KR20020010709A - IL-8 Receptor Antagonists - Google Patents

Abstract

The invention provides a method of treating a chemokine mediated disease wherein the chemokine is coupled to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, chemokine is IL-8.

Description

IL-8 receptor antagonists {IL-8 Receptor Antagonists}

Interleukin-8 (IL-8) contains many different names such as neutrophil attractant / activator protein-1 (NAP-1), monoclonal inductive neutrophil chemotactic factor (MDNCF), neutrophil activation factor (NAF) Cell lymphocyte chemotactic factors have been used. Interleukin-8 is a chemoattractant substance in the subpopulations of neutrophils, basophils and T-cells. It has been shown that neutrophils themselves, when exposed to many nucleated cells, including macrophages, fibroblasts, endothelial and epithelial cells, and LPS or chemotactic factors (such as FMLP) exposed to TNF, IL-1 alpha, IL- Lt; / RTI > M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al., J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).

GROα, GROβ, GROγ and NAP-2 also belong to the chemokine α family. Like IL-8, these chemokines have also been called by different names. For example, GRO alpha, beta and gamma have been referred to as MGSA alpha, beta and gamma (melanoma growth promoting activity), respectively (Richmond et al J. Cell Physiology 129, 375 (1986) ), J. Immunol., 148, 451 (1992)). All of the alpha-family chemokines with ELR motifs just prior to the CXC motif bind to the IL-8 B receptor.

IL-8, GRO [alpha], GRO [beta], GRO [gamma] and NAP-2 promote a number of actions in vitro. All of them showed chemoattractant properties for neutrophils, and IL-8 and GROα showed T-lymphocyte and basophil chemotactic activity. In addition, IL-8 can induce histamine release from both basophils in both normal and atopic individuals, and can also induce lysosomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase surface expression of Mac-1 (CD11b / CD18) in neutrophils without new protein synthesis. This may be due to increased neutrophil adhesion to vascular endothelial cells. Many of the diseases are characterized by massive neutrophil infiltration. IL-8, GROα, GROβ, GROγ and NAP-2 promote neutrophil accumulation and activation, but these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis (Bargeolini et al. FEBS Lett 307, 97 (1992) ];.... Miller (Miller), such as reference [Crit Rev. Immunol 12, 17 ( 1992)] of .; literature [Annu Rev. Immunol, such as Oppenheim (Oppenheim) 9, 617 Rev. Respir. Dis. 146, 427 (1992); Miller et al., J. Clin. Invest. 87, 463 (1991); Seitz et al. ]; Donnely et al. Lancet 341, 643 (1993)). In addition, ELR chemokines (which contain amino acid ELR motifs immediately before the CXC motif) have also been associated with hemostasis (Streiter et al., Science 258, 1798 (1992)).

In vitro, IL-8, GRO [alpha], GRO [beta], GRO [gamma] and NAP-2 bind to receptors of seven dural G-protein-binding classes to activate, in particular IL-8 receptors, most notably B- Chemotaxis, granule release and respiratory burst (see, for example, Thomas et al. , J. Biol. Chem. 266, 14839 (1991) and Holmes et al. , Science 253, 1278 (1991)). The development of nonpeptide small molecule antagonists for members of this receptor class has precedent. R. Freidinger et al., Progress in Drug Research , Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993). Thus, IL-8 receptors represent promising targets for the development of novel anti-inflammatory agents.

GRO [alpha], GRO [beta], GRO [gamma] and NAP-8 as well as IL-8R [alpha], which binds only to IL-8 with high affinity, and IL- 2 with high affinity to IL-8R? Holmes et al., Supra; Murphy et al., Science 253, 1280 (1991); Lee et al ., J. Biol. Chem. 267, 16283 (1992); LaRosa et al ., J. Biol. Chem. 267, 25402 (1992); And Gayle et al ., J. Biol. Chem. 268, 7283 (1993).

There is still a need for compounds that are capable of binding to the IL-8 [alpha] or [beta] receptor for therapeutic use in this area. Thus, compounds that are inhibitors of IL-8 receptor binding will be favored for diseases associated with increased IL-8 production, which are the cause of chemotaxis of neutrophils and T-cell currents to inflammatory sites.

SUMMARY OF THE INVENTION [

The present invention provides a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, the chemokine is IL-8.

The present invention also relates to a method of inhibiting the binding of IL-8 to its receptor in said mammal, comprising administering an effective amount of a compound of formula I to a mammal in need of such inhibition of the binding of said IL-8 receptor will be.

The compounds of formula (I) useful in the present invention are the compounds represented by the following structures or pharmaceutically acceptable salts thereof.

Wherein X is oxygen or sulfur;

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

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy, arylC _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Another embodiment of this invention is directed to a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, .

The present invention also relates to a method of inhibiting the binding of IL-8 to its receptor in a mammal in need thereof which comprises administering to a mammal in need of such inhibition of IL-8 an effective amount of a compound of formula II as defined herein Lt; / RTI >

The present invention also relates to a novel compound of formula (II) or a pharmaceutically acceptable salt thereof, as defined herein.

Another embodiment of the present invention provides a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor comprising administering an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof as defined herein .

The present invention also relates to a method of inhibiting the binding of IL-8 to its receptor in a mammal in need thereof which comprises administering to a mammal in need of such inhibition of IL-8 an effective amount of a compound of formula III as defined herein Lt; / RTI >

The present invention also relates to a novel compound of formula (III), or a pharmaceutically acceptable salt thereof, as defined herein.

The present invention relates to a group of novel phenylurea compounds, their preparation, their use in treating IL-8, GROa, GROß, GROg and NAP-2 mediated diseases and pharmaceutical compositions for use in such treatment.

The compounds of formula I can also be used in conjunction with veterinary treatment of non-human mammals in need of inhibition of IL-8 or other chemokines that bind to IL-8 alpha and beta receptors. The chemokine mediated diseases for therapeutic or prophylactic treatment in animals include disease states such as those shown in the Therapeutic Methods section herein.

In the compounds of formula (I), R is any functional group that provides an ionizable hydrogen having a pKa of suitably less than 10, preferably from about 3 to 9, more preferably from about 3 to 7. Non-limiting examples of such functional groups include hydroxy, carboxylic acid, thiol, -SR ₂ , -OR ₂ , -NH-C (O) R _a , -C (O) NR ₆ R ₇ , ₂ R _b , -S (O) ₂ NHR _c , NHC (X ₂ ) NHR _b or tetrazolyl, wherein X ₂ is oxygen or sulfur, preferably oxygen. Preferably the functional group is not an aryl, heteroaryl or heterocyclic moiety ring, such as a SR ₂ or OR ₂ phase, either directly or as a substituent. More preferably, R is OH, SH, or NHS (O) ₂ R _b . Suitably, R < ₂ > is a substituted aryl, heteroaryl or heterocyclic residue having a functional group that provides an ionizable hydrogen whose ring has a pKa of 10 or less.

Suitably, R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ together with the nitrogen to which they are attached form a 5-membered ring optionally containing another heteroatom selected from oxygen, nitrogen or sulfur To 7-membered ring. The heterocycle may be optionally substituted as defined herein.

Suitably, R _a is optionally substituted to all as defined alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl group to be.

Suitably, R < _b > is independently selected from the group consisting of halogen; Nitro; Halo substituted C _1-4 alkyl, such as CF ₃ ; C _1-4 alkyl, such as methyl; C _1-4 alkoxy, such as methoxy; NR ₉ C (O) R _a ; C (O) NR ₆ R ₇ ; S (O) ₃ H, or C (O) OC _1-4 alkyl with from 1 to 3 times any NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl which may be substituted, Heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl, camphor. R _b is preferably optionally substituted phenyl, benzyl or styryl. When R < _{b &} gt _; is heteroaryl, an optionally substituted thiazole, an optionally substituted thienyl or an optionally substituted quinolinyl ring is preferred. If R ₉ is hydrogen or C _1-4 alkyl, preferably hydrogen, and suitably the substituent is NR ₉ C (O) R _a , R _a is preferably an alkyl group, such as a methyl group.

