R^R^q S(0)2 R4R5, (CR8R8)qC(NR4)NR4R5; (CR8R8)q R4C(NR5)Ri j; or two Y moieties together may form 0-(CH2)sO- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted; q is 0 or an integer having a value of 1 to 10; 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 Q-4 alkyl; RlO is Ci-io alkyl QO)2R8; Rl i is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi^alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC i-4alkyl; E i the asterix * denoting point of attachment of the ring; with the proviso that at least one E ring being present; or a pharmaceutically acceptably salt thereof.

Formula (lib) compounds contain the R functionality of X1R2 wherein R2 is R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety providing the ionizable hydrogen having a pKa of 10 or less; and the remaining variables as defined above for compounds of Formula (I) and (Π).

Formula (lie) compounds contain the R functionality XjH, wherein X is oxygen or sulfur and the remainder of the variables are as defined in Formula (I) and (Π) above.

Exemplified compounds of Formula (Π) include: N-[2-hydroxy-5-indanone]-N'-[2-bromophenyi] urea; N-[ 1 -hydroxyfluorenel- '-P-bromophenyl] urea; N-[3-hydroxy-9,10-anthraquinon-2-yl]-N'-[2-bromophenyl] urea Another aspect of the present invention are the novel compounds of Formula (ΙΠ , 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 (ΙΠ) and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (ΙΠ) are also useful for treating a chemokine mediated disease, wherein the chemoicine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (ΙΠ) or a pharmaceutically acceptable salt thereof.

Compounds of Formula (HI) are represented by the structure: wherein X is oxygen or sulfur, is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Cl-ioalkoxy; azide; S(0)tR4i (CRgR8)q S(0)tR4 hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocycIicCi-4alkyloxy; heterocyclicC2-10 alkenyl; (CRgRg)q R4R5; (CRgRg)q C(0) R4R5; C2-10 alkenyl C(0)NR4R5; (CR8Rg)q C(O) R4Rl0; S(0)3R8; (CRgR8)q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1; C2-10 alkenyl C(0)ORii; (CRgRgta C(0)ORn; (CRgRg)q OC(0)Rn; (CRgR8)q R4C(0)Rir, (CRgR8)q C( R4)N 4R5; (CRgR8)q R4C(NR5)R11, . (CRgRg)q NHS(0)2 i3; (CRgRg)q S(0)2NR4 s, or two Rl moieties together may form O(CH2)s0- or a S to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; q is 0 or an integer having a value of 1 to 10, t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R and Rs are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryi, optionally substituted heteroaryl Ci-4alkyi, heterocyclic, heterocyclicCi-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 hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-IO alkenyl; Q-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0)tR4, (CR8R8)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl CM alkyl; aryloxy; arylC M alkyloxy; aryl C2-IO alkenyl; heteroaryl; heteroarylalkyl; heteroaryl CM alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl C(0) R4R5; (CR8R8)qC(0)NR4R5; (CRgRg)q C(O) R4Rl0; S(0)3R8; (CR8R8)qC(0)Rn; C2-l0 alkenylC(O)Rii; (CRgR8)qC(0)ORu; C2-10alkenylC(O)ORii; (CR8R8)qOC(0) Rn; (CR8R8)q R4C(0)Rn; (CR8Rg)q NHS(0)2Rb; (CR8R8)q S(0)2 4R5; (CR8R8)qC( R4)NR4R5; (CR8R )q R4C(N 5)Rj j ; or two Y moieties together may form 0-(CH2)sO- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, aryialkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; R6 and R7 are independently hydrogen or a CM alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, R8 is hydrogen or CM alkyl; RlO is Q-io alkyl C(0)2R8; Rl 1 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i^alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted aryialkyl; Rl3 is suitably C alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4aikyl; Rb is NR^R7, alkyl, aryl, aryl C ar l C2.4 alkenyl, heteroaryl, heteroaryl CM alky.. heteroarylC2-4 alkenyl, heterocyclic, heterocyclic CM alkyl, heterocyclic C2. alkenyl, or camphor, ail of which groups may be optionally substituted; E is optionally selected from the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptably salt thereof.

Suitably, the variables, etc. for Formula (ΠΙ) are the same as those defined for Formula (I) above, such as for example the R, and Y variables. Suitably the E term is the same as previously defined for Formula (Π).

Exemplified compounds of Formula (ΙΠ) include: N-<2-Hydroxy-4-iutrophenyl)-^-<3-memoxy-2-thieayl)i-rea; and N-(2-hydroxy-5-nitrophenyl)-NX3-methoxy-2-thienyl)urea.

Another aspect of the present invention is the novel compounds of Formula (la), a subset of compounds of Fonnula (I) useful for treating a chemoidne mediated disease as defined herein. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (la) and a pharmaceutically acceptable diluent or carrier.

The compounds of Fonnula (la) are represented by the structure: wherein X is oxygen or sulfur, Ra is an alkyl, aryl. arylCi-4alkyl, heteroaryl, heteroaryl Ci^alkyl, heterocyclic, or a heteiocyclic Ci^alkyl moiety, all of which may be optionally substituted; Rb is a R6R7, alkyl, aryl, arylCi-4alkyl, aryl C2-4alkenyl, heteroaryl, heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic O 97/29743 C i^alkyl, or a heterocyclic C2-4aIkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; haiosubstituted C1-4 alkyl; CM alkyl; CM alkoxy; NR9C(0)Ra; S(0)m Suitably, the variables for Formula (la) are the same as those defined for Formula (I) above, such as for examples the R, Rj, and Y variables. A preferred ring substitution for the Ri 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 Ri is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4R5.

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 unsubstituted. If the ring is di-substituted, substituents are preferably in the 2'-, 3'- positions of a monocyclic ring. While both Ri 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 is more preferably a mono-substituted halogen, disubstituted halogen, mono- substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably these groups are substituted in the 2'- position or 2'-,3'-position.

Exemplified compounds of Formula (la) are N-(4-Nitro 2-(phenylsulfonylamino)phenyl)- -phenyl urea N-[(2-PhenyIsulfamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea 2-[(3,4 Di-memoxyphenyIsulfonyl)amino] phenyl) '-(2-bromo phenyl) urea N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino 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-(Trifluoromerayl)phenyl]su^^ N-(2-Bromophenyl)-N,-[2Hdimemylan-mosulfonylannno]phenyl]urea N-[2-[(2-Acetarmdc^ -rnemylthiazol-5-yl)sulfonylanun bromophenyl)urea N-[2-[(2 -DicWorothien-5-yl)]siilf^^^ N-[2-[(3 -Bistrifluoromemylpheny N-[2-[(2-Benzyl)sulfonylammo]-(5-trffl^ N-[2-[2-(3-Nitrophenyl)sulfonylaniino]phenyl]-N,-(2-bromophenyl)urea N-[2-[2-(4-Phenoxyphenyl)sulfonylanimo]phenyl]-N'-(2-bromophenyl) ure^ N-[[2-( IS)- 10-C^phoreulfonylamino]phenyl]-N,-(2-bromophenyl)urea N-[[2^1R 10-Camphorsulfonylammo]phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(2-Nitro 4-trifluoromemyl)phenyl)sulfonylamb bromophenyl)urea N-[2-(2-Amino-(4-trifluorome±yl) phenyl) sulfonylamino] phenyl]- N*-(2- bromophenyl)urea N-[2-(arninosulfonyl phenyl)-3-aminophenyl] N'-(2-bromo phenyl) urea N-[2-[2-(4 Moro-3-ammophenyl)sulfonylammo]phenyl]- -(2-bromophe^ N-[2-(3-Animopbenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea N-(2-Beiuenesulfonylamino-4- yanophenyl)-N'-(2-methoxyphenyl)urea N-(2-Benzenesulfonylammo-4-cyanopte^ N-(2-Benzenesulfonylammo-4-cyanophenyl)-^-(3^ N-(2-Benzenesulfonylammo-4-cyano N-[2-(Benzylsulfonylannno)-4^ya∞ N-[2-(Phenylsiilfonylanimo)-4-triflu^ N-[2-(3-Pyridinesulfonyiammo)-4-cyano N-[2-(5-fcoqu oknes fonylainmo)-4^ N-[2-(Phenylsulfonyianuno^ N-[(Phenylsulfonylam-jQO)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea N-[2-(Phenylsulfonylanimo)-4-cyanopte N-[2-(Phenylsulfonylanuno)-4^MO N-[2-(Phenylsulfonylanrino)-4-cyan^ N-[2^Phenylsulfonylanimo)-4-cyanophenyl]-N'-(2-methylphenyl) urea N-[2-(Phenylsulfonylainino)-4-cyano phenyll-fT-^-methoxy 3-chloro phenyl) urea N-[2-( ^yanophenyl)-W-(3-fluoro phenyl) urea N-(2-Thiophenesulfonylam o-4-cya∞ N-[(2-Pyrid-2-yl)thiophene-5-sulfonyta N-[(2-Acetarmno-4-memyl-5-thi^ dichlorophenyl)urea N-((2-aminosulfonylphenyl) 4-cyano phenyl) N*-(2-methyl 3-chloro phenyl) urea N-(2-beiizenesulfonylamtoo-3-<^ara N-[(Benzylsulfonylammo)-5 N-[(2-Phenykulfonylanuno)-4 The compounds of Fonnula (lb) are represented by the structure: wherein X is oxygen or sulfur, X i is oxygen or sulfur; Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci-io alkyl; C2-10 alkenyi; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted Ci-4alkyi; aryl; aryl CM alkyl; aryl C2-10 alkenyi; aryloxy; aryl CM alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyi; heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi^talkyloxy; heterocyclicC2-lO alkenyi; (CRgRg)q R4R5; (CRgRg)q C(0)NR4Rs; C2-10 alkenyi C(0)NR4R5; (CRgRg)q C(0)NR4RlO; S(0)3 8; (CRgRg)q C(0)Ri 1; C2-10 alkenyi C(0)Ri 1; C2-10 alkenyi C(0)ORi 1; (CRgRg)q C(0)ORi 1; (CRgRg)q OC(0)Ri 1 ; (CRgR8)qNR4C(0)Ri 1; (CR8Rg)q C( R4)NR4R5; (CRgRg)q NR4C(NR5)R1 χ ; (CRgRg)q NHS(0)2 i3; (CRg 8)q S(0>2 R4R5; or two Rl moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, aiylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; t is 0, or an integer having a value of 1 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 ionizable hydrogen having a pKa of 10 or less; R4 and Rs are independently hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci^alkyl, heterocyclic, heterocyclic M alkyl, or R4 and Rs 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 hydrogen; halogen; nitro; cyano; halosubstituted C O alkyl; Ci-io alkyl; C2-10 alkenyi; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyi; heteroaryl; heteroarylalkyl; heteroaryl C alkyloxy; heteroaryl C2-IO alkenyi; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicC2-10 alkenyi; (CRgRg)qNR4R5; C2-10 alkenyi C(0) R4R5; (CRgR8)qC(0)NR4R5; (C gR8)q C(0) R4RlO; S(0)3R8; (CR8R8)qC(0)Ri i; C2-10 alkenylC(0)Ri l; (CR8R8)qC(0)ORi i; C2-10alkenylC(O)ORl i; (CR8R8)qOC(0) Rn; (CR8R8)q R4C(0)Rn; (CR8R8) NHS(0)2Rb; (CRsR8)q S(0>2 R4R5; (CR8R8)qC(NR4)N 4R5; (CR8R8)q NR4C(NR5)Ri j; or two Y moieties together may form 0-(CH2)sO- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryi alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted; q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; R6 and R7 are independently hydrogen or a C alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur; R8 is hydrogen or C 1 -4 alkyl; R 10 is C MO alkyl C(0)2R8 Rl 1 is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCl-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkyl; Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 is suitably Q-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl; RD is NR5R7, alkyl, aryl, aryl Ομ alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl Cj_4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci_4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted; or a pharmaceutically acceptable salt thereof.

Suitably, the variable, etc. for Formula (lb) are the same as those defined for Formula (I) above, such as for example the functional moieties on the R2 group having an ionizable hydrogen with a pKa of 10 or less. Suitably such functional groups include, but are not limited to, hydroxy, carboxylic acid, thiol, -NH-C(0)Ra, -C(0) R6R7, substituted sulfonamides of the formula -NHS(0)2Rb. -S(0)2NHRc NHC(X2) HRb» or tetrazoyl (as defined for Formula (I).

Suitably for compounds of Formula (lb), a preferred ring substitution for R\ is in the 3-position, the 4- position or is preferably di substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably Ri is nitro, halogen, cyano, trifluoromethyi group, or C(0)NR4R5.

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 unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3* position of a monocyclic ring. While both Ri 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.

Suitably for compounds of Formula (lb), Y is more preferably disubstituted halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, methylenedioxy, aryl, or alkyl, preferably in the 2'position or 2\3'-position.

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 invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ic) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (Ic) are represented by the strucuture: wherein X is oxygen or sulfur; X l is oxygen or sulfur, Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Cl-io alkyl; C2-10 alkenyl; Ci-io alkoxy halosubstituted Ci-ioalkoxy; azide; S(0)tR4; (CRg 8 q S(0)tR4 hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Q-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci^alkyl; heterocyclicCi^alkyloxy; heterocyclicC2-lO alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(0) R4R5; C2-10 alkenyl C(0)NR4R5; (CR8R8)q C(O)NR4Rl0; S(0)3R8; (CRg^q C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)ORi i; (CRgR^q C(0)ORi l; (CRg sJq OC(0)Rn; (CR8Rg)q R4C(0)Rli; (CR8Rg)q C(NR4)N 4R5; (CRg^q 4C(NR5)Rn, 743 (CRgRg)q NHS(0)2Ri3 (CRgRg)q S(0)2N R5, * two Ri moieties together may form 0-(CH2)s - or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, aryialkyl, heteroaryl, heterocyclic moities may be optionally substituted; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl CM alkyl, heterocyclic, heterocyclic CM 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 hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci- 10 alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl CM alkyl; aryloxy; arylCM alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic Ci_4alkyl; heterocyclicC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl C(0)NR4R5; (CRgRg)qC(0)NR4R5; (CRgRg)q C(0)NR4RlO; S(0)3R8; (CRgRg)qC(0)Rii; C2-10 alkenylC(0)Rn; (CRgRg)qC(0)ORii; C2-10alkenyIC(O)ORii; (CRgRg)qOC(0) Rn; (CRgR8)qNR4C(0)Rii; (CRgRg)q NHS(0)2RD; (CRgRg)q S(0)2 R4R5, (a¾Rg)qC(NR4) R4R5; (CRgRg)q R4C(NR5)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, aryialkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted; q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3 ; m is an integer having a value of I to 3; R6 and R7 are independently hydrogen or a C M alkyl group, or R6 and R7 together . with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur; Rg is hydrogen or C alkyl; RlO is Ci-10 alkyl C(0)2R8i Rl 1 is hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Ri3 is suitably Q-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi -4alkyl; R¾ is NR6R7, alkyl, aryl, aryl Ci_4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl Ci_4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally 0 substituted: provided that when n si than Y is substituted in the 2- or 3- position; when n =2 than Y is di-substituted in the 2'- 3'- position, the 2-5'- position, the 2-6' position, the 3 -5' or the 3 -6' position; when n ■ 3 than Y is trisubstituted in the 2'-3'-5' or the 2 -3 -6'- positions; S further provided that when Xi is O, m=2, Ri is 2-t-butyl, 4-methyl, and n=3 than Y is not 2*-OH '-t- butyl, 5'-methyl; when Xi is O, m=l, Ri is 4-methyl, and n=2 than Y is not 2 -OH, 5'-methyl; when Xi is O, m=l, Ri is hydrogen, and n=2 than Y is not 2'-6'-diethyl; 0 when Xi is O, m=l, Ri is 6-OH, and n=2 than Y is not 2'-5'-methyl; when Xl is S, m=l, Ri is 4-ethyl, and n=l than Y is not 2-methoxy; or a pharmaceutically acceptably salt thereof.

Suitably, the variables, etc. for Formula (Ic) are the same as those defined for S Formula (I) above unless indicated. .

Suitably for compounds of Formula (Ic), a preferred ring substitution for Ri is in the 3-position, the 4- position or di substituted in the 3,4- position. Preferably R\ is other than hydrogen. The substituent group is suitably an electron withdrawing moiety. Preferably R\ is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4Rs. 0 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 unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Ri 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.

Suitably for compounds of Formula (Ic), Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'position or 2v3-position.

