NZ514695A - IL-8 receptor antagonists - Google Patents

IL-8 receptor antagonists

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Publication number
NZ514695A
NZ514695A NZ514695A NZ51469500A NZ514695A NZ 514695 A NZ514695 A NZ 514695A NZ 514695 A NZ514695 A NZ 514695A NZ 51469500 A NZ51469500 A NZ 51469500A NZ 514695 A NZ514695 A NZ 514695A
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NZ
New Zealand
Prior art keywords
urea
hydroxy
phenyl
alkyl
mmol
Prior art date
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NZ514695A
Inventor
Gregory Martin Benson
Robert P Hertzberg
Anthony J Jurewicz
Melvin Clarence Rutledge
Daniel F Veber
Katherine L Iddowson
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Smithkline Beecham Corp
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Publication of NZ514695A publication Critical patent/NZ514695A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are phenyl urea compounds of formula (I) that is useful for the prophylactic or therapeutic treatment of a chemokine mediated disease such as atherosclerosis, wherein the chemokine is one that binds to an IL-8 a or b receptor, and wherein the variables are as disclosed in the specification.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 514695 <br><br> 514695 <br><br> WO 00/76495 PCT/US00/16499 <br><br> IL-8 RECEPTOR ANTAGONISTS <br><br> FIELD OF THE INVENTION <br><br> This invention relates to a novel group of phenyl urea compounds, processes for 5 the preparation thereof, the use thereof in treating IL-8, GROa, GROP, GROy and NAP-2 mediated diseases and pharmaceutical compositions for use in such therapy. <br><br> BACKGROUND OF THE INVENTION <br><br> Many different names have been applied to Ihterleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil 10 chemotactic factor (MDNCF), 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, n^ip or LPS, and by neutrophils themselves when exposed to US or 15 chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84,1045 <br><br> (1989); J. Schroder et al, J. Immunol. 139,3474 (1987) and J. Immunol. 144.2223 <br><br> (1990) ; Strieter, et al, Science 243.1467 (1989) and J. Biol. Chem. 264.10621 (1989); Cassatellaet al, J. Immunol. 148. 3216 (1992). <br><br> GROa, GROp, GROy and NAP-2 also belong to the chemokine a family. Like 20 IL-8 these chemokines have also been referred to by different names. For instance <br><br> GROa, p, y have been referred to as MGSAa, P and 7 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. 25 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-Iymphocytes, 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 30 enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 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 neutrophil infiltration. As IL-8, GROa, GROp, GROy and NAP-2 promote the 35 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. Resoir. Pis. 146.427 <br><br> - 1 - <br><br> WO 00/7(495 <br><br> PCT/US00/16499 <br><br> (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). <br><br> In vitro, IL-8, GROa, GROp, GROy and NAP-2 induce neutrophil shape 5 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 10 precedent For a review see R. Freidinger in: Progress in Drug Research. Vol. 40. pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the DLr8 receptor represents a promising target for the development of novel anti-inflammatory agents. <br><br> Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8R0, which 15 has high affinity for IL-8 as well as for GRO-a, GRO(3, GROy and NAP-2. See <br><br> Holmes et al., supra; Murphy et al., Science 253.1280 (1991); Lee et al., J. Biol. Chem. 267,16283 (1992); LaRosa et al., J. Biol. Chem. 267.25402 (1992); and Gayle et al., J. Biol. Chem. 268.7283 (1993). <br><br> There remains a need for treatment, in this field, for compounds which are 20 capable of binding to the IL-8 a or p 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. <br><br> Intellectual Property Office of NZ <br><br> 10 MAR 2004 <br><br> aECtivfeP <br><br> SUMMARY OF THE INVENTION <br><br> This invention provides the use of a compound of Formula (I) in the manufacture of a medicament for the prophylactic or therapeutic treatment of atherosclerosis; with the proviso that the compound of Formula (I) is not selected from the compounds listed on page 91, line 35 to page 94, line 4 herein. <br><br> Described herein is a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or P receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8. <br><br> Also described herein is a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I). <br><br> Compounds of Formula (I) useful in the present invention are represented by the structure: <br><br> n(Y) <br><br> 'Ri)m <br><br> (D <br><br> wherein: <br><br> InteHectual Property Office of NZ <br><br> to mar 2004 <br><br> 2a <br><br> 100069170J.DOC <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> X is oxygen or sulfur; <br><br> R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; <br><br> Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cj-io alkyl; Ci-io alkyl; C2-10 alkenyl; Cj-io alkoxy; halosubstituted Ci-io 5 alkoxy; azide; S(0)tR4; hydroxy; hydroxy Ci_4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Cj-4alkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4Rs; C(O)NR4Rl0; S(0)3H; S(0)3R8; Ci-io alkyl C(0)Ri 1; C2-10 alkenyl C(0)Rn; 10 C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Rj 1; NR4C(0)Rn; or two Ri moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> 15 R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci_4alkyl, heterocyclic, heterocyclic Ci-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 20 selected from O/N/S; <br><br> Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cj-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxyC 1 -4alkyl; aryl; aryl Cl-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; 25 heterocyclic, heterocyclic Ci_4alkyl; aiyl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4Rs; C(0)NR4R10; S(0)3H; S(0)3R8; Ci-io alkyl C(0)Rji; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Ri 1; NR4C(0)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated 30 ring; <br><br> n is an integer having a value of 1 to 3; <br><br> m is an integer having a value of 1 to 3; <br><br> R8 is hydrogen or Ci-4 alkyl; <br><br> RlO is Cl-10 alkyl C(0)2R8; <br><br> 35 Ri 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl <br><br> Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4 alkyl; <br><br> -3- <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; <br><br> or a pharmaceutically acceptably salt thereof. <br><br> 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 IL-8 or 25 other chemokines which bind to the IL-8 a and (3 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. <br><br> In compounds of Formula CD, R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 30 9, more preferably from about 3 to 7. Such functional groups include, but ate not limited to, hydroxy, carboxylic acid, thiol, -SR2 -OR2. -NH-C(0)Ra, -C(0)NR&lt;&gt;R7, a substituted sulfonamides of the formula -NHS(0)2Rb» -S(0)2NHRc, NHC(X2)NHRb, 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 35 on the aiyl, heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2. More preferably R is OH, SH, or NHS(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. <br><br> DETAILED DESCRIPTION OF THE INVENTION <br><br> Intellectual Property Office of NZ <br><br> -4- <br><br> 10 MAR 2004 <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> Suitably, R6 and R7 are independently hydrogen oraCi-4 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 5 as defined herein. <br><br> Suitably Ra is an alkyl, aryl, aiylCi-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted, as defined herein below. <br><br> Suitably, Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, 10 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 C1-4 alkyl, such as CF3; Ci-4 alkyl, such as methyl; Ci-4 alkoxy, such as methoxy; NR9C(0)Ra; C(0)NR6R7, S(0)3H, or C(0)0Ci_4 alkyl. Rb is preferably an optionally substituted 15 phenyl, benzyl, or styryl. When Rb is a heteroaryl preferably it is an optionally substituted thiazole, optionally substituted thienyl, or optionally substituted quinolinyl ring. Wherein R9 is hydrogen or a Ci_4 alkyl, preferably hydrogen, and suitably when the substituent group is NR9C(0)Ra, then Ra is preferably an alkyl group, such as methyl. <br><br> 20 Suitably Rc is hydrogen, alkyl, aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl, <br><br> heteroarylCi-4alkyl, heteroarylC 1 ^.alkenyl, heterocyclic, or heterocyclic Ci-4alkyl, or a heterocyclic Ci-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Ci-4 alkyl, Ci-4 alkyl, Ci_ 4 alkoxy, NR9C(0)Ra, C(0)NR6R7, S(0)3H, or C(0)0Ci_4 alkyl, wherein R9 is 25 hydrogen or a Ci_4 alkyl. Preferably, Rc is an optionally substituted phenyl. <br><br> 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 30 limited to, halogen, nitro, halosubstituted Ci-4 alkyl, Ci_4 alkyl, Ci-4 alkoxy, <br><br> hydroxy, SH, -C(0)NR6R7&gt; -NH-C(0)Ra, -NHS(0)2Rb, S(0)2NR6R7, C(0)0Rs, or a tetrazolyl ring. <br><br> In compounds of Formula (I), suitably Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; Ci_io 35 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 trifluoromethoxy; azide; S(0)tR4, wherein t is 0,1 or 2; hydroxy; hydroxy Ci-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aiyl Ci-4 alkyl, such as benzyl; aiyloxy, such as phenoxy; aryl Ci-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; <br><br> -5- <br><br> WO 00/76495 PCT/USOO/16499 <br><br> heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; NR4R5; C2-10 alkenyl-C(0)NR4R5; C(0)NR4R5; C(0)NR4Rio; S(0)3H; S(0)3R8; Cl-10 alkyl C(0)Ri 1; C2-10 alkenyl C(0)Ri 1, C2-10 alkenyl C(0)0Ri 1; C(0)Rn; C(0)0Ri2, such as carboxy, methylcarboxylate or phenylbenzoate; OC(O) Ri 1; NR4C(0)Ri 1; <br><br> 5 azido; or two Ri 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 aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties may all be optionally substituted as defined herein below. Preferably Ri is other than azido or S(0)3Rg. 10 When Ri forms a dioxybridge, s is preferably 1. When Ri 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. <br><br> Suitably, R4 and R5 are independently hydrogen, optionally substituted Ci-4 15 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. <br><br> 20 R10 is suitably C1 -10 alkyl C(0)2R8, such as CH2C(0)2H or CH2C(0)2CH3. <br><br> Rl 1 is suitably hydrogen, C1-4 alkyl, aryl, aryl Ci-4 alkyl, heteroaryl, <br><br> heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4alkyl. <br><br> Rl2 is suitably hydrogen, Cl-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl. <br><br> 25 Preferably Ri is halogen, cyano, nitro, CF3, C(0)NR4R5, alkenyl C(0)NR4R5, <br><br> C(O) R4R10, alkenyl C(0)0Ri2, 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 Ri is in the 4-position of the phenyl ring. <br><br> When R is OH, SH or NS02Rb than Ri is preferably substituted in the 3-30 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)NR4R5. <br><br> When R is carboxylic acid, than Rl is preferably hydrogen, or Ri is preferably substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro. 35 In compounds of Formula (I), suitably Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxy Ci-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl Ci_4 alkyloxy; heteroaryl C2-10 <br><br> -6- <br><br> WO 00/76495 PCT/US00/16499 <br><br> alkenyl; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5; C(O)NR4Rl0; S(0)3H; S(0)3Rs; Ci_io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Rn; C(0)Rn; C(0)0Ri2", 0C(0) Ri 1; NR4C(0)Ri 1; azido; or two Y moieties together may form 0-(CH2)sO-5 or a 5 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 other Y moieties as defined above. The aryl, heteroaryl and heterocyclic moieties noted above may all be optionally substituted as defined herein. Preferably Ri is other than 10 azido or S(0)3R8- <br><br> Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci_4alkyl, thioaiyl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, 15 disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2 - position or 2'-, 3-position. <br><br> While Y may be substituted in any of the 5 ring positions, preferably when R is OH, SH, or NS02Rb&gt; Y is preferably mono-substituted in the 2-position or 3-position, with the 4 - preferably being unsubstituted. If the ring is disubstituted, when 20 R is OH, SH, or NS02Rb. substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted. <br><br> In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen. While not explicitly covered by Formula (I), (Ia-c), (II), or (III), another aspect 25 of this invention are the symmetrical bis compounds which are included for each structure. <br><br> Compounds exemplified by this bis like structure include: <br><br> N-(Bis (2-hydroxy-4-nitro phenyl) N'-(dianisdine) diurea; and 4-Methylene bis(N-(2-chloro phenyl) N'-(2-hydroxy 4-nitro phenyl) urea). Exemplified 30 compounds of Formula (I) include: <br><br> N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea; N-[5-Nitro-2-hydroxyphenyl]-N'-phenyl urea; <br><br> 3-Hydroxy-4- {[(phenylamino)carbonyl] amino }benzamide N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea; 35 2- {[(Phenylamino)carbonyl]amino} thiphenolN-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea; <br><br> N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea; <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-(4-Nitro-2-(phenylsulfonylamino)phenyl)-N-phenyl urea; N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea (N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea; 5 N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxyphenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl)imea N-(2-Hydroxy-4-nitrophenyl)-N-(2-trifluoromethylphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea; 10 N-(2-Hydroxy-4-nitrophenyl)-N-(3-bromophenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(1 -naphthyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl)urea;N-(2-Hydroxy-4-nitrophenyl)-N-(2-fluorophenyl)urea 15 N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(2-ethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N-(2-trifluoromethoxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea 20 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-bromophenyl) urea; <br><br> N-(4-Carbomethoxy 2-hydroxy phenyl) N-(2-bromophenyl) urea; N-(4-Trifluoromethyl-2-hydroxy phenyl) N-(2-phenyl phenyl) urea; 25 N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea; <br><br> N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea;N-(2-Hydroxy-4-nitrophenyl) N'-(2,4-dichloro phenyl) urea; <br><br> N-(2-Hydroxy-4-nitrophenyl) N-(2-chloro phenyl) urea; <br><br> N-(2-Hydroxy-4-nitrophenyl) N-(2,4-dibromo phenyl) urea; 30 N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea;N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea;N-(2-Hydroxy-4-nitrophenyl) N'-(2-methyl phenyl) urea; <br><br> N-[4-(Benzylamino)carbonyI-2-hydroxyphenyl]-N,-(2-bromophenyl)urea; 35 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxy phenyl) urea; N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea;N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea; N-(3,4-Difluoro 2-hydroxy phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea;N-(2-Hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea; <br><br> -8- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-(2-Hydroxy-4-nitro phenyl) N'-(2-phenylamino phenyl) urea; <br><br> N-(2-Hydroxy 3-carboxyphenyl) N'-(2-bromo phenyl) urea N-(2-Sulfhydiyl 4-bromo phenyl) N-(2-bromo phenyl) urea;N-(2-Hydroxy 4-nitro phenyl) N-(2-iodo phenyl) urea; N-(2-Hydroxy 4-nitro phenyl) N-(2-bromo phenyl) 5 thiourea;N-[(2-Phenylsulfamido) 4-cyanophenyl]- N-(2-bromo phenyl) urea; N-(2-(Amino sulfonamide phenyl) phenyl) N-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea;2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N-(2-bromo phenyl) urea; N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N-(2-bromo phenyl) urea; 10 N-(2-(Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl (3-tolyl) phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl benzyl) phenyl) N-(2-bromo phenyl) urea; N-(2-Hydroxy-4-azidophenyl)-N-(2-methoxyphenyl)urea; 15 N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea; 20 N-[2-Hydroxy-3,4-diphenyl-phenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N-[2-bromophenyl] urea; N- [2-hHydroxy-3-glycincarbonylphenyl] -N[2-bromophenyl] urea; N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-3,4-25 dichlorophenylJ-N'-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-4-cyanophenyl]-N-[4-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N-[2-phenylphenyl] urea; <br><br> 30 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea; <br><br> N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea;N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea; SN-[2-Hydroxy-4-ethylphenyl]-N'-[2-35 bromophenyl] urea; <br><br> N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-cyano-4-methylphenyl]-N-[2-bromophenyl] urea;N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea; <br><br> -9- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-[3-Benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl] urea; <br><br> (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea; (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N-[2-bromophenyl] urea-N'-[2-bromophenyl] urea; <br><br> 5 (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea-N -[2-bromophenyl] urea; <br><br> (E)-N-[4-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea; 10 N-[4-Aminocarbonyl-2-hydroxyphenyl]-N-[2-bromophenyl] urea; N-(2-Hydroxy-3,5,6-trifluorophenyl)-N-(2-bromophenyl)urea; N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea;N-(2-Hydroxy-3-iodophenyl)-N-(2-bromophenyl)urea; <br><br> N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea; 15 N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea; N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea; N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea;N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N-[2,3-dichlorophenyl] urea; 20 N-[2-Hydroxy-4-cyanophenyl]-N-[2-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N-[3-methoxyphenyl] urea; N-[2-Hydroxy-5-fluorophenyl] -N'-[2-bromophenyl] urea; N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea;N-[Trans-3-styrl-2-hydroxyphenyl]-N-25 [2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2-methoxyphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N-[4-methoxyphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea;N-[2-Hydroxy-3,4-30 dichlorophenyl]-N-[4-phenylphenyl] urea; <br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea; N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea;N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea;N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N-(2-bromophenyl)urea;N-[2-[(3,5-35 Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea;N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea; N-[2-[2-(3-Nitrophenyl)sulfonylaxnino]phenyl]-N'-(2-bromophenyl)urea; N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea; N-[[2-(lS)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea; <br><br> -10- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-[[2-(lR)- 10-Camphorsulfonylamino]phcnyl]-N'-(2-bromophenyl)urca; <br><br> N-[2-[2-(2-Nitro-(4-tn#uoromethyI)phenyI)sulfc®ylaimno]phenyl-N-(2-bromophenyl)urea; <br><br> N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea^-(2-Hydroxy-3-azidophenyl)-5 N-(2-bromophenyl)urea;N-[2-Hydroxy-3-cyanophenyl]-N-[2-methoxyphenyl] urea;N-[2-Hydroxy-3-cyanophenyl]-N-[3-trifluoromethylphcnyl] urea; N-[2-Hydroxy-3-cyanophenyl]-N-[2-phenylphenyl] urea; N-[2-Hydroxy-3-cyanophcnyl]-N'-[23-&lt;iichlorophenyl] urea; N-[2-Hydroxy-4-isopropylphenyl]-N-[2,3-dichlorophenyl] urea; 10 N-[2-Hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea; <br><br> N-[2-Hydroxy-3-phenylphenyl]-N-[2,3-dichlorophenyl] urca;N-[2-Hydxoxy-5-nitrophenyl] -N - [2-methoxyphenyl] urea;N-[2-Hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea;N-[2-Hydroxy-5-nitrophenyl]-N-[2-phenylphenyl] urea; N-[2-Hydroxy-5-nitrophenyl]-N-[2,3-dichlorophenyl] urea^N-[2-Hydroxy-5-15 ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea;N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N-(2-bromophenyl)urea;N-[2-(Aminosulfonyl phenyl) 3-amino phenyl] N-(2-bromo phenyl) urea;N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2,4 dimethoxyphenyl] urea; <br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2-chloro-5-trifluoromethylphenyl] urea; 20 N-[2-Hydroxy-3-naphtbyl]-N-[3-trifluoromethylphenyl] urea; <br><br> N-[2-Hydroxy-5-naphthalenesulfonic acid]-N-[2-bromophenyl] urea; N-[2-Hydroxy-4-naphthalenesulfonic acid]-N-[2-bromophenyl] urea; l,l'-(4-Methyl-2-phenylene)bis[2-thio-3-3-tolylurea] N-(2-Caiboxyphenyl)-N-phenylurea; 25 N-(2-Hydroxy-4-nitrophenyl)-N-phenylurea; l-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea; 2-(3,4-Dichlorophenylcarbonyldiimino&gt;5-trifluoromethylbenzoicacid; 2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid; l-(p-Anisyl&gt;3-(2-carboxyphenyl)uiea; 30 l-(2-Caii)oxyphenyl)-3-(3-fluorophenyl)urea; l-(2-Carboxyphenyl)-3-(3-chlorophenyl)urea; <br><br> 1 -(m-Anisyl)-3-(2-carboxyphneyl)urea; <br><br> 1 -(o-Anisyl)-3-(2-carboxyphenyl)urea; l-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea; 35 1 -(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea; <br><br> N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N-phenylurea; and Preferred compounds of Formula (I) include: N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea; <br><br> -11- <br><br> IntoHectual Property <br><br> Office of N2 <br><br> 10 MAR 2004 <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(2-phenylphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methy]thiophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(2,3-dichlorophenyl)urea; <br><br> 5 N-(2-hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2,3-methylenedioxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea; <br><br> N-(2-hydroxy 4-nitro phenyl) N-(2-phenyloxy phenyl) urea; N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea; 10 N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea; N-(3-Nitro-2-hydroxyphenyl)-N'-&lt;2-bromophenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea; N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea; N-(3-Cyano-2-hydroxyphenyl)-N-(2-bromophenyl)urea; 15 N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N-(2-phenylphenyl)urea; N-(2-Hydroxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea; N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea; 20 N-(4-Cyano-2-hydroxyphenyl)-N-(2-trifluoromethylphenyl)urea; N-(3-Trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea; N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea; <br><br> N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea; <br><br> N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea; 25 N-(2-phenylsuIfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea; <br><br> (E)-N-[3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N-(2-bromophenyl)urea; N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea; N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea; N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl)urea; 30 N-(2-Hydroxy-5-nitrophenyl)-N'-(2,3-dichlorophenyl)urea; and N-(2-Hydroxy-3-cyanophenyl)-N'-(2,3 dichlorophenyl)urea. <br><br> As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; <br><br> hydroxy substituted Ci-ioalkyl; Ci-io alkoxy, such as methoxy or ethoxy; S(0)m' Ci-35 10 alkyl, wherein m' is 0,1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono &amp; di-substituted amino, such as in the NR4R5 group; NHC(0)R4! C(0)NR4R5; C(0)0H; S(0)2NR4R5; NHS(0)2Rl3, Ci-io alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Ci-io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such <br><br> -12- <br><br> WO 00/7(495 <br><br> PCTAJS00/I6499 <br><br> oi as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aiyl, hetroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy, S(0)m€i-io alkyl; amino, mono &amp; di-substituted amino, such as in the NR4R5 group; Ci-io alkyl, or halosubstituted Ci-io alkyl, such as CF3. <br><br> Rl3 is suitably C1-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi^alkyl, heterocyclic, or heterocyclicC 1 -4alkyl. <br><br> Also described herein are compounds of Formula (II), or a pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (II) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or P receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof. Compounds of Formula (II) are represented by the structure: <br><br> en) <br><br> wherein 20 X is oxygen or sulfur, <br><br> R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; <br><br> Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy, azide; S(0)tR4; hydroxy; hydroxyCi-4aIkyl; aryl; aryl Ci_4 alkyl; aryloxy; O 25 arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC 1 -4alkyl; heteroarylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-IO alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2-IO alkenyl C(0)NR4Rs; C(0)NR4R5; C(0)NR4Rio; S(0)3H; S(0)3Rs; Ci-io alkyl C(0)Ri 1; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Rn; C(0)Rn; C(0)0Ri2; OC(O) Rn; NR4C(0)Rn; or <br><br> C4 ^ <br><br> 5 oc ill <br><br> 8 * O <br><br> I 2 Mi <br><br> D ^30 two Ri moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally 35 substituted aryl, optionally substituted aiyl Ci^alkyl, optionally substituted <br><br> -13- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, <br><br> heterocyclicC i_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; <br><br> 5 Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cl-10 alkyl; Cl-10 alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Cj-io alkoxy; azide; S(0)tR4; hydroxy; hydroxy Ci-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; aiyl Ci-4 alkyloxy; heteroaiyl; heteroarylalkyl; heteroaiylCj-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; <br><br> 10 heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5; <br><br> C(0)NR4R10; S(0)3H; S(0)3Rg; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Ri 1; NR4C(0)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> 15 n is an integer having a value of 1 to 3; <br><br> m is an integer having a value of 1 to 3; <br><br> R8 is hydrogen or C1-4 alkyl; <br><br> RlO is Cl-10 alkyl C(0)2R8; <br><br> Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl <br><br> 20 Ci_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl; <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; <br><br> 25 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. <br><br> Suitably, the variables for Formula (II), such as X, R, Ri, R4, R5, Rs, R7, R8&gt; 30 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 it is not present the ring is a phenyl moiety which is substituted by the R and Rl terms as shown. At least one E ring is necessary. The E ring may be substituted by <br><br> . 14- <br><br> WO 00/76495 <br><br> PCT/USOQ/16499 <br><br> the Ri moiety in any ling, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s). <br><br> Exemplified compounds of Formula (II) are: N-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea; 5 N-[ 1 -hydroxyfluorene]-N'"[24&gt;romophenyl] urea; <br><br> N-[3-hydroxy-9,10-anthraquinon-2-yll-N-[2-bromophenyl] urea „ <br><br> Also described herein are compounds of Formula (III), 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 (III) and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (III) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which . binds to an IL-8 a or P receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof. Compounds of Formula (III) are represented by the formula: <br><br> wherein <br><br> X is oxygen or sulfur; <br><br> R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; <br><br> 20 Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cl-10 alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicCi-4alkyl; heteroarylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; 25 heterocyclicC2-lO alkenyl; NR4R5; C2-10 alkenyl C(0)NR4Rs; C(0)NR4R5; <br><br> C(0)NR4Rio; S(0)3H; S(0)3Rs; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-IO alkenyl C(0)0Rii; C(0)Rn; C(O)0Ri2; OC(0) R11; NR4C(0)Rn; or two Ri moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> 30 t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, <br><br> 35 heterocyclicC 1 -4 alkyl, or R4 and R5 together with the nitrogen to which they are <br><br> -15- <br><br> WO 00/76495 <br><br> PCT/USOQ/16499 <br><br> attached fonn a 5 to 7 member ring which may optionally comprise an additional heteroatom selected fmm O/N/S; <br><br> Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylCi-4 alkyloxy; heterocyclic, heterocyclicCi-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-IO alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4Rs; C(OJNR4R5; C(0)NR4Rio; S(0)3H; S(0)3Rs; Cl-10 alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; 10 C2-10 alkenyl C(0)0Rn; C(0)Ri 1; C(0)0Ri2; OC(O) Rn; NR4C(0)Rn; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> n is an integer having a value of 1 to 3; <br><br> m is an integer having a value of 1 to 3; <br><br> 15 Rs is hydrogen or C1-4 alkyl; <br><br> RlO is Ci_io allqrl C(0)2R8; <br><br> Rl 1 is hydrogen, Cl-4 alkyl, optionally substituted aiyl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i-20 4alkyl; <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aiyl or optionally substituted arylalkyl; <br><br> or a pharmaceutically acceptably salt thereof <br><br> Suitably, the variables, etc. for Formula (III) are the same as those defined for <br><br> Formula (I) above, such as for example the R variable. <br><br> Exemplified compounds of Formula (ID) are N-(2-Hydroxy-4-nitrophenyl)-N-(3-methoxy-2-thienyl)urea; and N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea. <br><br> Also described herein are compounds of Formula (la), a subset of compounds of Formula (I) useful for treating a chemokine 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 Formula (la) are represented by the structure: <br><br> 5 alkoxy; azide; S(0)tR4; hydroxy, hydroxyCi-4alkyl; aryl; aiyl C1-4 alkyl; aryloxy; <br><br> t»|&gt; <br><br> 35 wherein <br><br> 10 MAR 2004 <br><br> t6CE»VED <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> X is oxygen or sulfur; <br><br> Ra is an alkyl, aryl, arylCi-4alkyl, heteroaryl, heteroaryl Ci_4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted; <br><br> Rb is a NR6R7, alkyl, aiyl, arylCi_4aIkyl, aryl C2-4alkenyl, heteroaryl, 5 heteroaiylCi-4alkyl, heteroarylC2~4 alkenyl, heterocyclic, or heterocyclic <br><br> 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 C1 -4 alkyl; C1 -4 alkyl; C1 -4 alkoxy; NR9C(0)Ra; C(0)NR6R7» S(0)3H, or C(0)0Ci-4 alkyl; <br><br> 10 R6 and R7 are independently hydrogen or a C1-4 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 substituted; <br><br> R9 is hydrogen or a Ci-4 alkyl, preferably hydrogen; <br><br> 15 Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-IO alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxy Ci_4alkyl; aryl; aiyl Ci-4 alkyl; aiyloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; 20 heterocyclicC2-i0 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5; <br><br> C(0)NR4R10; S(0)3H; S(0)3R8; Cl-10 alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Rn; C(0)Rn; C(0)0Ri2; OC(O) R11; NR4C(0)Rn; or two Rl moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> 25 t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 30 heterocyclicC 1-4 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 tin additional heteroatom selected from O/N/S; <br><br> Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io 35 alkoxy; azide; S(0)tR4; hydroxy; hydroxyCi_4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylCi-4 alkyloxy; heterocyclic, heterocyclicC i-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-lO alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5; C(0)NR4R10; S(0)3H; S(0)3Rg; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; <br><br> -17- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Rl 1; NR4C(0)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> n is an integer having a value of 1 to 3; <br><br> 5 m is an integer having a value of 1 to 3; <br><br> R8 is hydrogen or C1-4 alkyl; <br><br> RlO is Cl-10 a^yl C(0)2R8'&gt; <br><br> Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-10 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC l-4alkyl; <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; <br><br> or a pharmaceutically acceptably salt thereof. <br><br> 15 A preferred ring substitution for Ri variable is monosubstituted in the 3- <br><br> position, or the 4- position, or di-substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably R'l is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4R5. <br><br> While Y may be substituted in any of the 5 ring positions, preferably the ring 20 with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- <br><br> preferably being unsubstituted. If the ring is di-substituted, substituents are preferably in the 2-, 3 - positions of a monocyclic ring. While both Rl and Y can both be hydrogen, it is preferred 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. 25 Y is more preferably a mono-substituted halogen, disubstituted halogen, mono- <br><br> substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably these groups are substituted in the 2 - position or 2'-,3-position. <br><br> Exemplified compounds of Formula (la) are; <br><br> N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N-phenyl urea; 30 N-[(2-Phenylsulfamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonamido phenyl) phenyl) N-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea; 2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea; N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea; 35 N-(2-(Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl (3-tolyl) phenyl) N-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea; <br><br> N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea; <br><br> - 18- <br><br> WO 00/76495 <br><br> PCT/US0W16499 <br><br> N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-broinophenyl)urea; N-(2-Bromophenyl)-N-[2-ditnfdiyIaiTiiiiost!!fonylaniino3phenyl]urea; N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea; N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-5 bromophenyl)urea; <br><br> N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea;N-[2-[(3^-Bistrifiuoromethylphenyl)sulfonylamino]pheiiyl]-N'-(2-bromophenyl)urca^-[2-[(2-Ben2yl)sulfonyiamino]-(5-trifluoromethyl)phenyl]-N-(2-bromophcnyl)urea^-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N-(2-bromophenyl)urea; 10 N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N-(2-bromophenyl) urea; N-[[2-( 1S)-10-Camphorsulfonylamino]phenyl]-N -(2-bromophenyl)urea; N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea; N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)ureiuN-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]-15 N'-(2-bromopheDyl)urea; <br><br> N-[2-(aminosulfonyl phenyl) 3-aminophenyl] N'-C2-brcwmo phpnyl) urea. <br><br> Also described herein are compounds of Formula (lb), a subset of compounds of <br><br> Formula (I) useful for treating a chemokine mediated disease. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (lb) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (lb) are represented by the structure: <br><br> H H (J,) <br><br> wherein <br><br> X is oxygen or sulfur, <br><br> 25 Xj is oxygen or sulfur, <br><br> Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci_io alkoxy; halosubstituted Ci_io alkoxy, azide; S(0)tR4; hydroxy; hydroxyCi_4alkyl; aryl; aryl Cm alkyl; aryloxy; aiylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Cj^alkyl; 30 heteroaryl Cm alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; <br><br> heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4Rs; C(0)NR4Rio; S(0)3H; S(0)3Rg; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Ri 1; NR4C(0)Ri 1; or two Ri moieties together may form 0-(CH2)s0~ or a 5 to 6 membered nnMtii^d 35 ring; <br><br> Intellectual Property -19 <br><br> Office of NZ <br><br> 10 MAR 2004 tECEIVED <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> 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; <br><br> R4 and R5 are independently hydrogen, optionally substituted C14 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci_4alkyl, heterocyclic, <br><br> heterocyclicC 1-4 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; <br><br> Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-IO alkenyl; Ci_io alkoxy; halosubstituted Ci-io alkoxy; azide; S(OXR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylCi-4 alkyloxy; heterocyclic, heterocyclicCi-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-l0 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4Rs; C(0)NR4R10; S(0)3H; S(0)3R8; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Rn; C(0)Rn; C(0)0Ri2; OC(O) R11; NR4C(0)Rn: or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> n is an integer having a value of 1 to 3; <br><br> m is an integer having a value of 1 to 3; <br><br> R8 is hydrogen or Ci-4 alkyl; <br><br> RlO is Cl-10 alkyl C(0)2R8". <br><br> Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aiyl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i-4alkyl; <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; <br><br> or a pharmaceutically acceptable salt thereof. <br><br> 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)NR6R7, substituted sulfonamides of the formula -NHS(0)2Rb» -S(0)2NHRc, NHC(X2)NHRb, or tetrazoyl (as defined for Formula (I). <br><br> Suitably for compounds of Formula (lb), a preferred ring substitution for Ri is in the 3-position, the 4- position or is preferably di substituted in the 3,4- position. The <br><br> -20- <br><br> WO 00/76495 <br><br> PCT/US00/I6499 <br><br> substituent group is suitably an electron withdrawing moiety. Preferably Rl is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4R5. <br><br> While Y maybe 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 die 4-5 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 preferred 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. <br><br> Suitably for compounds of Formula (lb), Y is more preferably disubstituted 10 halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, methylenedioxy, aryl, or alkyl, preferably in the 2£osition or 2'.3-position. <br><br> Also described herein are compounds of Formula (Ic), a subset of compounds of <br><br> Fonnula (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 structure: X ^ H <br><br> " " 00 <br><br> wherein <br><br> X is oxygen or sulfur, <br><br> 20 Xi is oxygen or sulfur; <br><br> Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Cj-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy, hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy, aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicCi-25 4alkyl; heteroaryICi-4 alkyloxy, aryl C2-10 alkenyl; heteroaryl C2-IO alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4Rs; C(0)NR4Rio; S(0)3H; S(0)3Rs; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Rn; C(0)Rn; C(O)0Ri2; OC(0) Rn; NR4C(0)Rn; or two Rl moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated 30 ring; <br><br> t is 0, or an integer having a value of 1 or 2; <br><br> s is an integer having a value of 1 to 3; <br><br> R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1 -4alkyl, optionally substituted 35 heteroaryl, optionally substituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic <br><br> -21- <br><br> 'nteffectual Property Office of NZ <br><br> 10 MAR 2004 <br><br> heceived <br><br> WO 00/76495 PCT/US00/16499 <br><br> Ci_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; <br><br> Y is independently selected from halogen; nitro; cyano; halosubstituted Cl-10 alkyl; 5 Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxy Ci_4alkyl; aryl; aiyl Ci_4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylCi-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4Rs; C(0)NR4R5; C(0)NR4Rio; 10 S(0)3H; S(0)3R8; Ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)0Ri 1; C(0)Ri 1; C(0)0Ri2; OC(O) Ri 1; NR4C(0)Rn; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; <br><br> n is an integer haying a value of 1 to 3; <br><br> m is an integer having a value of 1 to 3; <br><br> 15 R8 is hydrogen or C1-4 alkyl; <br><br> RlO is Ci-io alkyl C(0)2R8; <br><br> Rl 1 is hydrogen, Ci-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-20 4alkyl; <br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that when n =1 than Y is substituted in the 2- or 3- position; <br><br> when n =2 than Y is di-substituted in the 2'- 3 - position, the 2-5 - position, the 25 2-6'position, the 3 -5'or the 3 -6'position; <br><br> when b = 3 than Y is trisubstituted in the 2-3-5'or the 2-3-6- positions; <br><br> 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.3-t-butyl, 5-methyl; <br><br> 30 when Xi is O, m=l, Ri is 4-methyl, and n=2 than Y is not 2-OH, 5-methyl; <br><br> when Xi is O, m=l, Rl is hydrogen, and n=2 than Y is not 2-6-diethyl; <br><br> when Xi is O, m=l, Rl is 6-OH, and n=2 than Y is not 2-5-methyl; <br><br> when Xi is S, m=l, Rl is 4-ethyl, and n=l than Y is not 2-methoxy; or a pharmaceutically acceptably salt thereof. <br><br> 35 Suitably, the variables, etc. for Fonnula (Ic) are the same as those defined for <br><br> Formula (I) above unless indicated. . <br><br> 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 Rl is <br><br> -22- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> other than hydrogen. The substituent group is suitably an electron withdrawing moiety. Preferably Ri is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4R5- <br><br> 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 4-5 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 preferred 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. <br><br> Suitably for compounds of Formula (Ic), Y is more preferably a mono-10 substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'position or 2,3-position. <br><br> Exemplified compounds of Formula (Ic) are: N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N-phenylurea; 15 N-[2-Hydroxy-5-nitro-phenyl]-N-phenyl urea N-(2-Hydroxy-4-fluorophenyl)-N-phenyl urea; N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N-phenyl urea; N-(2-Hydroxy-4-nitrophenyl)-N-(2-hydroxy-4-nitrophenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N-phenyl-thiourea; 20 N-(2-Hydroxy-5-nitrophenyl)-N '-(3-methoxy-2-thienyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(3-methoxy-2-thienyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(3-methoxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(3-trifluoromethylphenyl)urea; 25 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(3-bromophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N-(4-bromophenyl)urea; 30 N-(2-Hydroxy-4-nitrophenyl)-N-(2-phenylphenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-nitrophenyl)urea;N-(2-Hydroxy-4-nitrophenyl)-N-(2-fluorophenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea;N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea; 35 N-(2-Hydroxy-4-nitrophenyl)-N-(2-ethylphenyl)urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-trifluoromethoxyphenyl)urea; N-(2-Hydroxy-4-nitrophenyl) N-(2-methylthiophenyl) urea; N-(2-Hydroxy-4-nitro-phenyl) N-(2-chloro 6-methyl