Suitably, R _c is hydrogen or phenyl which is optionally substituted with up to three substituents independently selected from halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, NR ₉ C (O) R _a , C _{NR 6 R 7, S (O} ) 3 H , or C (O) OC _1-4 1 to 3 times by alkyl which may be optionally substituted alkyl, aryl, aryl C _1-4 alkyl, aryl C _1-4 alkenyl, HeteroarylC _1-4 alkyl, heteroarylC _1-4 alkenyl, heterocyclic, heterocyclicC _1-4 alkyl, heterocyclicC _1-4 alkenyl, R ₉ is hydrogen or C _1-4 alkyl. Preferably, R < _c > is optionally substituted phenyl.

When R is OR ₂ or SR ₂ group, the aryl ring is appreciated by those skilled in the art the latter is required including an ionizable hydrogen as required. The aryl ring may also be further substituted with one to three groups that may include independently ionizable groups, including, but not limited to, halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, SH, -C (O) NR 6 R 7, -NH-C (O) R a, -NHS (O) 2 R b, S (O) 2 NR 6 R 7, C (O) OR < ₈ > or a tetrazolyl ring.

In the compounds of formula I suitably R < ₁ > is hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl such as CF ₃ ; C _1-10 alkyl such as methyl, ethyl, isopropyl or n-propyl; C _2-10 alkenyl; C _1-10 alkoxy, such as methoxy or ethoxy; Halo substituted C _1-10 alkoxy, such as trifluoromethoxy; Azide; S (O) _t R ₄ (where, t is 0, 1 or 2); Hydroxy; HydroxyC _1-4 alkyl such as methanol or ethanol; Aryl such as phenyl or naphthyl; Aryl C _1-4 alkyl, such as benzyl; Aryloxy, such as phenoxy; Aryl C _1-4 alkyloxy, such as benzyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ , such as carboxy, methylcarboxylate or phenyl benzoate; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ ; Gt; is independently selected from < RTI ID = 0.0 > Or two R ₁ moieties may together form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring, and s is an integer of 1 to 3. Aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclic alkyl and heterocyclic alkenyl moieties may be optionally substituted as defined below. Preferably R ₁ is not azido or S (O) ₃ R ₈ .

When R &_lt; ₁ > forms a dioxy bridge, s is preferably 1. When R < ₁ > forms an additional unsaturated ring, a 6-membered naphthylene ring system is preferred. The naphthylene ring may be independently substituted by another R ₁ moiety as defined above.

Suitably R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 -4} alkyl, heterocyclic, or heterocyclic C _1-4 alkyl, or R ₄ and R ₅ is from 5 to 7 to which they contain an additional heteroatom selected from O / N / S together with the nitrogen Form a circular ring.

R ₁₀ is suitably C _1-10 alkyl C (O) ₂ R ₈ , such as CH ₂ C (O) ₂ H or CH ₂ C (O) ₂ CH ₃ .

R ₁₁ is suitably hydrogen, C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl.

R ₁₂ is suitably hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Preferably R ₁ is selected from the group consisting of halogen, cyano, nitro, CF ₃ , C (O) NR ₄ R ₅ , alkenyl C (O) NR ₄ R ₅ , C (O) R ₄ R ₁₀ , alkenyl C ) OR ₁₂ , heteroaryl, heteroarylalkyl, heteroarylalkenyl or S (O) NR ₄ R ₅ , preferably R ₄ and R ₅ are both hydrogen or one phenyl. The preferred ring substitution for R < ₁ > is at the 4-position of the phenyl ring.

If R is OH, SH or NSO ₂ R _b then R ₁ is preferably substituted in the 3-position, 4-position or in the 3,4-position. The substituent is suitably an electron withdrawing group. Preferably R is OH, SH or NSO ₂ R _b , R ₁ is nitro, halogen, cyano, trifluoromethyl, C (O) NR ₄ R ₅ .

If R is a carboxylic acid, R < _{1 >} is preferably hydrogen or, preferably, R < ₁ > is substituted at the 4-position and is more preferably substituted by trifluoromethyl or chloro.

In the compounds of formula I, suitably Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heteroaryl C _2-10 alkenyl; Heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ ; Or two Y moieties may together form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring. When Y forms a dioxy bridge, s is preferably 1. When Y forms an additional unsaturated ring, a six-membered ring which forms a naphthylene ring system is preferred. The naphthylene ring may be substituted one to three times by other Y moieties as defined above. The above-mentioned known aryl, heteroaryl and heterocyclic moieties may all optionally be substituted as defined herein. Preferably R ₁ is not azido or S (O) ₃ R ₈ .

Y is preferably selected from the group _consisting of halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR ₄ R ₅ , thioC _1-4 alkyl, thioaryl, halo substituted alkoxy , Optionally substituted C _1-4 alkyl or hydroxyalkyl. Y is more preferably monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, more preferably these groups are 2'- - position. ≪ / RTI >

Where Y is substituted at any five ring positions, preferably when R is OH, SH or NSO ₂ R _b, then Y is preferably monosubstituted at the 2'- or 3'- position and is at the 4'-position . If the ring is disubstituted, then if R is OH, SH or NSO ₂ R _b then the substitution is preferably at the 2'- or 3'-position of the monocyclic ring. When R ₁ and Y are both hydrogen, it is preferred that at least one ring is substituted, and more preferably two rings are substituted.

In the compounds of formula I, X is suitably oxygen or sulfur, preferably oxygen.

Another embodiment of the present invention is a symmetrical bis compound, although not explicitly protected by formula (I), (Ia-Ic), (II) or (III), each of the following structures.

Exemplary compounds of the bis-like structural compounds include N- (bis (2-hydroxy-4-nitrophenyl) -N'- (dianisidine) diurea and 4-methylenebis (N- -N'- (2-hydroxy-4-nitrophenyl) urea. Exemplary compounds of the compounds of formula (I)

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

N- [5-nitro-2-hydroxyphenyl] -N'-phenylurea;

3-hydroxy-4 - {[(phenylamino) carbonyl] amino} benzamide N- (2-Hydroxy-4-fluorophenyl) -N'-phenylurea;

2 - {[(phenylamino) carbonyl] amino} thiophenol N- (2-carboxy-4-hydroxyphenyl) -N'-phenylurea;

N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenylurea;

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'-phenylurea;

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-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-nitrophenyl) -N '- (2-chloro-6-methylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-sulfoxymethylphenyl) urea;

N- (4-trifluoromethyl-2-hydroxyphenyl) -N '- (2-bromophenyl) urea;

N- (4-carbomethoxy-2-hydroxyphenyl) -N '- (2-bromophenyl) urea;

N- (4-trifluoromethyl-2-hydroxyphenyl) -N '- (2-phenylphenyl) urea;

N- (4-carbomethoxy-2-hydroxyphenyl) -N '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dibromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (3-chloro-2-methoxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylphenyl) urea;

N- [4- (benzylamino) carbonyl-2-hydroxyphenyl] -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenoxyphenyl) urea;

N- (2-hydroxy-4-fluorophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3-naphthyl) -N '- (2-bromophenyl) urea;

N- (3,4-difluoro-2-hydroxyphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-phenylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-methylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylaminophenyl) urea;

N- (2-hydroxy-3-carboxyphenyl) -N '- (2-bromophenyl) urea;

N- (2-sulfopyridyl-4-bromophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea;

N - [(2-phenylsulfamido) 4-cyanophenyl] -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonamidophenyl) phenyl) N '- (2-bromophenyl) urea;

N- (2- (aminosulfonylstyryl) phenyl) N '- (2-bromophenyl) urea;

2 - [(3,4-dimethoxyphenylsulfonyl) amino] phenyl) N '- (2-bromophenyl) urea;

N- (2 - [(4-acetamidophenylsulfonyl) amino] phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (2-thiophene) phenyl) -N'- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (3-tolyl) phenyl) -N'- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (8-quinolinyl) phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonylbenzyl) phenyl) -N '- (2-bromophenyl) 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;