Exemplified compounds of Formula (Ic) are: N-p-Hydroxy^memoxycarbonylJphenyll-N'-phenylurea; N-[2-Hydroxy-5-nitro-phenyl]-N'-phenyl urea N-(2-Hydroxy-4-fluorophenyl)- '-phenyl urea N-P-Hydroxy-^itrifluoromethy^phenyll-N'-phenyl urea N-(2-Hydroxy^mtrophenyl)-^-(2-hydroxy-4-nitrophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea N-(2-Hydroxy-5-nitrophenyl)- '-(3-niethoxy-2-thienyl)urea N-(2-Hyciroxy-4-nitrOphenyl)-^-(3-methoxy-2-thienyl)urea N^-Hydroxy-^nitrophenyl -NHS-methoxypheny urea N-(2-Hydroxy-4-iiitrophenyl)-r -(2-methoxyphenyl)urea N-(2-Hyciroxy^mtrophenyl)-N,-(3-trifluoromethylphenyl)urea N-{2-Hy(iroxy-4-idtrophenyl)-N 2-tr^^ N-(2-HydTOxy^iutrophenyl)-N'-(4-trifluoromethylphenyl)urea N^-Hydroxy-^nitrophenylJ-N'^-bromophenyliurea N^-Hydroxy-^nitrophenylJ-r -CS-bromopheny^urea N-(2-Hydroxy- -nitrophenyl)- ,-(4-bromophenyl)urea N-(2-Hymo phenyl) urea N-(2-Hydroxy 4-methyl phenyl)- ,-{2-bromo phenyl) urea N-(2-Hydroxy-4-nitro phenyl r^ 2-phenylamino phenyl) urea N-(2-Hydroxy 3-carboxyphenyD-N'-(2-bromo phenyl) urea N-(2-Sulfhydr l-4-bromo phenyl N'-(2-bromo phenyl) urea N-(2-Hydroxy 4-nitro phenyD- *-(2-iodo phenyl) urea N-(2-Hydroxy 4-nitro phenyl>N'-(2-bromo phenyl) thiourea N-(2-Hydroxy-4-azidophenyl)-r^-(2-methoxyphenyl)urea N-p-Hydroxy-S-cyanophenylJ-N'-P-bromophenyU urea N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-fluorch5-bromophenyl]-^-[2-bromoptenyl] urea N-p-Hydroxy-S^hlorophenyil- -p-broinophenyll urea N-P-Hydroxy-S-trifluoromethylphenyy- '-P-bromophenyl] urea N-[2-hydroxy-3,4-diphenyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromopte^ N-P-Hydroxy-S-glycincarbonylphenyll- T-^-bromophenyll urea N-[2-Hydroxy-3,5-dichlorophenyl]-N,-[2-bromophenyl] urea N-[2-Hydroxy-3-nitrophenyl]-N,-[2-bromophenyl] urea N-[2-Hydroxy-3,4-^chlorophenyl]-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-P-Hydroxy-^yanophenyll- T-P-phenylphenyll urea N-P-Hyaroxy-^yanophenylj-N'-P-methylphenylJ urea N-[2-Hydroxy-4 7anophenyl]-N'-[2-trifluoromediylphenyl] urea N-P-Hydroxy-^yanophenyll-N'-P-trifluoromethylphenyll iuea N-[2-Hydroxy-4-cyanophenyl]- T-[4-tr^^ N-P-Hydroxy -n-propylphenyll-N'-P-bromophenyl] urea N-[2-Hyaroxy-4-eraylphenyl]-> -[2-bromophenyl] urea N-[2-Hydroxy-3-phenylarninocarbonyl phenyl]-N'-[2-bromophenyl] urea N-P-Hydroxy-S^yano-^methylphenyll-N'-P-bromophenyl] urea N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl3 urea N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-benzyioxy phenyl]-N'-[2-bromophenyl] urea (E)-N-[4-[2-(Methoxycarbonyl) ethenyll^-hydroxyphenyll-N'-P-bromophenyl] urea (E)-N-[3-[2 Methoxycarbonyl)el ehyl]-2-hydroxyphenyl]-I^-[2-brom [2-bromophenyl] urea (E)-N-[3-[2-(Aminocarbonyl)e&enyl]-2-hy^ [2-bromophenyl] urea (E)-N-[4-[2-(Aniinocarbonyl)ethenyl]-2-hyc [2-bromophenyl] urea N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea N- [2-Hydroxy^aminocarbonyl phenyll- 1- [2-bromophenyl] urea N-(2-Hydroxy-3^,6-ttifluorophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-fluoro-4-trifluoroi∞^ N-(2-Hydroxy-3-iodophenyl)-N,-(2-bromophenyl)urea N-P-Hydroxy-^yanophenyli- -t -phenylphenyll urea N-[2-Hydroxy-4-cyanophenyl]- -[2,3-a chlorophenyl] urea N-[2-Hyaroxy- -cyanophenyl]-N'-[2-methoxyphenyl] urea N-P-Hydroxy-^yanophenyll- T-IS-methoxyphenyl] urea N-[2-Hydroxy-5-fluorophenyl]-N*-[2-bromophenyl] urea N-P-Hydroxy-S-trifluoromethylphenyll- '-p-bromophenyl] urea N-[2-Hydroxyphenyl]->T-[2-bromopnenyl] urea N-rrrans-S-styrl^-hydroxyphenylJ- -P-bromophenyl] urea N-[2-Hydroxy-3,4-d chlorophenyl]- ,-[2-methoxyphenyl] urea N-P-Hyaroxy-3,4H¾cWorophenyl]-^-[4-methoxyphenyl] urea N-[2-Hyo^xy-3A iicmorophenyl]- r-[3-trifluoromethylphenyl] urea N-P-Hydroxy-S.^cbiorophenyll-N'-P-phenylphenylJ urea N-P-HydjOxy-S.^cWorophenylJ- '-l^phenylphenyll urea N-[2-Hydroxy-3,4^cmorophenyl]-N'-[2 ^cWoropb*nyl] iirea N-[2-Hy(iroxy-4-isopropylphenyl]-I^-[3-aifluoromemylpte N-[2-Hydroxy-3-naphmyl]- r-[2 -dichiorophenyl] urea N-(2-HyT-[2^^ N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[ben2yl] urea N-[2-Hydroxy-4-isopropylphenyl]-^ urea N-[2-Hydroxy-3-(phenylan.inocarbonyl) phenyl]-N*-[benzoyl] urea N-[2-Hydroxy-3-trifluoi methyIphenyl]-N'-[ben2oyl] urea N-[2-Hydroxy-4-cyanophenyl]- ,-[benzoyl] urea N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl3 urea N-P-Hydroxy-S-naphthyll-N'-p^-dichlorophenyl] urea N-[2-Hydroxy-3-naphthyl]-N-[ben2yl] urea N-[2-Hydroxy-S-naphthaIenesuIfoaic acid]-^-[2-bromophenyl] urea; N-[2-Hyckoxy-4-naphthalenesulfonic acid]-l>r-[2rbromophenyl] urea; N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea; N-(2-Hydroxy- l-napthyl)-N'-(2-bromo phenyl) urea; N-(2-Hydroxy^nitrophenyl)-N,-(l-naphthyl)urea; N-(2-Hydroxy-3-rutrophenyl)-N 2-methoxyphenyl)urea N-(2-Hydroxy-3-rdtrophenyl)-N'-(4-methoxyphenyl)urea N-(2-Hydroxy-3-mtrophenyl)-I^^ N 2-Hy(iroxy-3-rutiophenyl)-N'-(2-phenylphenyi)urea N 2-Hydroxy-3-dtrophenyl^N,-(2 dichlorophenyl)urea N^2-Hydroxy-3-nitrophenyl)-N,-<4-phenylphenyl)urea N-(2-Hyckoxy-3-ru^phenyl N'-(2,4-dimethoxyphenyl)urea N-(2-Hydroxy-3-Mtrophenyl)- T-(2-cWor^^ N-(2-Hy^ N-(2-Hydroxy^mtrophenyl)- T-[2 4-trifluorophenyl)phenyl]urea N-(2-Hydroxy-3-trifloromethylphenyl)-NX2-methoxy^^ N-(2-Hydroxy^mtrophenyl)- ,-(2-acetoxyphenyl)urea N-(2-Hydroxy-4-iutrophenyl)- -[^^ N-(2-hydroxy-3-trifluoron^ N-(2-HydroxyeAyl)-N,-(2-hydroxy^nitrophenyl)urea N-2^eiizyoxyphenyl)-N 2-hydroxy-4-nitrophenyl)urea N-(2-Hydroxy-4^anophenyl> -(2^ N-[2-(2-Pyridyline oxy)phenyl3-]!^-(2-hy^ N-[2-(2-Meraoxycarbonylrjeiizyloxy)phen^ N-[2-(2-Carboxybenzyloxy)ph«nyl]- -(2-hy^ N-[2-(Benzoylam o)phenyl3-N42-hydro^^ N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy^iutrophenyl)urea N-[2-(4-PyridylmeAoxy)phenyl]-N^^^^ N-[2-(Methoxycarbonylainmo)phenyl]- ^ N-(2-Hydroxye -l-yloxyphenyl W-(2-hyd^ N-(2-Hydn>xy- ^anophenyl ^^2-benzylamjjiophenyl)ui,∞ -[2-(2-Pyridylme&oxy)phenyl]- -(2-H^^ N-[2-(2-Meraoxycarbonylbeiizylox:yphenyfl^ N-[2-(2-Carboxybeiizyloxy)phenyl)-^-(2-hydroxy^nitropheny0 N-[2-(Benzoylanuno)phenyl]->T-(2-hydroxy^-r-itrophenyl)urea Additionally exemplified compounds of Formula (Ic) include: N-(2-Hyoroxy-4-cyanophenyl)-lvr-(2-^^ N-(2-Hydroxy-4-<^anophenyl)-NH2-(2-pyrid N-(2-Hydroxy^yanophenyl T-(2-(3-pyridylmemyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)- T-(2-(^ N-(2-Hyd oxy-4-trifluoroacetophenone)-^ N-(2-Hydroxy^trifluorosulfonylphenyO-NH2-bromophenyl)urea -(2-Hya^oxy-3-bromc*-4^anophen l '-(2-bromo henyl)urea N-(2-Hydroxy-3 Woro-4-cyanophenyl)-l^^ N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl-3 The following terms, as used herein, refer to: • "halo" - all halogens, that is chloro, fluoro, bromo and iodo.

• "Ci.ioalkyr or "alkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iro-butyl, iert-butyl, n-pentyl and the like.

• The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 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 ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1 -propeny 1, 1-butenyl, 2-butenyl and the like. · "aryl" - phenyl and naphthyl; • "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring 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, isoquinoline, quinazolinyl, pyridine, pyrirnidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole. • "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring 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, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.

• The term "arylalkyl" or "heteroarylalkyl" or "heterocycUcalkyl" is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. · "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2 moiety.

• The term "wherein two Ri moieties (or two Y moieties) may together form a 5 or 6 membered unsaturated ring" is used herein to mean the formation of a napthylene ring system-or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a C6 cycloalkenyl, i.e hexene, or a Cs cyloalkenyi moiety, cyclopentene.

The compounds of Formula (I), (la), (lb), (Ic), (Π, (Ha ), (lib), (He), and (D3) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I), (la), (lb), (Ic), (Π, (Ha ), (lib), (He), and (HI) having a variety of different R, Ri, and Ar groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art While the schemes are shown with compounds only of Formula (I) this is merely for illustration purposes only.

Scheme 1 1 * Rs Hj, OH, C(¾H. SH a)PhNCO NHS02R Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard conditions involving the condensation of commercially available ortho substituted aniline(Aldrich Chemical Co., Milwaukee, Wi) with the commercially available optionally substituted aryl isocyanate (Aldricfa Chemical Co., Milwaukee, Wi) in an aprotic solvent (DMF, toluene). When the l-(RS02NH)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 triethyl amine or NaH in an aprotic solvent (like methylene chloride or DMF).

Scheme z HWH. NH* NHSOgR a>HN03' 23 °C b>Sn<¾' Et0H If the desired 2-substituted aniline 5-scheme 2. is not commercially available the corresponding nitro compound can be prepared from 3-scheme 2. under standard nitration conditions (using HNO3 or BF4NO3) at 23 °C. The nitro compound is then reduced to the corresponding aniline using SnCl2 in EtOH(or alternately H2 Pd or UAIH4).

Scheme 3 £ Z & a) NH4SCN. Br2 b) NaOH EtOH If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3. This thiazole can men be hydrolyzed to the desired 2-amino benzenethiol 8-scheme 3 with a strong base like NaOH in a protic solvent (i.e., EtOH). x=s, o 11 a)TBSCI, imid, D F b)i)CICXCI, NaHCC¾. ii)PhNH2 c)Et3 «HF, CH3CN In the case where the thioisocyanate or phenyl isocyanate is not commercially available, the thiourea or urea 11 -scheme 4 may be prepared from the commercially available ortho substituted aniline. This compound is first protected with a protecting group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art(see Greene, T Protecting Groups in Organic Synthesis. Wiley&Sons, New York, 1981). This protected aniline is then reacted, in the presence of a base(like triethyl amine or sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic solvent (ie. DMF, toluene), followed by aniline to produce the protected thiourea or urea respectively. The corresponding urea or thiourea is then deprotected, using conditions standard in the art, to form the desired thiourea or urea 11 -scheme 4. 141121/2 Schem ? a)(PhO)2PON3.Et3N bJPhXNH, X=OH. NHS<¾R. SH Alternately the urea can be formed using a Curtius rearrangement from the corresponding aromatic ox thiophene caiboxylic acid 12-scheme 5. The carboxylic acid is submitted to standard Curtius conditions ({PhO)2PON3, Et3N or ClCOCOCl followed by NaN3) and the intermediate isocyanate is trapped by an appropriately substituted aniline.

Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent Another aspect of the present invention is the novel synthesis of cyano phenol intermediates. Numerous conversions of aryl halides to aryl cyano derivatives 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 failed. Using known conditions of elevated temperatures, greater than 170°C such as from 180 to 210° did not yield displacment of the halogen to a cyano moiety. Standard bases, such as DMF and pyridine further provided no desired product. Intermediates such as 2-amino-5-fluorophenol, 2-ditro-5-fiuorophenol, 2-nitro-5-methyl-6-bromophenol were tried with a change of halogens, from fluorine to chlorine to bromine, and with use of copper (I) cyanide. The use of a bromine derivative, such as 2>nitro-5-methyl-6-bromophenol, with dimemylformamide and using triethylamine with a catalytic amount of dimethylamino pyridine and copper (I) cyanide at reduced temperatures,, i.e. <100° C, preferably 60 to about 80° C for reduced times from sirandarized procedures, i.e., < 18 hours, preferably about 4 to 6 hours yielded the desired products.

Therefore one aspect of the invention is to a process for producing a cyano phenol derivative of the formula: wherein Ri is as defined for Formula (I) above, which method comprises reacting a compound of the formula: (I) cyanide, dimemylformamide, triemylamine and a catalytic amount of dimemylamino 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 (°Q. 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 Broker AM 250 or Am 400 spectrometer, respectively.

Multiplicities indicated are: s=singlet, d=doublet, tstriplet, 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 of the present invention. All temperatures are given in degrees centigrade, all solvents used herein are of 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 of substituted phenyl isocyanate (1.0 equiv.) in toluene (5 rniliLiters (hereinafter "mL")) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at about 80°C until complete (24-48 hours (hereinafter "hrs" or "h")), then cooled to room temperature. The purifications, yields and spectral characteristics for each individual compound are listed below.

General Method B: Synthesis of N, Ν'· phenyl urea To a solution of phenyl isocyanate (1.0 equiv.) in dimethyl formamide (lmL) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at about 80_C until complete (24-48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics for 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 chloride and allowed to stir at about 23 °C until complete (12-36 h). The reaction mixture was partitioned between water and methylene chloride. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The purifications of each compound are listed below.

Passages of the description which are not within the scope of claims do not constitute part of the invention.

Example 1 Preparation of N-r2-Hvdroxv-4^memoxvcarbonvl)phenvl1.N'-phenvl urea N-[2-HyaxOxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from memyl-4-ainmo-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate (1.19 mmol) according to the procedure noted above in General Method A. The product was purified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp: 188.4-188.8eC; *H MR (CD3OD CDCI3): d 8.15 (d. 1H, J s 8.25 Hz), 7.70 (s. 1H), 7. 1 (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, IH, J ■ 8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H)+; Anal.

(Ci5Hi4 204) C H, N.

Sxam te ¾ Preparation of -r^nitjTv-Z-hYdrp^YphffnYn- -phcnyl urea The N-(5-nitro-2-hydroxyphenyi]-N,-phenyl urea was prepared from the 5-nitro 2-hydroxy aniline and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (100 mg, 30%). 1H NMR (C 3OD): d 9.48 (s. IH. NH), 9.07 (d, J = 1.56 Hz, NH), 8.55 (s, IH), 7.80 (dd, IH, J - 6.25 Hz and J = 1.56 Hz), 7.50 (d, 2H, J = 6.25. Hz), 7.30 (1, 2H, J = 6.25 Hz), 7.01 (m, 2H). EI-MS m z 273 (M+H)+ Example 3 Preparation of ^-hvdmxv-4-j f/phenvl-timno)carrK>nvI1aininolr^aimde a)Preparation of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents To a suspension of the appropriate hydrochloride (0.02 mole (hereinafter "mol")) in dry toluene (20 mL) at about 0°C, was slowly added a solution of (2M, 10 mL) of trimethyl aluminum in toluene. After the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for about 1-2 hours until gas evolution has ceased. b)Preparation of 3-hydroxy^{[(phenylaniino)carbonyl]animo}benzamide To a solution of the N-P-hydroxy-^imemoxycarbonylJphenyll- '-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 at reflux for about 12 hours. The reaction mixture was cooled to room temperature and was carefully quenched with 5% HQ. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS04, 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. leC; lH NMR (CD3OD/CDCI3): d 7.98 (d, 1H, J = 8.25 Hz), 7.35 (d, 2H, J = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (t, 2H, J = 8.25 Hz), 6.91 (t, lH, J = 825 Hz); EI-MS m/z 271 (M+H)+; Anal. (C14H13N3O3) C, H, N.

Example 4 Preparation of N- S-hvdroxv-^fluorophenvlVNr-phenvl urea a)Preparation of 2-amino-5-fluoro phenol A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (Π) chloride (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 MgS04 and filtered. Evaporation of the solvent gave the tide compound(335 mg, 83%). *H NMR (CD3OD/CDCI3): d 6.6 (m, 1H), 6.38 (dd, 1H, J = 8.3 Hz and J = 2.8 Hz), 6.29 (m, 1H). b)Preparation of N^-hydroxy-^fluorophenyl^r ^phenyl urea N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91 %). mp: 195.5-195.7eC; H NMR (CD3OD/CDCI3): d 7.70 (m, 1H), 7.3 (d, 2H, J = 82 Hz), 7.15 (t, 2H, J = 8.25 Hz), 6.89 (t, 1H, J « 8.25 Hz), 6.50 - 6.38 (m, 2H); EI-MS m z 246 (M+H)+; AnaL (Ci3Hi iN202 F) C, H, N.

