ZA200109479B

ZA200109479B - IL-8 receptor antagonists.

Info

Publication number: ZA200109479B
Application number: ZA200109479A
Authority: ZA
Inventors: Katherine L Widdowson; Daniel F Veber; Anthony J Jurewicz; Melvin C Rutledge; Robert P Hertzberg; Gregory M Benson
Original assignee: Smithkline Beecham Corp
Priority date: 1999-06-16
Filing date: 2001-11-16
Publication date: 2002-11-18
Also published as: NZ514695A; EP1185261A1; HUP0201571A2; EP1185261A4; AU766083B2; WO2000076495A1; CZ20014471A3; NO20016053D0; NO20016053L; MXPA01013004A; PL352232A1; IL145761A0; AU5741300A; KR20020010709A; CN1355697A; JP2003501459A; HK1044483A1; HUP0201571A3; CA2377341A1; CO5200760A1

Description

IL-8 RECEPTOR ANTAGONISTS

FIELD OF THE INVENTION

This invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8, GROo, GRO, GROy and

NAP-2 mediated diseases and pharmaceutical compositions for use in such therapy.

BACKGROUND OF THE INVENTION

Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCEF), 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-1, IL-1P or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990) ; Strieter, et al, Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al, J. Immunol. 148, 3216 (1992).

GROa, GRO, GROy and NAP-2 also belong to the chemokine a family. Like

IL-8 these chemokines have also been referred to by different names. For instance .

GROG, B, yhave been referred to as MGSAa, PB 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.

IL-8, GROo, GROB, 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 GRO have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-o and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 1b/CD18) 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, GROo, GROB, GROy and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev.

Immunol. 12, 17 (1992); Oppenheim et al, Annu. Rev. Immunol. 9, 617 (1991); Seitz etal, J Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 v WO 00/76495 PCT/US00/16499 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 (1992).

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

Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8Rf3, which has high affinity for IL-8 as well as for GRO-o,, GROf3, GROy and NAP-2. See

Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosaet al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al.,

J. Biol. Chem. 268, 7283 (1993).

There remains a need for treatment, in this field, for compounds which are : 20 capable of binding to the IL-8 ot or B receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T- cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVENTION

This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or B receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.

This invention also relates to 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).

Compounds of Formula (I) useful in the present invention are represented by the structure:

X R n(Y) ND Ji§ R,)m

N N

H H @ wherein

X is oxygen or sulfur; ~ Ris any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

R1 is independently selected from hydrogen; halogen, nitro; cyano; halosubstituted

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted Ci-10 alkoxy; azide; S(O){R4; hydroxy; hydroxy C].qalkyl; aryl; aryl Cj_4 alkyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Cj. 4alkyl; heteroaryl C}-4 alkyloxy; aryl C210 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4Rs; C210 alkenyl C(O)NR4R5; C(O)NR4Rs5;

C(O)NR4R 10; S(0)3H; S(O)3Rg; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R] 1;

C2-10 alkenyl C(O)OR]1; C(O)R1}; C(O)OR]2; OC(O) R11: NR4C(O)R |]; or two R] moieties together may form O-(CH?2)gO- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

R4 and Rj are independently hydrogen, optionally substituted C]_4 alkyl, optionally substituted aryl, optionally substituted aryl C|_galkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1 _4alkyl, heterocyclic, heterocyclic

C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; .

Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted : C1-10 alkyl; Cj-10 alkyl; C2-10 alkenyl; Cj.10 alkoxy; halosubstituted C110 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-galkyl; aryl; aryl C1.4 alkyl; aryloxy; arylC| 4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Cj-4 alkyloxy; heterocyclic, heterocyclic Cj _galkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl, heterocyclic C2-)0 alkenyl; NR4Rs; C2.10 alkenyl C(O)NR4Rs; C(O)NR4RS5;

C(O)NR4R 10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R 1]; C2-10 alkenyl C(O)R] 1;

C2-10 alkenyl C(O)OR 11; C(O)R]1; C(O)OR}2; OC(O) R11; NR4C(O)R{ 1; or two Y moieties together may form O-(CH2)sO- or a S to 6 membered unsaturated ring; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;

Rg is hydrogen or C4 alkyl;

R10 is C1-10 alkyl C(O)2RsS;

R11 is hydrogen, C14 alkyl, optionally substituted aryl, optionally substituted aryl

C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1.-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC{.4 alkyl,

R12 is hydrogen, C}.10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.

Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or f3 receptor and which method compriscs administering an effective amount of a compound of

Formula (IT) or a pharmaceutically acceptable salt thereof, as defined herein.

This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (II), as defined herein.

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

Another aspect of the present invention is to a method of treating a chemokine mediated disease, whercin the chemokine is one which binds to an IL-8 a or § receptor and which method comprises administering an effective amount of a compound of

Formula (IIT) or a pharmaceutically acceptable salt thereof, as defined herein.

This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (III), as defined herein. : 20 This invention also relates to the novel compounds of Formula (III), or a pharmaceutically acceptable salt thereof, as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

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 other chemokines which bind to the IL-8 o 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.

In compounds of Formula (I), R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to 7. Such functional groups include, but are not limited to, hydroxy, carboxylic acid, thiol, -SR2 -OR2, -NH-C(O)R3, -C(O)NRgR7, a substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHR¢, NHC(X2)NHRp, or a tetrazolyl; wherein X?2 is oxygen or sulfur, preferably oxygen. Preferably, the functional group is other than a sulfonic acid, either directly or as a substituent group on the aryl, heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2. More preferably R is OH, SH, or NHS(O)2Rp. Suitably, R7 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.

Suitably, Rg and R7 are independently hydrogen ora Cj_4 alkyl group, or Rg and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.

Suitably Rj is an alkyl, aryl, arylC_galkyl, beteroaryl, heteroarylC1-4alkyl, . heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted, as defined herein below.

Suitably, Rp is a NRgR7, alkyl, aryl, arylC-4alkyl, arylC2_4alkenyl, heteroaryl, heteroarylCj_4alkyl, heteroarylC3-4 alkenyl, heterocyclic, or heterocyclic C1-4alkyl, or _ a heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C14 alkyl, such as

CF3; Ci-4 alkyl, such as methyl; C)-4 alkoxy, such as methoxy; NR9C(O)Ry;

C(O)NRgR7, S(0)3H, or C(O)OC1-4 alkyl. Rp is preferably an optionally substituted phenyl, benzyl, or styryl. When Rp is a heteroaryl preferably it is an optionally - substituted thiazole, optionally substituted thienyl, or optionally substituted quinolinyl - ring. Wherein Rg is hydrogen or a Cj.4 alkyl, preferably hydrogen, and suitably when .. the substituent group is NR9C(O)Ra, then Rj is preferably an alkyl group, such as methyl. - Suitably Re is hydrogen, alkyl, aryl, arylC_qalkyl, arylC]-galkenyl, heteroaryl, - heteroarylC|-4alkyl, heteroarylC]-4alkenyl, heterocyclic, or heterocyclic Cy-4alkyl, or a heterocyclic Cj-galkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C}4 alkyl, C}_4 alkyl, C|- 4 alkoxy, NRgC(O)R3, C(O)NRgR7, S(0)3H, or C(0)OC|-4 alkyl, wherein Rg is hydrogen or a C14 alkyl. Preferably, Rc is an optionally substituted phenyl.

When R is an OR? or SR) moiety it is recognized by one of skill in the art that the aryl ring must, therefore, contain the required ionizable hydrogen. The aryl ring may also be additionally substituted, independently, by one to three groups, which groups may also contain an additional ionizable group, and which include but are not limited to, halogen, nitro, halosubstituted C-4 alkyl, C]-4 alkyl, C4 alkoxy, hydroxy, SH, -C(O)NRgR7, -NH-C(O)R3, -NHS(O)2Rp, S(O)2NRgR7, C(O)ORg, or a tetrazolyl ring.

In compounds of Formula (I), suitably R] is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl, such as CF3; C1-10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; C1-10 alkoxy, such as methoxy, or ethoxy; halosubstituted C-1¢ alkoxy, such as trifluoromethoxy; azide;

S(O)R4, wherein t is 0, | or 2; hydroxy; hydroxy C].galkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C]_4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C1.4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl;

To WO 00/76495 PCT/US00/16499 heteroaryl C}-4 alkyloxy; aryl C2-10 alkenyl! ; heteroaryl C2-10 alkenyl; NR4Rs5; Co. 10 alkenyl-C(O)NR4R5; C(O)NR4R5; C(O)NR4R 10; S(O)3H; S(O)3R8g; C1-10 alkyl

C(O)R11; C2-10 alkenyl C(O)R]1], C2-10 alkenyl C(O)OR1 |; C(O)R]]; C(O)OR12, such as carboxy, methylcarboxylate or phenylbenzoate; OC(O) R11; NR4C(O)R 1}; azido; or two R] moieties together may form O-(CH?2)3O- 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 moicties may all be optionally substituted as defined herein below. Preferably Rj is other than azido or S(O)3R§.

When R| forms a dioxybridge, s is preferably 1. When R| 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 R} moieties as defined above.

Suitably, R4 and R5 are independently hydrogen, optionally substituted C14 alkyl, optionally substituted aryl, optionally substituted aryl Cj-galkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cj 4alkyl, heterocyclic, heterocyclicCj-4 alkyl, or R4 and Rs together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S. : 20 R10 is suitably C1-10 alkyl C(O)2Rg, such as CH2C(O)2H or CH2C(0O)2CH3. : R11] is suitably hydrogen, C]-4 alkyl, aryl, aryl C1.4 alkyl, heteroaryl, heteroaryl C14alkyl, heterocyclic, or heterocyclic C1_4alkyl. ) R12 is suitably hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Preferably R1 is halogen, cyano, nitro, CF3, C(O)NR4RS§, alkenyl C(O)NR4RS5,

C(O) R4R 0, alkenyl C(O)OR 12, heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or

S(O)NR4Rj5, and preferably R4 and R5 are both hydrogen or one is phenyl. A preferred ring substitution for R1 is in the 4-position of the phenyl ring.

When R is OH, SH or NSO2Rp, than R) is preferably substituted in the 3- position, the 4- position or di substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably when R is OH, SH or NSO2Rp, than R] is nitro, halogen, cyano, trifluoromethyl group, C(O)NR4Rs.

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

In compounds of Formula (I), suitably Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-1¢ alkyl; Cj-10 alkyl; C2-10 alkenyl; C1.10 alkoxy; halosubstituted C]-]0 alkoxy; azide; S(O)tR4; hydroxy; hydroxy C]-4alkyl; aryl; aryl C|.4 alkyl; aryloxy; arylCj.4 alkyloxy; aryl C2_10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C]-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic C1-4alkyl; heterocyclicC2-10 alkenyl; NR4Rj5; Co. 10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R 10; S(O)3H; S(0)3Rg; C}_10 alkyl

C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR 1; C(O)R]1; C(O)OR 2;

OC(0) R11; NR4C(O)R11; azido; or two Y moieties together may form O-(CH32),0- ora 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 Rj is other than azido or S(O)3RS§. - Y is preferably a halogen, C14 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R3, thio C1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1.4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2*- position or 2, 3-position.

While Y may be substituted in any of the 5 ring positions, preferably when R is

OH, SH, or NSO2Rb, Y is preferably mono-substituted in the 2-position or 3*- position, with the 4’- preferably being unsubstituted. If the ring is disubstituted, when

Ris OH, SH, or NSO2Rp, substituents arc preferably in the 2’ or 3” position of a - monocyclic ring. While both R] and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings arc substituted.

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

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

Compounds exemplified by this bis like structure include:

N-(Bis (2-hydroxy-4-nitro phenyl) N’-(dianisdine) diurea; and 4-Methylene bis(N-(2-chloro phenyl) N’-(2-hydroxy 4-nitro phenyl) urea). Exemplified compounds of Formula (I) include:

N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;

N-{5-Nitro-2-hydroxyphenyl}-N'-pheny! urea; 3-Hydroxy-4-{[(phenylamino)carbonyl]amino } benzamide

N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea; 2-{{(Phenylamino)carbonyl]amino }thiphenolN-(2-Carboxy-4-hydroxyphenyl)-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;

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; N-(2-Hydroxy-4-nitrophenyl)-N’-(2-methoxyphenyl)urea;

N-(2-Hydroxy-4-nitrophenyl)-N"-(3-trifluoromethylphenyl)urea

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; N-(2-Hydroxy-4-nitrophenyl)-

N’-(2-phenylphenyl)urea;

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 N-(2-Hydroxy-4-nitrophenyl)-N’-(2,6-difluorophenyljurea;

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; : N-(4-Carbomethoxy 2-hydroxy phenyl) N’-(2-bromophenyl) urea;

N-(4-Trifluoromethyl-2-hydroxy phenyl) N’-(2-phenyl phenyl) urea; N-(4-Carbomethoxy 2-hydroxy phenyl) N’-(2-pheny! phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl) N-(2,3-dichloro phenyl) urea;N-(2-Hydroxy-4- nitrophenyl) N'-(2,4-dichloro phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl) N-(2-chloro phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl) N-(2,4-dibromo phenyl) urea;

N-(2-Hydroxy-1-napthyl)-N’-(2-bromo phenyl) urea;N-(2-Hydroxy-4-nitrophenyl)-N'- (2,3-methylenedioxyphenyl)urea;

N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea;N-(2-Hydroxy-4- nitrophenyl) N'-(2-methyl phenyl) urea;

N-[4-(Benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea; N-(2-Hydroxy-4-nitrophenyl)-N’-(2-phenoxy phenyl) urea; N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea;N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea;

N-(3,4-Difluoro 2-hydroxy phenyl) N'-(2-bromo phenyl) urea;

N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea;N-(2-Hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea;

N-(2-Hydroxy-4-nitro phenyl) N-(2-phenylamino phenyl) urea,

N-(2-Hydroxy 3-carboxyphenyl) N*-(2-bromo phenyl) urea

N-(2-Sulfhydryl 4-bromo phenyl) N*-(2-bromo phenyl) urea;N~(2-Hydroxy 4-nitro phenyl) N-(2-iodo phenyl) urea; N-(2-Hydroxy 4-nitro phenyl) N*-(2-bromo phenyl) . 5 thiourea;N-[(2-Phenylsulfamido) 4-cyanophenyl]- N*-(2-bromo phenyl) urea;