phenyl) urea; <br><br> -23- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-(2-Hydroxy-4-nitro-phenyl) N'-(2-sulfoxymethyl phenyl) urea;N-(2-Hydroxy-4-trifluoromethyl phenyl)-N-(2-bromo phenyl) urea; <br><br> N-(2-Hydroxy-4-trifluoromethyl phenyl)-N-(2-phenyl phenyl) urea; N-(2-Hydroxy-4-carbomethoxy phenyl)-N-(2-phenyl phenyl) urea; 5 N-(2-Hydroxy-4-nitrophenyl)-N-(2,3-dichloro phenyl) urea;N-(2-Hydroxy-4-nitrophenyl)-N-(2,4-dichloro phenyl) urea; <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro phenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dibromo phenyl) urea; N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea; 10 N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-niethylenedioxyphenyl)iirea; N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea; N-[2-Hydroxy-4-(Benzylamino)caibonyl phenyl]-N'-(2-bromophenyl)urea; N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenoxy phenyl) urea; <br><br> N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea; 15 N-(2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea; <br><br> N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea;N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea; <br><br> N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea; <br><br> N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea; 20 N-(2-Sulfhydryl-4-bromo phenyl)-N'-(2-bromo phenyl) urea; <br><br> N-(2-Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea; N-(2-Hydroxy 4-nitro phenyl)-N'-(2-bromo phenyl) thiourea; <br><br> N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea; N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea; 25 N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea <br><br> N-[2-hydroxy-3,4-diphenylphenyl]-N'-[2-bromophenyI] urea;N-[2-Hydroxy-3-30 glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] 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-dichlorophenyl]-N'-[2-bromophenyl] urea; 35 N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-4-cyanophenyI]-N'-[4-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea; <br><br> N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea; <br><br> -24- <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-n-propylphenyl]-N-[2-bromophenyl] urea; 5 N-[2-Hydroxy-4-ethylphenyl]-N-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxy-3-cyano-4-methylphenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea; 10 N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea; <br><br> (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea; (E)-N-[3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N-[2-bromophenyl] urea; <br><br> (E)-N-[3-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N-15 [2-bromophenyl] urea; <br><br> (E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N-[2-bromophenyl] urea; <br><br> N-[2-Hydroxy-4-benzamide phenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxy-4-aminocarbonyl phenyl]-N'-[2-bromophenyI] urea 20 N-(2-Hydroxy-3,5,6-trifluorophenyl)-N-(2-bromophenyl)urea; <br><br> N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea; N-(2-Hydroxy-3-iodophenyl)-N-(2-bromophenyl)urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea; N-[2-Hydroxy~4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea; <br><br> 25 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyI] urea; N-[2-Hydroxy-5-fluorophenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxy-5-trifluoromethylphenyl]-N-[2-bromophenyl] urea; N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea;N-[Trans-3-styrI-2-hydroxyphenyl]-N-30 [2-bromophenyl] urea; <br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N-[4-methoxyphenyl] urea;N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea;N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea;N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-phenylphenyl] urea; 35 N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2,3-dichlorophenyl] urea; <br><br> N-[2-Hydroxy-4-isopropylphenyl]-N-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea; <br><br> N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea;N-(2-Hydroxy-3-azidophenyl)-N-(2-bromophenyl)urea;N-[2-Hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea; <br><br> -25- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-[2-Hydroxy-3-cyanophenyl]-N-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea; N-[2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichlorophenyl] urea; N-[2-Hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea; 5 N-[2-Hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea;N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea; N-[2-Hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea; 10 N-[2-Hydroxy-5-nitrophenyl]-N-[2,3-dichlorophenyl] urea; <br><br> N-[2-Hydroxy-5-ethylsulfonylphenyl]-N-[2,3-dichlorophenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea; N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[benzyl] urea; 15 N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea; N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea; N-[2-Hydroxy-3-naphthyl]-N-[benzyl] urea; <br><br> N-[2-hydroxy-3-(phenylaminocarbonyl) phenyl]-N'-[benzoyl] urea; 20 N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[benzoyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[benzoyl] urea; <br><br> N-[2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea; N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea; <br><br> N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea; 25 N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea; and <br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(l-naphthyl)urea. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic 30 acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, <br><br> maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well 35 known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. <br><br> The following terms, as used herein, refer to: <br><br> • "halo" - all halogens, that is chloro, fluoro, bromo and iodo. <br><br> -26- <br><br> WO 00/76495 PCT/US00/16499 <br><br> • "Ci_ioalkyl" 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, wo-propyl, n-butyl, .sec-butyl, wo-butyl, /erf-butyl, n-pentyl and the like. <br><br> 5 • The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 <br><br> to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. <br><br> • The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 caibon atoms, unless the chain length is limited thereto, <br><br> 10 including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. <br><br> • "aryl" - phenyl and naphthyl; <br><br> • "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 <br><br> 15 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, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole. <br><br> • "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") 20 - 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. <br><br> • The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein 25 to mean Cl-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. <br><br> • "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" <br><br> refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2 moiety. <br><br> • The term "wherein two Ri moieties (or two Y moieties) may together form a 30 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 C5 cyloalkenyl moiety, cyclopentene. <br><br> The compounds of Formula (I), (la), (lb), (Ic), (II) and (M) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. 35 The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I), (la), (II) and (DI) having a variety of different R, Rj, 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 <br><br> -27- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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. <br><br> Scheme 1 <br><br> L 2- <br><br> R=NH 2, OH, CO 2H, SH a)PhNCO NHSO 2R <br><br> 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 (Aldrich Chemical Co., Milwaukee, Wi) in an aprotic solvent (DMF, toluene). When the l-(RSC&gt;2NH)2-(NH2)Ph is not commercially available it can be made by treating the commercially available RSO2CI with the corresponding 2-phenylene diamine in the presence of an base like triethyl amine or NaH in an aprotic solvent (like methylene chloride or DMF). <br><br> Scheme 2 <br><br> 10 <br><br> R"= OH. NH 2, NHSO 2R a&gt;HNO 3- 23 ^ b)SnCI 2, BOH <br><br> 15 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). <br><br> -28- <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> Scheme 3 <br><br> o_, - a&gt;~ — a: <br><br> 6. 7_ 8_ <br><br> a)NH 4SCN, Br 2 <br><br> b)NaOH EtOH <br><br> 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. <br><br> 5 This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8-scheme 3 with a strong base like NaOH in a protic solvent (i.e., EtOH). <br><br> Scheme 4 <br><br> x=s, o -n a)TBSCI, imid, DMF b)i)ClCXCI, NaHCO 3,ii)PhNH 2 c)Et 3N HF, CH 3CN Li 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 10 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&amp;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 15 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. <br><br> -29- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> SchamaS <br><br> a)(PhO) 2PON 3,B3Nb)PhXNH 2 X=OH, NHSO 2R.SH <br><br> Alternately the urea can be formed using a Curtius rearrangement from the corresponding aromatic or thiophene carboxylic acid 12-scheme 5. The carboxylic acid is submitted to standard Curtius conditions ((PhO^PONs, Et3N or C1COCOC1 followed by NaN3) and the intermediate isocyanate is trapped by an appropriately substituted aniline. <br><br> Pharmaceutically acceptable salts of compounds of Fonnula (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 <br><br> Also described herein is the synthesis of cyano nitrophenol 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 hydroxyl 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°C did not yield displacement 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-nitro-5-fluorophenol, 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 dimethylformamide and using triethylamine with a catalytic amount of dimethylamino pyridine and copper (I) cyanide at reduced temperatures, i.e. &lt;100°C, preferably 60 to about 80°C for reduced times from standardized procedures, i.e. &lt;18 hours, preferably about 4 to 6 hours yielded the desired products. <br><br> Described herein is a process for producing a cyano phenol derivative of the fonnula: <br><br> 10 MAR 2004 <br><br> -30- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> wherein Ri is as defined for Fonnula (I) above, which method comprises reacting a compound of the fonnula: <br><br> R, <br><br> wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a 5 catalytic amount of dimethylamino pyridine. Preferably, the process is run at reduced temperatures of about 60 to about 80°C. Preferably X is bromine. <br><br> In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, <br><br> unless otherwise indicated. ^H-NMR (hereinafter "NMR") spectra were recorded at 10 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, equiv. indicates the proportion of a molar equivalent of reagent relative to the principal reactant. <br><br> Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh). 15 SYNTHETIC EXAMPLES <br><br> 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 20 conditions in an argon atmosphere unless otherwise indicated. <br><br> General Method A: Synthesis of N, N'- phenyl urea To a solution of substituted phenyl isocyanate (1.0 equiv.) in toluene (5 miliLiters (hereinafter "mL")) the conesponding 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 25 temperature. The purifications, yields and spectral characteristics for each individual compound are listed below. <br><br> General Method B: Synthesis of N, N'- 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 (24-30 48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics for each individual compound are listed below. <br><br> 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 35 reaction mixture was partitioned between water and methylene chloride. The organic <br><br> -31 - <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The purifications of each compound are listed below. <br><br> Example 1 <br><br> Preparation of N-r2-Hvdroxv-4-(methoxvcari&gt;onvl)phenvn-N'-phenvl urea N-f2-5 Hydroxy-4-(methoxycarbonyl)phenyl]-N-phenyl urea was prepared from methyl-4-amino-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: 188.4-188.8°C; *H NMR (CD3OD/CDCI3): 5 8.15 (d, 1H, J = 8.25 Hz), 10 7.70 (s, 1H), 7-51 (d, 1H, J = 8.25 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, J = 8.25 Hz), 7.01 (t, 1H, J = 8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H)+; Anal. (C15H14N2O4) C, H, N. <br><br> Example 2 <br><br> Preparation of N-r5-nitro-2-hvdroxyphenvl1-N'-phenvl urea The N-[5-nitro-2-15 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 (CD3OD): 8 9.48 (s, 1H, NH), 9.07 (d, J = 1.56 Hz, NH), 8.55 (s, 1H), 7.80 (dd, 1H, J = 6.25 Hz and J = 1.56 Hz), 7.50 (d, 2H, J = 6.25 Hz), 7.30 (t, 2H, 20 J = 6.25 Hz), 7.01 (m, 2H). EI-MS m/z 273 (M+H)+. <br><br> Example 3 <br><br> Preparation of 3-hvdroxv-4-i ffphenvlaminokarbonvllaminolbenzamide 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 25 "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. <br><br> b)Preparation of 3-hydroxy-4-{[(phenylamino)carbonyl]amino}benzamide 30 To a solution of the N-[2-hydroxy-4-(methoxycarbonyl)phenyI]-N'-phenyl urea <br><br> (60 milligram (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% HC1. The organic layer was separated and the aqueous layer was 35 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: 106.8-107.1°C; ]H NMR (CD3OD/CDCI3): 8 7.98 (d, 1H, J = 8.25 Hz), 7.35 (d, 2H, J <br><br> -32- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (t, 2H, J = 8.25 Hz), 6.91 (t, 1H, J = 8.25 Hz); EI-MS m/z 271 (M+H)+; Anal. (C14H13N3O3) C, H, N. <br><br> Example 4 <br><br> Preparation of N-C2-hvdroxv-4-fluorophenvl)-N-phenyl urea 5 a) Preparation of 2-amino-5-fluoro phenol <br><br> A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (II) 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% 10 aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSC&gt;4 and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). *H NMR (CD3OD/CDCI3): 8 6.6 (m, 1H), 6.38 (dd, 1H, J = 8.3 Hz and J = 2.8 Hz), 6.29 (m, 1H). <br><br> b) Preparation ofN-(2-hydroxy-4-fluorophenyl)-N'-phenylurea 15 N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5- <br><br> 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; 195.5-195.7°C; *H NMR (CD3OD/CDCI3): 8 7.70 (m, 1H), 7.3 (d, 2H, J = 8.25 Hz), 7.15 (t, 2H, J = 8.25 Hz), 20 6.89 (t, 1H, J = 8.25 Hz), 6.50 - 6.38 (m, 2H); EI-MS m/z 246 (M+H)+; Anal. (C13H11N2O2 F) C, H, N. <br><br> Example 5 <br><br> Preparation of 2-1Kphenvlaminolcarbonvll amino I thiophenol <br><br> 2- {[(Phenylamino)carbonyl]amino} thiophenol was prepared from 2-25 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: 194.5°C; ]H NMR (CD3OD/CDCI3): 8 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. (Ci3Hi2N2OS) C, H, N. 30 Example 6 <br><br> Preparation of N-(2-Carboxv-4-hvdroxvpherivl)-N'-phenvl urea <br><br> 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 35 phase was washed with brine, dried over MgSC&gt;4 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%). 'H NMR (CD3OD/CDCI3): 8 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. <br><br> -33- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Example 7 <br><br> Preparation of N - f2 - hydroxy - 4- (trifluoromethyl') phenyl! - N'- phenyl urea a) Preparation of 2-nitro-5-trifluoromethylphenol 2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 <br><br> 5 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 10 tided compound as an oil(l.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) <br><br> b) Preparation of 2-amino-5-trifluoromethylphenol 2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5- <br><br> trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2(3.5g, mmol) in 15 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 H2O 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. 20 1H NMR (CDCI3): 7.6 (s, 1H), 7.39(d, 1H, J = 8.5 Hz), 7.08(d, 1H, J= 8.5 Hz) c)Preparation of N - [2 - hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea <br><br> N - [2 - Hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea was prepared from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) and phenyl isocyanate(1.09 mmol) according to the procedure in General method A. The product 25 was purified by precipitation from methylene chloride and filtering to afford the titled compound (230 mg, 87%). mp: °C; 1H NMR (DMSO-d6): 8 9.45 (s, 1H, NH), 8,50 (s, 1H, NH), 8.31 (d, 1H, 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, 1H, J = 6.67 Hz). EI-MS m/z 296 (M+). Anal. (Ci4Hi1N202F3)C,H,N. <br><br> 30 Example 8 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-hvdroxv-4-nitrophenvl) urea a) Preparation of 2-(terf-butyldimethylsilyloxy)-4-nitroaniline To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g, 35 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 % HC1 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 <br><br> -34- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> acetate; 5:1) gave the titled compound (1.7 g, 98 %). NMR (CDCI3): 8 7.78 (dd, 1H, J = 6.7 Hz and J = 2.7 Hz), 7.61 (d, 1H, J = 2.7 Hz), 6.7 (d, 1H, J = 8.8 Hz), 1.0 (s, 9H), 0.28 (s, 6H). <br><br> b) Preparation of N-[(2-ter/-buty]dimethylsilyloxy)-4-nitrophenyl]-N'-[(2-5 tert-butyldimethylsiloxy)-4- nitrophenyl] urea <br><br> To a solution of 2-(tert-butyldimethyIsilyloxy)-4-nitroaniline(200 mg, 0.75 mmol) in toluene (10 mL) triethylamine (0.13 mL, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours, then cooled to room temperature. Then more 2-(tert -butyldimethylsilyloxy)-4-nitroaniline 10 (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70°C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water 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, 10:1) gave the 15 titled compound(130 mg, 31%). *H NMR (CDCI3): 8 8.36 (d, 2H, J = 8.3 Hz), 7.90 (dd, 2H, J = 8.3 Hz and J = 2.8 Hz), 7.71 (d, 2H, J = 2.8 Hz), 7.22 (s, 2H), 1.02 (s, 18H), 0.35 (s, 12H). <br><br> c) Preparation of N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea <br><br> 20 To a solution of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N'-[(2-tert- <br><br> butyldimethylsilyloxy)-4- nitrophenyl] urea(50 mg, 0.089 mmol) in THF (2 mL), tetrabutylammonium fluoride (1 M, 0.09 mL, 0.089 mmol) was added at 0°C. The reaction mixture was stirred at 23°C. After 1 hour, the starting material had disappeared. The reaction mixture was partitioned between water and ethyl acetate. The 25 combined organic phase was dried over MgSC&gt;4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl acetate; 1:1 to 100% ethyl acetate) gave the titled compound(24 mg, 81%). 5H NMR (CD3OD/CDCI3): 8 8.32 (d, 2H, J = 8.25 Hz), 7.80 (dd, 2H, J = 8.25 Hz and J = 2.06 Hz), 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H)+. Anal. (C13H10N4O7) C, H, N. 30 Example 9 <br><br> Preparation of N-C2 -hvdrox v-4-nitrophenvl)-N'-phenvl-thiourea a) Preparation of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea <br><br> N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared 35 by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHC03 in CHC13:H20(2.5:1,7mL) with thiophosgene at 0°C. The solution was allowed to warm to 23 °C and the reaction was continued overnight. The CHCI3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline <br><br> -35- <br><br> WO 00/76495 PCT/US00/16499 <br><br> (100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexane) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-^"C^H NMR (CD3OD/CDCI3): 8 8.65 (d, IH, J = 10.0 Hz), 7.58 (d, IH, J = 10.0 Hz), 7.47 (d, IH, J = 1.25 Hz), 7.26 (m, 4H), 5 7.10 (m, IH). <br><br> b) Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N*HF (lOOuL, 0.62 mmol) in acetonitrile for 10 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: 144-145°C;1H NMR (CD3OD/CDCI3): 8 8.65 (d, IH, J = 10.0 Hz), 7.58 (d, IH, J = 10.0 Hz), 7.47 (d, IH, J = 1.25 Hz), 7.26 (m, 4H), 7.10 (m, IH). <br><br> Example 10 <br><br> 15 Preparation of N-C4- nitro 2-(phenvlsulfonvlamino)phenvlVN'-phenvl urea a) Preparation of 4-nitro 2-(phenylsulfonylamino) aniline A solution of 4-nitro 1,2-phenylene diamine(1.53 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 20 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%). 