Example 5 Preparation of 2-f ffphenvlaminokarijonvnarnino^thiophenol 2-{[(Phenylam o)carbonyl]amino}tbiophenol was prepared from 2-aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85 %). mp: 194.5eC; *H NMR (CD3OD/CDCI3): d 7.48 - 7.26 (m, 4H), 7.25 - 7.10 (m, 3H), 7.04 - 6.79 (m, 2H); EI-MS m/z 244 (M+H)+; Anal. (C13H12N2OS) C, H, N.

Example 6 Preparation of N-^-rarboxv-^hvdroxvphenvlV '-phenvt urea N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-5-hydroxy benzoic acid (1 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 brine, dried over MgS04 and filtered. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate, 1:1 to 100% ethyl acetate) gave the titled compound (1.5 g, 84%). lH NMR (a¾OD/CDCl3): d 8.36 (d, 1H, J * 8.25 Hz), 7.63 (m, 4H), 7.48 (t, 2H, J = 8.25 Hz), 7.20 (m, 1H); EI-MS m z 272 (M+H)+; Anal. (C14H12N2O4) C, H, N.

Example 7 Preparation of N - Γ2 - hydroxy - 4- ftrifluoromethvn phenvll - ' - phenyl urea a) Preparation of 2-nitro-5-trifluoromethylphenol 2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 mL) drop-wise to a,a,a-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 sulfate and filtered. Concentration of the solution in vacuo afforded an oil which was purified by -column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to afford the tided compound as an oil( 1.7 g, 27%). 1H NMR (CDCI3): 10.6 (s, 1H, OH), 8.26(d, 1H, J = 7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H. J* 7.8 Hz) b) Preparation of 2-arnino-5-trifluoromethylphenol 2-Ainino-5-trifluoromethylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2(3.5g, mmol) in EtOH at 23 °C for 12h. The mixture was concentrated to 50 mL and adjusted to pH 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between ¾0 and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification. IH NMR (CDCI3): 7.6 (s, IH), 7.39(d, IH, J ¾ 8.5 Hz), 7.08(d, lH- J* 8.5 Hz) c)Preparation of N - [2 - hydroxy - 4- (trifluoromethy 1) phenyl] - N' - phenyl urea N - [2 - Hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea was prepared from 2-amino-5-trifiuoromethylphenol (150 mg, 1.09 mmol) and phenyl isocyanate(1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to afford the titled compound ( 230 mg, 87% ). mp: °C; IH NMR (DMSO-d6): d 9.45 (s, IH, NH), 8.50 (s, IH, NH), 8.31 (d, IH, 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, IH, J « 6.67 Hz). EI-MS m/z 296 (M+). Anal.

(Ci4Hi lN202F3)C, H, N.

Examp e 8 Preparation of N-^-hvdrnxv^nitrophenvn-^-^-hvdroxv^riitrophenvn urea a) Preparation of 2-(ierf-butyldimethylsilyloxy)^mtroaniJLuie To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g, 12.3 mmol) in DMF (15 mL), tert -butyldimethylsilyl chloride (11.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction mixture was partitioned between 0.1 % HQ and ethyl acetate. The combined organic phase was washed with brine, dried over MgS04 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl acetate; 5: 1) gave the titled compound (1.7 g, 98 %). lH NMR (CDCI3): d 7.78 (dd, IH, J = 6.7 Hz and J = 2.7 Hz), 7.61 ( Example 9 Preparation of N^-hvdroxv^nitroDhenvn-N'-Dhenvl-thiourea a) Preparation of N-C -tert-butyldimethysUyloxy^dtrophenyl^N'-phenyl-t ourea N-(2-tert-Butyld iethysUyloxy-4-nit^^ by treating a biphasic solution of 2-teit-butyldimemysUyloxy-4-nitroaniline(80 mg, 0.308 mmol) andNaHC03 in CHCl3:H20(2.5:l, 7mL) with thiophosgene at 0eC. 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 vacuo 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: 144-145eC;lH NMR (CD3OD/CDCI3): d 8.65 (d, 1H, J * 10.0 Hz), 7.58 (d, 1H, J * 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H), 7.l0 (m, lH). b) Preparation of N^-hyo^xy^mtrophenyl^N'-phenyl-thiourea N-(2-Hydroxy^nitrophenyl)-N1-phenyl-2-thiourea was prepared by treating a solution of N^2-tert-butyldimethysilyloxy^m (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N»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: 144-145eC;lHNMR (CD3OD/CDCI3): d 8.65 (d, 1H, J « 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz).7.26 (m.4H), 7.10 (m, lH).

Example 10 Preparation of Ν-Γ4- nitro -fphenvlsulfonvlaminofahenvlV '-phenvl urea a) Preparation of 4-nitro 2-(pfaenylsulfonylamino) aniline A solution of 4-nitro 1,2-phenylene diarnine(L53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride(1.76 g, 10.0 mmol) and triethyl amine(1.01 g) in DMF for 12 h at 23 °C. The reaction mixture was partitioned between saturated NH4CI and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired (0.275 g, 9%). lH NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7J5( Example 12 Preparation of N-(2-hvdroxv-4-rutrophenvn-N'-( 3-methoxv-2-thienvnurea To a solution of 3-methoxy-2-thiophene carboxylic acid (example 1 la, 200 mg, 1.27 mmol) in toluene, (PhO)2PON3 (0.33 mL) and triemylarnine (1.1 equiv., 0.25 mL) were added. The reaction mixture was stirred at 70°C for 2 hours and cooled down to room temperature then 2-amino-5-nitrophenol was added. The reaction mixture was stirred at 70°C overnight. The reaction mixture was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 1:1) gave the product (190 mg, 48%). *H NMR (CD3OD/CDCI3): d 8.38 (d, 1H, J = 5.0 Hz), 7.85 (dd, 1H, J = 5.0 Hz and J = 1.25 Hz), 7.76 (d, 1H, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS m/z 309 (M+H)+; Anal. (Ci2Hi iN305S) C, H, N.

Example Preparation of N-f2-hvdroxv-4-nitrophenvn-N'-f3-methoxvDhenvnurea N-{2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro 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. Filtering afforded the title compound (140 mg, 46%). EI-MS m z 302(M-H) - Example H Preparation of N-f2-hvdroxv-4-nitrophenvn-NW 2-methoxvphenvl)urea N-(2-Hydroxy-4-njtrophenyl)-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 tide compound (82 mg, 27%). EI-MS m/z 302(M-H)~ Example IS Preparation of N-f 2-hvdroxv-4-nitroDhenvlVN,-f 3-trifluoromethvlphenvnurea N-(2-Hydroxy-4-nitrophenyl)-^-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-trifluoromethyl phenyl isocyanate (1 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 (180 mg, 52%). EI-MS m z 342(M+H) + Example 16 Preparation of N-f -hvdroxv-4-nitrophenvlVN'-f 2-trifluoromethvlphenvnurea N-(2-Hyo^xy-4-mtrophenyl)-NH2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethyl 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.

Filtering afforded the title compound (180 mg, 52%). EI-MS m z 342(M+H) + Exam le 17 Preparation of N-f2-hvQ^xv-4-nitrophenvlV r-f4-trifluoromethvlphenvnurea N-(2-Hyo^xy^iiitrophenyl)-NH4-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl 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.

Filtering afforded the tide compound (111 mg, 32%). EI-MS m/z 340(M-H)~ Example 18 N-(2-Hydroxy-4-nitrophenyl)-N,-(2-bromophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl 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(530 mg, 47%). EI-MS m/z 350(M-H) " Example 19 Preparation of N-f2-hvdroxv^nitrophenvlVNV3-bromophenvnurea N-(2-Hydroxy-4-aitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro ariiline (500 mg, 3.24 mmol) and 3-bromo 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(0.96g, 87%). EI-MS m/z 350(M-H) " Example 20 Preparation of N-r2-hvdroxv-4-nitroDhenvlVN,-f4-brornnphenvniirea N-(2-Hydroxy-4-nitrop enyl)-N,-(4-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol) according to the procedure in General Method 8. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.41 g, 37%). EI-MS m/z 352(M+H) + Example 2\ Preparation of N-f -hvdroxv-4-nitrophenvlV '-(2-phenvlphenvnurea N-(2-Hydroxy-4-nitrophenyl)-N,-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3 4 mmol) and 2-phenyl 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(0.22 g, 19%). EI-MS m/z 350(M+H) + Example 22 Preparation of N-f2-hvdroxv-4-nitrophenviyNV 1-naohthvnurea N-(2-Hydroxy-4-nitrophenyl)-N'-(l-naphthyl)urea was prepared from 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 titruated with 1:3 triethyl amine:methylene chloride. The filterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with IN HQ in water. The desired product precipitated from solution and was collected by filtration(0.1 lg, 10%). EI-MS m z 324(M+H) + Example 23 Preparation of N-f2-hvrimxv-4-nttrophenvn-N'-f2-nitmphenvnurea N-(2-Hydroxy^iutrophenyl^-(2-nitro henyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-oitro phenyl isocyanate (3.24 mmoi) 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 m/z 319(M+H) + Example 24 Preparation of N 2-hv(ijoxv-4-nitroDhenvl r-(2-fluoroDhenvl^urea N-(2-Hydroxy-4-nitrophenyl)-N,-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro 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 c0mpound(0.59 g, 31%). EI-MS m/z 292(M+H) + Example 25 Preparation of N-f2-hvdroxv-4-nitro henvlVN'-f 2.6-difluorophenvnurea N-(2-Hy(iroxy-4-mtrophenyl)-N,-(2,6^difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro 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(0.91 g. 91 ). EI-MS mz 308(M-H) - Example 26 Preparation of N- -hvdroxv^nttrophenvlVlNr-f -ethoxvphenvl^urea N-(2-Hydroxy-4-nitrophenyl N,-(2-ethoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethoxy 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.S4 g, 81%). EI-MS m z 318(M+H) + E ample 21 Preparation of N-(2-hvdroxv-4-nitrophenvl '^-ethvlphenvl^area N-(2-Hydroxy-4Hiitrophenyl)-N,-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 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 dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H) + Example 28 Preparation of N-f2-hvdroxv-4-mtro phenvlV^-f2-trifluoromethoxvphenvnurea 43 N-(2-Hydroxy^nitrophenyl)-^-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy 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(0.69 g, 60%). EI-MS m/z 358(M+H) + Example 29 Synthesis of N-f2-hvdroxv-4-nitro ohenvn N 2-n¾.thvlthio phenvn urea The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg , 3.24 mmol) and 2-methylthio phenyl isocyanate(3 4 mmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes.

Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H) + Example 30 Synthesis of N-f2-hvdroxv-4-nitro ohenvn ,-(2-chloro 6-methvl phenvn urea The urea was prepared from 2-hydroxy 4-nitro 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 precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). O-MS m z 322(M+H) + Synthesis of N-(2-hvdroxv-4-nitro phenyl) N-(2- methvl sulfoxvphenvn urea The urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) *-(2-methyl thio phenyl) urea(example 28, 100 mg) with sodium periodate(100 mg) in t-butanol/water for 12 hours at 23 °C. The product precipitated from the reaction mixture(30 mg, 29%). EI-MS m/z 336(M+H) + Example 32 Synthesis of N-f2-hvdroxv 4-trifluoromethvl phenvn '-(f2-bromo phenvn urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171g, 1 mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0 5 g, 54%). EI-MS m z 375(M+H) + Example 33 Synthesis of N-f 2-hvdroxv 4-carbomethoxv phenvn T-f 2-bromo ohenvn urea The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-faromo phenyl isocyanate(l 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) * Synthesis of N-r2-hvdroxv 4-trifluoromethvl phenyl) N*-(2-phenvl phenyl) urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aniiine(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.24 g, 64%). EI-MS m z 373(M+H)+ Exam le 35 Synthesis of N-f 2-hvdroxv 4-carbomethoxv phenyl) N'-f2-phenvl phenyl) urea The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-phenyl phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.185 g, 50%). EI-MS m z 363(M-H) " fix,ampte 36 Synthesis of N-(2-hvdroxv 4-nitm phenyl) NV2.3-dichloro nhenvn urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,3-dichloro 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(0.5 g, 73%). EI-MS m/z 342(M+H) + ynthesis of N-f2-hvdroxv 4-nitro phenyl) Ν 2.4-<1κη1οτο phenvn urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,4-dicbioro 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(0.26 g, 38%). EI-MS m/z 342 (M+H) + Exampte 38 Synthesis of N-ri-hvdroxv-4-nitro phenyl) N^-chloro phenyl) urea The urea was prepared from 4-oitro 2-hydroxy aniiine(308 mg, 2 mmol) and 2-chloro 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(0.29 g, 47%). EI-MS m z 308(M+H) + Eaampte 39 Synthesis of N-f2-hvdroxv-4-nitrophenvn I>T-(2.4-dibromo phenvH urea The urea was prepared from -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 mz 430(M+H) + Example 40 Synthesis of N-tt-hvdroxvnapthvl) NV2-bromo phenyl) urea The urea was prepared from 1-amino 2-hydroxy napthalene(195 mg, 1 mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.030 g, 8%). EI-MS m/z 357(M+H) + Example 41 Synthesis of N-(2-hvdroxv-4-nitrophenvlVN'-f 2.3-memvlenedioxvphenvhurea a) Preparation of 23-methylenedioxyphenylcarboxylic acid A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10°C with 2.5 M n-butyllithium (IS mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq. NaHC03 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HQ, and extracted with chloroform. The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure (1.1 g, 20 %). EI-MS m z 167 (M+H)+ b) Preparation of N-(2-hya^roxy-4-nitrophenyl)-^ To a solution of the 2,3-methylenedioxyphenylcarboxylic acid in toluene, triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryi azide (DPPA) (0.32 mL, 1.5 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours, then 2-amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred - 59 - - at.100°C for 18 hours. After the reaction mixture was cooled to room temperature, it was partitioned between 5 % citric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS0 , 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-/3-hvrfmxv 4-nitro ohenvh -r2-me hoxv 3-chlnm phenvn urea The urea was prepared from 2-hydroxy 4-nitro aniiine(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-f 2-hvdroxv 4-nitro phenvn NW2-methvl phenvn urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-methyl 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(0.38 g, 53%). EI-MS m z 288(M+H) + Example 44 Synthesis of Nfbis f2-hvdroxv 4-nitro phenvn NVdianisdine diurea The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and dianidisdine diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound( 0.08 g, 6%)£I-MS m/z 605(M+H) + Synthesis of 4-methylene hisrN-(2-chloro phenvn N'- 2-hvdroxv 4-nitro phenvn ureal The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and 4-methylene bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.10 g, 8%). FJ-MS m/z 627(M+H) + Example 4$ Synthesis of N-r2-hvdmxv 4-fbenzvlamino^carbonvl phenvn-N'-tt-bromophenvnurea a)Synthesis of N-(2-hydroxy 4-carboxyIate phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mxnol) 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/2351(M+H) + b)Preparation of N-[4-(benzylammo)cari)onyl-2-hydroxyphenyl]-N,-(2-bromophenyDurea To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.S8 mmol) in DMF (IS mL), EDC (121.9 mg, 0.58 mmol), HOBT (156.6 mg, 11.6 mmol) were added . The reaction mixture was stirred at room temperature for 16 hours. Then the benzyl amine (123 mg, 11.6 mmol) was added. The reaction mixture was stirred at same temperature for 24 hours. Then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSC*4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 1:1) gave benzylamino product (500 mg, 65 %). EI-MS m/z 441 (M+H)+ Example 47 Synthesis of N-f2-hvdroxv 4-nitro phenvn N'-f2-phenoxv phenvH urea The urea was synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol,) with diphenyi phosphoryl azide(0.475 mL) and triethyl amine(.14 mL) in DMF at 80 °C after 24 hours the 2-amino 5-nitro phenol (1 equiv.) was added. The reaction was heated for 24 hours at 80°C. The reaction product was oiled out with hexane. The residue was dissolved in methanol and the solid was precipitated out with water.(180 mg, 24%) EI-MS m/z 364(M-H) " E ampte 4 , Synthesis of N-f2-hvdroxv-4-fluoro phenvn N^-bromo phenvh urea a)Synthesis of 2-hydroxy 4-fluoro aniline 3-fluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(l g) at 23 °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 vacuo to afford the tide compound (1.4 g, 77%). EI-MS m/z 169(M+H) + b)Synthesis of N-(2-hydroxy-4-fiuoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-fluoro aniline(2S4 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m z 325 (M+H) + Example 49 Synthesis of N-f 2-hvdroxv 3.4-difhioro phenvn Νν2-ΡΓοηιο phenvh urea a) Synthesis of 2-hydroxy 3,4-difiuoro aniline 2 difluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(l g) at 23 °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 vacuo to afforded the tide compound (1.6 g, 97%). EI-MS m/z 146(M+H)+ b) Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) '-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H) + Example SO Synthesis of N 2-hvdroxv 3-napthvn *-f 2-bromo phenyl) urea The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g, 2 mmol) and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339, 47%)JE2-MS m z 357(M+H)+ Example 51 Synthesis of N-f 2-hvdroxv 4-nhenvl nhenvH N*-f 2-bromo phenyl! urea a)Synthesis of 2-nitro 5-phenyl phenol A solution of 3-phenyl phenol(2 g, 11 mmol) in acetic acid was treated with concentrated nitric acid drop-wise until all starting material was consumed. The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and concentrated in - 62 - ■ vacuo. The residue was purified by silica gel cnromatography(ethyl acetate/hexanes) to afford desired (1.2 g, 50%).lH MR CGDC13): d I0.65(s, 1H), 8.18 (d, 1H, J * 10.0 Hz), 7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J=10.0Hz). b) Synthesis of 2-amino 5-phenyl phenol A solution of 2-nitro 5-phenyl phenoi(1.2 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 reaction 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-phenyI 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%).EI-MS m/z 383(M+H) + Exampte 52, Synthesis of N-(2-hvdroxv 4-methvl phenyl) N'-(2-bromo ohenvn urea The urea was prepared from 2-hydroxy 4-methyl 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) " Ex mple 5? Synthesis of Nf 2-hvdroxv 4-nitro phenvh -(2-phenvlamino ohenvn ureaThe urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro phenyl isocyanate(example 9a, 0.419g, 1.5 equiv.) with 2-anilino aniline(0.184 g, 1 equiv.) in THF overnight at 40 °C. The desired product precipitated out of the reaction mixture(30 mg, 8%). EI-MS m z 365(M+H) + S m le 5 Synthesis of N-C2-hvdroxv 3-carboxvlate phenyl) l^-f 2-bromo phenyl) urea The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(.287 g, 41%). EI-MS m z 351(M+H) + Exflmpte 55 Synthesis of Nf2-gn1fhvdrvl 4-bromo ohenvh IV-J^-bromo phft yf) ν&ηΜϊγη* * 0f 2-amino 6-bromo thiazole 4-Bromo aniline(4.3 g, 25 mmol, 1 equiv.) and ammonium thiocyanate(5.7 g, 3equiv.) was dissolved in acetic acid and treated with bromine(4 g, lequiv.) at room temperature. After complete disappearance of starting material the reaction mixture was poured into water and the solid was collected. The solid was used in the next step without any purification(3.6 g, 46%). EI-MS m/z 229(M+H) + b) Synthesis of bis (3-bromo 6-amino phenyl) disulfide The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in water(5mL) was treated with OH (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 chloride. The methylene chloride mixture was concentrated in vacuo. The residue was dissolved in DMSO and treated with 12· After stirring overnight at room temperature the reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The resulting solid was purified by flash chromatography(ethyl acetate/hexane) to afford the title compound (230 mg, 34%). EI-MS m/z 405(M+H) + c) Synthesis of N(2-sulfhydryi 4-bromo phenyl) N*-(2-bromo phenyl) urea A solution of (3-bromo 6-amino phenyl) disulfide(201 mg, .5 mmol) in DMF was treated with 2-bromo phenyl isocyanate(l mmol) at 80 °C overnight The reaction mixture was diluted with methylene chloride and a solid was precipitated out with hexanes. The solution was dissolved in MeOH and treated with NaBH4. After gas evolution ceased the reaction mixture was carefully acidified with IN HQ and the resulting solid was filtered(52 mg, 13%). EI-MS m z 399 (M-H) ~ Example 56.