N-(2-(Amino sulfonamido phenyl) phenyl) N*-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl styryl) phenyl) N*-(2-bromo phenyl) urea;2-[(3,4 Di- methoxyphenylsulfonyl)amino] phenyl) N*-(2-bromo phenyl) urea;

N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl (3-tolyl) phenyl) N-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N*-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl benzyl) phenyl) N*-(2-bromo phenyl) urea;

N-(2-Hydroxy-4-azidophenyl)-N"-(2-methoxyphenyl)urea;

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-bHydroxy-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;

N-[2-Hydroxy-3-cyanophenyl}-N-[2-bromophenyl] urea;

N-[2-Hydroxy-4-cyanophenyl]-N-[2-bromophenyl] urea;N-[2-Hydroxy-4- cyanophenyl]-N"-[4-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N*-{2- phenylphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N-[2-methylphenyl] urea;

N-[2-Hydroxy-4-cyanophenyl]-N*-[2-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- bromophenyl] urea;

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;

v WO 00/76495 PCT/US00/16499

N-[3-Benzyloxy-2-hydroxyphenyl]-N’-[2-bromophenyl]} urea; (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; (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N"-[2-bromophenyl] urea-N’- [2-bromophenyl] urea; (E)-N-[4-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N*- [2-bromophenyl] urea;

N-[2-Hydroxy-4-benzamide phenyl]-N*-[2-bromophenyl} urea; 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;

N-[2-[[[2-(Trifluoromethyl)phenyl}sulfonyl]aminojphenyl]-N*-(2-bromophenyl)urea; N-(2-Bromophenyl)-N-[2-dimethylaminosulfonylamino]phenyljurea;

N-[2-(Phenethylsulfonylamino)phenyl]-N-(2-bromophenyl)urea;

N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N"-(2- bromophenylurea;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-fluoropheny!]-N’-[2-bromophenyl] urea;

N-{2-Hydroxy-5-trifluoromethylphenyl]-N’-[2-bromophenyl] urea;

N-[2-Hydroxyphenyl]-N*-[2-bromophenyl] urea; N-[Trans-3-styrl-2-hydroxyphenyl]-N- [2-bromophenyl] urea;

N-(2-Hydroxy-3.4-dichlorophenyl]-N’-[2-methox yphenyl} 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;

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- Bistrifluoromethylphenyl)sulfonylamino]phenyl])-N’-(2-bromophenyl)urea;N-[2-[(2-

Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N>-(2-bromophenyl)urea;

N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N’-(2-bromophenyl)urea;

N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N’-(2-bromophenyl) urea;

N-[[2-(1S)-10-Camphorsulfonylamino]phenyl]-N’-(2-bromophenyl)urea;

N-[[2-(1R)-10-Camphorsulfonylamino]phenyl]-N™-(2-bromophenyl)urea;

N-[2-[2-(2-Nitro-(4-triflucromethyl)phenyl)sulfonylamino]phenyl-N>(2- bromophenyl)urea;

N-(2-Hydroxy-4-azidophenyl)-N-(2-iodophenyl)urea;N-(2-Hydroxy-3-azidophenyl)- N-(2-bromophenyljurea;N-[2-Hydroxy-3-cyanophenyl}-N*[2-methoxyphenyl] urea;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;

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- trifluvoromethylphenyl] urea;N-[2-Hydroxy-5-nitrophenyl]-N"-[2-phenylphenyl] urea;

N-(2-Hydroxy-5-nitrophenyl]-N*-[2,3-dichlorophenyl] urea;N-[2-Hydroxy-5- ethylsulfonylphenyl]-N*[2,3-dichlorophenyl] urea;N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N~(2-bromophenyljurea;N-[2-(Aminosuifonyl phenyl) 3-amino phenyl] N-(2-bromo phenyl) urea;N-[2-Hydroxy-3,4-dichlorophenyl]-N*-[2,4 dimethoxyphenyl] urea; : N-[2-Hydroxy-3,4-dichlorophenyl]-N’-[2-chloro-5-trifluoromethylphenyl]} urea; N-[2-Hydroxy-3-naphthyl]-N*-[3-trifluoromethylphenyl] urea; :

N-[2-Hydroxy-5-naphthalenesulfonic acid}-N*-[2-bromophenyl] urea; - N-[2-Hydroxy-4-naphthalencsulfonic acid}-N*-[2-bromophenyl] urca; 1,1-(4-Methyl-2-phenylene)bis[2-thio-3-3-tolylurea]

N-(2-Carboxyphenyl)-N"-phenylurea;

N-(2-Hydroxy-4-nitrophenyl)-N-phenylurea; 1-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea ; 2-(3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid, 2-(4-Chlorophenylcarbonyldiimino)-S-trifluoromethylbenzoic acid; 1-(p-Anisyl)-3-(2-carbox yphenyl)urea; 1-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea; 1-(2-Carboxyphenyl)-3-(3-chlorophenyl)urea; 1-(m-Anisyl)-3-(2-carboxyphneyl)urea; 1-(0-Anisyl)-3-(2-carboxyphenyl)urea ; 1-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea; 1-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea;

N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N*-phenylurea; and

N-(2-Hydroxy-4-nitrophenyl)-N’-(4-nitrophenyl)urea. Preferred compounds of

Formula (I) include:

N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxyphenyl)urea;

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-methylthiophenyl)urea;

N-(2-Hydroxy-4-nitrophenyl)-N’-(2,3-dichlorophenyl)urea;

N-(2-hydroxy 4-nitro phenyl) N-(2-chloro phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl)-N"-(2,3-methylenedioxyphenyl)urea;

N-(2-Hydroxy-4-nitrophenyl)-N’-(2-methoxy-3-chlorophenyl)urea;

N-(2-hydroxy 4-nitro phenyl) N’-(2-phenyloxy phenyl) urea;

N-(3-Chloro-2-hydroxyphenyl)-N’-(bromophenyl)urea;

N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N’-(2-bromophenyl)urea;

N-(3-Nitro-2-hydroxyphenyl)-N’-(2-bromophenyl)urea;

N-(2-Hydroxy-4-cyanophenyl)-N™-(2-bromophenyl)urea;

N-(2-Hydroxy-3,4-dichlorophenyl)-N’-(2-bromophenyl)urea;

N-(3-Cyano-2-hydroxyphenyl)-N-(2-bromophenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N’-(2-methoxyphenyl)urea;

N-(2-Hydroxy-4-cyanophenyl)-N’-(2-phenylphenyl)urea;

N-(2-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;

N-(2-hydroxy 4-nitro phenyl) N’-(2-iodo phenyl) urea;

N-(2-hydroxy 4-nitro phenyl) N’(2-bromo phenyl) thiourea; N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea; (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;

N-(2-Hydroxy-5-nitrophenyl)-N>-(2,3-dichlorophenyl)urca; and

N-(2-Hydroxy-3-cyanophenyl)-N’-(2,3 dichlorophenyl)urea.

As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C-10alkyl; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m’C]- 10 alkyl, wherein m’is O, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR4R§5 group;

NHC(O)R4; C(O)NR4R5; C(O)OH; S(O)2NR4R5; NHS(0)2R13, C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Cj-}0 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , hetroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Cj.10 alkoxy; S(O)mCi-10 : 5 alkyl; amino, mono & di-substituted amino, such as in the NR4R5 group; C1-10 alkyl, ~or halosubstituted C1-10 alkyl, such as CF3. : R13 is suitably C|_4 alkyl, aryl, aryl C}-4alkyl, heteroaryl, heteroarylC|_4alkyl, heterocyclic, or heterocyclicC]_galkyl. - Another aspect of the present invention are the novel compounds of Formula (II), or a pharmaceutically acceptable salt thereof, as described below, which are also ..useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.

This invention also relates to the pharmaceutical compositions comprising a compound : of Formula (IT) 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 B 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:

X R

] . * N N ” } : E H H 1 E * (ID wherein

Xs oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

R] is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C].10 alkoxy; halosubstituted C}-10 alkoxy; azide; S(O)R4; hydroxy; hydroxyC-galkyl; aryl; aryl C}-4 alkyl; aryloxy; arylC) 4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC]-4alkyl; heteroarylC] 4 alkyloxy; aryl C2.]0 alkenyl; heteroaryl C2-]10 alkenyl; heterocyclicC)-10 alkenyl; NR4R5; C2.10 alkenyl C(O)NR4R5; C(O)NR4RS5;

C(O)NR4R 10; S(O)3H; S(0)3Rg; C1-10 alkyl C(O)R 11; C2-10 alkenyl C(O)R} 1;

C2-10 alkenyl C(O)OR] 1; C(O)R11; C(O)OR]2; OC(O) R11; NR4C(O)R]y; or two R] moieties together may form O-(CH?2)sO- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

Ry4 and Rs are independently hydrogen, optionally substituted C}-4 alkyl, optionally substituted aryl, optionally substituted aryl C]-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C] -4alkyl, heterocyclic, heterocyclicC]-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O){R4; hydroxy; hydroxy C] _galkyl; aryl; aryl C}_4 alkyl; aryloxy; aryl C1.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC] 4 alkyloxy; heterocyclic, heterocyclic C1-galkyl; aryl C;.10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R35; C2.10 alkenyl C(O)NR4R5; C(O)NR4Rs;

C(O)NR4R10; S(O)3H; S(O)3Rg; C1-10 alkyl C(O)R | 1; C2-10 alkenyl C(O)R 1];

C2-10 alkenyl C(O)OR] 1; C(O)R11: C(O)OR12; OC(O) R11; NR4C(O)R1]; or two Y moieties together may form O-(CH?2)5O- or a 5 to 6 membered unsaturated ring; nis an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;

Rg is hydrogen or Cj-4 alkyl;

R10 is C1-10 alkyl C(O)2R8;

C14alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC]-4 alkyl;

R12 is hydrogen, C]-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

Eis optionally selected from 0] *

SNe 4

Ri (ID © ; © ; Ri ; or Ar ; the asterix * denoting point of attachment of the ring, with at least one E being present, or a pharmaceutically acceptably salt thereof.

Suitably, the variables for Formula (I), such as X, R, R1,R4, R5, Rg, R7, Rg,

Ro, Y,Ra Rp, Rc, n,m, and s terms, ctc. 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

R1 terms as shown. At Jeast one E ring is necessary. The E ring may be substituted by the R] moiety in any ring, saturated or unsaturated, and is shown for purposes herein ~ substituted only in the unsaturated ring(s).

Exemplified compounds of Formula (II) are:

N-[2-hydroxy-5-indanone}-N"-[2-bromophenyl] urea; . 5 N-[l-hydroxyfluorene]-N’-[2-bromophenyl] urea;

N-[3-hydroxy-9,10-anthraquinon-2-y1]-N*-[2-bromophenyl] urea Another aspect of -the present invention are the novel compounds of Formula (IIT), 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 ] 10 relates to the pharmaceutical compositions comprising a compound of Formula (III) -and a pharmaceutically acceptable diluent or carrier. Compounds of Formula (IIT) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 o 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 (II) are represented by the formula:

Y)

Ra J i R,)m ” ’ S N N - : H H (I) wherein - X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; :

C1-10 alkyl; C}-10 alkyl; C2-10 alkenyl; C}-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC|_4alkyl; aryl; aryl C}-4 alkyl; aryloxy; arylC|-4 alkyloxy; heteroaryl; heteroarylatkyl; heterocyclic, heterocyclicC | -galkyl; heteroarylCj-4 alkyloxy; aryl C3.10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC)- 10 alkenyl; NR4Rs; C2_10 alkenyl C(O)NR4R§s; C(O)NR4R35;

C(O)NR4R 10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R{ 1;

C2-10 alkenyl C(O)OR]]; C(O)R] 1; C(O)OR]2; OC(O) R11; NR4C(O)R]; or two R] moieties together may form O-(CH?2)sO- or a 5 to 6 membered unsaturated ring; tis O, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

R4 and R35 are independently hydrogen, optionally substituted C].4 alkyl, optionally substituted aryl, optionally substituted aryl Cj.galkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C)_4alkyl, heterocyclic, heterocyclicCj.4 alkyl, or R4 and R5 together with the nitrogen to which they are

] attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 h] alkoxy; azide; S(O)tR4; hydroxy; hydroxyC]-galkyl; aryl; aryl C|_4 alkyl; aryloxy; arylC1.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC]-4 alkyloxy; heterocyclic, heterocyclicC]_4alkyl; aryl C2.10 alkenyl; heteroaryl C2.10 alkenyl, heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R35; C(O)NR4RS;

C(O)NR4R 10; S(0)3H; S(0)3Rg; C1-10 alkyl C(O)R] J; C2-10 alkenyl C(O)R] j;

C2-10 alkenyl C(O)OR] 1; C(O)R]}; C(O)OR 12: OC(O) R11; NR4C(O)R 1; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;

Rg is hydrogen or C4 alkyl;

R10 1s C1-10 alkyl C(O)2RS;

R11 is hydrogen, Cy-4 alkyl, optionally substituted aryl, optionally substituted aryl

Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1- 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCj- : 20 4alkyl;

R12 is hydrogen, C1.10 alkyl, optionally substituted aryl or optionally substituted . arylalkyl; i or a pharmaceutically acceptably salt thereof. ’ Suitably, the variables, etc. for Formula (IT) are the same as those defined for ~ 25 Formula (I) above, such as for example the R variable.

Exemplified compounds of Formula (III) are N-(2-Hydroxy-4-nitrophenyl)-N*- (3-methoxy-2-thienyl)urea ; and N-(2-hydroxy-5-nitrophenyl)-N-(3-methoxy-2- thienyl)urea.