'H NMR(DMSO) 9.5(s, IH, br), 7.83 (dd, IH, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, IH, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,lH, J=2Hz), 6.79 (d, IH, J=8Hz), 6.5(s, 2H, br) <br><br> 25 b) Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea <br><br> N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea was prepared from 4- nitro 2-(phenylsulfonylamino) aniline(82 mg) and phenyl isocyanate(33 mg) by method A. The reaction was cooled and then partitioned between saturated 30 ammonium chloride and 9:1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane) to afford desired(30.8 mg, 26%). EI-MS m/z 413(M+H)+ <br><br> Example 11 <br><br> 35 Preparation of N-(2-hvdroxv-5-nitrophenvl)-N'-(3-methoxv-2-thienvl)urea a) Preparation of 3-methoxy-2-thienylcarboxlic acid To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at -78°C, butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78°C for 1 hour, then it was warmed to 0 °C for 3 hours. After to recooling -78°C the <br><br> - 36 - <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> reaction mixture was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice (10 g) to which conc. HC1 (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96 5 %). EI-MS m/z 159 (M+H)+. <br><br> b)Preparation of N-(2-hydroxy-5-nitrophenyl)-N-(3-methoxy-2-thienyl)urea <br><br> To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg, 1.27 mmol) in benzene, (PhO)2PON3 (0.33 mL), 2-amino-4-nitrophenol (195.7 mg, 1.27 mmol) and triethylamine (1.1 equiv., 0.25 mL) were added. The reaction mixture was stirred at 10 reflux 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 MgSC&gt;4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexanerethyl acetate;l:l) gave a solid product (160 mg, 41 %). mp: 15 172.6-173.0°C; »H NMR (CD3OD/CDCI3): 8 8.96 (d, IH, J = 2.5 Hz), 7.74 (dd, IH, J =5.0 Hz and J = 1.25 Hz), 6.82 (d, IH, J =7.5 Hz), 6.76 (s, 2H), 3.80 (s, 3H); EI-MS m/z 309 (M+H)+; Anal. (C12H11N3O5S) C, H, N. <br><br> Example 12 <br><br> Preparation of N-f2-hvdroxv-4-nitrophenvI)-N'-(3-methoxv-2-thienvl)urea 20 To a solution of 3-methoxy-2-thiophene carboxylic acid (example 1 la, 200 mg, <br><br> 1.27 mmol) in toluene, (PhO)2PON3 (0.33 mL) and triethylamine (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 25 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&gt;4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate;l:l) gave the product (190 mg, 48%). ]H NMR (CD3OD/CDCI3): 8 8.38 (d, IH, J = 5.0 Hz), 7.85 (dd, IH, J = 5.0 Hz and J = 1.25 Hz), 30 7.76 (d, IH, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS m/z 309 (M+H)+; Anal. (C12HIIN305S)C,H,N. <br><br> Example 13 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(3-methoxvphenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 35 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate(1.0 mmol) <br><br> according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (140 mg, 46%). EI-MS m/z 302(M-H)" <br><br> Example 14 -37- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvlVN-('2-methoxvphenvDurea N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate(l mmol.) according to the procedure in General Method B. The product was purified by dilution 5 with methylene chloride and precipitation with hexane. Filtering afforded the title compound (82 mg, 27%). EI-MS m/z 302(M-H)* <br><br> Example 15 <br><br> Preparation of N-f2-hvdroxv-4-nitrophenvlVN-f3-trifluoromethvlphenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N-(3-methoxyphenyl)urea was prepared from 2-hydroxy 10 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 hexane. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H) + <br><br> Example 16 <br><br> 15 Preparation of N-('2-hvdroxv-4-nitrophenvl1-N'-r2-trifluoromethvlphenvi)urea <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-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 hexane. Filtering afforded 20 the tide compound (180 mg, 52%). EI-MS m/z 342(M+H)+ <br><br> Example 17 <br><br> Preparation of N-f2-hvdroxv-4-nitrophenvlVN'-('4-trifluoromethvlphenvl'&gt;urea N-(2-Hydroxy-4-nitrophenyl)-N-(4-trifiuoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate 25 (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340(M-H)~ <br><br> Example 18 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-bromophenvl)urea 30 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 hexane. Filtering afforded the title compound(530 mg, 47%). EI-MS m/z 350(M-H) * 35 Example 19 <br><br> Preparation of N-f 2-hvdrox v-4-nitrophenvl VN -f 3-bromophenvPurea N-(2-Hydroxy-4-nitrophenyl)-N-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (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 <br><br> -38- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.96g, 87%). EI-MS m/z 350(M-H)" <br><br> Example 20 <br><br> Preparation of N-f2-hvdroxv-4-nitrophenvl)-N'-(4-bromophenvl')urea 5 N-(2-Hydroxy-4-nitrophenyl)-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 B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.41 g, 37%). EI-MS m/z 352(M+H)+ 10 Example 21 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-phenvlphenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution 15 with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.22 g, 19%). EI-MS m/z 350(M+H) + <br><br> Example 22 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvlVN'-(l-naphthvl)urea <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(l-naphthyl)urea was prepared from 2-hydroxy 20 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 triturated with 1:3 triethyl amine:methylene chloride. The filtrate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with IN HCl in water. The 25 desired product precipitated from solution and was collected by filtration(0.1 lg, 10%). EI-MS m/z 324(M+H) + <br><br> Example 23 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N-(2-nitrophenvI)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy 4-30 nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24 mmol) <br><br> according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.44 g, 44%). EI-MS m/z 319(M+H) + <br><br> Example 24 <br><br> 35 Preparation of N-f 2-hvdroxv-4-nitrophenvl)-N-f 2-fluorophenvl)urea <br><br> 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 <br><br> -39- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.59 g, 31 %). EI-MS m/z 292(M+H)+ <br><br> F.xamnlg 25 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvn-N'-f2.6-difluorophenvDurea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniUne (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 hexane. Filtering afforded the title compound(0.91 g, 91%). EI-MS m/z 308(M-H) - <br><br> Example 26 <br><br> Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-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 hexane. Filtering afforded the title compound(0.84 g, 81%). EI-MS m/z 318(M+H) + <br><br> -40- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> Example 27 <br><br> Preparation of N-f2-hvdroxv-4-nitrophenvl')-N-f2-ethvlphenvl")urea N-(2-Hydroxy-4-nitrophenyl)-N-(2-ethylphenyI)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) 5 according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H)+ <br><br> Example 28 <br><br> Preparation of N-(2-hvdroxv-4-nitro phenvl)-N'-(2-trifluoromethoxvphenvI)urea 10 N-(2-Hydroxy-4-nitrophenyl)-N-(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 hexane. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H)+ 15 Example 29 <br><br> Synthesis of N-(2-hvdroxv-4-nitro phenyl") N-(2-methvIthio phenyl) urea <br><br> The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-methylthio phenyl isocyanate(3.24 mmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. 20 Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H)+ <br><br> Example 30 <br><br> Synthesis of N-(2-hvdroxv-4-nitro phenyl) N-(2-chloro 6-methvl phenyl) urea <br><br> 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 25 with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). EI-MS m/z 322(M+H)+ <br><br> Example 31 <br><br> Synthesis of N-(2-hvdroxv-4-nitro phenyl) N-(2- methyl sulfoxvphenvl) urea <br><br> The urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) N-(2-30 methyl thio phenyl) urea(example 28, 100 mg) with sodium perorate(100 mg) in t-button/water for 12 hours at 23 °C. The product precipitated from the reaction mixture(30 mg, 29%). EI-MS m/z 336(M+H) + <br><br> Example 32 <br><br> Synthesis of N-(2-hvdroxv 4-trifluoromethvl phenyl) N-(2-bromo phenyl) urea The 35 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(0.25 g, 54%). EI-MS m/z 375(M+H)+ <br><br> Example 33 -41 - <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> Synthesis of N-(2-hvdroxv 4-carbomethoxv phenyl) N'-(2-bromo phenyl-) urea <br><br> The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 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 5 the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H) - <br><br> Example 34 <br><br> Synthesis of N-(2-hvdroxv 4-trifluoromethvl phenyl) N'-(2-phenvl phenyl) urea <br><br> The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was 10 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)+ <br><br> Example 35 <br><br> Synthesis of N-(2-hvdroxv 4-carbomethoxv phenyl) N-C2-phenvl phenyl) urea <br><br> The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 15 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) <br><br> Example 36 <br><br> Synthesis of N-C2-hvdroxv 4-nitro phenyl) N'-(2.3-dichloro phenyl) urea The urea 20 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) + <br><br> Example 37 <br><br> 25 Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2.4-dichloro phenyl) urea <br><br> The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,4-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(0.26 g, 38%). EI-MS m/z 342 (M+H)+ 30 Example 38 <br><br> Synthesis of N-(2-hvdroxv-4-nitro phenyl) N'-(2-chloro phenyl) urea <br><br> The urea was prepared from 4-nitro 2-hydroxy aniline(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 35 compound(0.29 g, 47%). EI-MS m/z 308(M+H)+ <br><br> Example 39 <br><br> Synthesis of N-(2-hvdroxv-4-nitrophenvl) N-(2.4-dibromo phenyl) urea <br><br> The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by <br><br> -42- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g, 39%). EI-MS m/z 430(M+H)+ <br><br> Example 40 <br><br> Synthesis of N-(2-hvdroxvnapthvl) N'-(2-bromo phenyl) urea 5 The urea was prepared from 1 -amino 2-hydroxy naphthalene(195 mg, 1 mmol) <br><br> 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) + <br><br> Example 41 <br><br> 10 Synthesis of N-(2-hvdroxv-4-nitrophenvl)-N'-(2.3-methvlenedioxvphenvl)urea a) Preparation of 2,3-methylenedioxyphenyIcarboxylic acid <br><br> 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 (15 mL, 35 mmol) in hexane. 15 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 HCl, and extracted with chloroform. The combined organic layers were dried over MgS04, 20 filtered and concentrated under reduced pressure (1.1 g, 20 %). EI-MS m/z 167 (M+H)+ <br><br> b) Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3- <br><br> ethylenedioxyphenyl)urea <br><br> To a solution of the 2,3-methylenedioxyphenylcarboxylic acid in toluene, triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL, 25 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 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 30 organic extracts were combined, dried over MgS04, 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)+ <br><br> Example 42 <br><br> Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-f2-methoxv 3-chloro phenyl) urea 35 The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2- <br><br> 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)+ <br><br> Example 43 -43- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2-methvl phenyl) urea <br><br> 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 5 compound(0.38 g, 53%). EI-MS m/z 288(M+H)+ <br><br> Example 44 <br><br> Synthesis of Nfbis (2-hvdroxv 4-nitro phenyl) N'-fdianisdine) 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 2-10 hydroxy aniline was used instead of 1 equiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound( 0.08 g, 6%).EI-MS m/z 605(M+H)+ <br><br> Example 45 <br><br> Synthesis of 4-methvlene bis(N-(2-chloro phenyl) N*-(2-hvdroxv 4-nitro phenyl) urea) 15 The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and 4- <br><br> 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%). EI-MS m/z 627(M+H)+ 20 Example 46 <br><br> Synthesis of N-r2-hvdroxv 4-fbenzvlamino)carbonvl phenvll-N'-C2-bromophenvl)urea a) Synthesis of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) <br><br> 25 and 2-bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%). EI-MS m/z 351 (M+H) + <br><br> b) Preparation of N-[4-(benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea <br><br> 30 To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.58 mmol) in DMF (15 mL), EDC (121.9 mg, 0.58 mmol), HOBT (156.6 mg, 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 35 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 MgS04, 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)+ <br><br> -44- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Example 47 <br><br> Synthesis of N-(2-hvdroxv 4-nitro phenvD N'-(2-phenoxv phenyl1) urea The urea was synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol,) with diphenyl phosphoryl azide(0.475 mL) and triethyl amine(.14 mL) in DMF at 80 °C 5 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)" <br><br> Example 48 <br><br> 10 Synthesis of N-(2-hvdroxv-4-fluoro phenyl) N'-f2-bromo phenyl) urea a) Synthesis of 2-hydroxy 4-fluoroaniline <br><br> 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 15 afford the title compound (1.4 g, 77%). EI-MS m/z 169(M+H)+ <br><br> b) Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and <br><br> 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 20 (M+H)+ <br><br> Example 49 <br><br> Synthesis of N-( 2-hvdroxv 3.4-difluoro phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-hydroxy 3,4-difluoro aniline <br><br> 2,3 difluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(l g) at 23 25 °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 title compound (1.6 g, 97%). EI-MS m/z 146(M+H)+ <br><br> b)Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea <br><br> The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) 30 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)+ <br><br> Example 50 <br><br> Synthesis of N-(2-hvdroxv 3-napthvI) N'-(2-bromo phenyl) urea 35 The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g, 2 mmol) <br><br> 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%).EI-MS m/z 357(M+H)+ <br><br> Example 51 <br><br> -45- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> Synthesis of N-(2-hvdroxv 4-phenvl phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-nitro 5-phenyl phenol <br><br> 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 5 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 vacuo. The residue was purified by silica gel chromatography(ethyl acetate/hexane) to afford desired (1.2 g, 50%).*11 NMR (CDCI3): 8 10.65(s, IH), 8.18 (d, IH, J = 10.0 10 Hz), 7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, IH), 7.10 (d, IH, J=10.0Hz). <br><br> b)Synthesis of 2-amino 5-phenyl phenol <br><br> A solution of 2-nitro 5-phenyl phenol(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 15 concentrated in vacuo to afford desired (1.01 g, 98%).EI-MS m/z 186(M+H) <br><br> c)Synthesis of N-(2-hydroxy 4-phenyl phenyl) N-(2-bromo phenyl) urea <br><br> 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, 20 56%).EI-MS m/z 383(M+H)+ <br><br> Example 52 <br><br> Synthesis of N-(2-hvdroxv 4-methvl phenyl) N-(2-bromo phenyl) urea <br><br> 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 25 dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39%). EI-MS m/z 319(M-H)" <br><br> Example 53 <br><br> Synthesis of N(2-hvdroxv 4-nitro phenyl) N'-(2-phenvlamino phenyl) urea The urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro phenyl 30 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)+ <br><br> Example 54 <br><br> Synthesis of N-(2-hvdroxv 3-carboxvlate phenyl) N'-(2-bromo phenyl) urea 35 The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg, 2 mmol) <br><br> 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)+ <br><br> Example 55 <br><br> -46- <br><br> WO 00/76495 PCT/USOO/16499 <br><br> Synthesis of N(2-sulfhvdrvl 4-bromo phenyl") N'-f 2-bromo phenyl) ureaa) Synthesis of 2-amino 6-bromo thiazole <br><br> 4-Bromo anihne(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, 1 equiv.) at room 5 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^.6 g, 46%). EI-MS m/z 229(M+H)+ <br><br> b) Synthesis of bis (3-bromo 6-amino phenyl) disulfide The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in 10 water(5mL) was treated with KOH (2.5 g) was heated at reflux for 8 h at reflux. The reaction mixture was then acidified to ph 4 with acetic acid and extracted with methylene chloride. The methylene chloride mixture was concentrated in vacuo. The residue was dissolved in DMSO and treated with I2. After stirring overnight at room temperature the reaction mixture was partitioned between methylene chloride and 15 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)+ <br><br> c)Synthesis of N(2-sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea 20 A solution of (3-bromo 6-amino phenyl) disulfide(201 mg, .5 mmol) in DMF <br><br> 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 hexane. The solution was dissolved in MeOH and treated with NaBH^ After gas evolution ceased the reaction mixture was carefully acidified with IN HCl and the 25 resulting solid was filtered(52 mg, 13%). EI-MS m/z 399 (M-H) <br><br> Example 56 <br><br> Synthesis of N-f2-hvdroxv 4-nitro phenyl) N-(2-iodo phenyl") urea <br><br> The urea was synthesized by the treatment of 2-iodo benzoic acid(5 g, 20 mmol) with diphenyl phosphoryl azide(l equiv.) and triethyl amine (1 equiv.) in DMF 30 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(l .08 g, 13%). EI-MS m/z 398(M-H)" <br><br> 35 Example 57 <br><br> Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2-bromo phenyl) thiourea <br><br> The thiourea was synthesized by treatment of the 2-ferf-butyldimethylsilyloxy 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 <br><br> -47- <br><br> WO 00/76495 PCT/US00/I6499 <br><br> by flash chromatography(EtOAc/Hexane). 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 5 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)+ <br><br> Example 58 <br><br> Synthesis of N-(2-phenvlsulfamido) 4-cvanophenvl N'-(2-bromo phenyl) urea a) Synthesis of 3-(phenylsulfamido) benzonitrile <br><br> 10 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%).1H NMR (CDC13): 8 7.95(s, IH), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t, IH, J = 8.0 Hz), 7.45 (m, 2H), 7.35 (m, 4H). <br><br> b) Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile <br><br> 15 The 3-(phenylsulfamido) 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 then partitioned between methylene chloride and water. The organic 20 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) + <br><br> c) Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile <br><br> 25 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 filtrate 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)+ 30 d) Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl) <br><br> urea <br><br> 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, 35 22%). EI-MS m/z 469(M-H) " <br><br> Example 59 <br><br> Synthesis of N-(2-fphenyl sulfamido) phenyl) N'-f 2-bromo phenyl) urea a) Synthesis of 2-( phenyl sulfamido) aniline <br><br> -48- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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 m/z 249(M+H)+ <br><br> b) Synthesis of N-(2-(phenyl sulfamido) phenyl) N-(2-bromo phenyl) urea 5 and 2-bromo phenyl isocyanate by general Method B. The urea was synthesized 2-(phenyl sulfamido) aniline(l mmol). 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)+ <br><br> Example 60 <br><br> 10 Synthesis of N-(2-( stvrvl sulfamido) phenyl) N'-f2-bromo phenyl) urea a) Synthesis of 2-( styryl sulfamido) aniline <br><br> 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(1.2 g, 60%)EI-MS m/z 199(M+H)+. <br><br> 15 b) Synthesis of N-(2-(styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea <br><br> 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)+ 20 Example 61 <br><br> Synthesis of 2-r(3.4 dimethoxvphenvDsulfonvl aminol phenyl) N-f 2-bromo phenyl) urea a) Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl anihne The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl <br><br> 25 chloride(0.01 mol) and o-phenylene diamine by general Method C. It was purified by recrystallization from EtOH(0.65 g, 21%). EI-MS m/z 309(M+H)+. <br><br> b) Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonylamino] phenyl) N-(2-bromo phenyl) urea <br><br> The urea was synthesized from 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl 30 aniline(l 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(0.062 g, 12%).EI-MS m/z 504(M-H) <br><br> Example 62 <br><br> Synthesis of N-(2-rf4-acetamidophenvl)sulfonvlaminol phenyl) N'-f2-bromo phenyl) 35 urea a) Synthesis of 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline The sulfonamide was synthesized from 4-acetamidophenyl 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) . <br><br> -49- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> b) Synthesis of N-(2-[(4-acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea <br><br> 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 5 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) <br><br> Example 63 <br><br> Synthesis of N-f2-(2-thiophene sulfamido phenyl) N'-(2-bromo phenyl) urea <br><br> 10 a) Synthesis of 2-(2-thiophene sulfamido) aniline <br><br> 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)+ <br><br> b) Synthesis of N-(2-(2-thiophene sulfonyl amino phenyl) N-(2-bromo phenyl) <br><br> 15 urea <br><br> 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) 20 Example 64 <br><br> Synthesis of N-(2-f3-tolvl sulfonyl amino phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-( 3-tolyl sulfonyl amino) aniline <br><br> The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by 25 recrystallization from EtOH(0.73g, 28%).EI-MS m/z 263 (M+H)+ <br><br> b) Synthesis of N-(2-((3-tolyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) <br><br> urea <br><br> 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 30 with methylene chloride and precipitation with hexane. It was recrysallized two times with EtOH(25 mg, 5%). EI-MS m/z 458(M-H)" <br><br> Example 65 <br><br> Synthesis of N-(2-f8-quinolinvl sulfonvl amino) phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-(8-quinolinyl sulfonyl amino) aniline <br><br> 35 The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride(0.01 mol) <br><br> and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.82 g, 27%).EI-MS m/z 300 (M+H). <br><br> b) Synthesis of N-(2-( (8-quinolinyl) sulfonyl amino) phenyl) N-(2-bromo phenyl) urea <br><br> -50- <br><br> WO 00/76495 PCT/US00/16499 <br><br> The urea was synthesized from 2-((8-quinolinyl) 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(0.23 g, 46%).EI-MS m/z 495(M-H). 