N- [2-hydroxy-3,4-diphenylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycine methyl ester carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycine carbonylphenyl] -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-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea;

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

N- [2-hydroxy-4-carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-carbonylphenyl] -N '- [2-bromophenyl] urea;

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' ] Urea-N '- [2-bromophenyl] urea;

(E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2- bromophenyl] urea-N' Urea;

-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] amino] phenyl] -N '- (2-bromophenyl) urea;

N- (2-bromophenyl) -N '- [2-dimethylaminosulfonylamino] phenyl] urea;

N- [2- (phenethylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea;

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

N- [2-hydroxy-4-cyanophenyl] -N '- [4-phenylphenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [2,3-dichlorophenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [2-methoxyphenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [3-methoxyphenyl] urea;

N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxyphenyl] -N '- [2-bromophenyl] urea;

N- [trans-3-styr-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 - [(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-trifluoromethyl) phenyl) sulfonylamino] phenyl-N '- (2-bromophenyl) 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-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-trifluoromethylphenyl] urea;

N- [2-hydroxy-5-nitrophenyl] -N '- [2-phenylphenyl] urea;

N- [2-hydroxy-5-nitrophenyl] -N '- [2,3-dichlorophenyl] urea;

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

N- [2- (2-amino- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea;

N- [2- (aminosulfonylphenyl) 3-aminophenyl] -N '- (2-bromophenyl) 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-naphthalenesulfonic acid] -N '- [2-bromophenyl] urea;

1,1 '- (4-methyl-2-phenylene) bis [2-thio-3,3-tolylurea];

N- (2-carboxyphenyl) -N'-phenylurea;

N- (2-hydroxy-4-nitrophenyl) -N'-phenylurea;

1- (2-carboxyphenyl) -3- (4-chlorophenyl) urea;

2- (3,4-dichlorophenylcarbonyldiimino) -5-trifluoromethylbenzoic acid;

2- (4-chlorophenylcarbonyldiimino) -5-trifluoromethylbenzoic acid;

1- (p-anyl) -3- (2-carboxyphenyl) urea;

1- (2-carboxyphenyl) -3- (3-fluorophenyl) urea;

1- (2-carboxyphenyl) -3- (3-chlorophenyl) urea;

1- (m-anyl) -3- (2-carboxyphenyl) urea;

1- (o-anyl) -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-nitrophenyl) -N '- (2-chlorophenyl) 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-nitrophenyl) -N '- (2-phenyloxyphenyl) urea;

N- (3-chloro-2-hydroxyphenyl) -N '- (bromophenyl) urea;

N- (2-hydroxy-3-glycine methyl ester carbonylphenyl) -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;

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-nitrophenyl) -N '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea;

N- (2-phenylsulfonamido) -4-cyanophenyl-N '- (2-bromophenyl) 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) urea; And

N- (2-hydroxy-3-cyanophenyl) -N '- (2,3-dichlorophenyl) urea.

As used herein, " optionally substituted ", unless specifically defined, includes halogens such as fluorine, chlorine, bromine or iodine; Hydroxy; Hydroxy substituted C _1-10 alkyl; C _1-10 alkoxy, such as methoxy or ethoxy; S (O) _{m'C 1-10} alkyl, wherein m 'is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; Amino, single-and disubstituted amino, such as NR ₄ R ₅ group; NHC (O) R ₄ ; _{C (O) NR 4 R 5} ; C (O) OH; _{S (O) 2 NR 4 R} 5; NHS (O) ₂ R ₁₃ , C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl or t-butyl; Halo substituted C _1-10 alkyl such as CF ₃ ; Means optionally substituted aryl such as phenyl or optionally substituted arylalkyl such as benzyl or phenethyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl Wherein said aryl, heteroaryl or heterocyclic moiety is selected from the group consisting of halogen; Hydroxy; Hydroxy substituted alkyl; C _1-10 alkoxy; S (O) _{m'C 1-10} alkyl; Amino, single-and disubstituted amino, such as NR ₄ R ₅ group; C _1-10 alkyl or halo substituted C _1-10 alkyl, such as CF ₃ , one or two times.

R ₁₃ is suitably C _1-4 alkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclic or heterocyclicC _1-4 alkyl.

Another embodiment of the present invention is the use of a novel compound of formula (II) as defined below or a pharmaceutically acceptable salt thereof, as defined below, which is also useful for inhibiting the binding of IL-8 to a receptor of a mammal in need of a binding inhibition of IL- Acceptable salt. The invention also relates to a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically acceptable diluent or carrier. The compounds of formula (II) are useful for treating chemokine mediated diseases that bind to IL-8 alpha or beta receptors and comprise administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof. The compounds of formula (II) are shown by the following structure or a pharmaceutically acceptable salt thereof:

Wherein X is oxygen or sulfur;

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

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy, arylC _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

E is

(Wherein at least one E is present and the symbol * represents the point of attachment of the ring);

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Suitably, for example, X, R, R _1, R _4, R _5, R _6, R _7, R _8, R _9, Y, R _a, R _b, R _c, n, m, and parameters for the formula Ⅱ s, etc. are as defined in the above formula (I). An E-ring in which a bonding point is defined by the symbol * may arbitrarily exist. If not present, the ring is a phenyl moiety substituted with R and R < ₁ > as indicated. The E ring may be substituted with the R < _{1 >} residue in any saturated or unsaturated ring, and only those that are substituted in the unsaturated ring herein.

Exemplary compounds of formula (III) include N- [2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea; N- [1 -hydroxyfluorene] -N '- [2-bromophenyl] urea; N- [3-hydroxy-9,10-anthraquinone-2-yl] -N '- [2-bromophenyl] urea. Another embodiment of the present invention is a novel compound of formula III, or a pharmaceutically acceptable salt thereof, as defined below useful for inhibiting the binding of IL-8 to a receptor of a mammal in need of inhibition of binding of IL-8 to its receptor to be. The present invention also relates to a pharmaceutical composition comprising a compound of formula (III) and a pharmaceutically acceptable diluent or carrier. The compound of formula (III) is useful for the treatment of a chemokine mediated disease which binds to an IL-8 alpha or beta receptor and comprises administering an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof. The compound of formula (III) is represented by the following structure or a pharmaceutically acceptable salt thereof:

Wherein X is oxygen or sulfur;

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

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy, arylC _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Is suitably as defined in the above formula (I) of the formula (II), for example in a variable such as R.

Exemplary compounds of formula (III) include N- (2-hydroxy-4-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea; And N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea.

Another embodiment of the present invention is a novel compound of formula Ia which is part of a compound of formula I useful for the treatment of chemokine mediated diseases as defined herein. The present invention also relates to a pharmaceutical composition comprising a compound of formula (Ia) and a pharmaceutically acceptable diluent or carrier. The compounds of formula (Ia) are represented by the following structure or a pharmaceutically acceptable salt thereof:

Wherein X is oxygen or sulfur;

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

R _b is NR ₆ R ₇ , alkyl, aryl, arylC _1-4 alkyl, arylC _2-4 alkenyl, heteroaryl, heteroarylC _1-4 alkyl, heteroarylC _2-4 alkenyl, heterocyclic Or a heterocyclic C _1-4 alkyl or a heterocyclic C _2-4 alkenyl group, camphor, which are all halogen; Nitro; Halo substituted C _1-4 alkyl; C _1-4 alkyl; C _1-4 alkoxy; NR ₉ C (O) R _a ; C (O) NR ₆ R ₇ , S (O) ₃ H or C (O) OC _1-4 alkyl;

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

R _a is alkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclic or heterocyclicC _1-4 alkyl group, all of which may be optionally substituted;

R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ together with the nitrogen to which they are attached may further contain a heteroatom selected from oxygen, nitrogen or sulfur, Form a 5- to 7-membered ring;

R ₉ is hydrogen or C _1-4 alkyl, preferably hydrogen;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

The preferred ring substitution for R < ₁ > is monosubstituted at the 3-position or the 4-position or is disubstituted at the 3,4-position. The substituent is suitably an electron withdrawing group. Preferably R ₁ is nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Y may be substituted at any 5 ring position, but preferably the ring with the Y moiety is monosubstituted at the 2- or 3-position and is preferably unsubstituted at the 4-position. When the ring is disubstituted, the substitution is preferably at the 2'- or 3'-position of the single cyclic ring. R ₁ and Y may all be hydrogen, but preferably one or more rings are substituted, preferably all rings are at least monosubstituted, that is, n and m are each 1 or more.