Another aspect of the present invention is the novel compounds of Formula (la), asubset 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 (Ia) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (la) are represented by the structure:

NHS(O) ,R, n(Y) NPN J R,)m

N N

H H (Ia) wherein

X is oxygen or sulfur;

Ra is an alkyl, aryl, arylC-4alkyl, heteroaryl, heteroaryl Cj-galkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;

Rp is a NRgR7, alkyl, aryl, arylCj_galkyl, aryl C2_4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC_4 alkenyl, heterocyclic, or heterocyclic

C1-4alkyl, 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; C14 alkyl; C]-4 alkoxy: NRQC(O)R,: C(O)NRgR7, - =. S(O)3H, or C(O)OC] -4 alkyl; r. 10 Rg and R7 are independently hydrogen or a C|-4 alkyl group, or Rg 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;

Ro is hydrogen or a Cj .4 alkyl, preferably hydrogen;

Rj} is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted . = C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C}-10 alkoxy; halosubstituted C-10 alkoxy; azide; S(O){R4; hydroxy; hydroxy C| 4alkyl; aryl; aryl C] 4 alkyl; aryloxy; aryl C14 alkyloxy; heteroaryl; hetcroarylalkyl; heterocyclic, heterocyclic Cy. - . 4alkyl; heteroaryl C]-4 alkyloxy; aryl C210 alkenyl; heteroaryl C310 alkenyl; -- 20. heterocyclicC2-10 alkenyl; NR4Rs5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R35; : = - C(O)NR4R 0; S(O)3H; S(O)3R8: C|-10 alkyl C(O)R] 1; C2-10 alkenyl C(O)R1 1; 3 C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR 2; OC(O) R11; NR4C(O)R] |; or two R| moieties together may form O-(CH2)O- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C]-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C}_galkyl, heterocyclic, heterocyclicC]-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;

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; Ci-10 alkoxy; halosubstituted C-10 alkoxy; azide; S(O){R4; hydroxy; hydroxyCj-4alkyl; aryl; aryl Cj-4 alkyl; aryloxy; arylCj-4 alkyloxy; heteroaryl; heteroarylalkyl; hetcroarylC 4 alkyloxy; heterocyclic, heterocyclicC|-qalkyl; aryl C2-10 alkenyl; heteroaryl C2-1() alkenyl; heterocyclicC2.-10 alkenyl; NR4Rs5; C2.10 alkenyl C(O)NR4Rs5; C(O)NR4R5;

C(O)NR4R 10; S(O)3H; S(0)3Rg; C)-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11;

tr WO 00/76495 PCT/US00/16499

C2-10 alkenyl C(O)OR 1; C(O)R11]; C(O)OR]2; OC(O) R); NR4C(O)R] 1; or two Y moieties together may form O-(CH?2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 3; mis an integer having a value of 1 to 3;

Rg is hydrogen or C4 alkyl;

R10 1s C1-10 alkyl C(O)2RS;

R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl

C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC}. 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC]- 4alkyl;

R12 is hydrogen, C1.10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.

A preferred ring substitution for R) variable is monosubstituted in the 3- position, or the 4- position, or di-substituted in the 3,4- position. The substituent group 1s suitably an clectron withdrawing moiety. Preferably R] is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.

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- preferably being unsubstituted. If the ring is di-substituted, substituents are preferably in the 2'-, 3% positions of a monocyclic ring. While both R} 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.

Y is more preferably a mono-substituted halogen, disubstituted halogen, mono- substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably these groups are substituted in the 2™- position or 2’-,3 position.

Exemplified compounds of Formula (Ia) are:

N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N’-phenyl urea;

N-[(2-Phenylsulfamido) 4-cyanophenyl]- N-(2-bromo phenyl) urea;

N-(2-(Amino sulfonamido phenyl) phenyl) N*-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl styryl) phenyl) N’-(2-bromo phenyl) urea; 2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N-(2-bromo phenyl) urea;

N-(2-[(4-Acetamidophenylsulfonyl)amino) phenyl) N-(2-bromo phenyl) urea; N-(2-(Amino sulfonyl (2-thiophene) phenyl) N-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl (3-tolyl) phenyl) N-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea;

N-(2-(Amino sulfonyl benzyl) phenyl) N’-(2-bromo phenyl) urea;

N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl}-N"-(2-bromophenyl)urea;

N-(2-Bromophenyl)-N*-[2-dimethylaminosulfonylamino)phenyl]jurea;

N-[2-(Phenethylsulfonylamino)phenyl]-N"-(2-bromophenyl)urea;

N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N-(2- bromophenyl)urea; :

N-[2-[(2,3-Dichlorothien-5-yl)]Jsulfonylamino]pheny!]-N'-(2-bromophenyl urea; N-[2- [(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N"-(2-bromophenyl)urea;N-[2- : [(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N*-(2-bromophenyl)urea;N-[2- . .[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N"-(2-bromophenyl)urea;

N-[2-[2-(4-Phenoxyphenyl)sulfonylamino)phenyl]-N*(2-bromophenyl) urea; . =N-[[2-(1S)-10-Camphorsulfonylamino}phenyl]-N"-(2-bromophenyl)urea;

N-[[2-(1R)-10-Camphorsulfonylamino}phcnyl}-N*-(2-bromophenyl)urea; . N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino)}phenyl-N(2- bromophenylurea;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. Another . aspect of the present invention is the novel compounds of Formula (Ib), a subset of ‘compounds of Formula (I) useful for treating a chemokine mediated disease. This _invention also relates to the pharmaceutical compositions comprising a compound of

Formula (Ib) and a pharmaceutically acceptable diluent or carrier. The compounds of :

Formula (Ib) are represented by the structure: xX, R 2

X n(Y) SO) JL R4)m 4

H H (Ib) wherein

X is oxygen or sulfur;

Xj is oxygen or sulfur;

C1-10 alkyl; C1-10 alkyl; C2. 10 alkenyl; C].10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O){R4; hydroxy; hydroxyC]_4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylCj-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C1-4alkyl; heteroaryl C).4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2.10 alkenyl; heterocyclicC2-1( alkenyl; NR4Rs; C210 alkenyl C(O)NR4Rs; C(O)NR4Rs;

C(O)NR4R10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11;

C2-10 alkenyl C(O)OR] 1; C(O)R}}; C(O)OR|2; OC(O) R11: NR4C(O)R] 3; or two R| moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;

tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

R72 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety providing the ionizable hydrogen having a pKa of 10 or less;

R4 and Rj are independently hydrogen, optionally substituted C14 alkyl, optionally substituted aryl, optionally substituted aryl Cj-galkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1_galkyl, heterocyclic, heterocyclicC1 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;

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O){R4; hydroxy; hydroxyC]-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC]-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC]-4 alkyloxy; heterocyclic, heterocyclicCj-4alkyl; aryl C2.10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2.10 alkenyl C(O)NR4Rs; C(O)NR4R5;

C(O)NR4R 10; S(O)3H; S(O)3R8g; C1-10 alkyl C(O)R]1; C2-10 alkenyl C(O)R11;

C2-10 alkenyl C(O)OR1 1; C(O)R]1; C(O)OR 12; OC(O) R11; NR4C(O)R1; 01 two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated : 20 ring; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;

Rg 1s hydrogen or C4 alkyl;

R10 is C1-10 alkyl C(O)2R8;

Rit is hydrogen, C4 alkyl, optionally substituted aryl, optionally substituted aryl

Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCj.- 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCj.- galkyl;

R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptable salt thereof.

Suitably, the variable, etc. for Formula (Ib) 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(O)Ra, -

C(O)NRgR7, substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHR,

NHC(X2)NHRp, or tetrazoyl (as defined for Formula (I).

Suitably for compounds of Formula (Ib), a preferred ring substitution for R1 is in the 3-position, the 4- position or is preferably di substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably R] is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.

While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2’ or 3’ position of a monocyclic ring. While both R| 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.

Suitably for compounds of Formula (Ib), Y is more preferably disubstituted halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, ‘.methylenedioxy, aryl, or alkyl, preferably in the 2’position or 2°,3"-position.

Another aspect of the present invention is the novel compounds of Formula (Ic), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.

This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ic) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (Ic) are represented by the structure: - X4H = n(Y) Jy —(R ,)M 1

ZL I N N § 7

H H (Io) “wherein

X is oxygen or sulfur; X) is oxygen or sulfur;

C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C110 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)R4; hydroxy; hydroxyC|-4alkyl; aryl; aryl C-4 alkyl; aryloxy, aryl Cj-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicCj. 4alkyl; heteroarylC-4 alkyloxy; aryl C210 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2.10 alkenyl; NR4R§5; C2.10 alkenyl C(O)NR4R 5; C(O)NR4RS5;

C(O)NR4R 10; S(O)3H; S(0)3R8; C1-10 alkyl C(O)R[1; C2-10 alkenyl C(O)R]1;

C2-10 alkenyl C(O)OR|1; C(O)R]]; C(O)OR]2; OC(O) R11: NR4C(O)R]]; or two R| moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;

R4 and R35 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj_galkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic

C1-4 alkyl, or R4 and R§ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is independently selected from halogen; nitro; cyano; halosubstituted C1-10 alkyl;

C1-10 alkyl; C2.10 alkenyl; C1.]10 alkoxy; halosubstituted C).]0 alkoxy; azide;

S(O)tR4; hydroxy; hydroxy C]-4alkyl; aryl; aryl C14 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC1i-4 alkyloxy; heterocyclic, heterocyclic C1-4alkyl; aryl C2.10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic

C2-10 alkenyl; NR4Rs5; C2-10 alkenyl C(O)NR4R35; C(O)NR4R5; C(O)NR4R 10;

S(O)3H; S(O)3R8; C1-30 alkyl C(O)R 11; C2-10 alkenyl C(O)R] 1; C2-10 alkenyl

C(O)OR] 1; C(O)R11; C(O)OR 12; OC(O) R11; NR4C(O)R]1; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;

Rg is hydrogen or C14 alkyl;

R10 is C}-10 alkyl C(O)2Rg;

R11 1s hydrogen, C14 alkyl, optionally substituted aryl, optionally substituted aryl

C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1- 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCj- . 20 4alkyl;

R12 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that ’ when n =1 than Y is substituted in the 2- or 3- position; when n =2 than Y is di-substituted in the 2*- 3 position, the 2-5 position, the 2°-6’ position, the 3-5’ or the 3-6’ position; when b = 3 than Y is trisubstituted in the 2°-3’-5" or the 2-3"-6"- positions; further provided that when X} is O, m=2, R] is 2-t-butyl, 4-methyl, and n=3 than Y is not 2>-OH,3*-t- butyl, 5-methyl; when X] is O, m=1, R} is 4-methyl, and n=2 than Y is not 2’-OH, 5-methyl; when X is O, m=1, R} is hydrogen, and n=2 than Y is not 2’-6™-diethyl, when X is O, m=1, R] is 6-OH, and n=2 than Y is not 2’-5-methyl; when X is S, m=1, R] is 4-cthyl, and n=1 than Y is not 2-methoxy; or a pharmaceutically acceptably salt thereof.

Suitably, the variables, etc. for Formula (Ic) are the same as those defined for

Formula (I) above unless indicated. .

Suitably for compounds of Formula (Ic), a preferred ring substitution for Rj is in the 3-position, the 4- position or di substituted in the 3,4- position. Preferably R1 is other than hydrogen. The substituent group is suitably an electron withdrawing moiety. ~ Preferably R] is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R35.

While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2’ or 3’ position of a monocyclic ring. While both R] 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.

Suitably for compounds of Formula (Ic), Y is more preferably a mono- substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2’position or 2,3-position.

Exemplified compounds of Formula (Ic) are:

N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;

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;

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-methoxypheny!)urea; N-(2-Hydroxy-4- nitrophenyl)-N"(3-trifluoromethyliphenyl)urea; 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;

N-(2-Hydroxy-4-nitrophenyl)-N-(2-phenylphenyl)urea;

N-(2-Hydroxy-4-nitrophenyl)-N"(2-nitrophenyl)urea;N-(2-Hydroxy-4-nitrophenyl)-N* (2-fluorophenyl)urea;

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;

N-(2-Hydroxy-4-nitro-phenyl) N-(2-chloro 6-methyl phenyl) urea;

N-(2-Hydroxy-4-nitro-phenyl) N-(2-sulfoxymethyl phenyl) urea;N-(2-Hydroxy-4- trifluoromethyl phenyl)-N*-(2-bromo phenyl) urea;

N-(2-Hydroxy-4-trifluoromethyl phenyl)-N-(2-phenyl phenyl) urea;

N-(2-Hydroxy-4-carbomethoxy phenyl)-N-(2-phenyl phenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N"-(2,3-dichloro phenyl) urea;N-(2-Hydroxy-4- nitrophenyl)-N’-(2,4-dichloro phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl)-N"-(2-chloro phenyl) urea;

N-(2-Hydroxy-4-nitrophenyl)-N’-(2,4-dibromo phenyl) urea;

N-(2-Hydroxy-1-napthyl)-N’-(2-bromo phenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea;

N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea;

N-[2-Hydroxy-4-(Benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)urea;

N-(2-Hydroxy-4-nitro phenyl)-N’-(2-phenoxy phenyl) urea;

N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea; N-(2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea;

N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea;N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea;

N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea;

N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea; : 20 N-(2-Sulfhydryl-4-bromo phenyl)-N'-(2-bromo phenyl) urea;

N-(2-Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea; N-(2-Hydroxy 4-nitro phenyl)-

N'-(2-bromo phenyl) thiourea;

N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea;

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

N-[2-hydroxy-3,4-diphenyl phenyl]-N'-[2-bromophenyl] urca;N-{2-Hydroxy-3- glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea;

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;

N-[2-Hydroxy-3-cyanophenyl])-N'-[2-bromophenyl] urea;

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea;N-[2-Hydroxy-4- cyanophenyl}-N'-[4-methoxyphenyl] urea; N-[2-Hydroxy-4-cyanophenyl]-N'-[2- phenylphenyl] urea;

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea;

N-[2-Hydroxy-4-cyanophenyl]-N"-[2-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;

N-[2-Hydroxy-4-ethylphenyl]-N’-[2-bromophenyl] urea;

N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N"[2-bromophenyl] urea;

N-[2-Hydroxy-3-cyano-4-methylphenyl]-N-[2-bromophenyl] urea;

N-[2-Hydroxy-4-carbophenyl phenyl]-N"-[2-bromophenyl] urea;

N-[2-Hydroxy-3-carbophenyl phenyl)-N*[2-bromophenyl] urea;