5 Example 66 <br><br> Synthesis of N-(2-( benzyl sulfonvl amino) phenyl) N-(2-bromo phenyl) urea a) Synthesis of 2-(benzyl sulfonyl amino) aniline <br><br> 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 10 recrystallization from EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+. <br><br> b) Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N-(2-bromo phenyl) <br><br> urea <br><br> 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 15 dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.11 g, 23%). EI-MS m/z 460 (M+H)+ <br><br> Example 67 <br><br> Synthesis of N-(2-hvdroxv-4-azidophenvl)-N'-(2-methoxvphenvl)urea a) Synthesis of N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea <br><br> 20 To a solution of N-(2-hydroxy-4-nitro phenyl)-N'-(2-methoxyphenyl)urea(l .0 g, <br><br> example 15) 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 25 m/z 274 (M+H)+ <br><br> b) Synthesis of N-(2-hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea The N-(2-hydroxy-4-aminophenyl)-N-(2-methoxyphenyl)urea (300 mg, 1.17 <br><br> mmol) was added to HC1/H20 (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 30 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 35 : ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+ <br><br> Example 68 <br><br> Preparation of N-f2-hvdroxv-5-cvanophenvll-N'-r2-bromophenvn urea a) Preparation of 2-amino-4-cyanophenol <br><br> -51 - <br><br> WO 00/76495 PCT/US00/16499 <br><br> To a solution of 2-nitro-4-cyanophenol(10g, 6lmmol) 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 5 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%). 'H NMR (cd3od): 6 6.96 (d, IH), 6.90 (dd, IH), 6.77 (d, IH). <br><br> b) Preparation of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-10 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%). 'H NMR (CD3OD): 8 8.10 (d, IH), 7.87 (d, IH), 7.43 (d, IH), 7.20 (t, IH), 7.09 (d, IH), 6.86 (t, IH), 6.77 (d, IH). <br><br> Example 69 <br><br> 15 Preparation of N-r2-hvdroxv-3-fluorophenvll-N'-r2-bromophenvll urea a) Preparation of 2-amino-3-fluorophenol <br><br> 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 20 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/ CH2C12) gave the desired product(650 mg, 80.2 %). 'H NMR (cd3od): 8 6.41-6.17 (m, 3H). <br><br> b) Preparation of N-[2-hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea <br><br> 25 N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromo phenyl] urea was prepared from 2- <br><br> amino-3-fluorophenol (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. (500 mg, 77%). ]H NMR (CD3OD): 8 8.05 (d, IH), 7.50 (d, IH), 7.26 (t, IH), 7.18 (d, IH), 6.92 (t, IH), 6.86-6.68 (m, 2H). 30 Example 70 <br><br> Preparation of N-2-ri-hvdroxvfluorenel-N'-r2-bromophenvll urea a) Preparation of 2-amino-1-hydroxyfluorene To a solution of l-hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in methanol(250mL) was added 10% Pd/C (lg). The mixture was flushed with argon, 35 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/ CH2C12) gave the <br><br> -52- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> desired product(171 mg, 81.2 %). ]H NMR (CD3OD): 8 7.60 (d, IH), 7.47 (d, IH), 7.28 (t, IH), 7.18 (m, 2H), 6.82 (d, IH), 3.76 (s, 2H). <br><br> b) Preparation of N-2-[l-hydroxyfluorene]-N-[2-bromophenyl] urea N-2-[l-hydroxyfluorene]-N-[2-bromo phenyl] urea was prepared from 2-5 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%). !H NMR (cd3ci): 8 8.04 (d, IH), 7.66 (d, IH), 7.49 (t, 2H), 7.35-7.20 (m, 4H), 7.09 (d, IH), 6.90 (t, IH). <br><br> 10 Example 71 <br><br> Preparation of N-3-f2-hvdroxv-9.10-anthraQuinonvll-N'-r2-bromophenvll urea N-3-[2-Hydroxy-9,10-anthraquinonyl]-N'-[2-bromophenyl] 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 15 chloride/hexane( 1/20) and filtering. (610mg, 70%). *H NMR (CD3OD): 8 8.93 (s,lH), 8.12 (m, 2H), 8.02 (d, IH), 7.77 (m, 2H), 7.61 (d, IH), 7.52 (s, IH), 7.38 (t, IH), 7.05 (t, IH). <br><br> Example 72 <br><br> Preparation of N-f2-hvdroxv-3-fluoro-5-bromophenvll-N-r2-bromophenvll ureaa) 20 Preparation of 2-amino-6-fluoro-4-bromophenol <br><br> A mixture of 4-bromo-2-fluoro 6-nitrophenol(lg, 4.2mmol) and tin (II) chloride (4.78 g, 21.2mmol) 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 was made slightly basic (pH7-8), by addition of solid 25 NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSC&gt;4 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 %). 'H NMR (CD3OD): 8 6.51-6.40 (m, 2H). <br><br> b) Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] <br><br> 30 urea <br><br> N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-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(l/20) and filtering. (500 mg, 77%). JH NMR (CD3OD): 8 7.98 (s, 35 IH), 7.91 (d, IH), 7.60 (d, IH), 7.33 (t, IH), 7.00 (t, IH), 6.94 (d, IH). <br><br> Example 73 <br><br> Preparation of N-f2-hvdroxv-3-chlorophenvll-N-f2-bromophenvll urea a) Preparation of 2-amino-3-chlorophenol <br><br> -53- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4mmol) and tin (II) 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, 5 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/ CH2C12) gave the desired product(143 mg, 69 %). 'H NMR (CD3OD): 8 6.75 (t,lH), 6.70 (d, IH), 6.65 (d, IH). <br><br> b) Preparation of N-[2-hydroxy-3-chlorophenyl]-N-[2-bromophenyl] urea 10 N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2- <br><br> 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): 8 7.81 (d, IH), 7.68 (d, IH), 7.47 (d, IH), 7.20 (t, IH), 6.90 (m, 2H), 6.70 (t, 15 IH). <br><br> Example 74 <br><br> Preparation of N-r2-hvdroxv-3-trifluoromethvlphenvn-N-r2-bromophenvll ureaa) Preparation of 2-nitro-6-trifluoromethylphenol <br><br> 2-trifluoromethylphenol (3.00g, 18.5mmol) was dissolved in methylene 20 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 MgS04 and filtered. The solvent was evaporated and 25 chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.84 g, 47 %). !H NMR (CD3COCD3): 8 8.35 (d,lH), 7.95 (d, IH), 7.13 (t,lH). <br><br> b) Preparation of 2-amino-6-trifluoromethylphenol <br><br> A mixture of 6-trifluoromethyl-2-nitrophenol(1.84 g, 8.67mmol) and tin (II) 30 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 MgS04 and filtered. The solvent was evaporated and 35 chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.35 g, 88 %). 'h NMR (CD3OD): 8 6.93 (d, IH), 6.82 (t, IH), 6.78 (d, IH). <br><br> c) Preparation of N-[2-hydroxy-3- trifluoromethylphenyl]-N-[2-bromophenyl] <br><br> urea <br><br> -54- <br><br> WO 00/76495 <br><br> PCT/USO0/16499 <br><br> 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 chloride/ hexane(l/20) and filtering. (390mg, 65%). 'H NMR (CD3OD): 8 7.99 (d, 5 IH), 7.60 (d, IH), 7.58 (d, IH), 7.34 (t, IH), 7.30 (d, IH), 7.00 (t, IH), 6.96 (d, IH). <br><br> Example 75 <br><br> Preparation of N-f3.4 diphenvl-2-hvdroxvphenvll-N-r2-bromophenvll urea <br><br> N-[3,4 diphenyl-2-hydroxyphenyl]-N-[2-bromophenyl] urea was prepared from 2-amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General 10 Method B. The product was purified by precipitation from methylene chloride/ <br><br> hexane(l/20) and filtering (61mg, 69%). *H NMR (CD3OD): 8 7.97 (d, IH), 7.66 (d, IH), 7.58 (d, IH), 7.31 (t, IH), 7.25-7.00 (m, 11H), 6.91 (d, IH). <br><br> Example 76 <br><br> Preparation of N-f2-hvdroxv-3-glvcinemethvlestercarbonvlphenvll-N-r2-bromophenvll 15 urea <br><br> N-[2-hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea was prepared from 6-glycinemethylestercarbonyl-2-aminophenol (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/ 20 hexane(l/20) and filtering (65mg, 69%). *H NMR (CD3OD): 8 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). <br><br> Example 77 <br><br> Preparation of N-r2-hvdroxv-3-glvcinecarbonvlphenvll-N-r2-bromophenvll urea N-[2-Hydroxy-3-glycinecarbonylphenyl]-N'-[2-bromophenyl] urea was prepared from N-25 [2-hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-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 CH2C12/ MeOH/ AcOH) to give the desired 30 product(195mg, 57%). *H NMR (CD3OD): 8 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). <br><br> Example 78 <br><br> Preparation of N-f2-hvdroxv-3.5-dichIorophenvll-N'-r2-bromophenvll urea a) Preparation of 2-amino-4,6-dichlorophenol 35 A mixture of 4,6-dichloro-2-nitrophenol(l g, 4.8mmol) and tin (II) chloride (3.2 <br><br> 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, <br><br> -55- <br><br> WO 00/76495 PCT/US00/16499 <br><br> dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(685 mg, 80 %). 'H NMR (CD3OD): 8 6.75 (s,lH), 6.61 (s, IH). <br><br> b) Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N-[2-bromophenyl] urea 5 N-[2-Hydroxy-3,5-dichlorophenyl]-N- [2-bromophenyl] urea was prepared from <br><br> 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%). 'H NMR (CD3OD): 8 7.96 (s, IH), 7.89 (d, IH), 7.60 (d, IH), 7.35 (t, IH), 7.00 (t, IH), 6.95 (dd, IH). 10 Example 79 <br><br> Preparation of N-r2-hvdroxv-3-nitrophenvl1-N'-r2-bromophenvn ureaN-[2-Hydroxy-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, 15 84%). *H NMR (CD3OD): 8 8.45 (d, IH), 7.94 (d, IH), 7.78 (d, IH), 7.60 (d, IH), 7.35 (t, IH), 7.01 (m, 2H). <br><br> Example 80 <br><br> Preparation of N-r2-hvdroxv-4-naphthalenesulfonic acidl-N'-f2-bromophenvll urea N-[2-hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea was 20 prepared from l-amino-2-hydroxy-4-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the procedure in General Method B and the addition of lmL of triethylamine. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (690 mg, 79%). 'H NMR (CD3OD): 8 8.14 (s, IH), 8.04 (d, IH), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, IH), 6.98 (t, IH). 25 Example 81 <br><br> Preparation of N-r2-hvdroxv-5-naphthalenesulfonic acidl-N'-f2-bromophenvn urea <br><br> N-3-[2-hydroxy-5-naphthalensulfonic acid]-N'-[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 30 triethylamine. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (715 mg, 82%). 'H NMR (CD3OD): 8 8.09 (s, IH), 7.96 (d, IH), 7.65-7.48 (m, 3H), 7.36 (t, IH), 7.25 (s, IH), 7.04 (m, 2H). <br><br> Example 82 <br><br> Preparation of N-r2-hvdroxv-3.4-dichlorophenvll-N'-f2-bromophenvll urea 35 a) Preparation of 2-nitro-5,6 dichlorophenol <br><br> 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, <br><br> -56- <br><br> WO 00/76495 PCT/US00/16499 <br><br> 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/ CH2C12) gave the desired product(1.8 g, 44 %). 'H NMR (CD3COCD3): 5 8.04 (d,lH), 7.15 (d, IH). <br><br> 5 b) Preparation of 2-amino-5,6 dichlorophenol <br><br> A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7mmol) and tin (13) chloride (5.8 g, 26.1 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 10 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/ CH2C12) gave the desired product(1.4 mg, 90 %). *H NMR (CD3OD): 5 6.71 (d, IH), 6.45 (d, IH). <br><br> c) Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea 15 N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from <br><br> 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%). 'H NMR (CD3OD): 8 7.90 (d, IH), 7.85 (d, IH), 7.59 (d, IH), 7.31 (t, IH), 6.99 (t, IH), 6.96 (d, (IH). 20 Example 83 <br><br> Preparation of N-r2-hvdroxv-3-cvanoDhenvll-N'-f2-bromophenvll urea a) Preparation of 2-nitro-6-cyanophenol <br><br> 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 25 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/ CH2C12) gave the desired product(1.4 g, 42 %). 30 *H NMR (CD3COCD3): 8 8.47 (d,lH), 8.15 (d, IH), 7.30 (t, IH). <br><br> b) Preparation of 2-amino-6-cyanophenol <br><br> A mixture of 6-cyano-2-nitrophenol(600 mg, l.Ommol) and tin (II) chloride (3.2 g, 14.4mmol) in acetic acid(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then 35 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/ CH2C12) gave the desired product(365 mg, 75 %). 'H NMR (CD3OD): 8 6.92 (d, IH), 6.85-6.69 (m,2H). <br><br> -57- <br><br> WO 00/76495 <br><br> PCT/USOO/l6499 <br><br> c) Preparation of N-[2-hydroxy-3-cyanophenyl]-N-[2-bromophenyl] urea <br><br> N-[2-Hydroxy-3-cyanophenyl]-N-[2-bromophenyl] urea was prepared from 2-amino-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ 5 hexane(l/20) and filtering. (260mg, 78%). 'H NMR (CD3OD): 8 7.98 (d, IH), 7.74 (d, IH), 7.57 (d, IH), 7.30 (t, IH), 7.22 (d, IH), 6.98 (t, IH), 6.94 (t, (IH). <br><br> Example 84 <br><br> Preparation of N-f2-hvdroxv-4-cvanophenvll-N'-r2-bromophenvll urea a) Preparation of 2-nitro-5-cyanophenol <br><br> 10 3-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL) <br><br> 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 15 over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(910 mg, 28 %). 'H NMR (CD3COCD3): 8 8.30 (d,lH), 7.67 (s,lH), 7.49 (d, IH). <br><br> b) Preparation of 2-amino-5-cyanophenol <br><br> A mixture of 5-cyano-2-nitrophenol(250 mg, 1.5mmol) and tin (II) chloride (3.2 20 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 25 resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(175 mg, 86 %). !H NMR (CD3OD): 8 7.00 (d, IH), 6.88 (s,lH), 6.69 (d, IH). <br><br> c) Preparation of N-[2-hydroxy-4-cyanophenyl]-N-[2-bromophenyl] urea <br><br> N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2- <br><br> amino-5-cyanophenol (170mg, 1.27 mmol) according to the procedure in General 30 Method B. The product was purified by precipitation from methylene chloride/ <br><br> hexane(l/20) and filtering (310mg, 74%). 'H NMR (CD3OD): 8 8.25 (d, IH), 7.91 (d, IH), 7.59 (d, IH), 7.33 (t, IH), 7.17 (d, IH), 7.07 (s, IH), 7.01 (t, (IH). <br><br> Example 85 <br><br> Preparation of N-r2-hvdroxv-4-cvanophenvll-N-r4-methoxvphenvll urea 35 N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea was prepared from <br><br> 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%). 'H NMR (CD3OD): 8 8.23 (d, IH), 7.61-7.51 (m, 2H), 7.32 (d, IH), 7.20 (d, IH), 7.15 (d, IH), 7.03 (s, IH). <br><br> -58- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> Example 86 <br><br> Preparation of N-f2-hvdroxv-4-cvanophenvll-N'-r2-phenvlphenvll 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. 5 The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (150mg, 85%). *H NMR (CD3OD): 8 8.20 (d, IH), 7.73 (d, IH), 7.51-7.20 (m, 8H), 7.13 (d, IH), 7.01 (s, (IH). <br><br> Example 87 <br><br> Preparation of N-r2-hvdroxv-4-cvanophenvll-N'-r2-methvlphenvll urea 10 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea was prepared from 2- <br><br> 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. (90mg, 75%). 'H NMR (CD3OD): 8 8.25 (d, IH), 7.59 (d, IH), 7.26-7.00 (m, 5H), 2.30 (s, 3H). 15 Example 88 <br><br> Preparation of N-f2-hvdroxv-4-cvanophenvll-N-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/ 20 hexane(l/20) and filtering. (1 lOmg, 76%). *H NMR (CD3OD): 8 8.25 (d, IH), 7.81 (d, IH), 7.68 (d, IH), 7.61 (t, IH), 7.32 (t, IH), 7.15 (dd, IH), 7.09 (s, (IH). <br><br> Example 89 <br><br> Preparation of N-f2-hvdroxv-4-cvanophenvll-N'-r3-trifluoromethvlphenvI1 urea N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-25 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%). 'H NMR (CD3OD): 8 8.30 (d, IH), 7.92 (s, IH), 7.60 (d, IH), 7.47 (t, IH), 7.29 (d, IH), 7.18 (dd, IH), 7.06 (s, IH). <br><br> Example 90 <br><br> 30 Preparation of N-r2-hvdroxv-4-cvanophenvll-N'-r4-trifluoromethvlphenvll urea N-[2-Hydroxy-4-cyanophenyl]-N-[4-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (108mg, 75%). 'H NMR (CD3OD): 8 8.31 (d, IH), 7.68 (d, 35 2H), 7.59 (d, 2H), 7.20 (dd, IH), 7.07 (s, IH). <br><br> Example 91 <br><br> Preparation of N-r2-hvdroxv-3-n-propvlphenvIl-N'-r2-bromophenvll urea a) Preparation of 2-nitro-6-n-propylphenol <br><br> -59- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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, <br><br> 5 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/ CH2C12) gave the desired product(3.2 mg, 48 %). JH NMR (CD3COCD3): 8 7.99 (d,lH), 7.46 dd, IH), 6.90 (t, IH), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H). <br><br> 10 b) Preparation of 2-amino-6-n-propylphenol <br><br> To a solution of 2-nitro-6-n-propylphenol(2g, 1 l.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 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and <br><br> 15 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(1.50 g, 80.2 %). 'H NMR (CD3OD): 8 6.65 (m, 2H), 6.55 (t, IH), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H). <br><br> c) Preparation of N-[2-hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea <br><br> 20 N-[2-Hydroxy-3-n-propyl phenyl]-N'-[2-bromo phenyl] urea was prepared from <br><br> 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%). *H NMR (CD3OD): 8 8.00 (d, IH), 7.58 (d, IH), 7.32 (t, IH), 126 (t, IH), 6.96 (dd, IH), 6.89 (t, IH), 6.78 (d, IH). <br><br> 25 Example 92 <br><br> Preparation of N-r2-hvdroxv-4-ethvlphenvll-N'-f2-bromophenvll urea a) Preparation of 2-nitro-5-ethylphenol <br><br> 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 <br><br> 30 acid (50mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.7 g, 25 %). <br><br> 35 lH NMR (CD3COCD3): 8 8.02 (d,lH), 6.99 (s,lH), 6.85 (d, IH), 2.69 (q, 2H), 1.30 (t, 3H). <br><br> b) Preparation of 2-amino-5-ethylphenol <br><br> 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 <br><br> -60- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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/ CH2C12) gave the desired product(750 mg, 91 5 %). 'H NMR (CD3OD): S 6.41-6.17 (m, 3H). <br><br> c) Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxyi4-ethylpheny]]-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/ 10 hexane(l/20) and filtering. (520 mg, 77%). 'H NMR (CD3OD): 8 7.96 (d, IH), 7.62 (s, IH), 7.56 (d, IH), 7.30 (t, IH), 6.96 (t, IH), 6.82 (d, IH), 6.76 (d, IH). <br><br> Example 93 <br><br> Preparation of N-r2-hvdroxv 3-phenvlaminocarbonvl phenvll-N'-r2-bromophenvll urea <br><br> 15 a) Preparation of 2-nitro-6-phenylaminocarbonylphenol <br><br> 2-Phenylaminocarbonylphenol (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, 20 the reaction mixture was diluted with methylene chloride and extracted with water. <br><br> The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(2.50 g, 42 %). 'H NMR (CD3COCD3): 8 8.15 (d,lH), 8.09 (d,lH), 7.51 (d, IH), 7.30 (d, IH), 7.10 (t, IH), 7.01 (t, IH). <br><br> 25 b) Preparation of 2-amino-6-phenylaminocarbonylphenol <br><br> 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 30 through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(800 mg, 91 %). *H NMR (CD3OD): 8 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, IH), 6.94 (t, IH), 6.74 (t, IH). <br><br> c) Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N'-[2-35 bromophenyl] urea <br><br> N-[2-hydroxy 3-Phenylaminocarbonyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amino-6-phenylaminocarbonylphenol (456mg, 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. (800mg,94%). 'H NMR (CD3OD): 'h <br><br> -61 - <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> NMR (CD3OD): 8 25 (d, IH), 7.94 (d, IH), 7.75-7.57 (m, 4H), 7.48-7.30 (m, 3H), 7.21 (t, IH), 7.02 (dd, IH), 6.92 (t, IH). <br><br> Example 94 <br><br> Preparation of N-r2-hvdroxv-3-cvano-4-methvlphenvll-N-r2-bromophenvl1 ureaa) 5 Preparation of the 2-nitro 5-methyl 6-bromo phenol <br><br> 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 2-nitro 5-methyl 6-bromo phenol (5 g, 1 equiv., in methylene chloride) was added drop-wise with vigorous stirring. The reaction mixture was slowly 10 wanned 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/ hexane) to remove dibrominated species. The 2-nitro 4-bromo 5-methyl phenol was then selectively 15 crystallized out of methylene chloride. A final silica gel column(5%ethyl acetate/ <br><br> hexane) yielded desired isomer in 90% purity.(1.05 g, 14%). ]H NMR (cdci3): 8 7.95 (d, IH, J = 10.0 Hz), 6.91 (d, IH, J = 10.0 Hz), 2.52 (s, 3H). <br><br> b) Preparation of 2-nitro-5-methyl-6-cyanophenol <br><br> 2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in <br><br> 20 dimethyl formarnide (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/ CH2C12) gave the desired product (70 mg, 25 91 %). 'H NMR (CD3COCD3): 8 8.30 (d,lH), 7.15 (d,lH), 2.61 (s, 3H). <br><br> c) Preparation of 2-amino-5-methyl 6-cyanophenol <br><br> A mixture of 5-cyano-2-nitrophenol(70 mg, O.39mmol) and tin (II) chloride (265 mg, 1.18mmol) in ethanol(20mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and 30 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/ CH2C12) gave the desired product(175 mg, 86 %). 'H NMR (CD3OD): 8 6.87 (d, IH), 6.75 (d,lH), 6.32 (s, 3H). 35 d) Preparation of N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl] <br><br> urea <br><br> N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-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 <br><br> -62- <br><br> WO 00/76495 <br><br> PCT/USOO/16499 <br><br> chloride/ hexane(l/20) and filtering. (70mg, 60%). *H NMR (CD3OD): 8 7.92 (d, IH), 7.68 (d, IH), 7.59 (d, IH), 7.31 (t, IH), 7.00 (t, IH), 6.62 (t, IH), 2.49 (s, (3H). <br><br> Example 95 <br><br> Preparation of N-r2-hvdroxv 4-Carboxvphenvl phenvl"l-N-f2-bromophenvll ureaa) 5 Preparation of 4-nitro-3-hydroxybenzophenone <br><br> 3-Hydroxybenzophenone (3.00g, 15.1mmol) 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, 10 the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSC&gt;4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.10 g, 30 %). 'h NMR (CD3COCD3): 8 8.25 (d,lH), 7.86 (d.lH), 7.71 (m, IH), 7.59 (d, IH), 7.48 (s, IH), 7.39 (dd, IH). <br><br> 15 b) Preparation of 4-amino-3-hydroxybenzophenone <br><br> A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (II) chloride (2.5 g, 1 l.