Y is more preferably monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, preferably at the 2'- or 2'-, 3'-position .

Examples of compounds of formula (Ia) are:

N- (4-nitro-2- (phenylsulfonylamino) phenyl] -N'-phenylurea;

N - [(2-phenylsulfamido) 4-cyanophenyl] -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonamidophenyl) phenyl) N '- (2-bromophenyl) urea;

N- (2- (aminosulfonylstyryl) phenyl) N '- (2-bromophenyl) urea;

N - [(3,4-dimethoxyphenylsulfonyl) amino] phenyl) N '- (2-bromophenyl) urea;

N- (2 - [(4-acetamidophenylsulfonyl) amino] phenyl) N '- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (2-thiophene) phenyl) -N'- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (3-tolyl) phenyl) -N'- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (8-quinolinyl) phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonylbenzyl) phenyl) -N '- (2-bromophenyl) urea;

N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl-N '- (2-bromophenyl) urea;

N- (2-bromophenyl) -N '- [2-dimethylaminosulfonylamino] phenyl] urea;

N- [2- (phenethylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea;

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

N- [2 - [(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-trifluoromethyl) phenyl) sulfonylamino] phenyl-N '- (2-bromophenyl) urea;

N- [2- (2-amino- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea;

N- [2- (aminosulfonylphenyl) 3-aminophenyl] -N '- (2-bromophenyl) urea.

Another embodiment of the present invention is a novel compound of formula (Ib) which is part of a compound of formula (I) useful in the treatment of chemokine mediated diseases. The present invention also relates to a pharmaceutical composition comprising a compound of formula (Ib) and a pharmaceutically acceptable diluent or carrier. The compounds of formula (Ib) are represented by the following structure or a pharmaceutically acceptable salt thereof:

Wherein X is oxygen or sulfur;

X ₁ is oxygen or sulfur;

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

R ₂ is a substituted aryl, heteroaryl or heterocyclic ring having a functional group that provides an ionizable hydrogen having a pKa of 10 or less;

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Suitable variables for formula (Ib), for example functional groups on the R ₂ group with ionizable hydrogen having a pKa of 10 or less, are the same as defined in formula (I) above unless otherwise indicated. Non-limiting examples of suitable functional groups are the hydroxy, carboxylic acid, thiol, -NH-C (O) R a, a _{-C (O) NR 6 R 7} , a substituted of the formula -NHS (O) ₂ R _b Sulfonamides, -S (O) ₂ NHR _c , NHC (X ₂ ) NHR _b or tetrazolyl (as defined in formula (I) above).

Suitably for the compound of formula (Ib), the preferred ring substitution for R < ₁ > is 3-position, 4-position or is preferably disubstituted at the 3,4-position. The substituent is suitably an electron withdrawing group. Preferably R ₁ is nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Y may be substituted at any 5 ring position, but preferably the ring with the Y moiety is monosubstituted at the 2- or 3-position and is preferably unsubstituted at the 4-position. If the ring is disubstituted, the substituent is preferably present at the 2 ' or 3 ' position of the monocyclic ring. R ₁ and Y may all be hydrogen, but preferably one or more rings are substituted, preferably all rings are at least monosubstituted, that is, n and m are each 1 or more.

Suitably, in the compound of formula (Ib), Y is more preferably a monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenediyl Oxy, aryl, or alkyl.

Another embodiment of the present invention is a novel compound of formula Ic, which is part of a compound of formula I useful for the treatment of chemokine mediated diseases. The present invention also relates to a pharmaceutical composition comprising a compound of formula (Ic) and a pharmaceutically acceptable diluent or carrier. The compounds of formula (Ic) are represented by the following structure or a pharmaceutically acceptable salt thereof:

Wherein X is oxygen or sulfur;

X ₁ is oxygen or sulfur;

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR < ₄ > C (O) R < _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring;

Y is independently halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy, arylC _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S ≪ / RTI >

R ₈ is hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

Provided that if n = 1 then Y is substituted in the 2- or 3-position;

When n = 2, Y may be substituted at the 2'-, 3'-, 2'-, 5'-, 2'-, 6'-, 3'-, 5'- or 3'-, 6'- positions ≪ / RTI >

If b = 3 then Y is trisubstituted at the 2'-, 3'-, 5'- or 2'-, 3'-, 6'- positions;

Y is not 2'-OH, 3'-t-butyl or 5'methyl, provided that when X ₁ is O, m = 2, R ₁ is 2-t-butyl, 4-methyl and n = 3;

When X ₁ is O, m = 1, R ₁ is 4-methyl, and n = 2, then Y is not 2'-OH, 5'-methyl;

X ₁ is O, m = 1, R ₁ is hydrogen, n = 2, Y is not 2'-, 6'-diethyl;

When X ₁ is O, m = 1, R ₁ is 6-OH, n = 2, Y is not 2'-5'-methyl;

When X ₁ is S, m = 1, R ₁ is 4-ethyl, and n = 1, Y is not 2'-methoxy.

Suitable variables for formula (Ic) are the same as defined in formula (I) above, unless otherwise indicated.

Suitably for compounds of formula (Ic), the preferred ring substitution for R < ₁ > is disubstituted at the 3-position, the 4-position or the 3,4-position. Preferably R < ₁ > is not hydrogen. The substituent is suitably an electron withdrawing group. Preferably R ₁ is nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Y may be substituted at any 5 ring position, but preferably the ring with the Y moiety is monosubstituted at the 2- or 3-position and is preferably unsubstituted at the 4-position. If the ring is disubstituted, the substituent is preferably present at the 2 ' or 3 ' position of the monocyclic ring. R ₁ and Y may all be hydrogen, but preferably one or more rings are substituted, preferably all rings are at least monosubstituted, that is, n and m are each 1 or more.

Suitably, in the compound of formula Ic, Y is preferably monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, more preferably 2-position or 2,3 - position.

Examples of compounds of formula (Ic) are:

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

N- [2-hydroxy-5-nitrophenyl] -N'-phenylurea;

N- (2-hydroxy-4-fluorophenyl) -N'-phenylurea;

N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenylurea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N'-phenylthiourea;

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 '- (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-nitrophenyl) -N '- (2-chloro-6-methylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-sulfoxymethylphenyl) urea;

N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-carbomethoxyphenyl) -N '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dibromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (3-chloro-2-methoxyphenyl) urea;

N- [2-hydroxy-4- (benzylamino) carbonylphenyl] -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenoxyphenyl) urea;

N- (2-hydroxy-4-fluorophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3,4-difluorophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-phenylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-methylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylaminophenyl) urea;

N- (2-hydroxy-3-carboxyphenyl) -N '- (2-bromophenyl) urea;

N- (2-sulfopyridyl-4-bromophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) 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-diphenylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycine methyl ester carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycine carbonylphenyl] -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-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea;

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

N- [2-hydroxy-4-carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-benzyloxyphenyl] -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' ] Urea;

(E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2- bromophenyl] urea-N' Urea;

-N'- [2-bromophenyl] urea-N '- [2-bromophenyl] Urea;

N- [2-hydroxy-4-benzamide phenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-4-aminocarbonylphenyl] -N '- [2-bromophenyl] urea;

N- (2-hydroxy-3,5,6-trifluorophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3-fluoro-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3-iodophenyl) -N '- (2-bromophenyl) urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [4-phenylphenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [2,3-dichlorophenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [2-methoxyphenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [3-methoxyphenyl] urea;

N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxyphenyl] -N '- [2-bromophenyl] urea;