N-[2-Hydroxy-3-benzyloxy phenyl]-N"-[2-bromophenyl] urea; - (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl)-N>{2-bromophenyl] urea; (E)-N-[3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl])-N"-[2-bromophenylJurea-N- [2-bromophenyl] urea; (E)-N-[3-[2-(Aminocarbonyl)ethenyl}-2-hydroxyphenyl]-N"-[2-bromophenyllurea-N*- [2-bromophenyl] urea; (E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N"-[2-bromophenylJurea-N*- [2-bromophenyl] urea;

N-[2-Hydroxy-4-benzamide phenyl}-N"-[2-bromophenyl] urea; : N-[2-Hydroxy-4-aminocarbonyl phenyl]-N>-[2-bromophenyl] urea N-(2-Hydroxy-3,5,6-trifluorophenyl)-N"-(2-bromophenyl)urea; :

N-(2-Hydroxy-3-fluoro-4-trifluoromethylpheny!)-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; N-[2-Hydroxy-4-cyanophenyl]-N*-[2-methoxyphenyl) urea,

N-[2-Hydroxy-4-cyanopheny!}-N’-[3-methoxyphenyl] urea;

N-[2-Hydroxy-5-fluorophenyl}-N*[2-bromophenyl] urea;

N-[2-Hydroxy-5-trifluoromethylphenyl}-N"-[2-bromophenyl] urea;

N-[2-Hydroxyphenyl]-N*[2-bromophenyl] urea;N-[Trans-3-styrl-2-hydroxyphenyl}-N- [2-bromophenyl] urea;

N-[2-Hydroxy-3,4-dichlorophenyl]-N-[2-methoxyphenyl] urea;

N-[2-Hydroxy-3.4-dichlorophenyl]-N*-[4-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; 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-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;

N-[2-Hydroxy-3-cyanophenyl]-N*[3-trifluoromethyliphenyl] 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; N-[2-Hydroxy-4-isopropylphenyl]-N*-[2-chloro-5-trifluoromethylphenyl] urea;

N-[2-Hydroxy-3-phenylphenyl]-N*[2,3-dichlorophenyl] urca;N-[2-Hydroxy-5- nitrophenyl}-N’-[2-methoxyphenyl] urea;

N-[2-Hydroxy-S-nitrophenyl])-N"-[3-trifluoromethylphenyl) urea;

N-[2-Hydroxy-5-nitropheny!]-N"-[2-phenylphenyl] urea;

N-[2-Hydroxy-5-nitrophenyl]-N"-{2,3-dichlorophenyl] urea;

N-[2-Hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea;

N-[2-Hydroxy-3,4-dichlorophcnyl]-N*-{2,4 dimcthoxyphenyl] urea;

N-[2-Hydroxy-3 4-dichlorophenyl]-N*-[2-chloro-5-trifluoromethylphenyl] urea;

N-[2-Hydroxy-3,4-dichlorophenyl)-N"-[benzyl] urca;

N-[2-Hydroxy-4-isopropylphenyl}-N*-[3-trifluoromethylphenyl] urea;

N-[2-Hydroxy-3-naphthyl]-N*[3-trifluoromethylphenyl] urca;

N-[2-Hydroxy-3-naphthy!]-N™{2,3-dichlorophenyl} urea;

N-[2-Hydroxy-3-naphthyl}-N"-[benzyl} urea; : N-[2-hydroxy-3-(phenylaminocarbonyl) phenyl]-N’-[benzoy]] urea; - : 20 N-[2-Hydroxy-3-trifluoromethylphenyl]-N*-[benzoyl] urea; : N-[2-Hydroxy-4-cyanophenyl]-N*[benzoyl] urea;

N-[2-Hydroxy-5-naphthalenesulfonic acid]-N*-[2-bromophenyl] urea;

N-[2-Hydroxy-4-naphthalenesulfonic acid)-N*{2-bromophenyl] urea;

N-(2-Hydroxy 3-napthyl) N’-(2-bromo phenyl) urea; N-(2-Hydroxy-1-napthyl)-N’-(2-bromo phenyl) urea; and

N-(2-Hydroxy-4-nitrophenyl)-N'-(1-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 acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, 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 known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to: "halo" - all halogens, that is chloro, fluoro, bromo and iodo.

> "Cj-10alkyl" or "alkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like. * The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. * The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1- butenyl, 2-butenyl and the like. * “aryl” - phenyl and naphthyl; * "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or “heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings _ contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, “ quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or : benzimidazole. ) * “heterocyclic” (on its own or in any combination, such as "heterocyclicalkyl") - asaturated or partially unsaturated 4-10 membered ring system in which one or more : i rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine. * The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl” is used herein tomean C].|( alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. * "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety. * The term "wherein two R] moieties (or two Y moieties) may together form a 5 or 6 membered unsaturated ring” is used herein to mean the formation of a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a Cg cycloalkenyl, i.e hexene, or a Cs cyloalkenyl moiety, cyclopentene.

The compounds of Formula (I), (Ia), (Ib), (Ic), (II) and (III) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.

The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I), (Ta), (IT) and (IT) 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 nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with compounds only of Formula (I) this is merely for illustration purposes only.

Scheme 1

R R

CL, — CQ

NH , AN N 1 2

R=NH 5, OH, CO 7H, SH a)PhNCO

NHSO ,R

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 1-(RSO2NH)2-(NH2)Ph is not commercially available it can be made by treating the commercially available RSO2Cl 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).

Scheme 2

A . Re X - . NO NH, 3 a 5

R= OH, NH 5, NHSO LR a)HNO 3,23 °C b)SnCl ,, EtOH

If the desired 2-substituted aniline S-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 SnCl; in EtOH(or alternately H,/Pd or

LiAlHy).

Scheme 3

N SH

> \ —>

Cr >~ NH CX

NH, a Ss b NH» 6 z 8 a)NH 4SCN, Br 2 b)NaOH EtOH

If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3. . 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). ] Scheme 4 : ON OH

ON oTBS

IEE C GENES s Be

K] soe D — . 9 - 10 ! B ON OH oo =" Q

A

X=8, 0 1 a)TBSCI, imid, DMF b)i)CICXCI, NaHCO 3.i)PhNH 5 c)Et 3N-HF, CH 3CN

In the case where the thioisocyanate or phenyl isocyanate is not commercially available, the thiourea or urea 11-scheme 4 may be prepared from the commercially available ortho substituted aniline. This compound is first protected with a protecting group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art(see

Greene, T Protecting Groups in Organic Synthesis, Wiley&Sons, New York, 1981).

This protected aniline is then reacted, in the presence of a base(like triethyl amine or sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic solvent (ie. DMF, toluene), followed by aniline to produce the protected thiourea or urca 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.

Scheme 5 a,, =— au 8 CO LH s N N 12 13 x a)(PhO) PON 3,EtzNb)PhXNH ,

X=OH, NHSO ,R, SH

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);PON3, EtzN or CICOCOCI followed by NaN3) and the intermediate isocyanate is trapped by an appropriately - substituted aniline.

Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.

Another aspect of the present invention is the novel synthesis of cyano nitrophenol intermediates. Numerous conversions of aryl halides to aryl cyano derivatives with copper (I) cyanide have becn published. However, no examples of an aryl ring with a hydroxy group present were mentioned. Several attempts to obtain a cyano phenol moicty with published results failed. Using known conditions of elevated : 15 temperatures, greater than 170°C, such as from 180 to 210° 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 tricd 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 () cyanide at reduced temperatures,. i.e. <100°C, preferably 60 to about 80°C for reduced times from standardized procedures, i.e., < 18 hours, preferably about 4 to 6 hours yielded the desired products.

Therefore one aspect of the invention is to a process for producing a cyano phenol derivative of the formula:

OH

Cr C=

R,

wherein R1 is as defined for Formula (I) above, which method comprises reacting a compound of the formula:

H

>

R, wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a ) catalytic amount of dimethylamino pyridine. Preferably, the process is run at reduced “temperatures of about 60 to about 80°C. Preferably X is bromine.

In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra * were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. |H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively. : Multiplicities indicated 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. g Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh).

SYNTHETIC EXAMPLES

The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents “used herein are of the highest available purity and all reactions are run under anhydrous : conditions in an argon atmosphere unless otherwise indicated.

General Method A: Synthesis of N, N’- phenyl urea To a solution of substituted phenyl isocyanate (1.0 equiv.) in toluene (5 miliLiters (hereinafter "mL")) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at about 80°C until complete (24-48 hours (hereinafter “hrs” or "h")), then cooled to room temperature. The purifications, yields and spectral characteristics for each individual compound are listed below.

General Method B: Synthesis of N, N’- phenyl urea To a solution of phenyl isocyanate (1.0 equiv.) in dimethyl formamide (1mL) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at about 80°C until complete (24- 48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics for each individual compound are listed below.

General Method C:Synthesis of sulfonamide The ortho substituted aniline (1 equiv.), triethyl amine (1 equiv.) and the desired sulfonyl chloride (1 equiv.) were combined in methylene chloride and allowed to stir at about 23 °C until complete (12-36 h). The reaction mixture was partitioned between water and methylene chloride. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The purifications of each compound are listed below.

Example 1

Preparation of N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N*-phenyl urea N-[2- 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; 1H NMR (CD30D/CDCl3): 8 8.15 (d, 1H, J = 8.25 Hz), 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. (C1sH14N204) C, H, N.

Example 2

Preparation of N-[S-nitro-2-hydroxyphenyl]-N'-phenyl urea The N-[5-nitro-2- hydroxyphenyl]-N'-phenyl urea was prepared from the S-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%). lH NMR (CD30D): 39.48 (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,

J =6.25Hz),7.01 (m, 2H). EI-MS m/z 273 (M+H)*.

Example 3

Preparation of 3-hydroxy-4-{[(phenylamino)carbonyl jamino }benzamide a)Preparation of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents

To a suspension of the appropriate hydrochloride (0.02 mole (hereinafter "mol")) in dry toluene (20 mL) at about 0°C, was slowly added a solution of (2M, 10 mL) of trimethyl aluminum in toluenc. 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 ccased. b)Preparation of 3-hydroxy-4-{{(phenylamino)carbonyl]amino}benzamide

To a solution of the N-[2-hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea (60 milligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mL) was added aluminum amide reagent (0.9 mL, 0.67M). The reaction mixturc was stirred at reflux for about 12 hours. The reaction mixture was cooled to room temperature and was carefully quenched with 5% HCI. The organic layer was separated and the aqucous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO0yj, 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 (CD30OD/CDCl3): 8 7.98 (d, 1H, J = 8.25 Hz), 7.35 (d, 2H, ]

= 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. (C14H3N303) C, H, N.

Example 4

Preparation of N-(2-hydroxy-4-fluorophenyl)-N'-phenyt! urea a) Preparation. of 2-amino-5-fluoro phenol

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% :aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). 'H NMR (CD30D/CDCl3): 8 6.6 (m, : 1H), 6.38 (dd, 1H, J = 8.3 Hz and J = 2.8 Hz), 6.29 (m, 1H). b) Preparation of N-(2-hydroxy-4-fluorophenyl)-N'-phenyl urea

N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5- ~fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91 %). mp: 195.5-195.7°C; 'H NMR (CD30D/CDCl3): 67.70 (m, 1H), 7.3 (d, 2H, J = 8.25 Hz), 7.15 (t, 2H, J = 8.25 Hz), 6.89 (1, IH, J =8.25 Hz), 6.50 - 6.38 (m, 2H); EI-MS m/z 246 (M+H)*: Anal. : (C13H)1N202 F) C, H, N.

Example 5

Preparation of 2-{[(phenylamino)carbonyl]amino }thiophenol 2-{[(Phenylamino)carbonyl]amino } thiophenol was prepared from 2- aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85 %). mp: 194.5°C; 'H NMR (CD30D/CDCl3): § 7.48 - 7.26 (m, 4H), 7.25 - 7.10 (m, 3H), 7.04 - 6.79 (m, 2H); El-

MS m/z 244 (M+H)*; Anal. (C13H2N20S) C, H, N.

Example 6

Preparation of N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea

N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-5- hydroxy benzoic acid (1 g, 6.53 mmol) according to the procedure in General Method

B. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgS0Oj 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 (CD30D/CDCl3): 6 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. (C;4H{2N204) C, H, N.

Example 7

Preparation of N - [2 - 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 ml) drop-wise to oct, 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 titled compound as an 0il(1.7 g, 27%). 1H NMR (CDCl): 10.6 (s, 1H, OH), 8.26(d, 1H, J = 7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H, J="7.8 Hz) b) Preparation of 2-amino-5-trifluoromethylphenol 2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5- trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl»(3.5g, mmol) in 15S 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

H20 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. 1H NMR (CDCl3): 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

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 was purificd by precipitation from methylene chloride and filtering to afford the titled compound ( 230 mg, 87% ). mp: °C; 1H NMR (DMSO-dg): 6 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. (C14H1N2O2F3)C, H, N.

Example 8

Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urca a) Preparation of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline

To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g, 12.3 mmol) in DMF (15 mL), tert -butyldimethylsilyl chloride (11.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction mixture was partitioned between 0.1 % HCI and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl acetate; 5:1) gave the titled compound (1.7 g, 98 %). 'H NMR (CDCl3): 7.78 (dd, 1H, F=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 (5, 9H), 0.28 (s, 6H). b) Preparation of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N"-[(2- tert-butyldimethylsiloxy)-4- nitrophenyl] urea ~ To a solution of 2-(tert-butyldimethylsilyloxy)-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 -. (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 MgSOy4 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%). 1H NMR (CDCl3): § 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). - c) Preparation of N-(2-Hydroxy-4-nitropheny!)-N'-(2-hydroxy-4- . nitrophenyl) urea

To a solution of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N'-[(2-tert- : _ butyldimethylsilyloxy)-4- nitrophenyl] urca(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 I hour, the starting material had disappeared. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was dried over MgSO4 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%). JH NMR (CD;0D/CDCl3): 68.32 (d, 2H, J = 8.25 Hz), 7.80 (dd, 2H, J = 8.25 Hz and J = 2.06

Hz), 7.7 (d, 2H, I = 2.06 Hz). EI-MS m/z 334 (M+H)*. Anal. (C13H0N4O7) C, H, N.