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 20 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/ CH2C12) gave the desired product(685 mg, 87 %). ]H NMR (CD3OD): 8 7.65 (d, 2H), 7.55 (d,lH), 7.49 (t, 2H), 7.26 (s, IH), 7.16 (dd, IH), 6.68 (d, IH). <br><br> 25 c)Preparation of N-[4-Carboxyphenyl-2-hydroxyphenyl]-N-[2-bromophenyI] urea N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from4-amino-3-hydroxybenzophenone (330mg, 1.5 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (490mg, 79%). 'H NMR (CD3OD): 8 30 8.40 (d, IH), 8.09 (d, IH), 7.83 (d, 2H), 7.65-7.60 (m, 4H), 7.48 (s, IH), 7.43 (d, IH), 7.35 (d,(lH), 7.10 (t,lH). <br><br> Example 96 <br><br> Preparation of N-r2-hvdroxv 3-carboxvphenvl phenvll-N-f2-bTomophenvll ureaa) Preparation of 3-nitro-2-hydroxybenzophenone 35 2-Hydroxybenzophenone (3.OOg, 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. <br><br> -63- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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 %). NMR (CD3COCD3): 8 8.30 (d,lH), 7.86 (m,3H), 7.71 (m, IH), 7.78 (d, IH), 7.56 (dd 2H), 7.24 (t, IH). <br><br> 5 b) Preparation of 3-amino-2-hydroxybenzophenone <br><br> A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5mmol) and tin (II) chloride (1.7 g, 7.5mmoI) 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 10 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): 8 7.65-7.40 (m, 5H), 6.98 (d,lH), 6.86 (d, IH), 6.67 (t, IH). <br><br> 15 c)Preparation of N-[2-hydroxy 3-carboxyphenyl phenyl]-N'-[2-bromophenyl] urea <br><br> N-[2-hydroxy 3-carboxyphenyl 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): 8 20 8.35 (d, IH), 7.96 (d, IH), 7.72 (d, 2H), 7.65-7.50 (m, 4H), 7.35 (d, IH), 7.30 (d, IH), 7.01 (dd, (IH), 6.92 (t, IH). <br><br> Example 97 <br><br> Preparation of N-f 2-hvdroxv 3-benzvloxv phenvll-N'-r2-bromophenvll urea a) Preparation of 2-nitro-6-benzyloxy phenol 25 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. 30 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 %). 'H NMR (CD3COCD3): 8 7.70 (d,lH), 7.50-7.28 (m, 5H), 7.14 (d, IH), 6.92 (t, IH), 5.21 (s, 2H). <br><br> b)Preparation of 2-amino-6-benzyloxy phenol 35 A mixture of 2-nitro-6-benzyloxy phenol (1.00 g, 4. lOmmol) and tin (II) <br><br> chloride (2.75 g, 12.2 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 <br><br> -64- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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(1.35 g, 88 %). 'H NMR (CD3OD): 87.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, IH), 6.40 (d, IH), 5.10 (s, 2H). <br><br> 5 b) Preparation of N-[2-hydroxy-3-benzyloxyphenyl]-N'-[2-bromophenyl] <br><br> urea <br><br> N-[3-benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 2-nitro-6-benzyloxy phenol (430mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ <br><br> 10 hexane(l/20) and filtering. (630mg, 76%). JH NMR (CD3OD): 8 7.93 (d, IH), 7.58 (d, IH), 7.54-7.42 (m, 3H), 7.40-7.25 (m, 4H), 7.00 (t, IH), 6.69 (d, 2H), 5.16 (s, 2H). <br><br> Example 98 <br><br> Preparation of N-3-r2-hvdroxv-5-indanonel-N'-r2-bromophenvll urea a) Preparation of 2-hydroxy-3-nitro-5-indanone <br><br> 15 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. <br><br> 20 The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.5 g, 39 %). *H NMR (CD3COCD3): 8 7.70 (d,lH), 7.04 (d, IH), 3.04 (d, 2H), 2.74 (d, 2H). <br><br> b) Preparation of 3-amino-2-hydroxy-5-indanone <br><br> 25 A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80mmol) and tin (II) <br><br> 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 <br><br> 30 washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.00 g, 79 %). 'H NMR (CD3OD): 8 6.85 (d,lH), 6.45 (d, IH), 2.95 (d, 2H), 2.60 (d, 2H). <br><br> c) Preparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea <br><br> 35 N-[2-Hydroxy-5-indanone]-N'-[2-bromophenyl] urea was prepared from 3- <br><br> 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): 8 7.92 (d, IH), 7.65 (m, 2H), 7.45 (t, IH), 7.09 (t, IH), 7.00 (d, IH), 2.90 (d, 2H), 2.66 (d, 2H). <br><br> -65- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Example 99 <br><br> Preparation of (EVN-f4- \2-(Methoxvcarbonvl) ethenvll-2-hvdroxvphenvll-N-f2-bromophenvll urea a) Preparation of 4-nitro-3-hydroxycinnamic acid <br><br> 5 3-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.70 g, 26.1mmol). The addition of sulfuric acid (25 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. 10 The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.0 g, 26 %). *H NMR (CD3COCD3): 8 8.07 (d, IH), 7.69 (d, IH), 7.51 (s, IH), 7.46 (d, 2H), 6.75 (d,lH). <br><br> b) Preparation of 4-nitro-3-hydroxymethylcinnamate <br><br> 15 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/ CH2C12) gave the desired product(1.0 g, 94 %). 'H NMR (CD3COCD3): 6 8.17 (d, IH), 7.69 (d, IH), 7.52 (s, IH), 7.45 (d, 2H), 6.75 (d,lH), 3.80 (s, 3H). <br><br> 20 c) Preparation of 4-amino-3-hydroxymethylcinnamate <br><br> A mixture of 4-nitro-3-hydroxymethylcinnamate (1.0 g, 4.50mmol) and tin (II) 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 25 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/ CH2C12) gave the desired product (650 mg, 75 %). 'H NMR (CD3OD): 87.50 (d,lH), 6.94 (s, IH), 6.89 (d, IH), 6.68 (d, IH), 6.18 (d, IH), 3.74 (s, 3H). <br><br> 30 d)Preparation (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea <br><br> (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyI] urea was prepared from 4-amino-3-hydroxymethylcinnamate (250mg, 1.3 mmol) according to the procedure in General Method B. The product was purified by 35 precipitation from methylene chloride/ hexane(l/20) and filtering. (300mg, 59%). lH NMR (CD3OD): 8 8.24 (d,lH), 8.05 (d, IH), 7.69 (d, IH), 7.65 (d, IH), 7.42 (t, IH), 7.21 (s, IH), 7.19 (d, IH), 7.10 (t, IH) 6,45 (d,lH) 3.81 (s, 3H). <br><br> Example 100 <br><br> -66- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Preparation of fEVN-r3-f2-fMethoxvcarbonvl'&gt; ethenvl1-2-hvdroxvphenvl1-N'-r2-bromophenvll urea N-f2-bromophenvn urea a) Preparation of 3-nitro-2-hydroxycinnamic acid <br><br> 2-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene <br><br> 5 chloride(40mL) followed by the addition of sodium nitrate (2.21 g, 26.1mmol). The addition of sulfuric acid (30 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 MgS04 and filtered. The solvent was evaporated and 10 chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(2.0 g, 52 %). JH NMR (CD3COCD3): 8 8.21 (d, IH), 8.16 (d, IH), 8.05 (d, IH), 7.19 (t, IH), 6.72 (d, IH) <br><br> b) Preparation of 3-nitro-2-hydroxymethylcinnamate <br><br> 3-nitro-2-hydroxycinnamic acid was stirred in excess methanol with a catalytic 15 amount of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.0 g, 94 %). 'H NMR (CD3COCD3): 8 8.25 (d, IH), 7.8.15 (d, IH), 8.06 (s, IH), 7.20 (t, 2H), 6.76 (d,lH), 3.80 (s, 3H). <br><br> c) Preparation of 3-amino-2-hydroxymethylcinnamate <br><br> 20 A mixture of 3-nitro-2-hydroxymethylcinnamate (1.0 g, 4.5 mmol) and tin (II) <br><br> 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 25 brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product (700 mg, 81 %). *H NMR (CD3OD): 8 8.04 (d, IH), 6.93 (d, 1H),6.79 (d, IH), 6.71 (t, IH), 6.43 (d, IH), 3.72 (s, 3H). <br><br> d) Preparation(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N-30 [2-bromophenyl] urea <br><br> (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 3-amino-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%).*H 35 NMR (CD3OD): 8 8.10 (d,lH), 8.00 (d, IH), 7.69 (d, IH), 7.65 (d, IH), 7.42 (t, IH), 7.38 (t, IH), 7.32 (d, IH), 7.05 (t, IH) 6.55 (d,lH) 3.81 (s, 3H). <br><br> Example 101 <br><br> Preparation of CEVN-\3-\2-(Aminocarbonvn ethenvll-2-hvdroxvphenvll-N'-f2-bromophenvll urea N-r2-bromophenvll urea <br><br> -67- <br><br> WO 00/76495 PCT/US00/16499 <br><br> a) Preparation of 2-hydroxycinnamide <br><br> 2-Hydroxycinnamic acid (2.(X)g, 12.3 mmol) was dissolved in dimethyl formamide(lOmL) followed by the addition of benzotriazol-1 -yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (5.4g, 12.3 mmol) and 5 triethylamine (1.7mL, 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/ CH2C12) gave the 10 desired product(1.5 g, 75 %). <br><br> b) Preparation of 3-nitro-2-hydroxycinnamide <br><br> 2-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (430 mg, 5.1mmol). The addition of sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic 15 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/ CH2C12) gave the desired product(350 mg, 36 %). 'H NMR (CD3COCD3): 8 8.19 (d, IH), 8.02 (d, IH), 20 7.88 (d, IH), 7.15 (t, IH), 6.84 (d, IH) <br><br> c) Preparation of 3-amino-2-hydroxycinnamide <br><br> A mixture of 3-nitro-2-hydroxymethylcinnamate (350 mg, 1.7 mmol) and tin (II) 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 25 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/ CH2C12) gave the desired product(244 mg,80%). <br><br> 30 d) Preparation of (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'- <br><br> [2-bromophenyl] urea <br><br> (E)-N-[3-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 3-amino-2-hydroxycinnamide (100 mg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from 35 methylene chloride/ hexane(l/20) and filtering. (110 mg, 52%).*H NMR (CD3OD): 8 8.00 (d,lH), 7.90 (d, IH), 7.63 (d, IH), 7.55 (d, IH), 7.35 (m, 2H), 7.05 (t, IH), 6.95 (t, IH), 6.70 (d,lH). <br><br> Example 102 <br><br> -68- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Preparation of fEVN-14-f2-(AminocarbonvD ethenvn-2-hvdroxvphenvll-N'42-bromophenvll urea N-12-bromophenvll urea a) Preparation of 3-hydroxycinnamide <br><br> 3-Hydroxycinnamic acid (2.00 g, 12.3 mmol) was dissolved in dimethyl 5 formamide( 10 mL) followed by the addition of benzotriazol-1 -yloxy- <br><br> tris(dimethylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and triethylamine (1.7 mL, 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 10 layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.3 g, 65 %). <br><br> b) Preparation of 4-nitro-3-hydroxycinnamide <br><br> 3-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene <br><br> 15 chloride(40 mL) followed by the addition of sodium nitrate (430 mg, 5.1 mmol). 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 MgSC&gt;4 and filtered. The solvent was evaporated and 20 chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(240 mg, 25 %). JH NMR (CD3COCD3): 8 8.09 (d, IH), 7.49 (d, IH), 7.26 (s, IH), 7.16 (d, IH), 6.71 (d, IH) <br><br> c) Preparation of 4-amino-2-hydroxycinnamide <br><br> A mixture of 4-nitro-3-hydroxymethylcinnamate (300 mg, 1.40 mmol) and tin 25 (II) chloride (980 mg, 4.30 mmol) in ethanol(50 mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8), by addition 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 30 and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product (200 mg, 74 %). <br><br> d)Preparation(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea <br><br> (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N-[2-bromophenyl] 35 urea was prepared from 4-amino-2-hydroxycinnamide (lOOmg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (125mg, 54%).'H NMR (CD3OD): 8 8.05 (d,lH), 7.92 (d, IH), 7.60 (d, IH), 7.4 5 (d, IH), 7.35 (t, IH), 7.05 (m, 2H), 6.50 (d,lH). <br><br> -69- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Example 103 <br><br> Preparation of N-f2-hvdroxv4-fphenyl amino carboxy) phenvl1-N-f2-bromophenvll urea <br><br> N-[2-hydroxy 4-(phenyl amino carboxy) phenyl]-N'-[2-bromophenyl] urea was 5 prepared from 5-(phenyl amino carboxy) 2-amino phenol (0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (150 mg, 70%). !H NMR (CD3OD): 5 8.25 (d, IH), 8.00 (d, IH), 7.75 (d, 2H), 7.64 (d, IH), 7.50 (d, 2H), 7.41 (m, 3H), 7.16 (t, IH), 7.05 (t, IH). <br><br> 10 Example 104 <br><br> Preparation of N-r4-aminocarbonvl-2-hvdroxvphenvll-N-r2-bromophenvll urea N-[4-Aminocarbonyl -2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 5-axninocarbonyl-2-amino phenol (304 mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ 15 hexane(l/20) and filtering. (440 mg, 62%). ]H NMR (CD3OD): 8 8.09 (d, IH), 7.91 (d, IH), 7.60 (d, IH), 7.45 (m, 3H), 7.00 (d, IH). <br><br> Example 105 <br><br> Preparation of N-(2-Hvdroxv-3.5.6-trifluorophenvl)-N-(2-bromophenvl)urea N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea was prepared from 3,5,6-20 trifluoro-2-hydroxyaniline (83 mg, 0.51 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)\ <br><br> Example 106 <br><br> Preparation of N-('2-Hvdroxv-3-fluoro-4-trifluoromethvlphenvl'&gt;-N'-f2-25 bromophenvDurea <br><br> N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea was prepared from 4-trifluoromethyl-3-fluoro-2-hydroxyaniline (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 30 resulting solid on silica gel (hexane:ethyl acetate) gave the title compound (20 mg, 4%). EI-MS m/z 391 (M-H)" <br><br> Example 107 <br><br> Preparation of N-(2-Hvdroxv-3-iodophenvl)-N-(2-bromophenvl)urea <br><br> N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-35 iodo-2-hydroxyaniline (200 mg, 0.85 mmol) and 2-(bromophenyl)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 (hexane:ether) gave the title compound (40 mg, 11%). 'h NMR (DMSO): 8 9.45 (s, <br><br> -70- <br><br> WO 00/76495 PCT/US00/16499 <br><br> IH), 9.15 (s, IH), 8.8 (s, IH), 7.95 (d, IH), 7.8 (d, 1H),7.65 (d, IH), 7.4 (d, IH), 7.3 (t, IH), 7.0 (t, IH), 6.65(t, IH). <br><br> Example 108 <br><br> Preparation of N-r2-rrf2-(trifhioromethvl)phenvllsulfonvriaminolphenvll-N'-(2-5 bromophenvDurea a) Preparation of [2-[2-(trifhioromethyl)phenyl](sulfonamido)aiiiline] The title compound was prepared according to General Method C using 2- <br><br> (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 10 317 (M+H)+. <br><br> b) Preparation of N-[2-[[[2-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea <br><br> The title compound was prepared using[2-[2(trifluoromethyl)phenyl] (sulfonamido)aniline (1.04 g, 3.2 mmol) and 2-(bromophenyl)isocyanate (652 mg, 3.2 15 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)+. <br><br> Example 109 <br><br> Preparation of N-(2-Bromophenvl'&gt;-N-r2-dimethvlaminosulfonvlamino1phenvllurea <br><br> 20 a) Preparation of [2-[ 1,1 -(dimethylamino)]sulfonamidoaniline] <br><br> The title compound was prepared according to General Method C using dimethylsulfamoyl chloride (1 equiv.). The product was purified by chromatography on silica gel (methylene chloride:methanol). ES-MS m/z 216 (M+H)+. <br><br> b) Preparation of N-(2-Bromophenyl)-N-[2-25 (dimethylaminosulfonylamino]phenyl]urea <br><br> The title compound was prepared from [2-[l,l-(dimethlyamino)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 acetaterhexane) gave the desired urea. EI-MS m/z 413 (M+H)+ 30 Example 110 <br><br> Preparation of N-f2-(Phenethvlsulfonvlamino) phenvll-N-f2-bromophenvl)urea [2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a Pan-shaker bottle containing palladium (180 mg) under an argon stream. Methanol (150 mL) was added and the container placed on a Parr shaker (55 psi) for several hours. 35 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)+. <br><br> b)Preparation of N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea <br><br> 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 <br><br> -71- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> General Method B. The desired urea was precipitated out of toluene/hexane (384 mg, 78%). EI-MS m/z 472 (M-H)\ <br><br> Example 111 <br><br> Preparation of N-r2-r(2-acetamido-4-methvIthiazol-5-vl)sulfonvlaminolphenvll-N-(2-5 bromophenvDurea a) Preparation of [2-[(2-acetamido-4-methyl-5-thiazole)sulfonamido]aniline3 The title compound was prepared using 2-acetamido-4-methyl-5- <br><br> thiazolesulfonyl chloride (1 equiv.) according to General Method C. A solid precipitated from the reaction mixture and was filtered to give the desired aniline (1.68 10 g, 52%). ES-MS m/z 327 (M+H)+. <br><br> b) Preparation of N-[2-[(2-acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea <br><br> The title compound was prepared from [2-[(2-acetamido-4-methyl-5-thiazole)sulfonamido]aniline] (1.68 g,5.14 mmol) and 2-(bromophenyl)isocyanate 15 (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)+. <br><br> -72- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> Example 112 <br><br> Preparation of N-r2-hvdroxv-4-cvanophenvH-N-F4-phenvlphenvH urea N-[2-Hydroxy-4-cyanophenyl]-N-[4-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The 5 product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (135 mg, 75%). *H NMR (CD3OD): 6 8.33 (d, IH), 7.71-7.29 (m, 9H), 7.25 (d, IH), 7.12 (s, IH). <br><br> Example 113 <br><br> Preparation of N-r2-hvdroxv-4-cvanophenvll-N-f2.3-dichlorophenvll urea 10 N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from <br><br> 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. (125mg, 86%). lB NMR (CD3OD): 8 8.27 (d, IH), 8.15 (m, IH), 7.39-7.20 (m, 2H), 7.16 (d, IH), 7.06 (s, IH). 15 Example 114 <br><br> Preparation of N-[2-hvdroxv-4-cvanophenvll-N-r2-methoxvphenvn urea <br><br> 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/ 20 hexane(l/20) and filtering (105mg, 83%). 'H NMR (CD3OD): 8 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). <br><br> Example 115 <br><br> Preparation of N-r2-hvdroxv-4-cvanophenvl1-N'-r3-methoxvphenvll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea was prepared from 2-amino-5-25 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): 8 8.25 (d, IH), 7.25-7.08 (m, 3H), 7.04 (s, IH), 6.90 (t, IH), 6.58 (d, IH). <br><br> Example 116 <br><br> 30 Preparation of N-r2-hvdroxv-5-fluorophenvn-N'-r2-bromophenvll urea a) Preparation of 2-amino-4-fluorophenol <br><br> A mixture of 4-fluoro-2-nitrophenol(lg, 4.64mmol) and tin (II) 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 35 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/ CH2C12) gave the desired product(622 mg, 85 %). JH NMR (CD3OD): 8 6.51 (dd, IH), 6.32 (dd, IH), 6.17 (ddd, IH). <br><br> -73- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> b) Preparation of N-[2-hydroxy-5-fluorophenyl]-N-[2-bromophenyl] urea N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-fluoro phenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ 5 hexane(l/20) and filtering. (520mg,80%). *H NMR (CD3OD): 8 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). <br><br> Example 117 <br><br> Preparation of N-r2-hvdroxv-5-trifluoromethvlphenvll-N'-r2-bromophenvl1 urea a) Preparation of 2-amino-4- trifluoromethylphenol 10 A mixture of 4-trifluoromethyl-2-nitrophenol( 1.0 g, 4.8mmol) and tin (II) <br><br> chloride (5.4 g, 24.2 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 15 washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(708 mg, 83 %). 'H NMR (CD3OD): 8 6.87 (s, IH), 6.80 (d, IH), 6.69 (d, IH). <br><br> b) Preparation of N-[2-hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] <br><br> 20 urea <br><br> 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(lequiv./20equiv.) and filtering. (490mg, 65%). *H NMR (CD3OD): 8 25 8.40 (s, IH), 7.94(d, IH), 7.60 (d, IH), 7.35 (t, IH), 7.18 (d, IH), 7.03 (t, IH), 6.95 (d, IH). <br><br> Example 118 <br><br> Preparation of N-f2-hvdroxyphenvll-N-r2-bromophenvll urea N-[2-hydroxyphenyl]-N'-[2-bromo phenyl] urea was prepared from 2- amino-phenol (141mg, 30 1.30 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (300mg,75%). 'H NMR (CD3OD): 8 8.05 (d, IH), 7.49 (d, IH), 7.25 (t, 2H), 6.96 (t, IH), 6.90 (t, 2H), 6.68 (t, IH). <br><br> Example 119 <br><br> 35 Preparation of N-ftrans-3-stvrl 2-hvdroxv phenyl!-Nf2-bromophenvl 1 ureaa) Preparation of trans-6-styrl-2-nitrophenol <br><br> 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 <br><br> -74- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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 MgSC&gt;4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the 5 desired product (200 mg, 36 %). JH NMR (CD3COCD3): 8 8.05 (d, IH), 7.90 (d, 2H),7.65-7.20 (m,7H),7.00 (t,lH). <br><br> b) Preparation of trans-6-styrl-2-aminophenol <br><br> A mixture of trans-6-styrl-2-nitrophenol (200 mg, 0.83 mmol) and tin (II) <br><br> chloride (560 mg, 2.60 mmol) in ethanol(50mL) was heated at 80°C under argon. 10 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 15 desired product (50 mg, 29 %). 'H NMR (CD3OD): 8 7.51 (m, 3H), 7.29 (m, 3H),7.11 (t, IH), 7.00 (m, 2H), 6.69 (m, 2H). <br><br> c) Preparation of N-[trans-3-styrl-2-hydroxyphenyl]-N-[2-bromophenyl] urea <br><br> N-[trans-3-styrl-2-hydroxyphenyl]-N-[2-bromophenyl] urea was prepared from trans-6-styrl-2-aminophenol (35mg, 0.17 mmol) according to the procedure in General 20 Method B. The product was purified by precipitation from methylene chloride/ <br><br> hexane(l/20) and filtering. (36mg, 53%). 'H NMR (CD3OD): 87.97 (d, IH), 7.62-7.48 (m, 4H), 7.45-7.26 (m, 5H), 7.25 (t, IH), 7.15 (d, IH), 7.01 (t, IH), 6.88 (t 2H). <br><br> Example 120 <br><br> Preparation of N-r2-hvdroxv-3.4-dichlorophenvll-N-f2-methoxvphenvll urea 25 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): 8 8.02 (d, IH), 7.79 (d, IH), 7.05-6.86 (m, 4H), 3.92 (s, 3H). 