N- [trans-3-styr-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-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-trifluoromethylphenyl] urea;

N- [2-hydroxy-5-nitrophenyl] -N '- [2-phenylphenyl] urea;

N- [2-hydroxy-5-nitrophenyl] -N '- [2,3-dichlorophenyl] urea;

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

N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2,4-dimethoxyphenyl] urea;

N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-chloro-5-trifluoromethylphenyl] urea;

N- [2-hydroxy-3,4-dichlorophenyl] -N '- [benzyl] urea;

N- [2-hydroxy-4-isopropylphenyl] -N '- [3-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-naphthyl] -N '- [3-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-naphthyl] -N '- [2,3-dichlorophenyl] urea;

N- [2-hydroxy-3-naphthyl] -N '- [benzyl] urea;

N- [2-hydroxy-3- (phenylaminocarbonyl) phenyl] -N '- [benzoyl] urea;

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-naphthyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea; And

N- (2-hydroxy-4-nitrophenyl) -N '- (1-naphthyl) urea. Suitable pharmaceutically acceptable salts are known in the art and include those derived from inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, malic, Maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and basic salts of mandelic acid. In addition, a pharmaceutically acceptable salt of formula I may be formed, for example, with a pharmaceutically acceptable cation if the substituent comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

As used herein, the following terms refer to the following.

&Quot; Halo " - all halogens, i.e. chloro, fluoro, bromo and iodo.

Unless otherwise limited, the term " C _1-10 alkyl " or " alkyl " chain length includes straight and branched chain having from 1 to 10 carbon atoms. Non-limiting examples thereof include methyl, ethyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

The term " cycloalkyl " is used herein to mean a cyclic radical of preferably 3 to 8 carbon atoms, and non-limiting examples include cyclopropyl, cyclopentyl, cyclohexyl and the like.

The term " alkenyl " is used herein to denote a straight or branched chain moiety having from 2 to 10 carbon atoms, unless otherwise specified in all cases, and non-limiting examples thereof include ethenyl, 1-propenyl Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

&Quot; Aryl " - phenyl and naphthyl.

&Quot; Heteroaryl " (by itself or in any combination, for example in "heteroaryloxy" or "heteroarylalkyl"), wherein one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S Non-limiting examples of 5- to 10-membered aromatic ring systems include pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, Triazole, imidazole or benzimidazole.

&Quot; Heterocyclic " (either by itself or in any combination, for example, " heterocyclic alkyl ") - a saturated or partially unsaturated ring containing one or more heteroatoms selected from the group consisting of N, Gt; is a 4 to 10 membered ring system, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine.

The term " arylalkyl " or " heteroarylalkyl " or " heterocyclicalkyl ", unless otherwise indicated, means a C _1-10 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety Is used.

"Alkylsulfinyl" means The term is to mean the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" is a fully oxidized S (O) ₂ moiety it means.

Alkenyl herein, the term "two R ₁ moieties (or two Y moieties) may form a 5 to 6 membered unsaturated ring together" is the naphthylene ring system or a C ₆ cycloalkenyl (i.e., hexane) or a C ₅ cycloalkenyl Quot; refers to the formation of a phenyl group to which a six membered unsaturated ring is bonded, such as a phenyl residue (cyclopentene).

Compounds of formula (I), (Ia), (Ib), (Ic), (II) and (III) can be obtained by applying a synthesis procedure in which a part thereof is described in the following reaction formula. The synthesis provided in these schemes can be carried out by reacting compounds of formula I, Ia, II and III having a variety of different R, R < ₁ > and aryl groups, which are reacted using any suitably protected substituents to achieve compliance with the reactions described herein It is applicable to generate. In these cases, subsequent deprotection generally provides a compound of the disclosed nature. Once the urea nuclei are made, additional compounds of these formulas can be prepared by applying standard techniques for functional group interchange well known in the art. The scheme is presented as the only compound of formula I, but for illustration purposes only.

Ortho-substituted phenylurea (2-scheme 1) is a commercially available ortho-substituted aniline (Aldrich Chemical Company, Milwaukee, Wis., USA) in an aprotic solvent (DMF, toluene) Dow Chemical Company, Milwaukee, Wis., USA). If the 1- (RSO ₂ NH) ₂ - (NH ₂ ) Ph is not commercially available it can be reacted with commercially available RSO ₂ Cl in an aprotic solvent (methylene chloride or DMF) in the presence of a base such as triethylamine or NaH With 2-phenylenediamine.

If the desired 2-substituted aniline (5-scheme 2) is not commercially available, the corresponding nitro compound is prepared from the compound (3-scheme 2) under standard nitrification conditions (using HNO ₃ or BF ₄ NO ₃ ) at 23 ° C . The nitro compound is then reduced to the corresponding aniline using SnCl ₂ in EtOH (or alternatively H ₂ / Pd or LiAlH ₄ ).

2-aminobenzothiazole (7-scheme 3) is synthesized by reacting phenylaniline with thiocyanate anion in the presence of an oxidizing agent (bromine) when the desired 2-aminobenzenethiol (8-scheme 3) Can be prepared. The thiazole can be hydrolyzed with the desired 2-aminobenzenethiol (8-Scheme 3) and a strong base such as NaOH in a protic solvent such as EtOH.

If thioisocyanate or phenylisocyanate is not commercially available, thiourea or urea (11-scheme 4) may be prepared from commercially available ortho-substituted anilines. This compound is first protected with a protecting group (tert-butyldimethylsilyl or benzyl) by conditions known in the art (see Greene, T. Protecting Groups in Organic Synthesis , Wiley & Sons, New York, 1981). The protected aniline is then reacted with a solution of thiophosgene or phosgene in an aprotic solvent (e.g., DMF, toluene) followed by aniline in the presence of a base (triethylamine or sodium bicarbonate) to form protected thiourea or urea . The corresponding urea or thiourea is then deprotected using standard conditions in the art to form the desired thiourea or urea (11-scheme 4).

Alternatively, urea can be formed from the corresponding aromatic or thiophenecarboxylic acid (12-scheme 5) using a Curtius rearrangement. The carboxylic acid is subjected to the Curtius conditions ((PhO) ₂ PON ₃ , Et ₃ N or ClCOCOCl, followed by NaN ₃ ) and the intermediate isocyanate is trapped with an appropriately substituted aniline.

The pharmaceutically acceptable salts of formula I can be obtained by known methods, for example by treatment with an appropriate amount of acid or base in the presence of a suitable solvent.

Another embodiment of the present invention is a novel process for the synthesis of cyanonitrotoluene intermediates. Various conversions of aryl halides to aryl cyano derivatives using copper (I) cyanide have been disclosed. However, no examples of aryl rings having a hydroxyl group are mentioned. Several attempts have been made to obtain cyano phenol residues, but the result has been failure. No relocation of the halogen to the cyano residue has been obtained using known conditions at elevated temperatures, for example above 170 ° C, for example between 180 and 210 ° C. Standard bases, such as DMF and pyridine, also failed to provide the desired product. Intermediates such as 2-amino-5-fluorophenol, 2-nitro-5-fluorophenol and 2-nitro-5-methyl-6-bromophenol are converted to halogen, Copper (I). Using bromine derivatives such as 2-nitro-5-methyl-6-bromophenol with dimethylformamide and using triethylamine with a catalytic amount of dimethylaminopyridine and copper (I) cyanide, I.e. less than 100 ° C, preferably 60 to about 80 ° C, for a time less than the standardized method, ie less than 18 hours, preferably about 4 to 6 hours.

Accordingly, one embodiment of the present invention is a compound of formula (I), dimethylformamide, triethylamine and dimethylaminopyridine with a catalytic amount of a compound of formula (I) wherein X is halogen. (Wherein R < ₁ > is as defined in the above formula (I)). Preferably the process is carried out at a reduced temperature of from about 60 to about 80 < 0 > C. Preferably, X is bromine.