Example 9

Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea a) Preparation of N-(2-tert-butyldimethysilyloxy-4-nitropheny!)-N'-phenyl- thiourea

N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO; in CHCl;:H,0(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

CHClI5 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline

(100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexane) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145°C;!H NMR (CD3;0D/CDCl3): 6 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H). 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 EtzN*HF (100ulL., 0.62 mmol) in acetonitrile for 10 minutes at 23°C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%). mp: 144-145°C;1H NMR (CD3OD/CDCl3): § 8.65 (4, 1H, J = 10.0 Hz), 7.58 (d, IH, J = 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).

Example 10

Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl 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

DMEF for 12 h at 23 °C. The reaction mixture was partitioned between saturated NH,C! : 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, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,1H, J=2Hz), 6.79 (d, 1H,

J=8Hz), 6.5(s, 2H, br) b) Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea

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 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)"

Example 11

Preparation of N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)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 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. HCI (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96 . 5 %). EI-MS mv/z 159 (M+H)". b)Preparation of N-(2-hydroxy-5-nitrophenyl)-N-(3-methoxy-2-thienyl urea

To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg, 1.27 mmol) . - in benzene, (PhO);PON3 (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 MgSQy, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 1:1) gave a solid product (160 mg, 41%). mp: 15 .172.6-173.0°C; 'H NMR (CD3OD/CDCl3): § 8.96 (d, 1H, J = 2.5 Hz), 7.74 (dd, 1H, J . ~=5.0 Hz and J = 1.25 Hz), 6.82 (d, 1H, J =7.5 Hz), 6.76 (s, 2H), 3.80 (s, 3H); EI-MS -m/z 309 (M+H)*; Anal. (CoH 1N30sS) C, H, N. ; ~ Example 12 - Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea

To a solution of 3-methoxy-2-thiophene carboxylic acid (example 11a, 200 mg, : 1.27 mmol) in toluene, (PhO), PON3 (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 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 MgSOy, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 1:1) gave the product (190 mg, 48%). |H NMR (CD30D/CDCl3): 68.38 (d, 1H, J = 5.0 Hz), 7.85 (dd, 1H, J =5.0 Hz and ] = 1.25 Hz), 7.76 (d, 1H,J =2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS m/z 309 (M+H)*; Anal. (C12H11N3OsS) C, H, N.

Example 13

Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate(1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (140 mg, 46%). EI-MS m/z 302(M-H) -

Example 14

Preparation of N-(2-hvdroxy-4-nitrophenyl)-N"-(2-methoxyphenyl)urea ~ N-(2-Hydroxy-4-nitrophenyl)-N*(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate(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 (82 mg, 27%). EI-MS m/z 302(M-H)-

Example 15

Preparation of N-(2-hydroxy-4-nitrophenyl)-N*(3-trifluoromethylphenylurea

N-(2-Hydroxy-4-nitrophenyl)-N"-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-trifluoromethyl phenyl isocyanate (1 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H) +

Example 16

Preparation of N-(2-hydroxy-4-nitrophenyl)-N"-(2-trifluoromethylphenyl)urea

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 thetitle compound (180 mg, 52%). EI-MS m/z 342(M+H) +

Example 17

Preparation of N-(2-hydroxy-4-nitrophenyl)-N*-(4-trifluoromethylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N’-(4-trifluoromethylphenyl)urea was prepared from 2- hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl! isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340(M-H)-

Example 18

Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea

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) -

Example 19

Preparation of N-(2-hydroxy-4-nitrophenyl)-N’-(3-bromophenyhurea

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 dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.96g, 87%). EI-MS m/z 350(M-H) -

Example 20

Preparation of N-(2-hydroxy-4-nitrophenyl)-N"-(4-bromophenyl)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) +

Example 21 . - Preparation of N-(2-hydroxy-4-nitrophenyl)-N>(2-phenylphenyl)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 with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.22 g, 19%). EI-MS m/z 350(M+H) +

Example 22

Preparation of N-(2-hydroxy-4-nitropheny)-N"-(1-naphthyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N"-(1-naphthyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was 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 desired product precipitated from solution and was collected by filtration(0.11g, 10%).

EI-MS nv/z 324(M+H) +

Example 23

Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N"-(2-nitro phenyl)urea was prepared from 2-hydroxy 4- nitro aniline (500 mg, 3.24 mmol) and 2-nitro 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(0.44 g, 44%). EI-MS m/z 319(M+H) +

Example 24

Preparation of N-(2-hydroxy-4-nitrophenyl)-N"-(2-fluorophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N"-(2-fluorophenyl)urea was prepared from 2-hydroxy 4- nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.59 g, 31%). EI-MS m/z 292(M+H) +

Example 25

Preparation of N-(2-hydroxy-4-nitrophenyl)-N*-(2,6-difluorophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N"-(2,6-difluorophenyl)urca was prepared from 2- hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro phenyl isocyanate(3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.91 g, 91%). EI-MS m/z 308(M-H) -

Example 26

Preparation of N-(2-hydroxy-4-nitropheny)-N"-(2-ethoxyphenyDurea

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) +

Example 27

Preparation of N-(2-hydroxy-4-nitrophenyl )-N’( 2-ethylphenylurea

N-(2-Hydroxy-4-nitrophenyl)-N"-(2-ethylphenyl)urea was prepared from 2-hydroxy 4- nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title . compound(0.44 g, 43%). EI-MS m/z 302(M+H) + ) . Example 28 ] Preparation of N-(2-hydroxy-4-nitro pheny))-N*(2-trifluoromethoxyphenyl)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) +

Example 29 . -Synthesis of N-(2-hydroxy-4-nitro phenyl) N-(2-methylthio phenyl) urea

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. i 20 Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H) + : . . Example 30 } Synthesis of N-(2-hydroxy-4-nitro phenyl) N*-(2-chloro 6-methyl phenyl) urea

The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). EI-MS m/z 322(M+H) +

Example 31

Synthesis of N-(2-hydroxy-4-nitro phenyl) N'-(2- methyl sulfoxyphenyl) urea :

The urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) N-(2- 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) +

Example 32

Synthesis of N-(2-hydroxy 4-trifluoromethyl phenyl) N-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171g, 1 mmol) and 2-bromo phenyl isocyanate(1 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) +

Example 33

Synthesis of N-(2-hydroxy 4-carbomethoxy phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with mcthylenc chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H)-

Example 34

Synthesis of N-(2-hydroxy 4-trifluoromethyl phenyl) N*-(2-phenyl phenyl) urea

The urca 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 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)"

Example 35

Synthesis of N-(2-hydroxy 4-carbomethoxy phenyl) N*-(2-phenyl phenyl) urea

The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-phenyl phenyl isocyanate(! 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) i

Example 36

Synthesis of N-(2-hydroxy 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) *

Example 37

Synthesis of N-(2-hydroxy 4-nitro phenyl) N*-(2,4-dichloro phenyl) urea

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) ©

Example 38

Synthesis of N-(2-hydroxy-4-nitro phenyl) N*-(2-chloro phenyl) urea

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 hexanc. Filtering afforded the title compound(0.29 g, 47%). EI-MS m/z 308(M+H) *

Example 39

Synthesis of N-(2-hydroxy-4-nitrophenyl) N*-(2.4-dibromo phenyl) urea

The urca was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g, 39%). EI-MS m/z 430(M-+H) *

Example 40

Synthesis of N-(2-hydroxynapthyl) N’-(2-bromo phenyl) urea

The urea was prepared from 1-amino 2-hydroxy naphthalene(195 mg, 1 mmol) and 2-bromo phenyl isocyanate(1 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) * . N Example 41

E 10 :Synthesis of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methvlenedioxyphenyl)urea a) Preparation of 2,3-methylenedioxyphenylcarboxylic acid

A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10°C with 2.5 M n-butyllithium (15 mL, 35 mmol) in hexane.

When the addition was complete, the mixture was stirred under reflux for one hour. - After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq. NaHCO, and ether. The alkali - layer was separated, washed with ether, then acidified with cold concentrated HC], and . : extracted with chloroform. The combined organic layers were dried over MgSO, filtered and concentrated under reduced pressure (1.1 g, 20 %). EI-MS m/z 167 (M+H)" . ~ b) Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3- oo N ethylenedioxyphenyl)urea : 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, 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 organic extracts were combined, dried over MgSQ,, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : cthyl acetate; 5:1) gave product (200 mg, 42 %). EI-MS m/z 318 (M+H)*

Example 42

Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-methoxy 3-chloro phenyl) urea

The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2- chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48 g, 63%). EI-MS m/z 338(M+H) *

Example 43

Synthesis of N-(2-hydroxy 4-nitro phenyl) N’-(2-methyl phenyl) urea

The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2- methyl phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.38 g, 53%). EI-MS m/z 288(M+H) *

Example 44

Synthesis of N(bis (2-hydroxy 4-nitro phenyl) N’-(dianisdine) diurea

The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and dianidisdine diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-nitro 2- hydroxy aniline was used instead of 1 equiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound( 0.08 g, 6%).ELI-MS m/z 605(M+H) ©

Example 45

Synthesis of 4-methylene bis(N-(2-chloro phenyl) N’-(2-hydroxy 4-nitro phenyl) urea)

The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and 4- methylene bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.10 g, 8%). EI-MS m/z 627(M+H) * : 20 Example 46

Synthesis of N-[2-hydroxy 4-(benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)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) and 2-bromo phenyl isocyanatc(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%). EI-MS m/z 351(M+H) © b) Preparation of N-[4-(benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2- bromophenyl)urea

To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.58 mmol) in DMF (15 mL), EDC (121.9 mg, 0.58 mmol),

HOBT (156.6 mg, 11.6 mmol) were added . The reaction mixture was stirred at room temperature for 16 hours. Then the benzyl amine (123 mg, 11.6 mmol) was added. The reaction mixture was stirred at same temperature for 24 hours. Then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 1:1) gave benzylamino product (500 mg, 65 %). EI-MS m/z 441 (M+H)*

Example 47

Synthesis of N-(2-hydroxy 4-nitro phenyl) N’-(2-phenoxy phenyl) 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 5S after 24 hours the 2-amino S-nitro phenol (1 equiv.) was added. The reaction was i 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) ~

Example 48

Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-hydroxy 4-fluoroaniline 3-fluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(1 g) at 23 °C. . The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afford the title compound (1.4 g, 77%). EI-MS m/z 169(M+H) + ) ) b) Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and .2-bromo phenyl isocyanate by general Method B. It was purified by dilution with i “methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m/z 325 ) 20 (M+H)"

Example 49 } Synthesis of N-( 2-hydroxy 3.4-difluoro phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-hydroxy 3,4-difluoro aniline 2,3 difluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(1 g) at 23 °C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title compound (1.6 g, 97%). EI-MS m/z 146(M+H)" b)Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H)*

Example 50

Synthesis of N-(2-hydroxy 3-napthyl) N'-(2-bromo phenyl) urea

The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g, 2 mmol) and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339, 47%).EI-MS m/z 357(M+H)*

Example 51

Er 2 HEHE ed

Synthesis of N-(2-hydroxy 4-phenyl phenyl) N’-(2-bromo phenyl) urea a) Synthesis of 2-nitro 5-pheny! phenol

A solution of 3-phenyl phenol(2 g, 11 mmol) in acetic acid was treated with concentrated nitric acid drop-wise until all starting material was consumed. The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted once more with methylene chloride.

The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography(ethyl acetate/hexane) to afford desired (1.2 g, 50%).1H NMR (CDCl): § 10.65(s, 1H), 8.18 (d, 1H, J = 10.0

Hz), 7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J=10.0Hz). b)Synthesis of 2-amino 5-phenyl] phenol

A solution of 2-nitro S-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 concentrated in vacuo to afford desired (1.01 g, 98%).EI-MS m/z 186(M+H)" c)Synthesis of N-(2-hydroxy 4-phenyl phenyl) N’-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and 2-bromo phenyl isocyanatc(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)*

Example 52

Synthesis of N-(2-hydroxy 4-methyl phenyl) N-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-methyl aniline(.274g, 2 mmol) and 2- bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39%). EI-MS m/z 319(M-H)

Example 53

Synthesis of N(2-hydroxy 4-nitro phenyl) N’-(2-phenylamino phenyl) urea The urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro phenyl isocyanate(example 9a, 0.419g, 1.5 equiv.) with 2-anilino aniline(0.184 g, 1 equiv.) in

THF overnight at 40 °C. The desired product precipitated out of the reaction mixturc(30 mg, 8%). EI-MS m/z 365(M+H)*

Example 54

Synthesis of N-(2-hydroxy 3-carboxylate phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the

DMEF solution with methylene chloride and precipitation with hexane(.287 g, 41%). EI-

MS m/z 351(M+H)*

Example 55

Synthesis of N(2-sulfhydryl 4-bromo phenyl) N*-(2-bromo phenyl) ureaa) Synthesis of 2-amino 6-bromo thiazole 4-Bromo aniline(4.3 g, 25 mmol, 1 equiv.) and ammonium thiocyanate(5.7 g, 3equiv.) was dissolved in acetic acid and treated with bromine(4 g, lequiv.) at room : 5S + temperature. After complete disappearance of starting material the reaction mixture : was poured into water and the solid was collected. The solid was used in the next step without any purification(3.6 g, 46%). EI-MS m/z 229(M+H)* ) b) Synthesis of bis (3-bromo 6-amino phenyl) disulfide - The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in } 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 [,. 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%). El- : MS m/z 405(M+H)* - 3 : 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 : } : was treated with 2-bromo phenyl isocyanate(1 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 HCI and the resulting solid was filtered(52 mg, 13%). EI-MS m/z 399 (M-H)

Example 56

Synthesis of N-(2-hydroxy 4-nitro phenyl) N*-(2-iodo phenyl) urea

The urea was synthesized by the treatment of 2-iodo benzoic acid(5 g, 20 mmol) with diphenyl phosphoryl azide(1 equiv.) and triethyl amine (1 equiv.) in DMF at 80 °C after gas evolution ceased the 5-nitro 2-amino phenol (3 g, 1 equiv.) was added. The reaction was heated overnight at 80°C. The reaction mixture was purified by filtering through a plug of silica with methylene chloride. The desired product was then precipitated out with hexane. Filtering afforded the desired compound(1.08 g, : 13%). EI-MS m/z 398(M-H)