30 Example 121 <br><br> Preparation of N-r2-hvdroxv-3.4-dichlorophenvn-N'-f4-methoxvphenvll 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 35 chloride/hexane(lequiv./20equiv.) and filtering. (120mg, 74%). *H NMR (CD3OD): 8 7.89 (d, IH), 7.35 (d, 2H), 6.99 (d, IH), 6.90 (dd, 2H), 3.80 (s, 3H). <br><br> Example 122 <br><br> Preparation of N-f2-hvdroxv-3.4-dichlorophenvn-N'-r3-trifluoromethvlphenvll urea <br><br> -75- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> * ' N-[2-hydroxy-3,4-dichlorophenyl]-N-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv720equiv.) and filtering. (130mg, 71%). *HNMR 5 (CD3OD): 5 7.96 (d, 2H), 7.60 (d, IH), 7.48 (t, IH), 7.30 (d, IH), 7.00 (d, IH). <br><br> Example 123 <br><br> Preparation of N-r2-hvdroxv-3.4-dichlorophenvll-N'-r2-phenvlphenvll urea N-[2-hydroxy-3,4-dichlorophenyl]-N-[2-phenylphenyl] urea was prepared from 2-amino-^ 5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in 10 General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (1 lOmg, 59%). JH NMR (CD3OD): 8 7.77 (d, IH), 7.73 (d, IH), 7.53-7.14 (m, 8H), 6.95 (d, IH). <br><br> Example 124 <br><br> Preparation of N-f2-hvdroxv-3.4-dichlorophenvIl-N-f2.3-dichlorophenvll urea N-15 [2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] 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. (130mg, 71%). NMR (CD3OD): 8 8.06 (dd, IH), 7.91 (d, IH), 7.25 (m, 2H), 7.00 (d, IH). 20 Example 125 <br><br> Preparation of N-r2-hvdroxv-4-isopropvIphenvll-N-f3-trifluoromethvlphenvll urea a) Preparation of 2-nitro-5-isopropylphenol <br><br> 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 25 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/ CH2CI2) gave the desired product(1.09g, 27 %). 'H 30 NMR (CD3COCD3): 8 7.95 (d,lH), 7.62 (d,lH), 7.11 (d, IH), 2.95 (m, IH), 1.24 (d, 6H). <br><br> b) Preparation of 2-amino-5-isopropylphenol <br><br> To a solution of 2-nitro-5-isopropylphenol(lg, 6.4 mmol) in methanol(50 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen 35 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/ CH2C12) gave the desired product(775 mg, 93 %). 'H NMR (CD3OD): 8 6.71-6.44 (m, 3H), 2.73 (m, IH), 1.20 (d, 6H). <br><br> -76- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> c) Preparation of N-[2-hydroxy-4-isopropylphenyl]-N-[3-trifluoromethylphenyl] urea <br><br> N-[2-hydroxy-4-isopropylphenyl]-N-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol (75mg, 0.50 mmol) according to the 5 procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (140mg, 83%). 'H NMR (CD3OD): 5 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). <br><br> Example 126 <br><br> 10 Preparation of N-f2-hvdroxv-3-naphthvll-N'-r2.3-dichlorophenvll urea N-[2-hydroxy-3-naphthyl]-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(lequiv./20equiv.) and filtering. (285mg, 82%). JH NMR (CD3OD): 8 8.48 (s, 15 IH), 8.10 (d, IH), 7.68 (d, IH), 7.57 (d, IH), 7.40-7.23 (m, 4H), 7.18 (d, IH). <br><br> Example 127 <br><br> Preparation of N-r2-f(2.3-Dichlorothien-5-vl)lsulfonvlaminolphenvll-N'-(2-bromophenvDurea a) Preparation of [2-[(2,3-Dichlorothien-5-yl)]sulfonylaminoaniline] <br><br> 20 The title compound was prepared according to General Method C using 2,3- <br><br> 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)" <br><br> b) Preparation of N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N-(2-25 bromophenyl)urea <br><br> The title compound was prepared from [2-[(2,3-dichlorothien-5-yl)]sulfonylaminoaniline (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-MS m/z 30 520 (M-H)" <br><br> Example 128 <br><br> Preparation of N-r2-r(3.5-Bistrifhioromethvlphenvl)sulfonvlamino1phenvll-N'-(2-bromophenvDurea a) Preparation of [2-(3,5-Bistrifluoromethylphenyl)sulfonylaminoaniline] 35 The title compound was prepared according to General Method C using 3,5- <br><br> (bistrifluoromethyl)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)" <br><br> -77- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> b) Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N-(2-bromophenyl)urea <br><br> The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 5 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate rhexane 30/70) (10 mg, 1 %).EI-MS m/z 580 (M-H)" <br><br> Example 129 <br><br> Preparation of N-r2-rf2-Benzvl1sulfonvlaminol-f5-trifluoromethvl)phenvll-N-(2-10 bromophenvl)urea a) Preparation of [(4-Benzylsulfonylamino)-(3 -nitro)-benzotrifluoride] 4-Amino-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 15 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 30/70) (878 mg, 52 %) EI-MS m/z 359 (M-H)". <br><br> 20 b) Preparation of [(4-Benzylsulfonylamino)-(3-amino)-benzotrifluoride] <br><br> t(4-Benzylsulfonylamino)-(3-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 Celite to give the 25 title compound. (210 mg, 99%) EI-MS m/z 329 (M-H)". <br><br> c) Preparation of N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea <br><br> The title compound was prepared from [(4-benzylsulfonylamino)-(3-amino)-benzotrifluoride (210 mg, 0.64 mmol) and 2-bromophenylisocyanate (126 mg, 0.64 30 mmol) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (70 mg, 21%) EI-MS m/z 526 (M-H)" <br><br> Example 130 <br><br> Preparation of N-r2-f2-(3-Nitrophenvl)sulfonvlaminoIphenvll-N'-(2-bromophenvl)urea <br><br> 35 <br><br> a) Preparation of [2-((3-Nitrophenyl)sulfonylamino)aniline] <br><br> The title compound was prepared according to General Method C using 3-nitrobenzenesulfonyl chloride (1 eq). The product was purified by flash chromatogrphy <br><br> -78- <br><br> WO 00/76495 <br><br> PCT/U S00/16499 <br><br> on silica gel (methylene chloride:methanol 96/4) .(1.07 g, 37 %) EI-MS m/z 294 (M+H)+ <br><br> b) Preparation of N-[2-[(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urca <br><br> 5 The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoaniline] <br><br> (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)* <br><br> 10 Example 131 <br><br> Preparation of N-r2-r2-(4-PhenoxvphenvDsulfonvlaminolphenvll-N'-f2-bromoDhenvl) ureaa) Preparation of [2-((4-Phenoxyphenyl)sulfonylamino)aniline] <br><br> The tide compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 15 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and toluene:methylene 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)+ <br><br> b) Preparation of N-[2-[(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-20 bromophenyl)urea <br><br> 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 25 536 (M-H)" <br><br> Example 132 <br><br> Preparation of N-IT2-( 1SV-1O-Camphorsulfonvlaminolphenvll-N-(2-bromophenvI)urea a) Preparation of 2-((lS)-10-Camphorsulfonylamino)aniline The tide compound was prepared according to General Method C using 30 (1 S)(+)-10-Camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenediamine <br><br> (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%) EI-MS m/z 323 (M+H)+ <br><br> 35 b) Preparation of N-[[2-(lS)-10-Camphorsulfonylamino]phenyl]-N'-(2- <br><br> bromophenyl)urea <br><br> The title compound was prepared from [2-(lS)-10-camphorsulfonylamino]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 <br><br> -79- <br><br> WO 00/76495 PCT/US00/16499 <br><br> evaporated and product was precipitated from methylene chloride:hexane. (200 mg, 95 %). EI-MS m/z 518 (M-H)" <br><br> Example 133 <br><br> Preparation of N- IT2-( 1RV10-Camphorsulfonvlaminolphenvll-N -(2-bromophenvl)urea 5 a) Preparation of 2-((lR)-10-Camphorsulfonylamino)aniline <br><br> The title compound was prepared according to General Method C using (1R)(-)-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(l:3). The organic phase was separated and the methylene 10 chloride evaporated leaving the toluene. Hexane was added and the product precipitated from solution. (563 mg, 38%). EI-MS m/z 323 (M+H)+ <br><br> b) Preparation of N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea <br><br> The title compound was prepared from [1-(1R)-10-15 camphorsulfonylaminoaniline] (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)" <br><br> Example 134 <br><br> 20 Preparation of N-f2-r2-f2-Nitro-(,4-trifluoromethvl)phenvl)sulfonvlaminolphenvl-N-(2-bromophenvDurea a) Preparation of [2-[(2-Nitro)-(4-trifluoromethyl)phenyl]sulfonylamino]aniline The title compound was prepared according to General Method C using 2-nitro- <br><br> 4-(trifluoromethyl)benzenesulfonyl chloride (1 eq). The product was purified by flash 25 chromatography on silica gel ( methylene chloride ^methanol 96/4) (875 mg, 25 %) EI-MS <br><br> m/z 362 (M+H)+ <br><br> b) Preparation of N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N-(2-bromophenyl)urea <br><br> 30 The title compound was prepared from [2-[(2-nitro)-(4-trifluoromethyl) <br><br> phenyl]sulfonylamino]aniline (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 35 557 (M-H) <br><br> Example 135 <br><br> Preparation of N-(2-hvdroxv-4-azidophenvI)-N-(2-iodophenvl)urea a) Preparation of N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea <br><br> -80- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> To a solution of N-(2-hydroxy-4-nitrophenyl)-N-(2-iodophenyl)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 5 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)+ <br><br> b) Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea The N-(2-hydroxy-4-aminophenyl)-N-(2-iodophenyl)urea(77 mg, 0.21 mmol) 10 was added to HC1/H20 (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 15 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)+. <br><br> Example 136 <br><br> Preparation of N-(2-hvdroxv-3-azidophenvl)-N-(2-bromophenvl)ureaa) Preparation of 20 N-(2-hydroxy-3-aminophenyl)-N-(2-bromophenyl)urea <br><br> To a solution of N-(2-hydroxy-3-nitrophenyl)-N'-(2-bromophenyl)urea (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 25 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)\ <br><br> b) Preparation of N(2-hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85 30 mmol) was added to HC1/H20 (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 35 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 (210 mg, 71%). EI-MS m/z 349 (M+H)+. <br><br> Example 137 <br><br> -81 - <br><br> WO 00/76495 PCT/US00/16499 <br><br> Preparation of N-f2-hvdroxv-3-cvanophenvll-N'-r2-methoxvphenvll 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/ 5 hexane(lequiv./20equiv.) and filtering. (230 mg, 81%). 5H NMR (CD3OD): 8 8.06 (d, IH), 7.79 (d, IH), 7.49-7.35 (m, 2H), 7.05-6,87 (m, 3H), 3.95 (s, 3H). <br><br> Example 138 <br><br> Preparation of N-r2-hvdioxv-3-cvanophenvll-N-r3-trifluoromethvlphenvll urea N-[2-hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] 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(lequiv./20equiv.) and filtering. (280mg, 87%). 'H NMR (CD3OD): 8 8.10 (d, IH), 7.96 (s, IH), 7.54 (d, IH), 7.55-7.25 (m, 3H), 7.01 (t, IH). <br><br> Example 139 <br><br> Preparation of N-r2-hvdroxv-3-cvanophepvll-N'-r2-phenvlphenvll urea N-[2-hydroxy-3-cyanophenyl]-N- [2-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(lequiv./20equiv.) and filtering. (270mg, 82%). 'H NMR (CD3OD): 8 7.81 (d, IH), 7.75 (d, IH), 7.56-7.15 (m, 9H), 6.91 (t, IH). <br><br> Example 140 <br><br> Preparation of N-f2-hvdroxv-3-cvanophenvll-N'-f2.3-dichlorophenvl1 urea N-[2-hydroxy-3-cyanophenyl]-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(lequiv./20equiv.) and filtering. (300mg, 93%). 'h NMR (CD3OD): 8 8.11 (d, IH), 8.01 (d, IH), 7.33-7.25 (m, 3H), 7.00 (t, IH). <br><br> Example 141 <br><br> Preparation of N-r2-hvdroxv-4-isopropvlphenvll-N'-f2.3-dichlorophenvll urea N-30 [2-hydroxy-4-isopropylphenyl]-N-[2,3-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%). !H NMR (CD3OD): 8 8.05 (d, 2H), 7.77 (s, IH), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m, IH), 1.25 35 (d, 6H). <br><br> Example 142 <br><br> Preparation of N-r2-hvdroxv-4-isopropvlphenvll-N'-r2-chloro-5-trifluoromethvlphenvll urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol (150mg, 1.00 mmol, example 128a) <br><br> -82- <br><br> WO 00/76495 <br><br> PCT/US0Q/16499 <br><br> according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (275mg, 82%). lH NMR (CD3OD): 8 8.50 (s, IH), 7.70 (s, IH), 7.51 (d, IH), 7.22 (d, IH), 6.70 (m, 2H), 6.62 (dd, IH), 2.76 (m, (1H), 1.16 (d, 6H). <br><br> 5 Example 143 <br><br> Preparation of N-f2-hvdroxv-3-phenvlphenvn-N-f2.3-dichlorophenvll ureaa) Preparation of 2-nitro-6-phenylphenol <br><br> 2-phenylphenol (3.00g, 17.6mmol) was dissolved in methylene chloride(40ml) followed by the addition of sodium nitrate (1.65g, 19.4mmol). The addition of sulfuric 10 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 MgS04 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 %). *H 15 NMR (CD3COCD3): 8 8.19 (d,lH), 7.79 (d,lH), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, IH), 7.22 (t, IH). <br><br> b) Preparation of 2-amino-6-phenylphenol <br><br> To a solution of 2-nitro-6-phenylphenol(900 mg, 4.2mmol) in methanol(50ml) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen 20 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/ CH2C12) gave the desired product(700 mg, 90 %). 'H NMR (CD3OD): 8 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H) 25 c) Preparation of N-[2-hydroxy-3-phenylphenyI]-N'-[2,3-dichlorophenyl] urea <br><br> N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-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%). ]H NMR (CD3OD): 8 8.06 (d, 30 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 Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea b)N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ 35 hexane(lequiv./20equiv.) and filtering. (150 mg, 81%). ]H NMR (CD3OD): 8 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). <br><br> Example 144 <br><br> -83- <br><br> WO 00/76495 PCT/US00/16499 <br><br> Preparation of N-r2-hvdroxv-5-nitrophenvll-N-r2-methoxyphenvll 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( 5 lequiv./20equiv.) and filtering. (270 mg, 89%). 'h NMR (CD3OD): 8 9.10 (s, IH), 8.10 (d, IH), 7.85 (d, IH), 7.08-6.88 (m, 4H), 3.96 (s, 3H). <br><br> Example 145 <br><br> Preparation of N-r2-hvdroxv-5-nitrophenvll-N-f3-trifluoromethvlphenvll urea N-[2-hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-10 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. (290 mg, 85%). 'H NMR (CD3OD): 8 9.12 (s, IH), 7.89 (d, IH), 7.68 (d, IH), 7.55 (m, 2H), 7.45 (d, IH), 7.00 (d, IH). <br><br> Example 146 <br><br> 15 Preparation of N-r2-hvdroxv-5-nitrophenvll-N'-r2-phenvlphenvll 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/ <br><br> hexane( 1 equiv./20equiv.) and filtering. (285 mg, 81%). *H NMR (CD3OD): 8 8.09 (s, 20 IH), 7.86 (d, IH), 7.58-7.20 (m, 9H), 6.95 (d, IH). <br><br> Example 147 <br><br> Preparation of N-r2-hvdroxv-5-nitrophenvll-N'-f2.3-dichlorophenvn urea N-[2-hydroxy-5-nitrophenyl]-N-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to the procedure in General Method B. The 25 product was purified by precipitation from methylene chloride/ <br><br> hexane(lequiv720equiv.) and filtering. (290 mg, 85%). 'I! NMR (CD3OD): 8 9.11 (s, IH), 8.17 (d, IH), 7.89 (d, IH), 7.34 (m, 2H), 6.95 (d, IH). <br><br> Example 148 <br><br> Preparation of N-f2-hvdroxv-5-ethvlsulfonvlphenvll-N'-r2.3-dichlorophenvIl urea N-30 [2-hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-(ethylsulfonyl)phenol (185 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (310 mg, 84%). 'H NMR (CD3OD): 8 8.65 (s, IH), 8.18 (d, IH), 7.45 (d, IH), 7.26 (m, 2H), 7.00 (d, IH), 3.33 (q, 2H), 1.24 (t, 3H). 35 The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above: <br><br> Example 149 : N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N-(2- bromophenyl)urea EI-MS m/z 527 (M-H)". <br><br> -84- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> Example 150 : N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N-(2-bromo phenyl) ureaEI-MS m/z 426 (M+H)+ <br><br> The following confounds of Fonnula (I) may be prepared in accordance with the examples and schemes as described above, or may also be purchased commercially S from well recognized sources. For instance, from Aldrich Chemical Company: N-(2-Hydroxy-4-nitrophenyl)-N-phenylurea For instance, from the Alfred Bader Collection of Aldrich Chemical: 1 -(2-Carboxyphenyl)-3-(3-fluorophenyl)urea 1 -(2~Carboxyphenyl)-3-(3-chlorophenyl)urea 10 Available from Gallard Schlesinger Company and/or the Sigma Aldrich Library of Rare Compounds: <br><br> 1 -(2-Carboxyphenyl)-3-(4-chlorophenyl)uriea <br><br> 1 -(p-Anisyl)-3-(2-carboxyphenyl)urea Available from Gallard Schlisinger Company: 2-(3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid 15 2-(4-Chloroplienylcaibonyldiiinino)-5-trifluoromethylbenzoic acid N-Phenyl-N-(2-carboxyphenyl)urea. <br><br> From Maybridge Chemical Company, Cambridge England: 1,1 '-(4-Methyl-2-phenylene)bis[3-tolyl)]thiourea; and N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea. <br><br> 20 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: <br><br> 1 -(m-Anisyl)-3-(2-carboxyphneyl)urea; <br><br> 1 -(o-Anisyl)-3-(2-carboxyphenyl)urea; 25 1 -(2-Carboxyphenyl)-3-{3,4-dichlorophenyl)urea; and 1 -(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea. <br><br> METHOD OF TREATMENT The compounds of Fonnula (1), (la), (10 and (III), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the 30 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 ^ receptor, also referred to as the type I or type II receptor. <br><br> 35 For purposes herein, the compounds of Formula (I), (la), (lb), (Ic), (II) and (HQ <br><br> all have the same dosages, and dosage formulations as that of Formula (£) are used interchangeably. <br><br> Accordingly, described herein is a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or p receptor <br><br> -85- <br><br> IfltaHectu&amp;l Property Office of N2 <br><br> 10 MAR 2004 <br><br> received <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> and which method comprises administering an effective amount of a compound of Fonnula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokines ars IL-8, GROa, GROp, GROy or NAP-2. <br><br> The compounds of Fonnula (I) are administered in an amount sufficient to 5 inhibit cytokine function, in particular IL-8,GROa, GROP, GROy or 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; 10 (ii) any cell associated IL-8, GROa, GROP, GROy or NAP-2 above normal physiological levels; or (iii)the presence of IL-8, GROa, GROp, GROy or NAP-2 above basal levels in cells or tissues in which IL-8, GROa, GROp, GROy or NAP-2 respectively, is produced. <br><br> There are many disease states in which excessive or unregulated IL-8 IS 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, 20 glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis or undesired hematopoietic stem cells release. <br><br> These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with increased IL-8, GROa, 25 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 DL-6), IL-8, GROa, GROp, GROy or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production 30 and activation. The a-chemokines but particularly, GROa, GROP, GROy or NAP-2, working through the IL-8 type I or E 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. <br><br> 35 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 <br><br> -86- <br><br> WO 00/76495 PCT/US00/16499 <br><br> assays which are described herein. The compounds of Formula (I) have been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably the compounds are inhibitors of only one receptor, preferably Type DL <br><br> As used herein, the term "IL-8 mediated disease or disease state" refers to any 5 and all disease states in which IL-8, GROa, GROp, GROy or NAP-2 plays a role, <br><br> either by production of IL-8, GROa, GROP, GROy or NAP-2 themselves, or by IL-8, GROa, GROP, 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 10 IL-8, would therefore be considered a disease stated mediated by IL-8. <br><br> Diseases for which the present compounds are useful 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, IS cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis or undesired hematopoietic stem cells release. <br><br> The present compounds are also useful for the treatment of diseases caused by respiratory viruses, including but not limited to rhinovirus and influenza virus, 20 herpesviruses, including but not limited to herpes simplex I and n, and hepatitis viruses, including but not limited to Hepatitis B and Hepatitis C virus. <br><br> 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 P receptor plays a role, such as but not limited to IL-8, GRO-a, GRO-P, GRO-y, or NAP-2. This 25 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. <br><br> 30 As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modtilates 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 35 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 <br><br> -87- <br><br> WO 00/76495 PCT/US00/16499 <br><br> (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-8). <br><br> 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 5 cells in the immune, inflammatory or hematopoietic response, similar to the term <br><br> "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, IL-8, GRO-a, 10 GRO-P, GRO-y, NAP-2, IP-10, MlP-la, MIP-p, PF4, and MCP 1,2, and 3. <br><br> In order to use a compound of Fonnula (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 15 compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. <br><br> Compounds of Fonnula (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 20 administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Fonnula (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 25 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 30 deleterious to the recipient thereof. <br><br> The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, tena alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearale, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the earner or 35 diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax. <br><br> A wide variety of pharmaceutical forms can be employed. Thus, if a solid earner 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 <br><br> -88- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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. <br><br> 5 Compounds of Fonnula (I) may be administered topically, that is by non- <br><br> 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 administration refers to oral, intravenous, 10 intraperitoneal and intramuscular administration. <br><br> 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 administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, 15 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. <br><br> 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 20 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. <br><br> Creams, ointments or pastes according to the present invention are semi-solid 25 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 30 such as almond, com, 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 soibitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose 35 derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. <br><br> 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 <br><br> -89- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> 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 5 container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmeicuric 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. <br><br> 10 Compounds of formula (I) may be administered parenteraly, 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 15 (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. <br><br> 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 20 body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, 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 25 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 the optimal course of treatment, i.e., 30 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 determination tests. <br><br> 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 35 scope of the present invention. <br><br> BIOLOGICAL EXAMPLES The IL-8, and Gro-a chemokine inhibitory effects of compounds of the present invention were determined by the following in vitro assay: <br><br> Receptor Binding Assays: <br><br> -90- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> [125j] 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 P receptors were individually expressed 5 in Chinese hamster ovaiy cells as described previously (Holmes, et al., Science, 1991, 253,1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)). Except that the homogenization buffer was changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra-acetic acid), ImMPMSF (a-toluenesulphonyl 10 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 125j jL_g (0.25 nM) or 125j Gro-a and 0.5 pg/mL of IL-8Ra or 1.0 ng/mL of IL-8RP membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HCl buffers, pH 15 8.0, containing 1.2 mM MgS04,0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM. The assay was initiated by addition of 125j_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 20 1% polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM <br><br> TrisHCl, 1 mM MgSC&gt;4,0.5 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 I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rp, or Type n, receptor is referred to as the permissive receptor. 