Synthesis of N-Q-hvdroxv 4-nitro phenvtt NW2-iodo phenvH urea The urea was synthesized by die treatment of 2-iodo benzoic acid(5 g, 20 mmol) with diphenyl phosphoryl azide(l equiv.) and triethyl amine (1 equiv.) in DMF at 80 °C after gas evolution ceased the 5-nitro 2-amino phenol (3 g, 1 equiv.) was added. The reaction was heated overnight at 80°C. The reaction mixture was purified by filtering through a plug of silica with methylene chloride. The desired product was then precipitated out with hexane. Filtering afforded the desired compound(1.08 g, 13%). EI-MS m/z 398(M-H) " Example 57 Synthesis of N- ?.hvriroxv 4-nitro phenvn N'-f2-bromo phenvn thiourea The thiourea was synthesized by treatment of the 2-½rr-butyidimethylsilyloxy 4-nitro phenyl thioisocyanate(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 purified by flash chromatography(EtOAc Hexanes). The fraction slightly lower rf than starting material contained the desired compound. This fraction was concentrated and then treated with triethyl amine hydrofluoride in acetonitrile for 15 minutes at 23 °C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash chromatography(ethyl actate hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea(52 mg, 4%) . EI-MS m/z 369(M+H) + Example 58 Synthesis of N-f2-phenvlsntfamido) 4-cvanoDhenvl N,-f2-bromo phenvn urea a)Synthesis of 3-(phenylsulfamido) benzonitrile The of 3-(phenylsulfamido) benzonitrile was synthesized from the 3-cyano aniline (23.9 g, .2 mol) by Method C. It was purified by recrystalization from EtOH(15.8 g, 31%).^ NMR (CDCI3): d 7.95(s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t, IH. J = 8.0 Hz), 7.45 (m, 2H).7.35 (m, 4H). b)Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile The 3-(phenylsuIfamido) benzonitrile(10 g, 39 mmol) was dissolved in acetic anhydride and treated with concentrated nitric acid dropwise at room temperature until all the starting material had been consumed. The reaction mixture was then quenched by carefully pouring it into sodium bicarbonate and left to sit until all gas evolution had subsided. It was men partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate and filtered. The reaction mixture was concentrated in vacuo, absorbed onto silica gel and purified by column chromatography(methylene chloride hexane) to afford the title compound (1.7g, 15%).

EI-MS m/z 302(M+H) + c)Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile The 3-(phenylsulfamido) 4-nitro benzonitrile(1.5 g, 4.9 mmol) was treated with tin chloride dihydrate in EtOH at 80 °C for 12h. It was then concentrated and flushed through a plug of silica gel with 5% methanol/methylene chloride. The fUterate was absorbed onto silica gel and purified by flash chromatography(ethyl acetate hexane) to afford the title compound (0.9 g, 60%). EI-MS m/z 274 (M+H) + d)Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N*-(2-bromo phenyl) urea P T/U 13632 The urea was synthesized from 2-(phenylsulfamido) 4-amino benzonitrile(77 mg, 0.28 mmol) and 2-bromo phenyl isocyanate by general Method C. It was purified by column chromatography(ethyl acetate/hexane) to afford the title compound (30 mg, 22%). EI-MS m z 469( -H) ' Example 59 Synthesis of N-(2-f phenyl sulfamido) phenyls N'-(2-bromo phenvtt urea a) Synthesis of 2-( phenyl sulfamido) aniline The sulfonamide was synthesized from phenyl sulfonyl chloride(0.01 mmol) and o-phenylene diamine( 1.08 g, 0.01 mmol) by general Method C. It was purified by recrystallization from EtOH(1.0 g, 40%).EI-MS mz 249(M+H) + b) Synthesis of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized 2-(phenyl sulfamido) aniline( 1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.234 g, 52%).EI-MS m/z 446(M+H) + Example 60 Synthesis of N-f2-f stvrvl sulfamido) phenyl) r-Q-bromo phenyl) urea a)Synthesis of 2-( styryl sulfamido) aniline The sulfonamide was synthesized from styryl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(12 g, 60 )EI-MS m z 199(M+H) +. b)Synthesis of N-(2-(styryI sulfamido) phenyl) N*-(2-bromo phenyl) urea The urea was synthesized from 2-(styryl sulfamido) aniline(l mmol) and 2-bromo phenyl isocyanate(l 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) + Exam le $\ Synthesis of 2-fi3.4 dimethoxvphenynsulfonvl aminol phenyl) NW2-bromo phenyl) tfflga a)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl chloride(0.01 mol) and o-phenylene diamine by general Method C. It was purified by recrystallization from EtOH(0.65 g, 21%). FJ-MS m/z 309(M+H) +. b)Synthesis of 2-[(3,4-dimemoxyphenyi)sulfonyIaniino] phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-[(3, -dimethoxyphenyl)sulfonyl aminojphenyl anilined mmol) and 2-bromo phenyl tsocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.062 g, 12%).EI-MS m/z 504(M-H) " Example 62 Synthesis of N- 2-rr4-acetanudoDhenvnsulfonvlaminol phenvH N'-f 2-bromo phenvh urea a) Synthesis of 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline The sulfonamide was synthesized from 4-acetaxnidophenyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(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) Synthesis of N<2-[(4-acetamidophenylsulfonyl)amino] phenyl) NM2-bromo phenyl) urea The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline(l mmol) and 2-bromo phenyl isocyanate(l 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, 24%). EI-MS m/z 501(M-H) " Example 63 Synthesis of N-f2-f2-thiophene sulfamido phenvtt N'.q-bromo phenvh urea a) Synthesis of 2-(2-thiophene sulfamido) aniline The sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol) and o-phenylene diamine(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) Synthesis of N-(2-(2-thiophene sulfonyl amino phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-( 2-thiophene sulfonyl amino) aniline(l mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.29 g, 64%). EI-MS m/z 450(M-H) " Example 64 Synthesis of N-f2-f3-tofv1 sulfonvl amino ηηβηνΠ *-f -bromo phenvtt urea a)Synthesis of 2-( 3-tolyl sulfonyl amino) aniline The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(O.Ol mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.73g, 28%).EI-MS m z 263 (M+H)+ b)Synthesis of N-(2-((3-tolyl sulfonyl amino) phenyl) N'-U-bromo phenyl) urea The urea was synthesized from 2-(3-tolyl sulfonyl amino) aniline(l mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexanes. It was recrysallized two times with EtOH(25 mg, 5%). EI-MS m/z 458(M-H) " Example 65 Synthesis of N-(2-( 8-auinolinvl sulfonvl aminos nhenvH NW2-bromo phenvH urea a) Synthesis of 2-(8-quinolinyl sulfonyl amino) aniline The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.82 g, 27 ).H-MS mz 300 (M+H) + b) Synthesis of N-{2-( (8-quinolinyl) sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-((8-quinolinyi) sulfonyl amino) aniline(l mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0 3 g, 46 ).EI-MS m z 495(M-H) " E ff 66 Synthesis of N-f2-( benzvl sulfonvl amino) phenvtt N'-f 2-bromo ohenvn urea a) Synthesis of 2-(benzyl sulfonyl amino) aniline The sulfonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%). EI-MS m z 263(Μ+Η)+· b) Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-{ benzyl sulfonyl amino) aniline(l mmol) and 2-bromo phenyl isocyanate(lmmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.11 g, 23%). EI-MS m/z 460 (M+H)+ Exam le, 67 Synthesis of N-/2.hvdroxv-4-azidophenvn-N'-r2-methoxvDhenvnurea a)Synthesis of N-(2-hyd^xy-4-anunophenyl)-I^-(2-methoxyphenyl)urea To a solution of N-(2-hydroxy-4-nitro phenyl)- -(2-methoxyphenyl)urea(1.0 g» example IS) in methanol, palladium (on activated carbon, 10%) (100 mg) was added. Then the reaction mixture was hydrogenated under a hydrogen balloon for 18 hours. The solid was filtered off by celite and washed three times by methanol. The filtrate was concentrated under reduced pressure to give amine compound (0.8 g, 89%). EI-MS m/z 274 (M+H)+ b)Synthesis of N-(2-hydroxy-4-azidophenyl)- ,-(2-methoxyphenyl)urea The N 2-hydroxy^aminophenyl)-N,-(2-methoxyphenyl)urea (300 mg, 1.17 mmol) was added to HCI/H2O (1.17 mL/2.34 mL), cooled to 0°C. Sodium nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+ Ex m te 6? Preparation of N-r2-hvdroxv-5-cvanophenvll-N'-r2-bromophenvn urea a)Preparation of 2-amino-4-cyanophenol To a solution of 2-nitro-4-cyanophenol(10g, 61mmol) in methanol(250mL) was added 10% Pd/C (lg). 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH CH2CI2) gave the desired product(8.0 g, 97%). lH NMR (CD3OD): d 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H). bJPreparation of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (540mg,81%). ½ NMR (CD3OD): d 8.10 (d, 1H), 7.87 (d, 1H), 7.43 (d, 1H), 7.20 (t, 1H), 7.09 (d, 1H), 6.86 (t, 1H), 6.77 (d, 1H).

Example 69 Preparation of Isr-r2-hYHrn¾v-3-fluorophenvn-N,-r2-bromophenvn urea a) Preparation of 2-anuno-3-fluorophenol To a solution of 2-nitro-3-fluorophenol(lg, 6.4mmol) in methanol(250mL) was added 10% Pd/C (lg). 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH CH2CI2) gave the desired product(650 mg, 80.2 %). H NMR (CD3OD): d 6. 1-6.17 (m, 3H). b) Preparation of N-[2-hydroxy-3-fluorophenyl]- '-[2-bromophenyl] urea N-[2-Hydroxy-3-fiuorophenyi]-N,-[2-bromo phenyl] urea was prepared from 2-amino-3-fiuorophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane( 1/20) and filtering. (500 mg, 77%). ½ NMR (CD3OD): d 8.05 (d, 1H), 7.50 (d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 (m, 2H).

Example 70 Preparation of N-2-ri-hvdroxvfluorene1-N,-r2-bromophenvn urea a) Preparation of 2-arnino-l-hydroxyfiuorene To a solution of 1 -hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in methanol(250mL) was added 10% Pd/C (lg). 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH7 CH2CI2) gave the desired product(171 mg, 8L2 %). ½ NMR (CD3OD): d 7.60 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H). b) Preparation of N-2-[l-hydroxyfluorene]-N'-[2-bromophenyl3 urea N-2-[ l-hydroxyfluorene]-N'-[2-bromo phenyl] urea was prepared from 2-amino-1- hydroxyfluorene (170mg, 0.86 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). lH NMR (CD3CI): d 8.04 (d, 1H), 7.66 (d, 1H), 7.49 (t, 2H), 7.35-7.20 (m, 4H), 7.09 (d, 1H), 6.90 (t, 1H).

Example 71 Preparation of N-3-r2-hvdroxv-Q TO-anthraguinonvn-N'.ri.hminnphenvn N-3-[2-Hydroxy-9,10-anthraquinonyl]-N'-[2-bromopheQyl] urea was prepared from 2-hydroxy-3-aminoanthraquinone(480mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (610mg, 70%). lK NMR (CD3OD): d 8.93 (s,lH), 8.12 (m, 2H), 8.02 (d, IH), 7.77 (m, 2H), 7.61 (d, 1H), 7.52 (s, IH), 7.38 (t, 1H), 7.05 (t, 1H).

Example 72 Preparation of N-r2-hvdroxv-3-fluoro-5-bromophenvn-N,-r2-bromnphenvn u a)Preparation of 2-amino-6-fluoro-4-bromophenol A mixture of 4-bromo-2-fluoro 6-nitrophenol(lg, 4.2mmol) and tin (Π) chloride (4.78 g, 21.2mmol) in ethanol(SOmL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(710 mg, 82 %). lH NMR (CD3OD): d 6.51-6.40 (m, 2H). b)Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N,-[2-bromophenyl] urea N-[2-hydroxy-3-fluoro-5-bromophenyl]-N,-[2-bromophenyl] urea was prepared from 2-am o-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (500 mg, 77%). H NMR (CD3OD): d 7.98 (s, IH), 7.91 (d, IH), 7.60 (d, IH), 7.33 (t, IH), 7.00 (t, IH), 6.94 (d, IH).

Example 73 Preparation of N-r2-hvdroxv-3-chloroDhenvn-N'-f2-bromophenvn urea a)Preparation of 2-amino-3-chlorophenol A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4mmoi) and tin (Π) chloride (1.2 g, 5.3mmol) 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 with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(143 mg, 69 %). H NMR (CD3OD): d 6.75 CUH), 6.70 (d, 1H), 6.65 (d, 1H). b)Preparation of N-P-hydroxy-S-chlorophenylJ- '-P-bromophenyl] urea N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-3-chlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product(195mg, 57%). *H NMR (CD3OD): d 7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d. 1H), 7.20 (t, 1H), 6.90 (m, 2H), 6.70 (t, 1H).

Example 74 Preparation of N-r2-hvdroxv-3-trifluoromethvlDhenvn-N'-r2-bromophenvn ureaalPreparation of 2-nitro-6-trifluoromethylphenol 2-trifluoromethylphenol (3.00g, 18.5mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.73g, 20.4mmol). The addition of sulfuric acid (23 ml/ 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 MgSCH and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2Q2) gave the desired product( 1.84 g, 47 %). *H NMR (CD3COCD3): d 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H). b) Preparation of 2-amino-6- trifiuoromethylphenol A mixture of 6-trifluoromethyl-2-nitrophenol( 1.84 g, 8.67mmol) and tin (Π) chloride (6.0 g, 26.2 mmol) in ethanol(150mL) 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 with brine, dried over MgSCH and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product 1.35 g, 88 %). *H NMR (CD3OD): d 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H). c) Preparation of N-[2-hydroxy-3- trifluoromethylphenyll-N-P-bromophenyl] urea N-[2-hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] 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 cfaioricie hexaneC 1/20) and filtering. (390mg, 65%). lR NMR (CD3OD): d 7.99 (d, IH), 7.60 (d, IH), 7.58 (d, 1H), 7.34 (t, IH), 7.30 (d, IH), 7.00 (t, IH), 6.96 (d, 1H).

Example 75 Preparation of Ν-Γ3.4 diphenvl-2-hV(iroxvphenvn- -r2-bromophenvn urea N-[3,4 olphenyl^-hydroxyphenyn-N'-P-bromophenyl] urea was prepared from 2-amino-5,6 diphenyiphenol (50mg, 0.19 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering (61mg, 69%). *H NMR (CD3OD): d 7.97 (d, IH), 7.66 (d, IH), 7.58 (d, IH), 7.31 (t, IH), 7.25-7.00 (m, 1 IH), 6.91 (d, IH).

Example 76 Preparation of N-r2-hvdroxv -rivcmememvlestercarbonvlphenvn-N^r2-bromoph--nvll urea N-[2-hydroxy-3-glycmeme&ylestercarbon^ was prepared from 6-glycmemethylestercaibonyl-2-axninophenol (50mg, 0.22 mmol), purchased from the University of New Hampshire, according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering (65mg, 69%). *H NMR (CD3OD): d 8.14 (d, IH), 7.96 (d, IH), 7.49 (d, IH), 7.24 (t, 2H), 6.89 (dd, IH), 6.81 (t, IH), 4.10 (s,2H), 3.74 (s,3H).