Example 57

Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea

The thiourea was synthesized by treatment of the 2-tert-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

» TT 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 chromatography (ethyl actate/hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2- bromo phenyl) thiourea(52 mg, 4%) . EI-MS m/z 369(M+H)*

Example 58

Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl) urea a) Synthesis of 3-(phenylsulfamido) benzonitrile

The of 3-(phenylsulfamido) benzonitrile was synthesized from the 3-cyano aniline (23.9 g, .2 mol) by Method C. It was purified by recrystalization from

EtOH(15.8 g, 31%).JH NMR (CDCl3): 8 7.95(s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.45 (m, 2H), 7.35 (m, 4H). b) Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile

The 3-(phenylsulfamido) benzonitrile(10 g, 39 mmol) was dissolved in acetic anhydride and trcated 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 se 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) © c) Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile

The 3-(phenylsulfamido) 4-nitro benzonitrile(1.5 g, 4.9 mmol) was treated with tin chloride dihydrate in EtOH at 80 °C for 12h. It was then concentrated and flushed through a plug of silica gel with 5% methanol/methylene chloride. The 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) * d) Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl) urea

The urea was synthesized from 2-(phenylsulfamido) 4-amino benzonitrile(77 mg, 0.28 mmol) and 2-bromo phenyl isocyanate by general Method C. It was purified by column chromatography(ethyl acetate/hexane) to afford the title compound (30 mg, 22%). EI-MS m/z 469(M-H)

Example 59

Synthesis of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl) urea a) Synthesis of 2-( phenyl sulfamido) aniline

The sulfonamide was synthesized from phenyl sulfonyl chloride(0.01 mmol) and o-phenylene diaminc(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)* b) Synthesis of N-(2-(pheny] sulfamido) phenyl) N’-(2-bromo phenyl) urea and 2-bromo phenyl isocyanate by general Method B. The urea was synthesized 2-(phenyl sulfamido) aniline(1 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)*

Example 60

Synthesis of N-(2-( styry! sulfamido) phenyl) N-(2-bromo phenyl) urea a) Synthesis of 2-( styryl sulfamido) aniline

The sulfonamide was synthesized from styryl sulfonyl chloride(0.01 mol) and o- phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(1.2 g, 60%)EI-MS m/z 199(M+H)*. b) Synthesis of N-(2-(styryl sulfamido) phenyl) N-(2-bromo phenyl) urea

The urca was synthesized from 2-(styryl sulfamido) aniline(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(0.309 g, 65%). EI-MS m/z 472(M+H)*

Example 61 :

Synthesis of 2-[(3.4 dimethoxyphenyl)sulfonyl amino] phenyl) N*-(2-bromo phenyl) urca a) Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline )

The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl chloride(0.01 mol) and o-phenylene diamine by general Method C. It was purified by recrystallization from EtOH(0.65 g, 21%). EI-MS m/z 309(M+H)t. b) Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonylamino} phenyl) N'-(2-bromo phenyl) urea :

The urea was synthesized from 2-[(3.4-dimethoxyphenyl)sulfonyl amino [phenyl aniline(1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.062 g, 12%).EI-MS m/z S04(M-H)

Example 62

Synthesis of N-(2-[(4-acetamidophenyl)sulfonylamino] phenyl) N'-(2-bromo phenyl) 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 £,40%)EI-MS m/z 304(M-H) "

b) Synthesis of N-(2-[(4-acetamidophenylsulfonyl)amino] phenyl) N-(2-bromo phenyl) urea

The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline(1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 24%). EI-MS m/z 501(M-H) i

Example 63

Synthesis of N-(2-(2-thiophene sulfamido phenyl) N-(2-bromo phenyl) urea a) Synthesis of 2-(2-thiophene sulfamido) aniline

The sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.77 g, 30%). EI-MS m/z 255 (M+H)* b) Synthesis of N-(2-(2-thiophene sulfonyl amino phenyl) N-(2-bromo phenyl) urea

The urea was synthesized from 2-( 2-thiophene sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(1 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) i

Example 64

Synthesis of N-(2-(3-tolyl sulfonyl amino phenyl) N*-(2-bromo phenyl) urea a) Synthesis of 2-( 3-tolyl sulfonyl amino) aniline

The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. Tt was purified by recrystallization from EtOH(0.73g, 28%).EI-MS m/z 263 M+H)* b) Synthesis of N-(2-((3-tolyl sulfonyl amino) phenyl) N*-(2-bromo phenyl) urea

The urea was synthesized from 2-(3-tolyl sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purificd by dilution with methylene chloride and precipitation with hexane. It was recrysallized two times with EtOH(25 mg, 5%). EI-MS m/z 458(M-H)

Example 65

Synthesis of N-(2-(8-quinolinyl sulfonyl amino) phenyl) N-(2-bromo phenyl) urea a) Synthesis of 2-(8-quinoliny! sulfonyl amino) aniline

The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.82 g, 27%).EI-MS m/z 300 (M+H). b) Synthesis of N-(2-( (8-quinolinyl) sulfonyl amino) phenyl) N-(2-bromo phenyl) urea

The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. Tt 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).

Example 66

Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N*-(2-bromo phenyl) urea a) Synthesis of 2-(benzyl sulfonyl amino) aniline

The sulfonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+. - b) Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N-(2-bromo phenyl) urea

The urea was synthesized from 2-( benzyl sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(1mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.11 g, 23%). EI-MS m/z 460 (M+H)+

Example 67

Synthesis of N-(2-hydroxy-4-azidophenyl)-N"(2-methoxyphenylurea ] a) Synthesis of N-(2-hydroxy-4-aminophenyl)-N’-(2-methoxyphenyl)urea

To a solution of N-(2-hydroxy-4-nitro phenyl)-N'-(2-methoxyphenyl)urea(1.0 g, : example 15) in methanol, palladium (on activated carbon, 10%) (100 mg) was added.

Then the reaction mixture was hydrogenated under a hydrogen balloon for 18 hours.

The solid was filtered off by celite and washed three times by methanol. The filtrate was concentrated under reduced pressure to give amine compound (0.8 g, 89%). EI-MS m/z 274 (M+H)* b) Synthesis of N-(2-hydroxy-4-azidophenyl)-N*-(2-methoxyphenyljurea

The N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg, 1.17 mmol) was added to HCI/H,O (1.17 m1/2.34 mL), cooled to 0°C. Sodium nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate.

The organic extracts were combined, dried over MgSO, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)*

Example 68

Preparation of N-[2-hydroxy-5-cyanophenyl]-N*-[2-bromophenyl] urea a) Preparation of 2-amino-4-cyanophenol

To a solution of 2-nitro-4-cyanophenol(10g, 61 mmol) in methanol(250mL) was added 10% Pd/C (1g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOl/ CH,Cl,) gave the desired product(8.0 g, 97%). 'H NMR (CD;0D): 8 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H). 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- 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(1/20) and filtering. (540mg,81%). 'H NMR (CD,0D): § 8.10 (d, 1H), 7.87 (d, 1H), 7.43 (d, 1H), 7.20 (1, 1H), 7.09 (d, 1H), 6.86 (1, 1H), 6.77 (d, 1H).

Example 69

Preparation of N-[2-hydroxy-3-fluorophenyl]-N*[2-bromophenyl} urea a) Preparation of 2-amino-3-fluorophenol

To a solution of 2-nitro-3-fluorophenol(lg, 6.4mmol) in methanol(250mlL) was added 10% Pd/C (1g). 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 (S5%MeOH/ CH,Cl,) gave the desired product(650 mg, 80.2 %). "HNMR (CD;0D): 3 6.41-6.17 (m, 3H). b) Preparation of N-[2-hydroxy-3-fluorophenyl}-N-[2-bromophenyl] urca

N-[2-Hydroxy-3-fluorophenyl]-N’-[2-bromo phenyl] urea was prepared from 2- amino-3-fluorophenol (254mg, 2.00 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chioride/ hexane(1/20) and filtering. (500 mg, 77%). "HNMR (CD;0D): 6 8.05 (d, 1H), 7.50 (d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 (m, 2H).

Example 70

Preparation of N-2-[1-hydroxyfluorene]-N’-[2-bromophenyl] urea a) Preparation of 2-amino-1-hydroxyfluorene

To a solution of 1-hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in methanol(250mL) was added 10% Pd/C (1g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH,Cl,) gave the desired product(171 mg, 81.2 %). 'H NMR (CD;0D): § 7.60 (d, 1H), 7.47 (4, 1H), 7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H). b) Preparation of N-2-[1-hydroxyfluorene}-N*[2-bromophenyl] urea

N-2-[1-hydroxyfluorene]-N™-[2-bromo phenyl] urea was prepared from 2- amino-1- hydroxyfluorene (170mg, 0.86 mmol) according to the procedure in General

Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). 'H NMR (CD4Cl): 8 8.04 (d, 1H), 7.66 (d, 1H), 7.49 (t, 2H), 7.35-7.20 (m, 4H), 7.09 (d, 1H), 6.90 (t, 1H).

Example 71

Preparation of N-3-[2-hydroxy-9,10-anthraquinonyl]-N*-[2-bromophenyl] 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 chloride/ hexane(1/20) and filtering. (610mg, 70%). 'H NMR (CD;0D): 68.93 (s,1H), 8.12 (m, 2H), 8.02 (d, 1H), 7.77 (m, 2H), 7.61 (d, 1H), 7.52 (s, 1H), 7.38 (1, 1H), 7.05 (t, 1H).

Example 72

Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N"-[2-bromophenyl] ureaa)

Preparation of 2-amino-6-fluoro-4-bromophenol .

A mixture of 4-bromo-2-fluoro 6-nitrophenol(1g, 4.2mmol) and tin (II) chloride (4.78 g, 21.2mmol) in cthanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid

NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(710 mg, 82 %). 'H NMR (CD;0D): 8 6.51-6.40 (m, 2H). b) Preparation of N-[2-hydroxy-3-fluoro-5-bromopheny}]-N*-[2-bromophenyl] urea

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(1/20) and filtering. (500 mg, 77%). 'H NMR (CD;0D): 8 7.98 (s, 1H), 7.91 d, 1H), 7.60 (d, 1H), 7.33 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H).

Example 73

Preparation of N-[2-hydroxy-3-chlorophenyl]-N*[2-bromophenyl] urea a) Preparation of 2-amino-3-chlorophenol

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, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(143 mg, 69 %). 'H NMR (CD,0D): 8 6.75 (t,1H), 6.70 (d, 1H), 6.65 (d, 1H). b) Preparation of N-{2-hydroxy-3-chlorophenyl}-N™[2-bromophenyl] urea

N-[2-hydroxy-3-chlorophenyl]-N>-[2-bromophenyl] urea was prepared from 2- amino-3-chlorophenol (143mg, 1.00 mmol) according to the procedure in General

Method B. The product was purified by chromatography of the resulting solid on silica gel B0%EtOAc/ Hexane) to give the desired product(195mg, 57%). 'H NMR (CD;OD): 8 7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.20 (t, 1H), 6.90 (m, 2H), 6.70 (t, 1H).

Example 74

Preparation of N-[2-hydroxy-3-trifluoromcthylphenyl]-N*-[2-bromophenyl] ureaa)

Preparation of 2-nitro-6-trifluoromethylphenol 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 MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.84 g, 47 %). 'H NMR (CD;COCD;): § 8.35 (d,1H), 7.95 (d, 1H), 7.13 (t, 1H). b) Preparation of 2-amino-6- trifluoromethylphenol

A mixture of 6-trifluoromethyl-2-nitrophenol(1.84 g, 8.67mmol) and tin (II) 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 MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.35 g, 88 %). 'H NMR (CD;0D): § 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H). c) Preparation of N-[2-hydroxy-3- trifluoromethylphenyl]-N’-[2-bromophenyl] urea

N-[2-hydroxy-3-trifluoromethylphenyl]-N-[2-bromophenyl] urea was prepared from 2-amino-6-trifluoromethylphenol (280mg, 1.60 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc(1/20) and filtering. (390mg, 65%). '"H NMR (CD;0D): 6 7.99 (d, 1H), 7.60 (d, 1H), 7.58 (d, 1H), 7.34 (t, 1H), 7.30 (d, 1H), 7.00 (t, 1H), 6.96 (d, 1H).

Example 75

Preparation of N-[3.4 diphenyl-2-hydroxyphenyl]-N*-[2-bromophenyl] urea

N-[3,4 diphenyl-2-hydroxyphenyl]-N-[2-bromophenyl] urea was prepared from 2-amino-35,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (61mg, 69%). 'H NMR (CD,0D): § 7.97 (d, 1H), 7.66 (, : 1H), 7.58 (d, 1H), 7.31 (t, 1H), 7.25-7.00 (m, ! 1H), 6.91 (d, 1H).

Example 76

Preparation of N-[2-hydroxy-3-glycincmethylestercarbonylphenyl]-N*[2-bromophenyl] urea

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/ hexane(1/20) and filtering (65mg, 69%). 'H NMR (CD;OD): 6 8.14 (d, 1H), 7.96 (d, : - 1H), 7.49 (d, 1H), 7.24 (t, 2H), 6.89 (dd, 1H), 6.81 (t, 1H), 4.10 (s,2H), 3.74 (s,3H). : Example 77

Preparation of N-[2-hydroxy-3-glycinecarbonylphenyl]-N*-[2-bromophenyl] urea N- [2-Hydroxy-3-glycinecarbonylphenyl]-N™-[2-bromophenyl] urea was prepared from N- [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 CH,Cl,/ MeOH/ AcOH) to give the desired product(195mg, 57%). 'H NMR (CD;0D): § 8.14 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.34 (1, 1H), 7.04 (t, 1H), 6.82 (t, 1H), 3.96 (2H).