In an embodiment, all temperatures are degrees Celsius (占 폚). Unless otherwise indicated, mass spectra were performed on a VG Zab mass spectrometer using fast atom bombardment. ¹ H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400 MHz using a Bruker AM 250 or Am 400 spectrometer. The multiplicity is expressed as: s = 1 median, d = 2 median, t = 3 median, q = 4 median, m = Sat represents the saturated solution, and equiv. Represents the ratio of the molar equivalents of the reagents to the main reactants.

Flash chromatography is performed over Merck silica gel 60 (230-400 mesh).

<Synthesis Example>

The present invention will now be described with reference to the following examples, which are for illustrative purposes only and are not to be construed as limiting the scope of the invention. Unless otherwise indicated, all temperatures are given in degrees centigrade, all solvents are the highest available purity, and all reactions are carried out under anhydrous conditions in an argon atmosphere.

<General Method A: Synthesis of N, N'-phenylurea>

Aniline (1.0 eq.) Corresponding to a solution of substituted phenyl isocyanate (1.0 eq.) In toluene (5 ml) was added. The reaction mixture was heated to about 80 & hrs " or " h ")) and then cooled to room temperature. The purification, yield and spectral characteristics of each compound are shown below.

<General Method B: Synthesis of N, N'-phenylurea>

Aniline (1.0 eq.) Corresponding to a solution of phenyl isocyanate (1.0 eq) in dimethylformamide (1 ml) was added. The reaction mixture was stirred at about 80 &lt; 0 &gt; C completely (24-48 h) and then the solvent was removed under vacuum. The purification, yield and spectral characteristics of each compound are shown below.

&Lt; General Method C: Synthesis of sulfonamide >

The ortho-substituted aniline (1 eq.), Triethylamine (1 eq.) And the desired sulfonyl chloride (1 eq.) Were combined in methylene chloride and stirred thoroughly at about 23 ° C (12-36 h). The reaction mixture was partitioned between water and methylene chloride. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The purification of each compound is shown below.

&Lt; Example 1 >

Preparation of N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -N'-phenylurea

(2-hydroxy-4- (methoxycarbonyl) -1H-pyrazol-3-yl) -methanol was obtained from methyl 4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate (1.19 mmol) Phenyl] -N'-phenylurea. &Lt; / RTI &gt; The product was precipitated from toluene and purified by filtration to give the title compound (309 mg, 90%). mp: 188.4-188.8 C; _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ8.15 (d, 1H, J = 8.25Hz), 7.70 (s, 1H), 7.51 (d, 1H, J = 8.25Hz), 7.43 (d, 2H J = 8.25Hz), 7.30 (t, 2H, J = 8.25Hz), 7.01 (t, 1H, J = 8.25Hz), 3.87 (s, 3H); EI-MS m / z 286 (M + H) &lt; ⁺ &gt;; Anal (C ₁₅ H ₁₄ N ₂ O ₄ ) C, H, N.

&Lt; Example 2 >

Preparation of N- [5-nitro-2-hydroxyphenyl] -N'-phenylurea

N [5-Nitro-2-hydroxyphenyl] -N'-phenylurea was prepared from 5-nitro-2-hydroxyaniline and phenyl isocyanate according to the procedure of General Method A, The product was precipitated from toluene and purified by filtration to give the title compound (100 mg, 30%). ¹ H NMR (CD ₃ OD):? 9.48 (s, 1H, NH), 9.07 (d, J = 1.56 Hz, NH), 8.55 = 1.56 Hz), 7.50 (d, 2H, J = 6.25 Hz), 7.30 (t, 2H, J = 6.25 Hz), 7.01 (m, 2H). EI-MS m / z 273 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 3 >

Preparation of 3-hydroxy-4 - {[(phenylamino) carbonyl] amino} benzamide

a) Preparation of 0.67 Molar (M ") stock solution of aluminum amide reagent

To a suspension of the appropriate hydrochloride salt (0.02 mol, mole, hereinafter) in anhydrous toluene (20 mL) was slowly added trimethylaluminum solution (2M, 10 mL) in toluene at about 0 ° C. After the addition was complete, Was allowed to warm to room temperature and stirred for about 1-2 hours until gas evolution ceased.

b) Preparation of 3-hydroxy-4 - {[(phenylamino) carbonyl] amino} benzamide

To a solution of N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -N'-phenylurea (60 mg (hereinafter referred to as "mg", 0.2 mmol) in toluene (2 ml) The reaction mixture was cooled to room temperature and quenched with care with 5% HCl The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate &lt; RTI ID = 0.0 &gt; It was extracted Combine the organic extracts, dried over MgSO _4, filtered, to give the reduced pressure, and concentrated by chromatography the resulting solid on silica gel (ethyl acetate) the purpose amide (28 ㎎, 49%) mp :.. 106.8 to ^{107.1 ℃; 1 H NMR (CD} 3 OD / CDCl 3): δ7.98 (d, 1H, J = 8.25Hz), 7.35 (d, 2H, J = 8.25Hz), 7.30 (d, 2H, J = 8.25 MS m / z 271 (M + H) ⁺ ; Anal. C ₁₄ H ₁₃ N ₃ O (t, 2H, J = ₃ ) C, H, N.

<Example 4>

Preparation of N- (2-hydroxy-4-fluorophenyl) -N'-phenylurea

a) Preparation of 2-amino-5-fluorophenol

5-Fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (II) chloride (1.76 g, 9.2 mmol) in ethanol (10 mL) were heated to 80 &lt; 0 &gt; C under an argon atmosphere. After 30 minutes, the starting material disappeared and the solution was cooled and poured into ice. The pH was slightly basic (pH 7-8) by adding 5% aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. Evaporation of the solvent gave the title compound (335 mg, 83%). _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ6.6 (m, 1H), 6.38 (dd, 1H, J = 8.3Hz and J = 2.8Hz), 6.29 (m 1H.).

b) Preparation of N- (2-hydroxy-4-fluorophenyl) -N'-phenylurea

(2-Hydroxy-4-fluorophenyl) -N'-phenylurea was prepared from 2-amino-5-fluorophenol (200 mg, 1.57 mmol) and phenyl isocyanate according to General Method A. The product Precipitation from toluene and purification by filtration afforded the title compound (352 mg, 91%). mp: 195.5 to 195.7 占 폚; _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ7.70 (. M 1H), 7.3 (d, 2H, J = 8.25Hz), 7.15 (t, 2H, J = 8.25Hz), 6.89 (t, 1H , J = 8.25 Hz), 6.50-6.38 (m, 2H); EI-MS m / z 246 (M + H) &lt; ⁺ &gt;; Anal (C ₁₃ H ₁₁ N ₂ O ₂ F) C, H, N.

&Lt; 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 following the general procedure A above. The product was precipitated from toluene and purified by filtration to give the title compound (330 mg, 85%). mp: 194.5 [deg.] C; _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ7.48-7.26 (. M 4H), 7.25-7.10 (. M 3H), 7.04-6.79 (m, 2H); EI-MS m / z 244 (M + H) &lt; ⁺ &gt;; Anal (C ₁₃ H ₁₂ N ₂ OS) C, H, N.

&Lt; Example 6 >

Preparation of N- (2-carboxy-4-hydroxyphenyl) -N'-phenylurea

(2-carboxy-4-hydroxyphenyl) -N'-phenylurea was prepared from 2-amino-5-hydroxybenzoic acid (1 g, 6.53 mmol) according to the procedure of General Procedure B above. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting solid was chromatographed on silica gel (hexane: ethyl acetate, 1: 1 to 100% ethyl acetate) to give the title compound (1.5 g, 84%). _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ8.36 (d, 1H, J = 8.25Hz), 7.63 (m, 4H), 7.48 (t, 2H, J = 8.25Hz), 7.20 (m, 1H ); EI-MS m / z 272 (M + H) &lt; ⁺ &gt;; Anal (C ₁₄ H ₁₂ N ₂ O ₄ ) C, H, N.