Example 77 Preparation of N-r2-hvdroxv-3-glvcinecarbonvlphenvn-N'-r2-bromophenvl1 urea N-[2-Hydroxy-3-glycinecarbonylphenyl]-N'-[2-broniophenyl] urea was prepared from N-[2-hyd^xy -glycmemethylestercarbonylphenyn-N'-P-bromophenyl] urea(50mg, 0.12 mmol) by stirring in a 3/1 ratio of methanol/water (10 mL). Addition of 1 equiv. of lithium hydroxide was added and stirring continued until the starting material had disappeared. (45mg, 92%). The product was purified by chromatography of the resulting solid on silica gel (9/1/0.1 CH2CI2 MeOH AcOH) to give the desired product(195mg, 57%). ½ NMR (CD3OD): d 8.14 (d, IH), 7.92 (d- IH), 7.60 (d, IH), 7.46 (d, IH), 7.34 (t, IH), 7.04 (t, IH), 6.82 (t, IH), 3.96 (2H).

Example 78 Preparation of N-r2-hvdroxv-3.5-dichIorophenvn-N'-r2-bromophenvn urea a)Preparation of 2-amino-4,6-dichlorophenol A mixture of 4,6-dichloro-2-nitrophenol(l g, 4.8mmoi) and tin (Π) chloride (3.2 g, 14.4mmol) in ethanol(50mL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(685 mg, 80 %). lH NMR (CD3OD): d 6.75 (s,lH , 6.61 (s, 1H). b)Preparation of N-P-hydroxy-S^-dichlorophenylJ- '-^-bromophenyl] urea N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-4,6-dichlorophenol (143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (660mg, 88%). ½ NMR (CD3OD): d 7.96 (s, 1H), 7.89 (d, 1H), 7.60 (d, lH), 7.35 (t, 1H), 7.00 (t, 1H), 6.95 (dd, 1H).

Example 79 Preparation of N-r2-hvdroxv-3-nitrophenvn-N,-r2-bromophenvn ureaN-r2-Hvdroxv-3-nitrophenyl]-N'- [2-bromophenyl] urea was prepared from 2-hydroxy-3-nitroaniline (1.25g, 8.1 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(l/20) and filtering. (2.4g, 84%). NMR (CD3OD): d 8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.01 (m, 2H).

Exam le 90 Preparation of N-r2.hvdroxv-4-naphthalenesulfonic acidVN,-r2-bromophenvll urea N-[2-hydroxy-4-naphthaienesulfonic acid]-N'-[2-bromophenyl] urea was prepared from l-ammc-2-hydroxy-4-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the procedure in General Method B and the addition of lmL of trie ylamine The product was purified by precipitation from methylene chloride hexane(l 20) and filtering. (690 mg, 79%). JH NMR (CD3OD): d 8.14 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 (t, 1H).

Preparation of N-r2-hvdroxv»5-naphthalenesulfonic acid%N,-r2-bromophenvn urea N-3-[2-hydroxy-5-naphthalensulfonic acid]-N1-[2-bromophenyl] urea was prepared from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the procedure in General Method B and the addition of lmL of triethylarnine The product was purified by precipitation from methylene chloride hexane(l 20) and filtering. (715 mg, 82%). lH NMR (CD3OD): d 8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 (s, 1H), 7.04 (m, 2H).

Example 82 Preparation of N-r2-hvdroxv-3.4-dichlorophenvn-N'-r2-bromophenvn urea a) Preparation of 2-nitro-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 with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Q2) gave the desired product(1.8 g, 44 %). H NMR (CD3COCD3): d 8.04 (d,lH), 7.15 (d, 1H). b) Preparation of 2-amino-5,6 dichlorophenol A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7mmol) and tin (Π) chloride (5.8 g, 26. lmmol) in ethanol(50mL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(1.4 mg, 90 %). H NMR (CD3OD): d 6.71 (d, 1H), 6.45 (d, 1H). c) Preparation of N-E2-hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(l 20) and filtering. (670mg, 89%). XH NMR (CD3OD): d 7.90 (d, 1H), 7.85 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 6.99 (t, 1H), 6.96 (d, (1H).

Example 83 Preparation of N-r2-hvdroxv-3-cvanophenvll-N,.r2-bromophenvll urea a)Preparation of 2-nitro-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 of sulfuric acid (20mLJ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, me reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(1.4 g, 42 %). lH NMR (CD3COCD3): d 8.47 (d,lH), 8.15 (d, 1H), 7.30 (t, 1H). b) Preparation of 2-amino-6-cyanophenol A mixture of 6-cyano-2-nitrophenol(600 mg, 1.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 slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Q2) ga e the desired product(365 mg, 75 ). *H NMR (CD3OD): d 6.92 (d, 1H), 6.85-6.69 (r¾2H). c) Preparation 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-cyanophenoi (134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (260mg, 78%). lH NMR (CD3OD): d 7.98 (d, 1H), 7.74 (d. 1H), 7.57 (d. 1H), 7.30 (t, 1H), 7.22 (d, 1H), 6.98 (t, 1H), 6.94 (t, (1H).

Example 84 Preparation of N-r2-hvdroxv-4-cvanophenvn-N,-r2-bromophenvn urea a) Preparation of 2-nitro-5-cyanophenol 3- cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid (20rnI73M) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2 I2) gave the desired product(910 mg, 28 %). lH NMR (CD3COCD3): d 8.30 (d,lH), 7.67 (s,lH), 7.49 (d, lH). b) Preparation of 2-amino-5-cyanophenol 97/29743 1 2 A mixture of 5-cyano-2-aitrophenol(250 mg, 1.5mmol) and tin (Π) chloride (3.2 g, 14.4mmol) 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 with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(175 mg, 86 %). lH NMR (CD3OD): d 7.00 (d, 1H), 6.88 (s.lH), 6.69 (d, lH). c)Preparation of N-[2-hydroxy-4-cyanophenyl]-N 2-bromophenyU 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(l/20) and filtering (3 lOmg, 74%). ½ NMR (CD3OD): d 8,25 (d, lH), 7. 1 (d, 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (s, 1H), 7.01 (t, (1H).

Sxampje 35 Preparation of N-r2-hvdroxv-4-cvanophenvn-N'-r4-methoxvphenvn urea N-[2-Hydroxy-4-cyanophenyl]-Nl-[4-methoxyphenyl] 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. (110mg,86%). ½ NMR (CD3OD): d 8.23 (d, 1H), 7.61-7.51 (m, 2H), 7.32 (d, lH), 7.20 (d, 1H), 7.15 (d, lH), 7.03 (s, 1H).

Preparation of N-r2-hvdroxy-4-cvanophenvn-N'-r2-phenvlphenvn urea N-(2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (170 mg, 1.27 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(l/20) and filtering. (150mg, 85%). [H NMR (CD3OD): d 8.20 (d, lH), 7.73 (d, 1H), 7.51-7.20 (m, 8H), 7.13 (d, 1H), 7.01 (s, (1H). farampte ¾7 Preparation of N-r2-hvdroxv-4-cvanoohenvn.N'-r2-methvlDhenvn urea N-[2-Hydroxy-4-cyanophenyl]-N,-[2-methylphenyl3 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( 1/20) and filtering. (90mg, 75%). H NMR (CD3OD): d 8.25 (d, 1H), 7.59 (d,. 1H), 7.26-7.00 (m, 5H), 2.30 (s, 3H).

Example 88 Preparation of N-r2-hvdroxv-4^anophenvn-^-r2-trifluoromethvlphenvn urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-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. (1 lOmg, 76%). ½ NMR (CD3OD): d 8 5 (d, 1H), 7.81 (d, 1H), 7.68 (d, 1H). 7.61 (t, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, (1H).

Exam le 39 N-[2-hydroxy-4^anophenyl]-^-[3-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. (114mg. 79%). lH NMR (CD3OD): d 8.30 (d, 1H), 7.92 (s. 1H), 7.60 (d, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H).

Example 90 Preparation of N-r2-hvdroxv-4^v.mophenvn-rr-f4-trifluorometlwlphenvn 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( 1/20) and filtering. ( 108mg, 75%). H NMR (CD3OD): d 8.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H), 7.20 (dd, 1H), 7.07 (s, 1H).

Example 1 Preparation of N-r2-hvdroxv-3-n-propvlphenvn-N'.r2-bromophenvn urea a)Preparation of 2-nitro-6-n-propylphenol 2-n-propylphenol (5.00g, 36.8mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (3.43g, 40.5mmol). The addition of sulfuric acid (45mL 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2O2) ave the desired product(3.2 mg, 48 %). ½ NMR (CD3COCD3): d 7.99 (d,lH), 7.46 dd, 1H), 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H). b) Preparation of 2-amino-6-n-propylphenol To a solution of 2-nitro-6-n-propylphenol(2g, 11.Ommol) in methanol( lOOmL) was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 rnin. 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 0¾<¾) gave the desired product( 1.50 g, 80.2 %). lH NMR (CD3OD): d 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H). c) Preparation of N-P-hydroxy-S-n-propylphenyll-N'-P-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/ hexane(l/20) and filtering. (640mg,92%). lK NMR (CD3OD): d 8.00 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, 1H), 6.78 (d, 1H). g ampte 92 Preparation of N-f2-hvdroxv-4-ethvlphenvn-N'-r2-bromophenvn urea a) Preparation of 2-nitro-5-ethylphenol 3-ethylphenol (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 (50mIV 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOW CH2CI2) gave the desired product(1.7 g, 25 %). ½ NMR (CD3COCD3): d 8.02 (d,lH), 6.99 (s,lH), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H). b) Preparation of 2-araino-5-ethylphenol 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH CH2O2) gave the desired product(750 mg, 91 %). ½ NMR (CD3OD): d 6.41-6.17 (m, 3H). c)Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (520 mg, 77%). ½ NMR (CD3OD): d 7.96 (d, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H).

E a ple 93 Preparation of N-r2-hvdroxv 3-phenvlaminocarbonvl phenvll-N'-r2-bromophenvn urea a) Preparation of 2-mtro^phenylaminocarbonylphenol 2-Pheayiaminocarbonylphenol (5.00g, 23 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.20g, 25.5 mmol). The addition of sulfuric acid (30mL/ 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) ave the desired product(2.50 g, 42 %). ½ NMR (CD3COCD3): d 8.15 (d,lH), 8.09 (d,lH), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H). b) Preparation of 2-arnmo-6^phenylaminocarbonylphenol To a solution of 2-nitro-6-phenylaminocarbonylphenol ( lg, 4.0 mmol) 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 cetite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(800 mg, 91 %). LH NMR (CD3OD): d 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H). c) Preparation of N-[2-hydroxy 3-phenylaxninocarbonyl phenyl]-N 2-bromophenyl] urea N-[2-hydroxy 3-Phenyiaminocarbonyl phenyl]-N*-[2-bromo phenyl] urea was prepared from 2-ammo-6-phenylaminocarbonylphenol (456mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (800mg,94%). lH NMR (CD3OD): 4 2 ½ NMR (CD3OD): d 25 (d, 1H), 7.94 (d, 1H), 7.75-7.57 (m, 4H), 7.48-7.30 (m, 3H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.92 (t, 1H).

Ex mple 94 Preparation of N-r2-hvdroxv-3-cvano-4-methvlphenvn- '-r2-bromophenvn urea^ Preparation of the 2-nitro 5-methyl 6-bromo phenol A solution of t-butyl amine(6.88 mL, 4.79 g, 2 equiv.) in methylene chloride was treated with bromine (1.67 mL, 5.2 g, 1 equiv.) at -20 °C. The flask was then cooled to -78 °C and the the 2-nitro 5-methyl 6-bromo phenol (5 g, 1 equiv., in methylene chloride) was added drop-wise with vigrous stirring. The reaction mixture was slowly warmed to -30 °C for 1 h, then to -10 °C for 2 hours. The reaction mixture was then partitioned between methylene chloride and 5% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (Ethyl acetate/ hexanes) to remove dibrominated species. The 2-nitro 4-bromo 5-methyl phenol was then selectively crystallized out of methylene chloride. A final silica gel column(5%ethyl acetate/ hexanes) yielded desired isomer in 90% purity. (1.05 g, 14%). *H NMR (CDCI3): d 7.95 (d, 1H, J ■ 10.0 Hz), 6.91 (d, 1H, J = 10.0 Hz), 2.52 (s, 3H). b) Preparation of 2-nitro-5-methyl-6-cyanophenol 2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2mL) followed by the addition of triethylamine (0.175g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155mg, 1.73mmol). The mixture was allowed to stir at 80_C for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2%MeOH CH2G2) gave the desired product (70 mg, 91 %). *H NMR (CD3COCD3): d 8.30 (d,lH), 7.15 (d,lH), 2.61 (s, 3H). c) Preparation of 2-arnino-5-methyl 6-cyanophenol A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmol) and tin (Π) 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 slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product 175 mg, 86 %). ½ NMR (CD3OD): d 6.87 (d, 1H), 6.75 (dJH), 6.32 (s, 3H). d) Preparation of N-[2-hydroxy 3-cyano4-methyl phenylJ-N'-P-bromophenyl] urea N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'- [2-bromophenyl] urea was prepared from 2-anuno-5-methyl-6-cyano phenol (50mg, 0.34 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (70mg, 60%). *H MR (CD3OD): d 7.92 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.62 (t, 1H), 2.49 (s, (3H).

Example 5 Preparation of N-i2-hvdroxv 4-Carboxvphenvl phenvll-N'-r2-bromophenvn ureaa^Preparation of 4-pitro-3-hvdroxvbenzophenone 3-Hydroxybenzophenone (3.00g, 15. lmmol) was dissolved in methylene chIoride(40mL) followed by the addition of sodium nitrate (1.42g, 16.7mmol). The addition of sulfuric acid (25mL 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Q2) gave the desired product(l.10 g, 30 %). lH NMR (CD3COCD3): d 8 5 (d,lH), 7.86 (d,lH), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, 1H). b) Preparation of 4-amino-3-hydroxybenzophenone A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (Π) chloride (2.5 g, 11. lmmol) 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 with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4 MeOH/ CH2Q2) gave the desired product(685 mg, 87 ). ½ NMR (CD3OD): d 7.65 (d, 2H), 7.55 ( Esampte °$ ureaa)Preparation of 3-nitro-2-hydroxybenzophenone 2-Hydroxybenzophenone (3.00g, 15.1 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.42g, 16.7mmol). The addition of sulfuric acid (25mL/ 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(1.60 g, 44 %). lH NMR (CD3COCD3): d 8.30 (d,lH), 7.86 (m,3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H). b) Preparation of 3-amino-2-hydroxybenzophenone A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5mmol) and tin (Π) chloride ( 1.7 g, 7.5mmol) in ethanol(SOmL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(490 mg. 92 %). H NMR (CD3OD): d 7.65-7.40 (m, 5H), 6.98 (d,lH), 6.86 (d, 1H), 6.67 (t, 1H . c) Preparation of N-[2-hydroxy 3-carboxyphenyl phenyl]-N*-[2-bn>mophenyl] urea N-[2-hydroxy 3-carboxyphenyi phenyl]-N,-[2-bromophenyl] urea was prepared from 3-amino-2-hydroxybenzophenone (250mg, 1.20 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (200mg, 78%). !H NMR (CD3OD): d 8.35 (d, 1H), 7.96 (d, 1H), 7.72 (d, 2H), 7.65-7.50 (m, 4H), 7.35 (d, 1H), 730 (d, 1H), 7.01 (dd, (lH), 6.92 (t, lH).

EMpte 97 Preparation of N-r2-hvdmxv 3-benzv.oxv Dhenvn-N'-r2-bromophenvn urea a)Preparation of 2-nitro-6-benzyloxy phenol 2-Benzyloxyphenol (5.00g, 25.0mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.30g, 27.5mmol). The addition of sulfuric acid (3 lmL/ 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(2.6 g, 43 %). NMR (CD3COCD3): d 7.70 ( Example 98 Preparation of N-3-r2-hvdroxv-5-indanone1-Nt-r2-bromophenvn urea a) Preparation of 2-hydroxy-3-nitro-5-indanone 2-Hydroxy-5-indanone(3.00g, 20.0mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.95g, 21.0mmol). The addition of sulfuric acid (25mL/ 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(l .5 g, 39 %). H NMR (CD3COCD3): d 7.70 (d,lH), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H). b) Preparation of 3-amino-2-hydroxy-5-indanone A mixture of 2-hydroxy-3-nitro-5-indanone ( 1.50 g, 7.80mmol) and tin (Π) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.00 g, 79 %). lH NMR (CD3OD): d 6.85 (d,lH), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H). c) Preparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea N-[2-Hydroxy-5-indanone]-N,-[2-broniophenyl] urea was prepared from 3-amino-2-hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (610mg, 85%). *H NMR (CD3OD): d 7.92 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 7.09 (t, 1H), 7.00 (d, 1H), 2.90 (d, 2H), 2.66 (d, 2H).

Example 99 Preparation of rEVN-r4-r2-fMethoxvcarbonvn ethenvn-2-hvdroxvohenvn-N'-r2-bromophenvn urea a) Preparation of 4-rdtro-3-hydroxycinnamic acid 3- Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.70 g, 26.1 mmol). The addition of sulfuric acid (25 mlJ 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 MgSCH and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2 I2) gave the desired product(1.0 g, 26 %). *H NMR (CD3COCD3): d 8.07 (d, 1H), 7.69 (d, 1H), . 7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,lH). b) Preparation of 4-nitro-3-hydroxymethylcinnamate 4- Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(1.0 g, 94 %).