25 All of the exemplified compounds of Formulas (I) to (HI) noted herein in the <br><br> Synthetic Chemistry Section, of Examples 1 to 150 plus the additional purchased compounds demonstrated an IC50 from about 45 to about &lt;1 jig/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-(2-30 Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea was found to be active at about 75 (ig/mL. <br><br> The following compounds, generally tested at levels of up to 45 jig/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: 35 l-(4-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenyl)thio]-5-chlorophenyl urea l-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenoxy)-5- <br><br> chlorophenyl]urea l-(2-Mercaptophenyl)-3-phenyl-2-thiourea <br><br> -91 - <br><br> WO 00/76495 <br><br> PCT/USOQ/16499 <br><br> l-(2-Hydroxyphenyl)-3-phenyl-2~thiourea 3,3-(Carbonothioyldiimino)bis[4-hydroxybenzoic acid] m,m-(1,3-thioureylene)di(4-hydroxybenzoic acid) l-(2-Tolyl)-3-(3-chloro-6-hydroxyphenyI)-2-thiouiea 5 1 -[(2-Hydroxy-4-aminophenyl)]-(3-phenyl)-urea <br><br> N-(2-Carboxy-4-trifluromethylphenyl)-N-(3-chlorophenyl)urea N-(2-Carboxyphenyl)-N-(2,5-dichlorophenyl)urea <br><br> 1-(2-Carboxyphenyl)-3-(2-Chloro-5-trifiuoromethylphenyl)urea <br><br> 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid 10 2-[2-[3-(4-Chlorophenyl)ureido]phenoxy]benozic acid <br><br> 2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid <br><br> N- (2-Hydroxyphenyl) -N-phenyl urea N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N - <br><br> phenylurea <br><br> N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea 15 N-(2-Hydroxy-4-nitrophenyl)-N-(4-nitrophenyl)urea l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea l-(6-Carboxy-2,4-dichlorophenyl)-3-(2,4,6-trichlorophenyl)urea l-(2-Carboxyphenyl)-3-(2,5-dimethoxyphenyl)urea l-(2-Carboxyphenyl)-3-(2-methylphenyl)urea 20 1 - [(2-Hydroxyphenyl)-3-(2-methyl)-5-nitrophenyl]urea l-(2,5-Dichlorophenyl)-3-(2-hydroxy-4-nitrophenyl)urea l-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea N-(2-phenylsulfonylaminophenyl-N-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N-(4-ethoxycarbonylphenyl)urea 25 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxycarbonylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N-(3-ethoxycarbonylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N-(4-phenylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-propylphenyl)urea 30 N-(4-Trifluromethyl-2-(4-nitrobenzenesulfonyl)amino]-N-phenylurea N-(3-Carboxyphenyl)-N-2-hydroxy-4-nitrophenyl)urea N-(4-Trifluromethyl-2-(methylsulfonyl)amino]-N'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(isopropyl)phenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N-(2,6-dimethylphenyl)urea 35 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluoro-5-nitrophenyl)urea <br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-chloro-5-trifluromethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-4-nitrophenyl)urea N-(2-Hydroxy-1 -napthyl)-N-(2-phenylphenyl)urea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-bromophenyl)urea <br><br> -92- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-(2-hydroxy 3,4 dichlorophenyl )-N-(4-phenylphenyl)urea N-(2-hydroxy-3-naphthyl)-N'-(2-methoxyphenyl)urea N-(2-hydroxy-3-naphthyl)-N-(2-phenylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N-(4-methoxyphenyl)urea 5 N-(2-Hydioxy-3-naphthyl)-N'-(3-trifluoroinethylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N-(4-pheiiylphenyl)urea N-[2-(2-Carboxyphenylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N-(4-methoxyphenyl)urea 10 N-(2-Hydroxy-3-phenylphenyl)-N'-(3-trifluoromethylphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N-(2-phenylphenyl)urca N-(2-Hydroxy-3-phenylphenyI)-N-(4-phenylphenyl)urea N-[2-[(2,5-Dichlorothien3-yl)sulfonylamino]phenyl]-N-(2-bromophenyl)urea N-(2-Hydroxy,3,4-dichlorophenyl)-N '-(2,4 dimethoxyphenyl)urea 15 N-(2-Hydroxy,3,4-dichlorophenyl)-N-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N-(2,4 dimethoxyphenyl)urea N-(2-Hydroxy-3-naphthyl)-N-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-3 phenylphenyl)-N'-(2,4-dimethoxyphenyl)urea N-(2-Hydroxy-4-isopropylphenyl)-N-(2,4-dimethoxyphenyl)urea 20 N-(2-Hydroxy-3-phenylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-5-nitrophenyl)-N-(2,4-dimethoxyphenyl)urea N-(2-Hydroxy-5-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-3-cyanophenyl)-N-(4-methoxyphenyl)urea N-(2-Hydroxy-3-cyanophenyl)-N'-(4-phenylphenyl)urea 25 N-(2-Hydroxy-3-cyanophenyl)-N-(2,4 dimethoxyphenyl)urea <br><br> N-(2-Hydroxy-3-cyanophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy- 5-phenylphenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy- 5-phenylphenyl)-N-(4-methoxyphenyl)urea N-(2-Hydroxy- 5-phenylphenyl)-N'-(3-trifluoromethylphenyl)urea 30 N-(2-Hydroxy- 5-phenylphenyl)-N-(2-phenylphenyl)urea N-(2-Hydroxy-5-phenylphenyl)-N'-(4-phenylphenyl)urea N-(2-Hydroxy-5-phenylphenyl)-N-(2,3-dichlorophenyl)urea N-(2-Hydroxy-5-phenylphenyl)-N-(2,4-diinethoxyphenyl)urea N-(2-Hydroxy-5-phenylphenyl)-N-(2-chloro-5-trifluoromethylphenyl)urea 35 N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(4-methoxyphenyI)urea <br><br> N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(3-trifluoromethylphenyl)urea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(4-phenylphenyl)urea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2,4-dimethoxyphenyl)urea <br><br> -93- <br><br> WO 00/76495 <br><br> PCT/US00/16499 <br><br> N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea. N-[2-Hydroxy-3,4-dichIorophenyl]-N'-[2,4 dimethoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea; and N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea 5 Chemotaxis Assay: <br><br> The in vitro inhibitory properties of these compounds were determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its entirety. Neutrophils where isolated from human blood as described in Current 10 Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1, whose disclosure is incorporated herein by reference in its entirety. The chemoattractants DL-8, GRO-a, GRO-J3, GRO-y and NAP-2 where placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers where separated by a 5um polycarbonate filter. When compounds of this 15 invention were tested, they where mixed with the cells (0.001 - 1000 nM) just prior to the addition of the cells to the upper chamber. Incubation was allowed to proceed for between about 45 and 90 min at about 37°C in a humidified incubator with 5% C02-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 20 (Baxter Products, McGaw Park, EL, 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 25 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. <br><br> Elastase Release Assay: <br><br> 30 The compounds of this invention where tested for their ability to prevent <br><br> 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 10^ cells suspended in Ringer's Solution (NaCl 118, KC14.56, NaHC03 25, KH2P04 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) where placed in each well of 35 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 IL-8, GROoc, GROp, GROy or NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction was allowed to proceed for <br><br> -94- <br><br></p> </div>

Claims (12)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> WO 00/76495<br><br> PCT/USOO/16499<br><br> 45 min before the 96 well plate was centrifuged (800 xg 5 min) and 100 ul of the supernatant removed. This supernatant 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.<br><br> 5 Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al J. Biol Chem 254 4027 (1979). The amount of Elastase released from the PMNs was calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation.<br><br> 10 The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples<br><br> 15 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.<br><br> -95-<br><br> WO 00/76495 PCT/US00/16499<br><br> What is claimed is:<br><br>
1. The use in the manufacture of a medicament for the prophylactic or therapeutic treatment of atherosclerosis, of a compound of the formula:<br><br> 10 wherein<br><br> X is oxygen or sulfur;<br><br> R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;<br><br> Rl is independently selected from hydrogen; halogen; nitro; cyano; 15 halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosiibstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxy C]_4alkyl; aryl; aryl Ci-4 alkyl; aiyloxy; aryl Cj-4 alkyloxy, heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; heteroaryl C1H4 alkyloxy; aiyl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R3; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5;tX 20 C(O)NR4Rl0; S(0)3H; S(0)3Rg; Ci-io alkyl C(0)Ri 1; C2-10 alkenyl C(0)Rn; C2-IO alkenyl C(0)0Rn; C(0)Rn; C(0)0Ri2*, 0C(0) RH; NR4C(0)Rn; or two v' _<br><br> Rl moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; ^ t is 0, or an integer having a value of 1 or 2;<br><br> s is an integer having a value of 1 to 3;<br><br> 25 R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl,<br><br> optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C]-4alkyl, heterocyclic, heterocyclic Ci-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 30 O/N/S;<br><br> Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci_io alkyl; Ci-io'alkyl; C2-IO alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; S(0)tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Cl-4 alkyl; arylox^; arylCi-4 alkyloxy; heterodryl; heteroarylalkyl; heteroarylC 1-4 alkyloxy; 35 heterocyclic, heterocyclicC 1 _4.alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5;<br><br> ' -96-<br><br> inteffectual Property Office of NZ<br><br> 10 MAR 2004<br><br> *eceive°<br><br> WO 00/76495<br><br> PCT7US0Q/16499<br><br> C(0)NR4Rio; s(6)3H; S(0)3Rs; ci-io alkyl C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 aWceny! C&lt;D)ORi 1; C(0)Rn; C(0)0Ri2t 0C(0) RH; NR4C(0)Ril; or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring;<br><br> n is an integer havjpg a value of 1 to 3;<br><br> m is an integer having a value of 1 to 3; i R8 is hydrogen or C1-4 alkyl;<br><br> RlO is Ci-io alkyl C(0)2R8;<br><br> Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optiqnally substituted aiyl Ci_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cl-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C]~ 4alkyl;<br><br> Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;<br><br> or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not selected from the group consisting of the following compounds:<br><br> l-(4-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenyl)thio]-5-<br><br> chlorophenyl urea l-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenoxy)-5-<br><br> chlorophenyljurea 1 -(2-Mercaptophenyl)-3-phenyl-2-thiourea 1 -(2-Hydroxyphenyl)-3-phenyl-2-thiourea 3 3 MCarbonothioyldiimino)bis[4-hydroxybenzoic acid]<br><br> 1,3-thioureylene)di(4~hydroxybenzoic acid) l-(2-Tolyl)-3-(3-chloro-6-hydroxyphenyl)-2-thiourea l-[(2-Hydroxy-4-aminophenyl)]-(3-phenyl)-urea N-^-Carboxy^trifluromethylphenyl^N'-^-chlorophenytyurea N-(2-Carboxyphenyl)-N-(2,5-&lt;lichlorophenyl)urea<br><br> 1-(2-Carboxyphenyl)-3-(2-Chloro-5-trifluoromethylphenyl)urea<br><br> 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoicacid 2-[2-[3-(4-Chlorophenyl)ureido]phenoxy]benozic acid 2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid<br><br> N- (2-Hydroxyphenyl) -N-phenyl urea N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N-phenylurea<br><br> N-[4-Carboxy-2-hydroxyphenyl]-n-phenylurea<br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(4-nitrophenyl)urea l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea l-(6-Carboxy-2,4-dichlorophenyl)-3-(2,4,6-trichlorophenyl)urea l-(2-Caiboxyphenyl)-3-(2,5-dimethoxyphenyl)urea fnteffectual Property<br><br> Office of NZ 97<br><br> 10 MAR 2004<br><br> received<br><br> N-(2-Hydroxy-3-phaaylphenyl)-N'-&lt;2-chl&lt;KX&gt;-5-trifluoromethylphenyl)urca<br><br> N-(24Iydroxy-5-nitrophenyl&gt;N,-{2,4-&lt;iimethoxyphenyl)tHea<br><br> N&lt;2-Hydroxy-5nitrophenyl)-N'-{2-chloro-5-trifluoromethylphenyl)urea<br><br> N^2-Hydroxy-3-cyanophenyl)-N-(4-methoxyphenyl)urea<br><br> N-{2-Hydxx)xy-3-cyanophcnyi)-N'-(4-phenylphenyl)urca<br><br> N-(2-Hydroxy-3-cyanophenyl)-N-(2,4 dimethoxyphenyl)urea<br><br> N-(2-Hydroxy-3-cyanophenyi)-N-(2-chloro-5-trifluoroincthylphenyl)urea<br><br> N-(2-Hydroxy- 5-phenylphenyl)-N-(2-methoxyphenyl)urea<br><br> N-(2-Hydroxy- 5-phenylphenyl)-N-(4-methoxyphenyl)urea<br><br> N-(2-Hydroxy- 5-phenylphcnyl)-N'-(3-trifluoromethylphenyl)urea<br><br> N-(2-Hydroxy- 5-phenylphenyl)-N-(2-phenylphenyl)urea<br><br> N-(2-Hydroxy-5-phenylphenyl)-N'-(4-phenylphenyl)urea<br><br> N-(2-Hydroxy-5-phenylphenyl)-N-(2,3-dichlorophenyl)uiea<br><br> N-(2-Hydroxy-5-phenylphenyl)-N'-(2,4-dimethoxyphenyl)urea<br><br> N-(2-Hydroxy-5-phenylphenyl)-N-(2-chloro-5-trifluoromethylphenyl)urea<br><br> N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-{4-methoxyphenyl)urea<br><br> N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(3-trifluoromethylphenyl)urea<br><br> N-(2-Hydroxy-5-ethylsulfonylphenyl)-N-(2-phenyiphenyl)urea<br><br> N-(2-Hydroxy-5-ethylsiilfonyiphcnyl)-N,-{4-phenyIphenyl)urea<br><br> N-(2-Hydroxy-5^thylsulfonylphenyl)-N'-{2,4-dimethoxyphenyl)urea<br><br> N-(2-Hydroxy-5-ethylsulfOTi)1pbcoyl&gt;N'-(2-chloro-5-tri£luoroinethylphenyl)virea.<br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea<br><br> N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2-chloro-5-trifluoromethylphenyl] urea; and<br><br> N-[2-Hydroxy-3-naphthylJ-N-[3-trifluororoethylphenyl] urea %<br><br>
2. The use according to Claim 1 wherein the ionisable hydrogen has a pKa of 3 to 10.<br><br>
3. The use according to Claim 2 wherein R is hydroxyl, carboxylic acid,<br><br> thiol, -SR2 -OR2, -NH-C(0)Ra, -C(0)NR6R7, -NHS(0)2Rb, -S(0)2NHRc,<br><br> NHC(X)NHRb, or tetrazolyl;<br><br> wherein 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;<br><br> R6 and Ry are independently hydrogen or a Ci^j. 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, £ (3i<br><br> Ra is an alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroaryl Ci_4alkyl, ^<br><br> heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally ^<br><br> substituted; —0<br><br> Rb is a NR6R7, alkyl, aryl, arylC]-4alkyl, arylC2-4alkenyl, heteroaryl, £ heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl, :g heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted: one to three times independently by halogen; nitro; halosubstituted C1-4 alkyl; Cm alkyl; Cm alkoxy; NR9C(0)Ra; C(0)NR6R7, S(0)3H, or C(0)0Cm alkyl;<br><br> 99<br><br> is<br><br> R9 is hydrogen or a Cm alkyl;<br><br> Rc is alkyl, aryl, aiylCi-4alkyl, arylC2-4alkenyl, heteroaryl,<br><br> heteroarylC i -4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic^ 1 -4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Cm alkyl, CM alkyl. Ci-4 alkoxy, NR9C(0)Ra, C(0)NR6R7, S(0)3H, or C(0)0Cm *lkyl.<br><br>
4. The use according to Claim 3 wherein the R2 is optionally substituted one to three times by halogen, nitro, halosubstituted Ci_io alkyl, Cj-io alkyl, Ci_io alkoxy, hydroxy, SH, -C(0)NR6R7, -NH-C(0)Ra, -NHS(0)Rb, S(0)NR6R7, C(0)0R8. or a tetrazolyl ring.<br><br>
5. The use according to Claim 3 wherein R is OH, -NHS(0)2Rb or ~<br><br> C(0)0H.<br><br>
6. The use according to Claim 1 wherein Ri is halogen, cyano, nitro, CF3, C(0)NR4R5, alkenyl C(0)NR4R5, C(0) R4R10, alkenyl C(0)DRi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(0)NR4Rs.<br><br>
7. The use according to Claim 1 wherein Y is halogen, Cm alkoxy,<br><br> optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Cj^alkyl,<br><br> hydroxy alkyl.<br><br>
8. The use according to Claim 1 wherein R is OH, SH, or NHS(0)?Rb and Ri is substituted in the 3-position, the 4- position or di substituted in the 3,4-position by an electron withdrawing moiety.<br><br>
9. The use according to Claims 1 or 8 wherein Y is mono-substituted in the 2-position or 3 - position, or is disubstituted in the 2 - or 3 - position of a monocyclic ring.<br><br>
10. The use according to Claims 1, 8 or 9 wherein n and m are each , equal to 1 or more.<br><br>
11. The use according to Claim 1 wherein R is a carboxylic acid, and Ri is hydrogen, or Ri is substituted in the 4-position.<br><br>
12. The use according to Claim 1 wherein the compound, or a pharmaceutically acceptable salt is selected from the group consisting of:<br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxyphenyl)urea;<br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-bromophenyl)urea;<br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2-phenylphenyl)urea;<br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-&lt;2-methylthiophenyl)urea;<br><br> N-(2-Hydroxy-4-nitrophenyl)-N-(2,3-dichlorophenyl)urea;<br><br> N-(2-Hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea;<br><br> N-(2-Hydroxy-4-nitrophenyl&gt;N-(2,3-methylenedioxyphenyl)urea; t<br><br> N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea;<br><br> N-(2-hydroxy 4-nitro phenyl) N-(2-phenyloxy phenyl) urea;<br><br> N-(3-Chloro-2-hydroxyphenyl)-N-(bromophenyl)urea; 3<br><br> N-(2-Hydioxy-3-glycinemethylestercait)onylphenyl&gt;N-(2-bromophenyl)urea; «<br><br> N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea; %<br><br> N-(2-Hydroxy-4-cyanophenyl)-N-(2-bromofl»nyl)urea; —<br><br> N-(2-Hydroxy-3,4-dichlorophenyl)-N-(2-biw»ophenyl)urea;<br><br> tee<br><br> WO 00/76495<br><br> PCT/USOO/16499<br><br> N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophcnyl)urea;<br><br> N-(2-Hydroxy-4-cyanopheuyl)-N'-(2-methoxyphenyl)urca;<br><br> N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea;<br><br> N-(2-Hydroxy-4-cyanophenyl-N-(2,3-&lt;iichlorophenyl)urea;<br><br> N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urca;<br><br> N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea;<br><br> N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea;<br><br> N-(3-Trifluoromethyl-2-hydroxyphenyl)-N-(2-bromophenyl)urea;<br><br> N-(3-Phenylaininocarbonyl-2-hydroxyphenyl)-N-(2-bromophenyl)urea;<br><br> N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea;<br><br> N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea;<br><br> N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea;<br><br> (E)-N-[3-[(2-Aimnocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-biomophenyl)uiea;<br><br> N-(2-Hydroxy,3,4-dichlorophenyl)-N -(2-methoxyphenyl)urea;<br><br> N-(2-Hydroxy,3,4-dichlorophenyl)-N-(2-phenylphenyl)urea;<br><br> N-(2-Hydroxy-3,4-dichlorophenyl)-N-(2,3-dichlorophenyI)urea;<br><br> N-(2-Hydroxy-5-nitrophenyl)-N'-(2,3-&lt;iichlorophenyl)urea; and<br><br> N-(2-Hydroxy-3-cyanophenyl)-N-(2,3 dichlorophenyl)urea;<br><br> or a pharmaceutically acceptable salt thereof.<br><br> t end of claims<br><br> Office"^*<br><br> ftECEIVED<br><br> 101<br><br> </p> </div>
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