&Lt; Example 7 >

Preparation of N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenylurea

a) Preparation of 2-nitro-5-trifluoromethylphenol

Nitro-5-trifluoromethylphenol was prepared by dropwise addition of concentrated HNO ₃ (6 mL) to α, α, α-trifluoro-m-cresol (5 g, 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 layer was separated, dried over sodium sulfate and filtered. The solution was concentrated in vacuo and the resulting oil was purified by column chromatography (50% EtOAc / hexanes gradient from 100% hexanes) to give the title compound (1.7 g, 27%) as an oil. ¹ H NMR (CDCl ₃ ): 10.6 (s, 1 H, 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

5-Trifluoromethylphenol (500 mg, 2.41 mmol) was treated with a solution of SnCl ₂ (3.5 g, mmol) in EtOH at 23 &lt; 0 & . The mixture was concentrated to 50 mL and the pH was adjusted to 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H ₂ O and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil (370 mg, 87%) was used without further purification. ¹ H NMR (CDCl ₃ ): 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'-phenylurea

(Trifluoromethyl) phenyl] -N- (2-hydroxy-4- (trifluoromethyl) phenyl) -N-phenyl-isobutyric acid was prepared from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) '-Phenylurea. &Lt; / RTI &gt; The product was precipitated from methylene chloride and purified by filtration to give the title compound (230 mg, 87%). mp. ° C; _{^{1 H NMR (DMSO-d 6}} ): δ9.45 (s, 1H, NH), 8.50 (s, 1H, NH), 8.31 (d, 1H, J = 10.0Hz), 7.45 (d, 2H, J = 1H), 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 ^&lt; ^{+ &} gt ^; ). Analysis (C ₁₄ H ₁₁ N ₂ O ₂ F ₃ ) C, H, N.

&Lt; Example 8 >

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

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) was added tert-butyldimethylsilyl chloride (11.2 mL, 64.9 mmol) . The resulting mixture was stirred at 23 &lt; 0 &gt; C for 48 hours. The reaction mixture was partitioned between 0.1% HCl and ethyl acetate. The combined organic phases were washed with brine, dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting oil was chromatographed on silica gel (hexane: ethyl acetate; 5: 1) to give the title compound (1.7 g, 98%). _{^{1 H NMR (CDCl 3):}} δ7.78 (dd, 1H, J = 6.7Hz and 2.7 Hz), 7.61 (d, 1H, J = 2.7Hz), 6.7 (d, 1H, J = 8.8Hz), 1.0 (s, 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) was added triethylamine (0.13 mL, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol ). The reaction mixture was stirred at 70 &lt; 0 &gt; C for 2 hours and then cooled to room temperature. Then, 2- (tert-butyldimethylsilyloxy) -4-nitroaniline (200 mg, 0.75 mmol) was further added. The resulting mixture was stirred at 70 &lt; 0 &gt; C for 48 hours and cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phases were washed with brine, dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting oil was chromatographed on silica gel (hexane: ethyl acetate, 10: 1) to give the title compound (130 mg, 31%). _{^{1 H NMR (CDCl 3):}} δ8.36 (d, 2H, J = 8.3Hz), 7.90 (dd, 2H, J = 8.3Hz and J = 2.8Hz), 7.71 (d , 2H, J = 2.8Hz) , 7.22 (s, 2H), 1.02 (s, 18H), 0.35 (s, 12H).

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

To a solution of N - [(2-tert-butyldimethylsilyloxy) -4-nitrophenyl] -N '- [(2- tert- butyldimethylsilyloxy) -4-nitrophenyl] urea (50 mg , 0.089 mmol) in dichloromethane (5 mL) was added tetrabutylammonium fluoride (IM, 0.09 mL, 0.089 mmol) at 0 &lt; 0 &gt; C. The reaction mixture was stirred at 23 &lt; 0 &gt; C. After 1 hour, the starting material disappeared. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phases were dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting oil was chromatographed on silica gel (hexane: ethyl acetate; 1: 1 to 100% ethyl acetate) to give the title compound (24 mg, 81%). _{^{1 H NMR (CD 3 OD /}} CDCl 3): δ8.32 (d, 2H, J = 8.25Hz), 7.80 (dd, 2H, J = 8.25Hz and J = 2.06Hz), 7.7 (d , 2H, J = 2.06 Hz). EI-MS m / z 334 (M + H) &lt; ⁺ & gt ^; . Anal (C ₁₃ H ₁₀ N ₄ O ₇ ) C, H, N.

&Lt; Example 9 >

Preparation of N- (2-hydroxy-4-nitrophenyl) -N'-phenyl-thiourea

a) Preparation of N- (2-tert-butyldimethylsilyloxy-4-nitrophenyl) -N'-phenyl-thiourea

A basic solution of NaHCO ₃ and 2-tert-butyldimethylsilyloxy-4-nitroaniline (80 mg, 0.308 mmol) in CHCl ₃ : H ₂ O (2.5: 1, 7 mL) at 0 ° C was treated with thiophosgene To give N- (2-tert-butyldimethylsilyloxy-4-nitrophenyl) -N'-phenyl-thiourea. The solution was warmed to 23 &lt; 0 &gt; C and the reaction was continued overnight. CHCl ₃ layer separated and dried over sodium sulfate. The solution was concentrated in vacuo, the residue was dissolved in toluene and treated with aniline (100 [mu] L) at 23 [deg.] C for 12 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc / hexanes) to give the title compound as a yellow solid (120.8 mg, 98%). mp: 144-145 占 폚; ¹ H NMR (CD ₃ OD / CDCl ₃ ):? 8.65 (d, IH, J = 10.0 Hz), 7.58 7.26 (m, 4 H), 7.10 (m, 1 H).

b) Preparation of N- (2-hydroxy-4-nitrophenyl) -N'-phenyl-thiourea

_{CH 3 CN (1 ㎖) N-} (2-tert- butyldimethylsilyloxy-4-nitrophenyl) -N'- phenyl-thiourea (100 ㎎, 0.248 mmol) Et 3 N · HF in acetonitrile solution of (2-hydroxy-4-nitrophenyl) -N'-phenyl-2-thiourea was prepared by treatment with a solution of triethylamine (100 μL, 0.62 mmol) at 23 ° C for 10 minutes. The solution was concentrated and flushed through a silica plug with EtOAc to give the title compound as an orange solid (55 mg, 77%). mp: 144-145 占 폚; ¹ H NMR (CD ₃ OD / CDCl ₃ ):? 8.65 (d, IH, J = 10.0 Hz), 7.58 7.26 (m, 4 H), 7.10 (m, 1 H).

&Lt; Example 10 >

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

a) Preparation of 4-nitro-2- (phenylsulfonylamino) aniline

A solution of 4-nitro 1,2-phenylenediamine (1.53 g, 10.0 mmol) in DMF was treated with phenylsulfonyl chloride (1.76 g, 10.0 mmol) and triethylamine (1.01 g) in DMF at 23 & Respectively. The reaction mixture was partitioned between saturated NH ₄ Cl and methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to give the desired compound (0.275 g, 9%). ^{1 H NMR (DMSO): δ9.5} (s, 1H, br), 7.83 (dd, 1H, J = 10Hz, 2Hz), 7.74 (d, 2H, J = 8Hz), 7.76 (t, 1H, J = 1H), 7.56 (t, 2H, J = 8 Hz), 7.55 (d, 1H, J = 2H), 6.79 (d, 1H, J = 8 Hz).