½ NMR (CD3COCD3): d 8.17 (d, 1H), 7.69 (d, 1H), 7.52 (s, 1H), 7.45 (d, 2H), 6.75 (d,lH), 3.80 (s, 3H). c)Preparation of 4-arnmo-3 -hydroxy methylcinnamate A mixture of 4-rutro-3-hydroxymethylcinnarnate (1.0 g, 4.50mmol) and tin (Π) chloride (3.0 g, 13.4 mmol) in ethanol(SOmL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4 MeOH CH2CI2) gave the desired product (650 mg, 75 %). *H MR (CD3OD): d7.50 (d,lH), 6.94 (s, 1H , 6.89 (d, 1H), 6.68 (d, 1H), 6.18 (d, 1H), 3.74 (s, 3H). d)Preparation (E)-N-£4-[2-(Memoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea (E)-N-[4-[2-(Memoxycarbonyl) ethenyl]-2-hydiOxyphenyl]-^ urea was prepared from 4-arnmo-3-hydroxymethylcinnamate (250mg, 1.3 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (300mg, 59%). H NMR (CD3OD): d 8.24 (d,lH), 8.05 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.21 (s, 1H), 7.19 (d, 1H), 7.10 (t, 1H) 6,45 (d,lH) 3.81 (s, 3H). fixa pfc ¾QQ bromophenvn urea N'-rc-bromophenvn urea a) Preparation of 3-nitro-2-hydroxycinnamic acid 2- Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The addition of sulfuric acid (30 mU 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(Z0 g, 52 %). lK NMR (CD3COCD3): d 8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H) b) Preparation of 3-nitro-2-hydroxymethylcinnamate 3- mtro-2-hydroxycirmarnic acid was stirred in excess methanol with a catalytic amount of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product (1.0 g, 94 %). 9743 'Η NMR (CD3COCD3): d 8.25 (d, 1H), 7.8.15 (d, 1H), 8.06 (s, 1H), 7.20 (t, 2H), 6.76 · (d,lH), 3.80 (s, 3H). c) Preparation of 3-anunc~2-hydroxymemylcinnamate A mixture of 3-nitro-2-hydroxymethyIcinnamate ( 1.0 g, 4.5 mmol) and tin (Π) chloride (3.0 g, 13.4 mmol) in ethanol(50mL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product (700 mg, 81 %). ½ NMR (CD3OD): d 8.04 (d, 1H), 6.93 (d, 1H),6.79 (d, 1H), 6.71 (t, 1H), 6.43 (d, 1H), 3.72 (s, 3H). d) Preparadon(E)-N-[3-[2 Memoxycarbonyl) emenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea (E)-N-[3-[2-(Methoxycarbonyl) ethenyll^-hydroxyphenyll- r-P-bromophenyl] urea was prepared from 3-ammo-2-hydroxymethylcinnamate (100 mg, 0.52 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (150mg, 74%). ½ NMR (CD3OD): d 8.10 (d,lH), 8.00 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.38 (t, 1H), 7.32 (d, 1H), 7.05 (t, 1H) 6.55 (d,lH) 3.81 (s, 3H).

Preparation of fEVN-r -f2-f Aminocarbonvn ethenvn-2-hvdroxvphenvI1-N'-r2-bromophenvn urea N'-r2-hromophenvn urea a)Preparation of 2-hydroxycinnamide 2-Hydroxycinnamic acid (2.00g, 12.3 mmol) was dissolved in dimethyl formamide(lOmL) followed by the addition of benzotriazol- 1 -yloxy-tris(dimemylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and triethylamine ( I rnL, 12.3mmol). Ammonia gas was bubbled into the reaction mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2G2) gave the desired product( 1.5 g, 75 %). b)Preparation of 3-nitro-2-hydroxycinnainide 2- Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (430 mg, S.lmmol). The addition of sulfuric acid (7 mL 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(350 mg, 36 %). ½ NMR (CD3COCD3): d 8.19 (d, 1H), 8.02 (d, 1H), 7.88 (d, 1H), 7.15 (t, 1H), 6.84 (d. 1H) c)Preparation of 3-ammo-2-hya^xycinnamide A mixture of 3-nitro-2-hydroxymethylcinnamate (350 mg, 1.7 mmol) and tin (Π) chloride (3.0 g, 13.4 mmol) in ethanol(50mL) 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 M gS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(244 mg, 80%). d)Preparation of (E)-N-[3-[2 Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea (E)-N-[3-[2-(Arnmocarbonyl) emeny^-Z-hydroxyphenyll-N'-P-bromophenyl] urea was prepared from 3-aminc-2-hydroxycirmamide (100 mg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (110 mg, 52%). ½ NMR (CD3OD): d 8.00 ( Example 1Q2 Preparation of ΓΕνΝ-Γ4-Γ2-ί Aminocarbonvn ethenvn-2-hvdroxvDhenvn-N'-r2- a)Preparation of 3-hydroxycinnamide 3- Hydroxycinnamic acid (2.00 g, 12.3 mmol) was dissolved in dimethyl formamide(10 mL) followed by the addition of benzotriazol-l-yloxy- tris(dimeraylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and triemylamine ( 1.7 mL, 123mmol). Ammonia gas was bubbled into the reaction mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product( 1.3 g, 65 %). b) Preparation of 4-nitro-3 -hydroxycinnamide 3-Hydroxycinnamide (750 mg, 4.6 mxnol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (430 mg, 5. lmmol). The addition of sulfuric acid (7 mL 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(240 mg, 25 ). *H NMR (CD3COCD3): d 8.09 (d, 1H), 7.49 (d, 1H), 7.26 (s, 1H), 7.16 (d, 1H), 6.71 (d, 1H) c) Preparadon of 4-ammo-2rhydroxycinnamide A mixture of 4-mtro-3-hydroxymethylcinnamate (300 mg, .40 mmol) and tin (Π) 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 of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over M gS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product (200 mg, 74 ). d) Preparation(E>N-[3-[2-(Ammocarbo^ bromopheh'yl] urea (E)-N-[3-[2 Example 103 Preparation of N-fLhvdroxv 4-fnhenvl amino carboxv) phenvn->T-r2-bromophenvI1 urea N-[2-hydroxy 4-(phenyl amino carboxy) phenyl]-I^-[2-bromophenyl] urea was prepared from 5-(phenyl amino carboxy) 2-amino phenol (0.50 nunol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(l 20) and filtering. (150 mg, 70%). H NMR (CD3OD): d 8.25 (d, 1H), 8.00 (d, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.50 (d, 2H), 7.41 (m, 3H), 7.16 (t, 1H), 7.05 (t, 1H).

Ex m te 10 Preparation of N-r4-amino(^i½>nvl-2-hvdroxvDhenvlVl^-r2-bromoDhenvn urea N-[4-Aminocarbonyl -2-hydroxypheny 1] -N'- [2-bromopheny 1] urea was prepared from 5-aminocarbonyl-2-arnino phenol (304 mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(l 20) and filtering. (440 mg, 62%). *H NMR (CD3OD): d 8.09 (d, 1H), 7. 1 (d, 1H), 7.60 (d, 1H), 7.45 (m, 3H).7.00 (d, 1H).

Example, 105 Preparation of N-f -Hvdroxv-3.5.6-trifluoroDhenvlVN,-f2-bromophenvl^urea N-(2-Hya^oxy-3^,6^trifluorophenyl)-N,-(2-bromophenyl)urea was prepared from 3,5,6-trifluoro-2-hydroxyaniline (83 mg, 0. 1 mmol) and 2-(bromophenyl)isocyanate (100 mg, 0.53 mmol) according to the procedure in General Method B. The product was purified by preparation thin layer chromatography. EI-MS m z 359 (M-H)~. ¾ample \ Preparation of N-f2-Hvdroxv-3-fluoro-^trifluoromethvl henvn-N'-r2-bromophenvnurea N-(2-Hyd¾xy-3-fluoro-4-trifluoro was prepared from 4-trifluoromethyl-3-fluoro-2-hycirox aniline (239 mg, 1.2 mmol) and 2-(bromophenyl)isocyanate (243 mg, 1.2 mmol) according to the procedure in General Method B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate) gave the title compound (20 mg, 4%). EI-MS m/z 391 (M-H)~.

Example 1Q7 N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-iodo-2-hydroxyaniline (200 mg, 0.85 mmol) and 2-( romophenyl)isocyanate (169 mg, 0.85 mmol) according to the procedure in General Method B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexanerether) gave the title compound (40 mg, 11%). H NMR (DMSO): d 9.45 (s, 1H), 9.15 (s, 1H), 8.8 (s, 1H), 7.95 (d, 1H), 7.8 (d, 1H),7.65 (d, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 7.0 (t, 1H), 6.65(t, 1H).

Example 108 Preparation of N-r2-rrr2-ftrifluoromethvnphenvnsulfonvnaminolphenvn-N'-(¾. bromophenvnurea a)Preparation of [2-[2-(trifluoromemyl)phenyl](sdfonarnido)aniline] The title compound was prepared according to General Method C using 2-(trifluoromethyl)benzenesulfonyl chloride (1 equiv.). The product was purified by chromatography on silica gel (methylene chloride:methanol) (1.04 g, 33%). EI-MS m/z 317 (M+H)+. bJPreparation of N-[2-[[[2-(trifluoromethy^ bromophenyl)urea The title compound was prepared using[2-[2(trifluoromethyl)phenyl] (sulfonamido)aniline (1.04 g, 32 mmol) and 2-(bromophenyl)isocyanate (652 mg, 3.2 mmol) according to General Method B. The solvent was evaporated to give the desired urea (1.03 g, 61%). EI-MS m z 514 (M+H)+.

Example 109 Preparation of N-f2-Bromophenvn-N'-r2-mmethvlanMnosulfonvl.m-ino1phenvnurea a) Preparation of [2-[l J^dmiemyla-Q_uno)3sulfonanudoaniline] The title compound was prepared according to General Method C using ciimethylsulfamoyl chloride (1 equiv.). The product was purified by chromatography on silica gel (methylene chloridermethanol). ES-MS m/z 216 (M+H)+. b) Preparation of N 2-Bromophenyl N'-[2^dimemylanimosuifonylamino]phenyl]urea The title compound was prepared from [2-[l,l-(dimetUyammo)sulfonamido-aniline (137 mg, 0.6 mmol) and 2-(bromophenyl)isocyanate (126 mg, 0.6 mmol) according to General Method B. The solvent was evaporated and chromatography on silica gel (ethyl acetate:hexane) gave the desired urea. EI-MS m/z 413 (M+H)+ Example 110 Preparation of N-r2-fPhenethvlsulfonvlamino phenvll-N'-f2-bromophenvnurea [2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a ?m shaker bottle containing palladium ( 180 mg) under an argon stream. Methanol (150 mL) was added and the container placed on a Parr shaker (55 psi) for several hours. The reaction mixture was filtered through Celite and the filtrate was evaporated to give the desired aniline (269 mg, 90%). EI-MS m z 277 (M+H)+. b)Preparation ofN-[2-(Phenemylsulfonylarnino)phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-(phenethylsulfonamido) aniline] (269 mg, 0.97 mmol) and 2-(bromophenyl)isocyanate (193 mg, 0.97 mmol) according to General Method B. The desired urea was precipitated out of toluene/hexane (384 mg, 78%). EI-MS m/z 472 (M-H)".

Ex mple i Preparation of N-rc-rf2-acetaniido-4-memvlftiazol-^^^ bromffphemyDurea a) Preparation of [2-[(2-acetamido^memyl-S-thiazole)sulfonanudo]ani^ The title compound was prepared using 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (1 equiv.) according to General Method C. A solid precipatated from the reaction mixture and was filtered to give the desired aniline (1.68 g, 52%). ES-MS m/z 327 (M+H)+.. b) Preparation of N-[2-[(2-ac«tarnido-4-rnethylthiazol-5-yl)sulfonylanmo (2-bromophenyl)urea The title compound was prepared from [2-[(2-acetamido-4-methyl-5-thiazole)sulfonarrddo]aniline] (1.68 g.5.14 mmol) and 2-(bromophenyl)isocyanate ( 1.02 g, 5.14 mmol) according to General Method B. The product was precipitated from ethyl acetate/hexane (220 mg, 8%). EI-MS m/z 524 (M+H)+.

E am le H¾ Preparation of N-r2-hvdroxv-4-cvanophenvn- ,-r4-phenvlphenvn urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-arnino-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. (135 mg, 75%). ½ NMR (CD3OD): d 8 3 (d, 1H), 7.71-7.29 (m, 9H), 7.25 (d, lH), 7.12 (s. 1H).

Example 113 Preparation of N-r2.hva^xv-4^vanonhenvn-N,-r2.3-dichloroDhenvn urea N-P-Hyojroxy-^ qranophenyll-N'-P.S dichlorophenyl] urea was prepared from 2-amino-S-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexaneU/20) and fdtering. (125mg, 86%). H NMR (CD3OD): d 8.27 (d, IH), 8.15 (m, 1H), 7.39-7.20 (m, 2H), 7.16 (d, IH), 7.06 (s. 1H).

Example 114 Preparation of N-r2-hvdroxv-4-cvanQphenvn-N'-r2-methoxvDhenvn urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] 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 (105mg, 83%). ½ NMR (CD3OD): d 8.26 (d, IH), 8.02 (d, IH), 7.14 (d, IH), 7.05 (s, IH), 7.00-6.83 (m, 3H), 3,84 (s, 3H).

Exam le 115 Preparation of N-r2-hvdroxv-4-cvanophenvn-Nr-r3-methoxvphenvn urea N-[2-HydiOxy-4-cyanophenyl]-N'-[3-methoxyphenyl] 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. (102mg, 80%). H NMR (CD3OD): d 8.25 (d, IH), 7.25-7.08 (m, 3H), 7.04 (s, IH), 6.90 (t, IH), 6.58 (d, IH).

Example 116 Preparation of N-r2-hvdroxv-5-fluorophenvn-N,-r2-bromophenvn urea a) Preparation of 2-amino-4-fluorophenol A mixture of 4-fluoro-2-nitrophenoI(lg, 4.64mmol) and tin (Π) chloride (5.4 g, 24.2mmol) in ethanol(50mL) 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 is 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(622 mg, 85 %). ½ NMR (CD3OD): d 6 1 (dd, IH), 6.32 (dd. IH), 6.17 (ddd, IH). b) Preparation of N-P-hyciroxy-S-fluorophenyll-N'-P-bromophenyl] urea N-P-Hydroxy-S-fluorophenyll-N'-P-bromophenyl] urea was prepared from 2-arnino-6-fluoro phenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (520mg,80%). lH NMR (CD3OD): d 7.88 (d, IH), 7.79 (dd, IH), 7.57 (d, IH), 7.31 (t, IH), 7.00 (t, IH), 6.76 (dd, IH), 6.57 (ddd,lH).

Example 117 Preparation of N-r^-hvdroxv-S-trifluoromethvlphenvn-l^-r^-hromoDhenvn urea a) Preparation of 2-amino-4- trifiuoromethylphenol A mixture of 4-trifluoromethyl-2-nitrophenol( 1.0 g, 4.8mmol) and tin (Π) chloride (5.4 g, 24.2 mmol) in ethanol(lSOmL) 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4 MeOH CH2Q2) gave the desired product(708 mg, 83 %). lH NMR (CD3OD): d 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H). b) Preparation of N-[2-hydroxy-5-trifluorome&yl^^ urea N-[2-hydroxy-5-trifluoromethylphenyl]-N,-[2-bromophenyl] urea was prepared from 2-amino-4-trifluoromethylphenol (354mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequivJ20equiv.) and filtering. (490mg, 65%). ½ NMR (CD3OD): d 8.40 (s, 1H), 7.94 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.18 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H).

Example 118 Preparation of -Γ2-ΗνάΓθχν Η6ηνη-Ν'-Γ2^Γθΐηο 1ΐ6ηνη urea N-[2-hydroxyphenyl]-N1-[2-bromo phenyl] urea was prepared from 2- amino-phenol (141mg, 1.30 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (300mg,75%). H NMR (CD3OD): d 8.05 (d, 1H), 7.49 (d, 1H), 7^ (t, 2H), 6.96 (t, 1H), 6.90 (t, 2H), 6.68 (t, 1H).

Exam le 1 9 Preparation of N-rtrans-3-stvrl 2-hvdroxv phenvn-N,-r2-bromophenvn ureaa)Preparation of trans-6-styrl-2-nitiOphenol Trans-2-styrlphenol (500 mg, 2.55 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (240 mg, 2.81mmol). The addition of sulfuric acid (3 mL of 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product (200 mg, 36 %). lH NMR (CD3COCD3): d 8.05 (d, 1H), 7.90 (d, 2H),7.65-7.20 (m,7H).7.00 (UH). b)Preparation of trans-6-styrl-2-aminophenol A mixture of trans-6-styrl-2-nitrophenoI (200 mg, 0.83 mmol) and tin (Π) chloride (S60 mg, 2.60 mmol) in ethanol(SOmL) 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 is 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 MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4 MeOH/ CH2CI2) gave the desired product (50 mg, 29 %). lK NMR (CD3OD): d 7.51 (m, 3H), 7.29 (m, 3H),7.11 (t, 1H), 7.00 (m, 2H), 6.69 (m, 2H). c)Preparation of N-[trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyI] urea N-[trans-3-styrl-2-hydroxyphenyl]-N'-[2-broniophenyl] urea was prepared from trans-6-styrl-2-aminophenol (35mg, 0.17 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l 20) and filtering. (36mg, 53%). H NMR (CD3OD): d7.97 (d, 1H), 7.62-7.48 (m, 4H), 7.45-7.26 (m, 5H), 7.25 (t, 1H), 7.15 (d, 1H), 7.01 (t, 1H).6.88 (t 2H). fiwmpte 120 Preparation of N-r2-hvdroxy-3.4-dichlorophenvn-N,.r2-methoxvt»henvn urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] 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 precipitation from methylene chloride/ hexane(l 20) and filtering. (125mg,77%). !H NMR (CD3OD): d 8.02 (d, 1H), 7.79 (d, 1H), 7.05-6.86 (m, 4H), 3.92 (s, 3H).