Example 78

Preparation of N-[2-hydroxy-3.5-dichlorophenyl]-N’-[2-bromophenyl] urea : a) Preparation of 2-amino-4,6-dichlorophenol

A mixture of 4,6-dichloro-2-nitrophenol(1l g, 4.8mmol) and tin (II) chloride (3.2 g. 14.4mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, : before being extracted with ethyl acetate. The organic phase was washed with brine,

dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH,Cl,) gave the desired product(685 mg, 80 %). 'H NMR (CD,0D): & 6.75 (s,1H), 6.61 (s, 1H). b) Preparation of N-[2-hydroxy-3,5-dichlorophenyli}-N"-[2-bromophenyl] urea

N-[2-Hydroxy-3,5-dichlorophenyl]-N*-[2-bromophenyl] urea was prepared from 2-amino-4,6-dichlorophenol (143mg, 1.00 mmol) according to the procedure in

General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (660mg, 88%). 'H NMR (CD;0D): 6 7.96 (s, 1H), 7.89 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.00 (t, 1H), 6.95 (dd, 1H).

Example 79

Preparation of N-[2-hydroxy-3-nitrophenyl]-N*-[2-bromophenyl] 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(1/20) and filtering. (2.4¢g, 84%). 'H NMR (CD;OD): § 8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.01 (m, 2H).

Example 80

Preparation of N-[2-hydroxy-4-naphthalenesulfonic acid]-N-[2-bromophcnyl] urea

N-[2-hydroxy-4-naphthalenesulfonic acid]-N*-[2-bromophenyl] urea was : 20 prepared from 1-amino-2-hydroxy-4-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the procedure in General Method B and the addition of mL of triethylamine. The product was purified by precipitation from methylene chloride/ ) hexane(1/20) and filtering. (690 mg, 79%). 'H NMR (CD,OD): & 8.14 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 (t, 1H).

Example 81

Preparation of N-[2-hydroxy-5-naphthalenesulfonic acid]-N-[2-bromophenyl] urea

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 1mL of triethylamine. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (715 mg, 82%). 'H NMR (CD;OD): 6 8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 (s, 1H), 7.04 (m, 2H).

Example 82

Preparation of N-[2-hydroxy-3.4-dichlorophenyl]-N*-[2-bromophenyl] urea a) Preparation of 2-nitro-5,6 dichlorophenol 2,3-dichlorophenol (3.26g. 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours,

the reaction mixture was diluted with methylene chloride and extracted with water.

The organic layer was dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.8 g, 44 %). 'H NMR (CD3COCD;): 8 8.04 (d,1H), 7.15 (d, 1H). b) Preparation of 2-amino-5,6 dichlorophenol

A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7mmol) and tin (I) chloride (5.8 g, 26.1mmol) 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 cthyl acetate. The organic phase was washed with brine, dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.4 mg, 90 %). 'H NMR (CD;0D): § 6.71 (d, 1H), 6.45 (d, 1H). c) Preparation of N-[2-hydroxy-3,4-dichlorophenyl)-N-{2-bromophenyl] urea

N-[2-Hydroxy-3,4-dichlorophenyl}-N™[2-bromophenyl} urea was prepared from 2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in

General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (670mg, 89%). 'H NMR (CD;0D): § 7.90 (d, -1H), 7.85 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 6.99 (t, 1H), 6.96 (d, (1H).

Example 83 : - Preparation of N-[2-hydroxy-3-cyanophenyl]-N’-[2-bromophenyl] urea a) Preparation of 2-nitro-6-cyanophenol 2-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mlL) followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.4 g, 42 %). 'HNMR (CD3COCD;): 88.47 (d,1H), 8.15 (d, 1H), 7.30 (t, LH). b) Preparation of 2-amino-6-cyanophenol

A mixture of 6-cyano-2-nitrophenol(600 mg, 1.0mmol) and tin (II) chloride (3.2 g, 14.4mmol) in acetic acid(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetatc. The organic phase was washed with brine, dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(365 mg, 75 %). 'H NMR (CD;OD): 86.92 (d, 1H), 6.85-6.69 (m,2H).

c) Preparation of N-[2-hydroxy-3-cyanophenyl}-N’-[2-bromophenyl] urea

N-[2-Hydroxy-3-cyanophenyl]-N™-[2-bromophenyl] urea was prepared from 2- amino-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (260mg, 78%). 'H NMR (CD;0D): § 7.98 (d, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 6.98 (t, 1H), 6.94 (1, (1H).

Example 84

Preparation of N-[2-hydroxy-4-cyanophenyl]-N’-[2-bromophenyl] urea a) Preparation of 2-nitro-5-cyanophenol 3-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid (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 MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(910 mg, 28 %). "HNMR (CD3COCD;): § 8.30 (d,1H), 7.67 (s,1H), 7.49 (d, 1H). b) Preparation of 2-amino-5-cyanophenol - A mixture of 5-cyano-2-nitrophenol(250 mg, 1.5mmol) and tin (I) 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, h dried over MgSO, and filtered. The solvent was evaporated and chromatography of the - 25 resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(175 mg, 86 %). '"H NMR (CD;0D): § 7.00 (d, 1H), 6.88 (s,1H), 6.69 (d, 1H). c) Preparation of N-{2-hydroxy-4-cyanophenyl]-N’-[2-bromophenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N-[2-bromophenyl] urea was prepared from 2- amino-5-cyanophenol (170mg, 1.27 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (310mg, 74%). 'H NMR (CD;0D): 8 8.25 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H), 7.33 (1, 1H), 7.17 (d, 1H), 7.07 (s, 1H), 7.01 (1, (1H).

Example 85

Preparation of N-[2-hydroxy-4-cyanophenyl]-N*-[4-methoxyphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N*-[4-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (110mg,86%). 'H NMR (CD,0D): § 8.23 (d, 1H), 7.61- 7.51 (m, 2H), 7.32 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H).

Example 86

Preparation of N-[2-hydroxy-4-cyanophenyl]-N-[2-phenylphenyl] urea ~~ N-[2-

Hydroxy-4-cyanophenyl]-N-[2-phenylphenyl) urea was prepared from 2-amino-5- cyanophenol (170 mg, 1.27 mmol) according to the procedure in General Method B.

The product was purificd by precipitation from methylene chloride/ hexane(1/20) and filtering. (150mg, 85%). 'H NMR (CD-OD): § 8.20 (d, 1H), 7.73 (d, 1H), 7.51-7.20 (m, 8H), 7.13 (d, IH), 7.01 (s, (1H).

Example 87

Preparation of N-[2-hydroxy-4-cyanophenyl]-N’-[2-methylphenyl] urea

N-[2-Hydroxy-4-cyanophenyl}-N-[2-methylphenyl] urea was prepared from 2- amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (90mg, 75%). 'H NMR (CD;0D): 6 8.25 (d, 1H), 7.59 (d, 1H), 7.26-7.00 (m, SH), 2.30 (s, 3H).

Example 88 . Preparation of N-[2-hydroxy-4-cyanophenyl]-N"-[2-trifluoromethylphenyl] 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 y -. Method B. The product was purified by precipitation from methylene chloride/ . 20 . hexane(1/20) and filtering. (110mg, 76%). 'H NMR (CD,0D): 6 8.25 (d, 1H), 7.81 (d, : : - 1H), 7.68 (d, 1H), 7.61 (1, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, (1H). - Example 89

Preparation of N-[2-hydroxy-4-cyanophenyl]-N"[3-trifluoromethylphenyl] urea N- [2-hydroxy-4-cyanophenyl]-N*[3-trifluoromethylphenyl] urea was prepared from 2- amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (114mg, 79%). 'H NMR (CD;,0D): 6 8.30 (d, 1H), 7.92 (s, 1H), 7.60 (d, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H).

Example 90

Preparation of N-[2-hydroxy-4-cyanophenyl]-N-[4-trifluoromethylphenyl] urea N- [2-Hydroxy-4-cyanophenyl]-N’-{4-trifluoromethylphenyl] urea was prepared from 2- amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (108mg, 75%). 'H NMR (CD;0D): 68.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H), 7.20 (dd, 1H), 7.07 (s, 1H).

Example 91

Preparation of N-[2-hydroxy-3-n-propylpheny!]-N*|2-bromophenyl| urca a) Preparation of 2-nitro-6-n-propylphenol

2-n-propylphenol (5.00g, 36.8mmol) was dissolved in methylene ~ chloride(40mL) followed by the addition of sodium nitrate (3.43g, 40.5mmol). The addition of sulfuric acid (45mlL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.

The organic layer was dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(3.2 mg, 48 %). 'H NMR (CD3COCD-): § 7.99 (d,1H), 7.46 dd, 1H), 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H). b) Preparation of 2-amino-6-n-propylphenol

To a solution of 2-nitro-6-n-propylphenol(2g, 11.0mmol) in methanol(100mL) 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 the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH,Cl,) gave the desired product(1.50 g, 80.2 %). 'H NMR (CD,;0D): 8 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H). c) Preparation of N-[2-hydroxy-3-n-propylphenyl}-N’-[2-bromophenyl] urea : 20 N-[2-Hydroxy-3-n-propy! phenyl]-N*-[2-bromo phenyl] urea was prepared from 2- amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (640mg, 92%). 'H NMR (CD;0D): & 8.00 (d, 1H), 7.58 (d, 1H), 7.32 (1, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, 1H), 6.78 (d, 1H).

Example 92

Preparation of N-[2-hydroxv-4-ethylphenyl]-N-[2-bromophenyl] urea a) Preparation of 2-nitro-5-ethylphenol 3-ethylphenol (5.00g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric acid (50mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO, and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl,) gave the desired product(1.7 g, 25 %). 'H NMR (CD3COCDs): 4 8.02 (d,1H), 6.99 (s,1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H). b) Preparation of 2-amino-5-ethylphenol

To a solution of 2-nitro-5-ethylphenol(lg, 6.4mmol) in methanol(250mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH,Cl,) gave the desired product(750 mg, 91 %). "HNMR (CD;0D): 8 6.41-6.17 (m, 3H). c) Preparation of N-[2-hydroxy-4-ethylphenyl]-N"-[2-bromophenyl] urea

N-[2-Hydroxy-4-ethylphenyl]-N"-[2-bromo phenyl] urea was prepared from 2- amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General

Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (520 mg, 77%). 'H NMR (CD;0D): 8 7.96 (d, 1H), 7.62 - = (s, IH), 7.56 (d, 1H), 7.30 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H).

Example 93 : Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N-[2-bromophenyl] urea a) Preparation of 2-nitro-6-phenylaminocarbonylphenol - 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. : - : The organic layer was dried over MgSO, and filtered. The solvent was evaporated and - chromatography of the resulting solid on silica gel (4%McOH/ CH,Cl,) gave the desired product(2.50 g, 42 %). 'H NMR (CD3COCD): § 8.15 (d,1H), 8.09 (d,1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H). b) Preparation of 2-amino-6-phenylaminocarbonylphenol

To a solution of 2-nitro-6-phenylaminocarbonylphenol (1g, 4.0 mmol) in methanol (250mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the cclite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH,Cl,) gave the desired product(800 mg, 91 %). '"H NMR (CD;0D): 6 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (1, 1H). : c¢) Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N*-[2- bromophenyl] urea

N-[2-hydroxy 3-Phenylaminocarbony! phenyl]-N’-[2-bromo phenyl] urca 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(1/20) and filtering. (800mg,94%). 'H NMR (CD,0D): 'H

Claims

What is claimed is: PCT/US00/16499

1. Use of a compound in the manufacture of a medicament for treating a : chemokine mediated disease state selected from the group consisting of malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, undesired hematopoietic stem cells release and diseases caused by.respiratory viruses, herpesviruses, and hepatitis virusss, including but not limited to' Hepatitis B and Hepatitis C virus wherein the chemokine binds to an I -8 &¢ or B.receptor in a mammal, the compound beinga compound of the formnla:: R n(Y) I J. R,)m N N H H ® wherein X is oxygen or sulfur; R is any functional moiety having an ionizable hydrogen and a pKa of 10 or ; less; : R1 is independently selected from hydrogen; halogen; nitro; cyano; : 15 halosubstimted C1-10 alkyl; C1-10 alkyl; C2.10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)R4; hydroxy; hydroxy Cj-4alkyl; aryl; aryl C14 alkyl; aryloxy; aryl C14 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C1- 4alkyl; heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4Rs; C2-10 alkenyl C(O)NR4R5; C(O)NR4R 5; C(O)NR4Rjg; S(0)3H; S(0)3Rg; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR] |; C(O)R11; C(O)OR 12; OC(O) R11; NR4C(O)R11; or two R1 moieties together may form O-(CH?2)sO- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R4 and R3 are independently hydrogen, optionally substituted C14 alkyl, optionally substituted aryl, optionally substituted aryl C}-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C14alkyl, heterocyclic, heterocyclic C14 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/NI/S; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstitnted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C3-10 alkoxy; halosubstituted Cj-i0 alkoxy; azide; S(O)R4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C14 alkyl; aryloxy; arylC].4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC14 alkyloxy; heterocyclic, heterocyclicC}-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2.1¢ alkenyl; NR4R3; C2-10 alkenyl C(O)NR4R35; C(O)NR4R 5; -96 - AMENDED 8Hz

C{OINR4R 16; S(O)3H; S(O)3Rg: C1-10 alkyl C(O)R 11; C2-10 alkeny! COR 11: C2-10 alkenyt C(O)OR] 1; C(O)R} 1; C{OYOR 2; OC(0) R11; NR4C(O)R 11; or two ¥ moieties together may form O-(CH2)sO- or a 3 to 6 membered unsaturated ring; n is an integer having a value of 1to 3; 3 ID is an integer having a value of 1 to 3; Rg is hydrogen or C1-4 alkyl; R10 is C1-10 alkyl C(O)2RS; R1] is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj -4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1- galkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic Cj- qalkyl; R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.