Exam le \%\ Preparation of N-r2-hvdmxv-3.4-dichlorophenvn-N'-r4-methoxvDhenvll urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] 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 precipitation from methylene chloride hexane(lequiv./20equiv.) and filtering. (120mg, 74%). HNMR (CD3OD): d 7.89 (d, 1H), 7.35 (d, 2H), 6.99 (d, 1H), 6.90 (dd, 2H), 3.80 (s, 3H). gxarnple \2 Preparation of N-r2-hvdroxv-3.4-dichlorophenvn- ,-r3-trifluoromethvlphenvn urea N-[2-hydroxy-3,4-dicrdorophenyl]-NH3-a^ urea was prepared from 2-anxino-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 hexane(lequiv720equiv.) and filtering. (130mg, 71%). *H NMR (CD3OD): d 7.96 (d, 2H), 7.60 (d, 1H), 7.48 (t, 1H), 7.30 (d, 1H), 7.00 (d, 1H).

Exarnpte 123 Preparation of N 2-hvdroxv-3.4-dichlorophenvl1-N'-r2-phenv1phenvn im»a N-[2-hydroxy-3,4-dichlorophenyl]- ,-[2-phenylphenyl] 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 precipitation from methylene chloride/ hexane(lequiv/20equiv and filtering. (l lOmg, 59%). NMR (CD3OD): d 7.77 (d, 1H), 7.73 (d, 1H), 7.53-7.14 (m, 8H), 6.95 (d, 1H).

Example 124 Preparation of N-r2-hvdroxv-3-4-dicrilorophenvn- r-r2.3- lichlo-^henvn urea N-[2-Hydroxy-3,4- iichlorophenyl]-N'-[23-dichlorophenyl3 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 precipitation from methylene chloride/ hexane(lequivJ20equiv.) and filtering. (130mg, 71%). ½ NMR (CD3OD): d 8.06 (dd, 1H), 7.91 (d, 1H), 7.25 (m, 2H), 7.00 (d, 1H).

Sam le 125 Preparation of N-r2-hvdroxv^isopropvlphenvn.N'-r3-trifluoromethvlphenyl1 urea a)Preparation of 2-oitro-5-isopropyiphenol 3-isopropylphenol (3.00g, 22 mmol) was dissolved in methylene chloride(40ml) followed by the addition of sodium nitrate (2.06g, 24mmol). The addition of sulfuric acid (25mL/ 3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2Q2) gave the desired product(1.09g, 27 %). ½ NMR (CD3COCD3): d 7.95 (d,lH), 7.62 (dJH), 7.11 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H). b) Preparation of 2-amino-5-isopropylphenol To a solution of 2-nitro-5-isopropy lphenol( 1 g, 6.4 mmol) in methanol(50 mL) 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH Cl¾Cl2) gave the desired product(775 mg, 93 %). ½ NMR (CD3OD): d 6.71-6.44 (m, 3H), 2.73 (m, IH), 120 (d, 6H). c) Preparation of N-P-hydroxy-^isopropylphenyn-N'-P-trifluoromethylphenyl] urea N-P-hydroxy-^isopropylphenyll- '-P-trifluoromethylphenyl] urea was prepared from 2-arnino-5-isopropylphenol (75mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(lequiv 20equiv.) and filtering. (140mg, 83%). ½ NMR (CD3OD): d 7.91 (d, 2H), 7.62 (d, IH), 7.47 (t, IH), 7.39 (d, IH), 6.75 (s, IH), 6.72 (d, IH), 2.80 (m, IH), 1.21 (d, 6H).

Preparation of N-r2-hvdroxv-3-naphthvn- '-r2.3-dichlorophenvn urea N-[2-hydroxy-3-naphmyl]-N'-{2,3-dichlorophenyl] urea was prepared from 3-amino 2-naphthol (160mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequivJ20equiv.) and filtering. (285mg, 82%). NMR (CD3OD): d 8.48 (s, IH), 8.10 (d, IH), 7.68 (d, IH), 7.57 (d, IH), 7.40-7.23 (m, 4H), 7.18 (d, IH).

Example 127 Preparation of N-r2-rf2.3-Dichlorothien-5-vnisulfonvlaminolphenvl1-N,-f2-bromophenvnurea a) Preparation of [2-[(2,3-Dichlorothien-5-yl)]sdfonylaminoaiiiline] The title compound was prepared according to General Method C using 23-dichlorothiophene-5-sulfonyl chloride ((1 eq). The product was purified by flash chromatography on silica gel (ethyl acetate hexane 20/80-methylene chloride:methanol 90/10) (1.25 g, 39 %). EI-MS m/z 321 (M-H)' b) Preparation of N-[2-[(2,3-Dichlorothien-5-y l)]sulf bnylamino]phenyl]-N'-(2-bromopheny urea The title compound was prepared from [2-[(2,3-dichlorothien-5-yl)]sulfonylammoaniline (1.25 g,3.9 mmol) and 2-(bromophenyl)isocyanate (768 mg, 3.9 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (272 mg, 13 %) EI- S m z 520 (M-H)" Example 128 Preparation of N-r2-rr3.5-BistrifluoromethvlphenvnsulfonvlaminolDhenvn-N'- 2. bromo henyPurea a) Preparation of [2-(3^-Bistrifluoromethylphenyl)sulfonylainmoaniline] The title compound was prepared according to General Method C using 3,5-(bistrifluoromemyl)phenylsulfonyl chloride (1.28 g, 4.1 mmol) and o-phenylenediamine (441 mg, 4.1 mmol). The product was purified by flash chromatography on silica gel (methylene chloride:methanol 95/5) (611 mg, 39 %). EI-MS m z 383 (M-H)" b) Preparation of N-[2-[(3,5-BistrifiuoromeAylpheny bromophenyl)urea The title compound was prepared from (2-(3,5-bistrifluoromethyiphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (10 mg, 1 %).EI-MS m z 580 (M-H)" Example 129 Preparation of N-r2-rr2-Benzvnsulfonvlanunol-( 5-trifluoromethvltahenvn- W2-frromo henyQurea a) Preparation of [(4-BenzylsulfonylaminoM3 -nitro benzotrifluoride] 4-Ammo-3-nitro-benzotrifluoride (1.0 g, 4.85 mmol) was mixed in DMF and the reaction mixture was cooled to 0°C. Sodium hydride (175 mg, 7.28 mmol) was added to the cold mixture and allowed to mix for ten minutes ( a deep red color was noted). Toluenesulfonyl chloride (925 mg, 4.85 mmol) was added ( reaction color changed to yellow) and the reaction was mixed for sixteen hours at room temperature. The reaction was quenched in NH4CI and extracted with ethyl acetate:hexane ( 1:1). The product was purified by flash chromatography on silica gel ( ethyl acetate:hexane 70) (878 mg, 52 %) H-MS m/z 359 (M-H)". b) Preparation of [(4-Benzylsulfonylarmno)-(3-anuno)-benzotrifluori [(4-BenzylsulfonylammoH3-nitro)-benzotrifluoride (230 mg, 0.64 mmol) was mixed in methanol and poured into a Parr bottle. Palladium on carbon (15 mg) was added under an argon stream. The reaction mixture was placed on a Parr shaker ( 55 psi, H2) for several hours. The reaction mixture was filtered through Ce!ite to give the title compound. (210 mg, 99%) EI-MS m/z 329 (M-H)". c)Preparation of N-[2-[(2-Benzyl)sdfonylanimo]-(5-uifIuoromethyl)phenyl]- ,-(2-bromophenyl)urea The title compound was prepared from [( -benzylsulfonylaniino)-(3-amino)-benzotrifluoride (210 mg, 0.64 mmol) and 2-bromophenylisocyanate (126 mg, 0.64 mmol) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetaterhexane 30/70) (70 mg, 21%) EI-MS m z 526 (M-H)" Example 130 a) Preparation of [2^(3-Nitrophenyl)sulfonylammo)amline] The tide compound was prepared according to General Method C using 3-nitrobenzenesulfonyl chloride (1 eq). The product was purified by flash chromatogrphy on silica gel (methylene chlorideimethanol 9674).(1.07 g, 37 %) EI-MS m z 294 (M+H)+ b) Preparation of N-[2-[(3-Nitrophenyl)sulfonylamino]phenyI]-N'-(2-bromophenyl)urea The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoaniline] (590 mg, 2.0 mmol) and 2-(bromophenyl)isocyanate (398 mg, 2.0 mmol) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (400 mg, 40%). EI-MS m/z 489 (M-H)~ Example, 131 Preparation of N-r2-r2-r4-Phenoxvphenvnsulfonvlarmnolphenvn- ,- 2-bromophenvn urea a) Preparation of [2-((4-Phenoxyphenyi)sulfonylammo)amline] The tide compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenyleneojamine (300 mg, 2.77 mmol). The reaction rnixture was partitioned between water (200 ml) and toluenermethylene chloride (1:3). The organic phase collected and the methylene chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg, 34 %) EI-MS m z 341 (M+H)+ b) Preparation of N-[2-[(4-Phenoxyphenyl)sulfonylamino]phenyl]- '-(2-bromophenyl)urea The title compound was prepared from [2-(4-phenoxyphenyl)sulfonyl aminoaniline (276 mg, 0.8 mmol) and 2-(bromophenyl)isocyanate (161 mg, 0.8 mmol) according to the procedured in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (240 mg.55 ) EI-MS m z 536 (M-H)' Exam le 2 Preparation of N-IT2-f 1 S 10-Cam horsulfonvlaminolphenvn-N'-r2-bmmnphenvnurea a)Preparation of 2-((lS)-10^an^horeulfonylarnino)aniline The title compound was prepared according to General Method C using (1S)(+)-10-Camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6 mmol). The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride (1:3). The organic phase was separated and the methylene chloride evaporated leaving the toluene. Hexane was added and solid precipitated from solution. (130 mg, 9%) EE-MS m z 323 (M+H)+ b)Preparation ofN-[[2-(lS)-10-C^phorsulfonyl^^ bromophenyl)urea The title compound was prepared from [2-(lS)-10-camphorsulfonylarnmo]aniline (130 mg, 0.4 mmol) and 2-(bromophenyl)isocyanate (80 mg, 0.4 mmol) according to the procedure in General Method B. The solvent was evaporated and product was precipitated from methylene chloride.hexane. (200 mg, 95 %). EI-MS m z 518 (M-H)* E am le ¾ Preparation of N-f Γ2-Τ lR 10-Camphoraulfonvlaminolphenvn-I^-(2-bromophenvnurea a) Prepararion of 2-((lR)-10-Camphorsulfonylamino)aniline The title compound was prepared according to General Method C using ( 1R)(-)-10-camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenedianiine (500 mg, 4.6 mmol). The reaction mixture was partitioned between water (200 mL) and toluenetmethylene chloride(l:3). The organic phase was separated and the methylene chloride evaporated leaving the toluene. Hexane was added and the product precipitated from solution. (563 mg, 38%). EI-MS m z 323 (M+H)+ b) I¾pararion ofN-[[2-(lR 10-Cai^hoisulfonyiamm bromophenyl)urea The title compound was prepared from [1-(1R)-10-camphorsulfonylammoaniline] (563 mg, 1.75 mmol) and 2-(bromophenyl)isocyanate (346 mg, 1.75 mmol) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (263 mg, 29 %) EI-MS m/z 518 (M-H)" Example 134 Preparation of N-r2-r2-f2-Nitro-(4-mfluoromethvl^ bromophenvnurea a) Preparation of [2-[(2-NitroM4-trifluoromemyl)pte The title compound was prepared according to General Method C using 2-nitro-4-(trifluoromethyl)benzenesulfonyl chloride (1 eq). The product was purified by flash chromatography on silica gel ( methylene chloride:methanol 96/4) (87S mg, 25 %) EI-MS m z 362 (M+H)+ b) .Preparation of N-[2-[2-(2-Niti -(4-tri^ (2-bromophenyl)urea The title compound was prepared from [2-[(2-rntroM4-trifluoromethyl) phenyl]sulfonylammojaniline (740 mg, 2.1 mmol) and 2-(bromophenyl)isocyanate (406 mg, 2.1 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70). The product was further purified by recrystallization in ethyl acetate:hexane. (320 mg, 28 %) EI-MS m/z 557 (M-H)" Ex,ampte ¾35 Preparation of N-f -hvdroxv-4-azidophenvlVN,-f2-iodophenvnurea a) Preparation of N-(2-hydroxy-4-aminophenyl)-N,-(2-iodophenyl)urea To a solution of N-(2-hydroxy-4-nitrophenyl)-N>(2-iodophenyI)urea (220 mg, 0.55 mmol) in ethanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl acetate (3x). The organic extracts were combined, dried over MgS04, 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-azidopheny l N,-(2-iodopheny l)urea The N-(2-hydroxy-4-arninophenyl)- '-(2-iodophenyl)urea(77 mg, 0.21 mmol) was added to HCI H2O (0.21 mL 0.42 mL), and cooled to 0°C. Sodium nitrate (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5: 1) gave product (20 mg, 24%). EI-MS m z 396 (M+H)+.

Example 136 Preparation of N-ri-hvdroxv-S-azidophenvlVN'-^bromophenvl^ima a) Preparation of N-(2-hydroxy-3-anunophenyl)-N,-(2-bromophenyl)urea To a solution of N^-hydroxy-S-nitrophenylVN'^-bromophenyOurea (300 mg, 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl acetate (3x). The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z 323 (M+H)+. b) Preparation of N(2-hydroxy-3-azidophenyl)- '-(2-bromophenyl)urea The N^2-hydroxy-3-ammophenyl)-NX2-bromophenyl)iirea(274 mg, 0.85 mmol) was added to HCI/H2O (0.85 mL 1.7 mL), cooled to 0°C Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 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 stirred at room temperature for 18 hours then it was extracted with three times with ethyl acetate. The organic extracts were combined, dried over MgSO.}, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5: 1) gave product (210 mg, 71%). EI-MS m/z 349 (M+H)+.

Ex ple 1 7 Preparation of N.r2-hvdroxv-3-cvanophenvn- ,-r2-methoxvphenvn urea N-[2-hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] 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 precipitation from methylene chloride hexane(lequiv. 20equiv.) and filtering. (230 mg, 8l%). H MR (CD3OD): d 8.06 (d, 1H), 7.79 (d, 1H), 7.49-7.35 (m, 2H), 7.05-6,87 (m, 3H), 3.95 (s, 3H).

Example 1 ¾ Preparation of N.r^-hvdroxv-^-cvanophenvn-N'-f trifluoromethviphenvn urea N-[2-hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyI] urea was prepared from 2-amino-6-cyanophenol (134mg, 1.00 mmol, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequivJ20equiv.) and filtering. (280mg, 87%). ½ NMR (CD3OD): d 8.10 (d, IH), 7.96 (s, IH), 7.54 (d, IH), 7.55-7.25 (m, 3H), 7.01 (t, IH).

Example 139 Preparation of N-r2-hvdroxv-3-cvanophenvn-N'-r2-phenvlphenvn urea N-P-hydroxy-S-cyanophenyll- T-P-phenylphenyl] urea was prepared from 2-amino-6-cyanophenol (134mg, 1.00 mmol, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv720equiv.) and filtering. (270mg, 82%). H NMR (CD3OD): d 7.81 (d, IH), 7.75 (d, IH), 7.56-7.15 (m, 9H), 6.91 (t, IH).

Example 140 Preparation of N-f2-hvdroxv-3-cvanophenvn-N,-r2.3-dichlorophenvn urea N-[2-hydroxy-3-cyanophenyl3-N'-[2,3 dichlorophenyl] urea was prepared from 2-amino-6-cyanophenol (134mg, 1.00 mmol, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( lequivJ20equiv.) and filtering. (300mg, 93%). ½ NMR (CD3OD): d 8.11 (d, IH), 8.01 (d, IH), 7.33-7.25 (m, 3H), 7.00 (t, IH).

Example 141 Preparation of N-r2-hvdroxv-4-»sopropvlphenvn-N'-r2-3-dichlorophenvn urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2 -dichlorophenyl] urea was prepared from 2-amino-5-isopropylphenol (150 mg, 1.00 mmol, example 128a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( lequiv 20equiv.) and filtering (285mg, 84%). lK NMR (CD3OD): d 8.05 (d, 2H), 7.77 (s, IH), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m, IH), 1.25 (d, 6H).

Example 142 Preparation of N-rc.hvdroxv^isopropvlphenvlW^ urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-^ urea was prepared from 2-amino-5-isopiOpylphenol (ISOmg, 1.00 mmol, example 128a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequivV20equiv.) and filtering. (275mg, 82%). ½ NMR (CD3OD): d 8.50 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.22 (d, 1H), 6.70 (m, 2H), 6.62 (dd, 1H), 2.76 (m, (1H), 1.16 (d, 6H).

Preparation of N-r2-hvdroxv-3-phenvlphenvn-N'-r2.3-dichlorophenvn urea a) Preparation of 2-nitro-6-phenylphenol 2-phenylphenol (3.00g, 17.6rnmol) was dissolved in methylene chloride(40ml) followed by the addition of sodium nitrate (1.65g, 19.4mmol). The addition of sulfuric acid (25ml/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSCU and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH CH2CI2) gave the desired product(900 mg, 24 %). lH NMR (CD3COCD3): d 8.19 (d,lH), 7.79 (d-lH), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H). 7.22 (t, 1H). b) Preparatipn of 2-amino-6-phenylphenol To a solution of 2-rutro-6-phenylphenol(900 mg, 4.2mmol) in memanol(50ml) 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH CH2CI2) gave the desired product(700 mg, 90 %). ½ NMR (CD3OD): d 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H) c) Preparation of N-P-hydroxy-S-phenylphenyU-N'-P^-dichlorophenyl] urea N-^-hydroxy-S-phenylphenyll-N-P^-dichlorophenyl] urea was prepared from 2- amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv 20equiv.) and filtering. (150mg,81%). lH NMR (CD3OD): d 8.06 (d, 1H),7.65 (d, 1H), 7.54 (d, 2H),7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88 Preparation of N-P-hydrox -S-phenylphenyil-iT-f^S-dichlorophenyl] urea b)N-[2-hydroxy-3-phenylphenyI]-N,-[2,3-dichlorophenyl] urea was prepared from 2-amino-6-phenylphenoi (92.5mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride hexane(lequiv./20equiv.) and filtering. (150 mg, 81 ). lH NMR (CD3OD): d 8.06 (d, 1H),7.65 (d, IH), 7.54 (d, 2H),7.40 (t, 2H), 7.32 (d. IH) 7.22 (m, 2H), 7.04-6.88 (m, 2H).

Example 144 Preparation of N-r2-hvdroxv-5-nitroDhenvn-N'-r2-methoxvphenvn urea N-[2-hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-amino-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( lequiv720equiv.) and filtering. (270 mg, 89%). ½ NMR (CD3OD): d 9.10 (s, IH), 8.10 (d, IH), 7.85 (d, IH), 7.08-6.88 (m, 4H), 3.96 (s, 3H).

Example 145 Preparation of N-f2-hvdroxv-5-nitTophenvn-N'-r3-trifluoromethvlphenvn urea N-[2-hyo^xy-5-mtrophenyl]-l^-[3-trifluoromethylphenyl] urea was prepared from 2-amino-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(lequiv720equiv.) and filtering. (290 mg, 85%). ½ NMR (CD3OD): d 9.12 (s, IH), 7.89 (d, IH), 7.68 (d. IH), 7.55 (m, 2H), 7.45 (d, IH), 7.00 (d, IH). fi ampte H$ Preparation of N-r2-hvdroxv-5-nitrophenvn-N,-r2-phenvlphenvn urea N-[2-hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-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. (285 mg, 81%). ½ NMR (CD3OD): d 8.09 (s, IH), 7.86 (d, IH), 7.58-7.20 (m, 9H). 6.95 (d, IH).

Exa le ¾47 Preparation of N-f2-hv(iroxv-5-nitrophenvn-N,-r2.3-dichloronhenvn urea N-P-hydroxy-S-nitrophenyn-N-P^-dichlorophenyl] urea was prepared from 2-amino-4-nitrophenoi (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%). lH NMR (CD3OD): d 9.11 (s, 1H), 8.17 (d. 1H), 7.89 (d, 1H), 7.34 (m, 2H), 6.95 (d, 1H).

Exam le H8 Preparation of N-r2-hvdroxv-5-ethvlsalfonv henvn-N,-r2.3-dichlomph-»nv nma N-[2-hydroxy-5-ethylsiilfonylphenyl]- T-[2,3- The following compounds of Formula (I) have been prepared in accordance with the examples and schemes as described above: Example 149 : N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N*-(2-bromophenyl)ureaEI-MS m z 527 (M-H)".

Example 150 : N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-{2-bromo phenyl) ureaEI-MS m z 426 (M+H)+; Example 151 : N-[2-[2-i4-CWoro-3-arnmophenyl)sulfonylammo]phenyl]-N*^ bromophenyl)urea Example 152 : N-[2-(3-Ammophenyl)sulfonylaminophenyi]-N'-(2-bromophenyl)urea Example 153 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyl)urea EI-MS m z 302.3 (M-H)".

Example 154 : N-(2-Hyo^xy-3-nitrophenyl)->r-(4-methoxyphenyl)urea urea EI-MS m/z 302.3 (M-H)'.

Example 155 : N^-Hyo^xy-S-nitrophenyl^ -iS-trifluoromethyphenyliurea urea EI-MS m z 340.3 (M-H)" Example 156 : N^-Hydroxy-S-nitrophenylJ-N'^-phenylpheny^urea ½ NMR (DMSO), 8.83(lH,s) 8.63(lH,s), 8.41 (lH-d) 7.79 (lH,d), 7.56 (lH,d) 7.51-7.32 (6Hjn) 7.23 (lH,ds) 7.18 (1H ) 6.97 (lH,t) Example 157 : N-(2-Hydroxy-3-nitrophenyl)-N,-(2,3dichlorophenyl) EI-MS m z 340.3 (M-H)" Example 158 : N^-Hydroxy-S-nitrophenylVN' ^phenylphenyl) EI-MS m/z 348.3 (M-H)" Example 15 : N-(2-Hytoxy-3-mtrophenyl)-N'-(2,4^ m/z 333.4 (M+H)+; 43 Example 160 : N-(2-Hydroxy-3-oitrophenyl)-N 2I^-(2,3-<-UcWorophenyl)uiea lH NMR (DMSO): 5 10.00 (lH,s) 9.05 (l¾s) 8.93 (lH,s) 8.19 (lH,dd) 8.00 (lH,dd) 7.72-7.42 (7Hjn) 7.35 (lH,d) 7.32 (lH,s) Example 192 : N-[(Beiizylsulfonylanuno)-5-cyanop EI-MS m/z 474.0 (M-H)- Example 193 : N-[(2-Phenylsulfonylammo)-4-2-hydroxy^nitrophenyl)- '-phenylurea The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above, or as indicated by their respective citations in Chemical Abstracts: 1 -(m-Anisyl)-3-(2-carboxyphneyl)urea l-(o-Anisyl)-3-(2-carboxyphenyl)urea H2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea l 2-C^rboxyphenyl)-3-(2,4-dichlorophenyl)urea METHOD OF TREATMENT The compounds of Formula (I), (la), (lb), (Ic), (Π), (Ha), (lib). (He), and (ΙΠ), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages, or other chemokines which bind to the IL-8 a or b receptor, also referred to as the type I or type Π receptor.

For purposes herein, the compounds of Formula (I), (la), (lb), (Ic), (Π, (Ha ), (lib), (13c), and (ΙΠ) all have the same dosages, and dosage formulations as that of Formula (I) and are used interchangeably.

Accordingly, the present invention provides a method of treating a chemokine " mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokines ars IL-8, GROa, GROP, GROy or NAP-2.

The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GROa, GROP, GROyor NAP-2 , such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state. Abnormal levels of IL-8, GROa, GROp, GROy or NAP-2 for instance in the context of the present invention, constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GROa, GROp, GROyor NAP-2 above normal physiological levels: or (iii)the presence of IL-8, GROa, GROP, GROyor NAP-2 above basal levels in cells or tissues in which IL-8, GROa, GROp, GROy or NAP-2respectively, is produced.

There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating 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, ulcerative 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, malaria, restinosis, angiogenesis or undesired hematopoietic stem cells release.

These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with increased IL-8 GROa, GROP, GROy or NAP-2 production which is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 GROa, GROp, GROy or AP-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 a-chemokines but particularly, GROa, GROP, GROy or NAP-2, working through the IL-8 type I or Π receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.

The compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of 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 of both recombinant type I and type Π IL-8 receptors. Preferably the compounds are inhibitors of only one receptor, preferably Type Π.

As used herein, the term "IL-8 mediated disease or disease state" refers to any and all disease states in which IL-8, GROa, GRC^, GROy or NAP-2 plays a role, either by production of IL-8, GROa, GRC^, GROy or NAP-2 themselves, or by IL-8 GROa, GRO , GROy or NAP-2 causing another monokine to be released, such as but 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 therefore be considered a disease stated mediated by IL-8.

As used herein, the term "chemokine mediated disease or disease state" refers to any and all disease states in which a chemokine which binds to an IL-8 a or b receptor plays a role, such as but not limited to IL-8, GROa, GRO^ GROy 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 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 therefore be considered a disease stated mediated by IL-8.

As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interieukin-6 (JL-6), Interleukin-8 flL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-β).

As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term "cytokine" above. A chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Examples of chemokines include, but are not limited to, 1L-S GROa, GRO , GROy, NAP-2, IP-10, MlP-la, MJP-b, PF4, and MCP 1, 2, and 3.

In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic adniinistration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for adniinistration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w w, more preferably from 0.1% to 1% w/w of the Formulation.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation 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. 7/ Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100 °C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration 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.

For all methods of use disclosed herein for the 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 ISO mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably 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 the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that die optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment detennination tests.

The invention will now be described by reference to the following biological examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

BTOLOGTCAL EXAMPLES The IL-8, and Gro-a chemokine inhibitiory effects of compounds of the present invention were determined by the following in vitro assay: Receptor Binding Assays: [125η IL-8 (human recombinant) was obtained from Amersham Corp., Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro-a was obtained from NEN- New England Nuclear. All other chemicals were of analytical grade. High levels of recombinant human IL-8 type a and b receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, etaL, 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 homogenization buffer was changed to lOmM Tris-HCL, lmM MgS04, OJmM EDTA (ethylene-diaminetetra-acetic acid), lmMPMSF (a-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, 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 125I IL-8 (0.25 nM) or 125I Gro-a and 0.5 μg/mL of JL-8Ra or 1.0 μgΛnL of IL-8Rb membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 12 mM MgS04, 0.1 mM EDTA, 25 mM Nad 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 O.OlnM and 100 uM. The assay was initiated by addition of ^I-IL-8. After 1 hour at room temperature the plate was harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/0.5% BSA and washed 3 times with 25 mM Nad, 10 mM TrisHCl, 1 mM MgS04, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter was then dried and counted on the Betaplate liquid scintillation counter. The recombinant IL-8 Ra, or Type L receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rb, or Type Π, receptor is referred to as the permissive receptor.

All of the exemplified compounds of Formulas (I) to (ΙΠ) noted herein in the Synthetic Chemistry Section, of Examples 1 to 222 plus the additional purchased compounds demonstrated an IC50 from about 45 to about <1 pg mL in the permissive models for IL-8 receptor inhibition. All of these compounds were also found to be inhibitors of Gro-a binding at about the same level. The compound l-(2- Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea was found to be active at about 75 pg/mL.

The following compounds, generally tested at levels of up to 45 ug/mL were found to not demonstrate levels of IL-8 receptor antagonism within the criteria set forth above at the dosage levels tested. These compounds are: l-(4-Chloro-alpha,alpha,alpha-trifluoi^ chlorophenyl urea l-(6-ChIoro- pha,alpha^pha-tr^ chlorophenyljurea l-(2-Mercaptophenyl)-3-phenyl-2-thiourea l-(2-Hydroxyphenyl)-3-phenyl-2-thiourea 3 '-(Carbonothioyldiiiiiino)bis[4-hydroxybenzoic acid] in^41,3-tMoureylene)di(4-hydroxybenzoic acid) H2-Tolyl)-3 3-cWoro^hydroxyphenyl)-2-thiourea l-{(2-Hydroxy-4-aminophenyl)]-(3-phenyl)-urea N-(2-(½rboxy-4-trifluromemy^ N-(2-Qtfboxyphenyl)-N'-(2,5-dichlorophenyl)urea 1- <2-C^oxyphenyl)-3-(2-Chlorc--5-trifluoromethylphenyl)urea 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid; 2- [2-[3-(4-CblorophenyI)ureido]phenoxy]benozic cid 2-[2-[3K4-CUoro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid N- (2-Hydroxyphenyl) -N'-phenyi urea N-P-Hydroxy-S-imethoxycarbonylJphenylJ-N'-phenylurea N-t^Carboxy^-hydroxyphenyll-n'-phenylurea N-(2-Hydroxy^nitrophenyl)-NX -nitrophenyl)urea; l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea l-(6-Carboxy-2,4^chlorophenyl) -(2,4,6-tricUorophenyl)ui^ H2 ;arboxyphenyl)-3-(2^-dimethoxyphenyl)urea l-(2-Carboxyphenyl)-3-(2-methylphenyl)urea l-[(2-HydroxyphenyI)-3 2-methyl)-5-mtrophenyl]iirea l-(2,5-Dichlorophenyl)-3-(2-hydroxy-4-nitrophenyl)urea 1 -(2 !arboxyphenyl)-3-(4-chloro-2-methy lphenyl)urea N-(2-phenylsuIfohylanunophenyl-l T-phenylurea N-(2-Hydroxy-4-nitrophenyl)- T-{4^thoxycarbonylphenyl)uiea N-(2-Hydimy-4-niaOphenyl)-^ N-(2-Hydbroxy-4Hiitrophenyl)-^ N^-Hydroxy^nitrophenyl^N'-i^phenylpnenylJurea N-(2-Hydroxy^nitrophenyl^-<4-phenoxyphenyl)urea N-(2-Hydroxy^mtrophenyl>I^K4-propyiphenyl)urea N-(4-Trifluromethyl-2-(4-iutrobenzenesulfon^^ N-(3-CIarboxyphenyl)-^-2-hydroxy-4-nitrophenyl)urea N-(2-Hyclroxy-4-mtiOphenyl ^-[2 isopropyI)phenyl)ur^ N-(2-Hydroxy-4-rutrophenyl)-N'-(2,6-dime-hylphenyl)urea N-(2-Hydroxy-4-nitrophenyl -(2-fluoi^ N-(2-Hydroxy-4-nitrophenyl)-N,-(2-cUoro-5-trifluromethylph^ N-(2-Hydroxy-4-nitrophenyl)-I^ N-(2-Hydroxy-l-napthyl)- ,-(2-phenylphenyl)urea N-(2-Hydroxy-5^thykulfonylphenyl)-^-(2-biX)mophenyl)urea N-(2-hydroxy 3,4 dichlorophenyl > T-(4-phenylphenyI)urea N-(2-hydroxy-3-naphthyl)-N'-(2-me±oxyphenyl)urea N-(2-hydroxy-3-naphthyl)-N,-(2-phenylphenyl)urea N-(2-Hydroxy-3-naphthyl> 4-methoxypbtoyl)urea N-(2-Hydroxy-3-ruphthyl)-N 3-trifluoromethylphenyl)urea N^-Hydroxy-S-na hthyl^K^phenyl hen urea N-[2-(2-Carboxyphenylsulfonylan^ N-(2-Hydroxy -phenylphenyl)-Isr-(2-methoxyphenyl)urea N-(2-Hydroxy-3-phenylphenyl N'-(4-inethoxyphenyl)urea N-(2-Hydroxy-3-phenyiphenyl)- -(3-a^ N-(2-Hydroxy-3-phenylphenyl)-N,-(2«phenylphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(4-phenylphenyl)urea N-(2-[(2,5-DicWorotMen3-yl)sulfo^ N-(2-Hydroxy,3,4-dichlorophenyI)-N,-{2,4 dimethoxyphenyl)urea N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2^Uoro-5-triflorom^ N-(2-Hydroxy-3-naphthyl)- ,-{2,4 dimethoxyphenyl)urea N-(2-Hydroxy-3-naph±yl)-N'-{2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-3 phenylphenyl)-^2,4-dimethoxyphenyl)urea N-(2-Hydroxy^isopropylphenyl N 2,4-diniethoxyphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-NX2T-(2-chlor^ N-(2-Hydroxy-3-cyanophenyl)-N,-(4-methoxyphenyl)uiea N-(2-Hydroxy-3-cyanophenyl)- '-(4-phenylphenyl)urea N-(2-Hydroxy w:yanophenyI ^-(2,4 diniethoxyphenyl)urea N-(2-Hydroxy-3-cyanophenyl)-N^2^2-methoxyphenyl)uiea N-(2-Hydroxy- 5-phenylphenyl)-N'-(4-methoxyphenyl)urea N-(2-Hydroxy- 5-phenylphenyl)-N 3-trifluoromethylpheoyl)ur^ N 2-Hydroxy- 5-phenylphenyl)- *-(2-phenylphenyl)urea N-(2-Hydroxy-5-phenylphenyl)- ,-(4-phenylphenyl)urea N^-Hydroxy-S-phenylphenyl '^.S-dichloropheny urea N 2-Hydroxy-5-phenylphenyl)-NH2,4-dimet oxyphenyl)urra N-(2-Hydroxy-5-phenylphenyl W^2 At the end of the incubation period, the polycarbonate membrane was removed and the top side washed, the membrane was then stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, XL, USA). Cell which had chemotaxed to the chemokine were visually counted using a microscope. Generally, four fields where counted for each sample, these number where averaged to give the average number of cells which had migrated. Each sample was tested in triplicate and each compound repeated at least four times. To certain cells (positive control cells) no compound was added, these cells represent the maximum chemotactic response of the cells. In the case where a negative control (unstimulated) was desired, no chemokine was added to the bottom chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells.

Elastase Release Assav: The compounds of this invention where tested for their ability to prevent Elastase release from human neutrophils. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1. PMNs 0.88 x 106 cells suspended in Ringer's Solution (NaCl 118, KCl 4.56, NaHC03 25, H2P04 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) where placed in each well of a 96 well plate in a volume of 50 uL To this plate was added the test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug ml) and Ringers buffer in a volume of 50 ul. These cells where allowed to warm (37 °C, 5% C02, 95% RH) for 5 min before BL-8, GROa, GROb, GROg or NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction was allowed to proceed for 45 min before the 96 well plate was centrifuged (800 xg 5 min) and 100 ul of the supernatant removed. This suppernatant was added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc-Ala- Ala-Pro- Val-AMC, Nova Biochem, La -Jolla, CA) to a final concentration of 6 ug ml dissolved in phosphate buffered saline. Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofiuor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al J. Biol Chem 2544027 (1979). The amount of Elastase released from the PMNs was calculated by measuring the rate of MeOS uc- Ala- Ala-Pro- Val-AMC degradation.

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of me embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration* it is believed mat one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent Therefore the-Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims (1)

1. What is 1 A method for a phenol derivative of the wherein is independently selected from a hydroxy substituted aryi CM heteroaryl heteroaryl C heterocyclic alkenyl 1 i or two moieties together may form or a 5 to 6 memhered unsaturated and wherein the heterocyclic may be optionally R4 and Rs are optionally optionally vyl optionally substituted heteroaryl heterocyclic C or R4 and together with the nitrogea to which they are attached form 5 to 7 member ring which may optionally comprise an additional selected from Rg hydrogea or C is C aikyl is optionally substituted C optionally optionally aryl optionally substituted heteroaryl optionally substituted optionally substituted or optionally substituted Rl3 is suitably aryl C heteroaryiC 1 or t is an integer from 0 to q is an integer from 0 to and s is an integer from 1 to method comprises of the wherein X is halogen with copper triethylamine and a catalytic amount of dimethylamino The process according to Claim wherein the temperature is about 60 to about and X is LU2ZATT0 insufficientOCRQuality