2. Use according to Claim 1 wherein the ionizable hydrogen has a pKa of 3 to 10.

3. Use: according to Claim 2 wherein R is hydroxy, carboxylic acid, thiol, -SR2 -OR2, -NH-C(O)Ra, -C(O)NRgR7, -NHS(O)2Rb, -S(O)2NHRc, NHC(X)NHRp, or tetrazolyl; 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; Re and R7 are independently hydrogen or a C}-4 alkyl group, or Rg 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; Ra is an alkyl, aryl, aryl C1 4alkyl, heteroaryl, heteroaryl Cj4alkyl, heterocyclic, or a heterocyclic C}—4alkyl moiety, all of which may be optionally substituted; Rp is a NRgR7, alkyl, aryl, arylC-4alkyl, arylC2-4alkenyl, heteroaryl, hsteroarylC}.4alkyl, heteroarylCo4 alkenyl, heterocyclic, heterocyclic Cj4alkyl, heterocyclic C7.4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C34 alkyl; C14 alkyl; C14 alkoxy; NRgC(O)Rz; C(OINRgR7, S(0)3H, or C(O)OC 4 alkyl; Rg is hydrogen or a C14 alkyl; Re is alkyl, aryl, arylC1-4alkyl, arylC24alkenyl, heteroaryl, heteroarylC]-4alkyl, heteroarylC-4alkenyl, heterocyclic, heterocyclic C14alkyl ora heterocyclic Co-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C14 alkyl, C14 alkyl, C3. 4 alkoxy, NR9C(O)Ra, C(O)NRgR7, S(0)3H, or C(0)OC1 4 alkyl. -97- AMENDED 8857

4. Use according to Claim 3 wherein the R2 is optonally substimted one to three times by halogen, nitro, halosubstituted C1-10 alkyl, C1-10 alkyl, C1-10 alkoxy, hydroxy, SE, -C{O)NR¢R7, -NH-C(O)Ra, -NHS(O)Rb. S(O)NRgR7, C(O)ORg, or a tetrazolyl ring.

5. Use according to Ciaim 3 wherein R is OH, -NHS(O)2Rp or C(O)YOH.

6. Use according to Claim 1 wherein Rj is halogen, cyano, nitro, CF3, C(O)NR4Rs5, alkenyl C(O)NR4RS, C(O) R4R 10, alkenyl C(O)OR 12, heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(O)NR4RS5.

7. Use according to Claim 1 wherein Y is halogen, C14 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4RS5, thioC}-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C14alkyl, hydroxy alkyl.

8. Use according to Claim 1 wherein R is OH, SH, or NHS(O)sRb and R} is substituted in the 3-position, the 4- position or di substituted in the 3,4- position by an electron withdrawing moiety.

9. The compound as defined in Claims 1 or 8 wherein Y is mono-substituted in the 2position or 3> position, or is disubstituted in the 2 or 3™ position of a monocyclic ring.

10. The compound as defined in Claims 1, 8 or 9 wherein n and m are each equal to 1 or more.

11. Use according to Claim 1 wherein R is a carboxylic acid, and R} is hydrogen, or Rj is substituted in the 4-position.

12. Use according to Claim 1 wherein the compound, or a pharmaceutically acceptable salt is selected from the group consisting of: N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxyphenyljurea; N-(2-Hydroxy-4-nitrophenyl)-N’-(2-bromophenyljurea; N-(2-Hydroxy-4-nitrophenyl)-N"-(2-phenylphenylurez; N-(2-Hydroxy-4-nitrophenyl)-N"-(2-methylthiophenyljurez; N-(2-Hydroxy-4-nitrophenyl)-N"-(2,3-dichlorophenyljure2; N-(2-Hydroxy 4-nitro phenyl) N*-(2-chloro phenyl) urea; N-(2-Hydroxy-4-nitrophenyl)-N*-(2,3-methylenedioxyphenyljurez; N~(2-Hydroxy-4-nitrophenyl)-N(2-methoxy-3-chlorophenyljurea; N-{2-hydroxy 4-nitro phenyl) N’-(2-phenyloxy phenyl) urez; N-(3-Chloro-2-hydroxyphenyl)-N-(bromophenylurea; N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N *(2-bromophenyl)urez; N-(3-Nitro-2-hydroxyphenyl)}-N ’-(2-bromophenyljurez; N-(2-Hydroxy-4-cyanophenyl)-N-(2-bromophenyljurea; N-(2-Hydroxy-3 4-dichlorophenyl)-N-(2-bromophenyljurea; -98- AMENDED SHES

WS U076495 BCTISHG 16498 N-(3-Cyanc-2-hydroxyphenyl)-N-{2-bromophznyljursa; N-(2-Hydroxy-4-cyanophenyl)-N-(2-methoxyphenyi)urea; N-( 2-Hydroxy~4-cyanophenyl)-N-(2-phenylpbenyljursa; N-(2-Hydroxy-4-cyanophenyl-N*(2,3-dichlorophenylurea; N-(2-Hydroxy-4-cyanophenyl)-N-(2-methylphenyljurea; N-(2-Hydroxy-3 -cyano-4-methylphenyl}N *(2-bromophenyl)urea; N-(4-Cyano-2-hydroxyphenyl)-N(2-trifluoromethylphenyhurea; N _(3-Trifluoromethyl-2-hydroxyphenyl)}-N"-(2-bromophenyhurea; N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N*-(2-bromophenyljurea; N-(2-hydroxy 4-nitro phenyl) N*~(2-iodo phenyl) urea; N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea; N-(2-phenylsulfonamido)-4-cyanophenyl-N X2-bromo phenyljuresa; (E)-N-[3- [(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl] -N-(2-bromophenyljurez; N-(2-Hydroxy,3 4-dichlorophenyl)-N"-(2-methoxyphenyljurea; N-(2-Hydroxy,3,4-dichlorophenyl)-N-(2-phenyiphenylurea, N-(2-Hydroxy-3 4-dichloropbenyl)-N-(2,3-dichlorophenylurez; N-(2-Hydroxy-5-nitropbenyl)-N*(2,3-dichlorophenyhjurea; and N-(2-Hydroxy-3-cyanophenyl}-N-(2,3 dichlorophenyl)urea; or a pharmaceutically acceptable salt thereof.

13. A compound for use in treating 2 chemokine mediated disease state selected from the group consisting of malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivits, undesired hematopoietic stem cells release and diseases caused by respiratory viruses, herpesviruses, and hepatitis viruses, including but not limited to Hepatitis B and Hepatitis C virus wherein the chemokine binds to an IL-8 o.or B receptor in a mammal, the compound being a cornpound of the formula: R, n(Y) PS Jig Rm N N i ® wherein X is oxygen or sulfur; R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; R1] is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-1¢ alkyl; C1-10 alkyl; C210 alkenyl; C}-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)R4; hydroxy; hydroxy C1 -4alkyl; aryl; aryl C1-4 alkyl; aryloxy; aryl C34 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Cj- 4alkyl; heteroaryl C4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl;

-99. SENDER heterocyclicC-10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R35; C(O)NR4RS; C(O)NR4R 0; S(0)3H; S(0)3R8; C1-10 alkyl C(O)R1}; C2-10 alkenyl C(O)R]1; C2-10 alkenyl C(O)OR] 1; C(O)R11; C(O)OR 12; OC(O) R11; NR4C(O)R11; or two R} moieties together may form O-(CEH2)sO- or a 5 to 6 membered unsaturated ring; tis 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R4 and Rj are independently hydrogen, optionally substituted C14 alkyl, optionally substituted aryl, optionally substituted aryl C}-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-qalkyl, heterocyclic, heterocyclic Ci-4 alkyl, or R4 and R35 together with the nitrogen to which they are attached forma 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstimted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O}R4; hydroxy; hydroxyC|-4alkyl; aryl; aryl C14 alkyl; aryloxy; arylC]-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC)4 alkyloxy; heterocyclic, heterocyclicCj-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-19 alkenyl; heterocyclicC2-10 alkenyl; NR4R 5; C2-10 alkenyl C(O)NR4R35; C(O)NR4R 5; C(OWR4R 10; S(0)3H; S(O)3R§: C1-10 alkyl C(O)R 11; C2-10 alkenyl C(O)R1]; C2-10 alkenyl C(O)OR] 1; C(O)R11; C(O)OR 12; OC(0) R11; NRAC(O)R 1}; or two ¥ moieties together may form C-(CH2)sO- or 2 5 to 6 membered unsaturaied ring; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; Rg is hydrogen or C14 alkyl; R10 is C1-10 alkyl C(O)2Rs; : Rj is hydrogen, C}-4 alkyl, optionally substituted aryl, optionally substituted : aryl C]-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1. alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic Cj- : galkyl; R12 is hydrogen, Cj.10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.

14. The compound according to Claim 1 wherein the ionizable hydrogen has a pKa of 3 to 10.

15. The compound according to Claim 2 wherein R is hydroxy, carboxylic acid, thiol, -SR7 -OR2, -NH-C(O)Ra, -C(O)NRGR7, -NHS(O)2Rb, -S(O)2NHRc, NHCX)NHRb, or tetrazolyl; wherein R» is a substituted aryl, heteroaryl, or heterocyclic moiety which nng has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less; Rg and R7 are independently hydrogen or aC14 alkyl group, or Rg and R7 m994 AMENDS §4530 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; Ra is an alkyl, aryl, aryl C]-4alkyl, heteroaryl, heteroaryl C1-4alkyl, } heterocyclic, or a heterocyclic C]-4alkyl moiety, all of which may be optionally substituted; Rp is a NRgR7, alkyl, aryl, arylCj4alkyl, arylC24alkenyl, heteroaryl, heteroary}C}-4alkyl, heteroarylCo-4 alkenyl, heterocyclic, heterocyclic Cj-4alkyl, heterocyclic C)-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C1-4 alkyl; C14 alkyl; C14 alkoxy; NR9C(O)R a; C(O)NRGR7, S(O)3H, or C(O)OC] 4 alkyl: Rg is hydrogen or a C}.4 alkyl; Rg is alkyl, aryl, arylCj alkyl, arylC2.4alkenyl, heteroaryl, heteroarylC]-4alkyl, beteroarylC2-4alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic Co_4alkenyl moiety, 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(O)Ra, C(O)NR6R7, S(0)3H, or C(0)YOC 4 alkyl.

16. The compound according to Claim 3 wherein the R) is opdonally substituted one to three times by halogen, nitro, halosubstitated Cj. alkyl, C1-10 alkyl, C1-10 alkoxy, hydroxy, SH, -C{O)NRgR7, -NH-C(O)Ra, -NHS(O)Rp, S(O)NRgR7, C(O)ORg, or a tetrazolyl ring.

17. The compound according to Ciaim 3 wherein R is OH, -NHS(O)2Rp or C(O)OH.

18. The compound according to Claim 1 wherein R] is halogen, cyano, nitro, CF3, C(O)NR4R 3, alkenyl C(O)NR4R3, C(O) R4R 1q, alkenyl C(O)OR]2, heteroaryl, heteroarylalkyl , heteroaryl! alkenyl, or S(O)NR4Rs.

19. The compound according to Claim 1 wherein Y is halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4RS, thioC1 -4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4alkyl, hydroxy alkyl.

20. The compound according to Claim 1 wherein R is OH, SH, or NHS(O)sRp and R] is substituted in the 3-position, the 4- position or di substituted in the 3,4 position by an electron withdrawing moiety.

21. The compound according to Claim | wherein R is a carboxylic acid, and Rj is hydrogen, or R} is substituted in the 4-position.

22. The compound according to Claim 1 wherein the compound, or a pharmaceutically acceptable salt is selected from the group consisting of: N-(2-Hydroxy-4-nitrophenyl)-N"-(2-methoxyphenylurea; N-(2-Hydroxy-4-nitrophenyl}-N’-(2-bromophenyl)urea; -99B- AVENDEG RET

N-(2-Hydroxy-4-nitrophenyl)-N-(2-phenylphenylurea; N-(2-Hydroxy-4-nitrophenyl)}-N-(2-methylthiophenyljurea; : N-(2-Hydroxy-4-nitrophenyl}-N*(2.3-dichlorophenyljurea; : N-(2-Hydroxy 4-nitro phenyl) N*-(2-chloro phepyl) urea; N-(2-Hydroxy~4-nitrophenyl)-N*-(2,3-msthylenedioxyphenylurez; N-(2-Hydroxy-4-nitrophenyl)-N-(2-methoxy-3-chlorophenyljurea; N-(2-hydroxy 4-nitro phenyl) N*-(2-phenyloxy phenyl) urea; N-(3-Chloro-2-bydroxypheny!)-N’-(bromophenyljurea; N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N*-(2-bromophenyljurea; N-(3-Nitro-2-hydroxyphenyl}-N-(2-bromophenyljurea; : N-(2-Hydroxy-4-cyanophenyi)}-N-(2-bromophenyljurea; N-(2-Hydroxy-3 ,A-dichlorophenyl)-N'-(2-bromophenylurea; N-(3-Cyano-2-bydroxyphenyl)-N-{2-bromophenyijurez; N-(2-Hydroxy-4-cyanophenyl)-N*-(2-methoxyphenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N*-(2-phenyiphenyljursa; N-(2-Hydroxy-4-cyanophenyl-N*(2,3-dichlorophenyl)urea; N-(2-Hydroxy-4-cyanophenyl)-N-(2-methylphenyljurea; - N-(2-Hydroxy-3-cyano-4-methylphenyl}-N(2-bromophenyljurea; N-(4-Cyano-2-hydroxypheny!)}-N-(2-trifluorondethylphenylurea; N-(3-Trifluoromethyl-2-hydroxyphenyl)-N-(2-bromophenylurea; N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N*-(2-bromophenylurea, N-(2-hydroxy 4-nitro phenyl) N*-(2-iodo phenyl) urea; N-(2-hydroxy 4-nitro phenyl) N(2-bromo phenyl) thiourea; N-(2-phenylsulfonamido)-4-cyanophenyl-N2-bromo phenyljurea; (E)-N-[3-[(2-Aminocarbonyl)ethenyl}-2-hydroxyphenyl]-N '(2-bromophenyl)urea; N-(2-Hydroxy,3,4-dichiorophenyl}-N-(2-methoxyphenyl)urea; N-(2-Hydroxy,3,4-dichlorophenyl)-N"-(2-pbenylphenyljurea; N-(2-Hydroxy-3,4-dichlorophenyl)-N*-(2,3-dichlorophenyl)urea; N-(2-Hydroxy-5-nitrophenyl)-N*-(2,3-dichlorophenyl)urea; and N-(2-Hydroxy-3-cyanophenyl)-N*-(2,3 dichlorophenylurea; or a pharmaceutically acceptable salt thereof.

23. Use according to Claim 1, substantially as herein described and exemplified.

24. The compound according to Claims 9 or 10, substantially as herein described and exemplified.

25. The compound according to Claim 13, substantially as herein described and exemplified. -99C- AMANGER Sr