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

(4-nitro-2- (phenylsulfonylamino) phenyl) -N ' -phenylurea (33 mg) was obtained as a colorless powder from 4-nitro- 2- (phenylsulfonylamino) aniline (82 mg) and phenylisocyanate . 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 give the desired compound (30.8 mg, 26%). EI-MS m / z 413 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 11 >

Preparation of N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea

a) Preparation of 3-methoxy-2-thienylcarboxylic acid

To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at-78 C was added butyllithium (17 mL, 47.6 mmol). The reaction mixture was stirred at -78 &lt; 0 &gt; C for 1 h and then allowed to warm to 0 &lt; 0 &gt; C for 3 h. After cooling again to -78 [deg.] C, the reaction mixture was poured into a beaker filled with ground dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. The reaction mixture was then poured into a mixture of ice (10 g) added with concentrated HCl (24 mL). The product was precipitated from ether and purified by filtration (6.42 g, 96%). EI-MS m / z 159 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea

To a solution of 3-methoxy-2-thiophenecarboxylic acid (200 mg, 1.27 mmol) in benzene was added (PhO) ₂ PON ₃ (0.33 ml), 2-amino-4-nitrophenol (195.7 mg, 1.27 mmol) And triethylamine (1.1 eq, 0.25 mL). The reaction mixture was stirred at 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 combined organic extracts, dried over MgSO _4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel (hexane: ethyl acetate; 1: 1) to give a solid product (160 mg, 41%). mp. 172.6-173.0 占 폚; _{^{1 H NMR (CD 3 OD /}} CDCl 3) δ 8.96 (d, 1H, J = 2.5Hz), 7.74 (dd, 1H, J = 5.0Hz and J = 1.25Hz), 6.82 (d , 1H, J = 7.5 Hz), 6.76 (s, 2 H), 3.80 (s, 3 H); EI-MS m / z 309 (M + H) &lt; ⁺ &gt;; Analysis (C ₁₂ H ₁₁ N ₃ O ₅ S) C, H, N.

&Lt; Example 12 >

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

To a solution of 3-methoxy-2-thiophenecarboxylic acid (Example 11a, 200 mg, 1.27 mmol) in toluene was added (PhO) ₂ PON ₃ (0.33 ml) and triethylamine (1.1 eq., 0.25 ml) . The reaction mixture was stirred at 70 &lt; 0 &gt; C for 2 hours, cooled to room temperature and 2-amino-5-nitrophenol was added. The reaction mixture was stirred at 70 &lt; 0 &gt; 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 combined organic extracts, dried over MgSO _4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel (hexane: ethyl acetate; 1: 1) to give the product (190 mg, 48%). _{^{1 H NMR (CD 3 OD /}} CDCl 3) δ 8.38 (d, 1H, J = 5.0Hz), 7.85 (dd, 1H, J = 5.0Hz and J = 1.25Hz), 7.76 (d , 1H, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS m / z 309 (M + H) &lt; ⁺ &gt;; Analysis (C ₁₂ H ₁₁ N ₃ O ₅ S) C, H, N.

&Lt; Example 13 >

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

4-nitroaniline (154 mg, 1.0 mmol) and 3-methoxyphenyl isocyanate (1.0 mmol) were reacted according to General Procedure B from N- (2-hydroxy- Methoxyphenyl) urea. The product was diluted with methylene chloride and purified by precipitation with hexane. Filtration afforded the title compound (140 mg, 46%). EI-MS m / z 302 (MH) ^- .

&Lt; Example 14 >

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

4-nitroaniline (154 mg, 1.0 mmol) and 2-methoxyphenyl isocyanate (1 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- Methoxyphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (82 mg, 27%). EI-MS m / z 302 (MH) ^- .

&Lt; Example 15 >

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

N- (2-hydroxy-4-nitrophenyl) -N ') 2-hydroxy-4-nitroaniline (154 mg, 1.0 mmol) and 3- trifluoromethylphenyl isocyanate - (3-methoxyphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (180 mg, 52%). EI-MS m / z 342 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 16 >

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

(2-hydroxy-4-nitrophenyl) -N ' - (2-hydroxy-4-nitro-phenyl) -4-nitroaniline was prepared from 2-hydroxy- (2-trifluoromethylphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (180 mg, 52%). EI-MS m / z 342 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 17 >

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

(2-hydroxy-4-nitrophenyl) -N ' - (2-hydroxy-4-nitro-phenyl) -4-nitroaniline was prepared from 2-hydroxy- (4-trifluoromethylphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (111 mg, 32%). EI-MS m / z 340 (MH) ^- .

&Lt; Example 18 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- 2-bromophenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (530 mg, 47%). EI-MS m / z 350 (MH) ^- .

&Lt; Example 19 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 3-bromophenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- 3-bromophenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.96 g, 87%). EI-MS m / z 350 (MH) ^- .

&Lt; Example 20 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 4-bromophenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- 4-bromophenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.41 g, 37%). EI-MS m / z 352 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 21 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-phenylphenyl isocyanate (3.24 mmol) according to General Method B to give N- (2-hydroxy- -Phenylphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.22 g, 19%). EI-MS m / z 350 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 22 >

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (1-naphthyl) urea

4-nitroaniline (500 mg, 3.24 mmol) and 1-naphthylisocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- -Naphthyl) urea. &Lt; / RTI &gt; The product was precipitated from methylene chloride and filtered. The resulting solid was triturated with 1: 3 triethylamine: methylene chloride. The filtrate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1N HCl in water. The desired product precipitated from the solution was collected by filtration (0.11 g, 10%). EI-MS m / z 324 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 23 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-nitrophenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- -Nitrophenyl) urea. &Lt; / RTI &gt; The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.44 g, 44%). EI-MS m / z 319 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 24 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-fluorophenyl isocyanate (3.24 mmol) were reacted according to General Method B to give N- (2-hydroxy- Fluorophenyl) urea was prepared. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.59 g, 31%). EI-MS m / z 292 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 25 >

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2,6-difluorophenyl) urea

4-nitroaniline (500 mg, 3.24 mmol) and 2,6-difluorophenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- - (2,6-difluorophenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.91 g, 91%). EI-MS m / z 308 (MH) ^- .

&Lt; Example 26 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-ethoxyphenyl isocyanate (3.24 mmol) were reacted in accordance with the general method B to give N- (2-hydroxy- 2-ethoxyphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.84 g, 81%). EI-MS m / z 318 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 27 >

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

4-nitroaniline (500 mg, 3.24 mmol) and 2-ethylphenyl isocyanate (3.24 mmol) were reacted according to General Procedure B to give N- (2-hydroxy- -Ethylphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.44 g, 43%). EI-MS m / z 302 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 28 >

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

N- (2-hydroxy-4-nitrophenyl) -N ', 4'-fluoropyridine was prepared from 2-hydroxy-4-nitroaniline (500 mg, 3.24 mmol) and 2- trifluoromethoxyphenyl isocyanate - (2-trifluoromethyloxyphenyl) urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.69 g, 60%). EI-MS m / z 358 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 29 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylthiophenyl) urea

Urea was prepared from 2-hydroxy-4-nitroaniline (500 mg, 3.24 mmol) and 2-methylthiophenyl isocyanate (3.24 mmol) according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.63 g, 61%). EI-MS m / z 320 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 30 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-chloro-6-methylphenyl) urea

Urea was prepared from 2-hydroxy-4-nitroaniline (500 mg, 3.24 mmol) and 2-chloro-6-methylphenyl isocyanate according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.31 g, 29%). EI-MS m / z 322 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 31 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylsulfoxyphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylthiophenyl) urea (Example 28, 100 mg) was dissolved in sodium perrulate (100 mg) in t- For 12 hours to synthesize urea. The product was precipitated from the reaction mixture (30 mg, 29%). EI-MS m / z 336 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 32 >

Synthesis of N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea

Urea was prepared from 2-hydroxy-4-trifluoromethylaniline (Example 7a, 0.171 g, 1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.25 g, 54%). EI-MS m / z 375 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 33 >

Synthesis of N- (2-hydroxy-4-carbomethoxyphenyl) -N '- (2-bromophenyl) urea

Urea was prepared from 2-hydroxy-4-carbomethoxy aniline (0.167 g, 1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.12 g, 33%). EI-MS m / z 363 (MH) ^- .

&Lt; Example 34 >

Synthesis of N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-phenylphenyl) urea

Urea was prepared from 2-hydroxy-4-trifluoromethylaniline (Example 7a, 0.171 g, 1 mmol) and 2-phenylphenyl isocyanate according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.24 g, 64%). EI-MS m / z 373 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 35 >

Synthesis of N- (2-hydroxy-4-carbomethoxyphenyl) -N '- (2-phenylphenyl) urea

Urea was prepared from 2-hydroxy-4-carbomethoxyaniline (0.167 g, 1 mmol) and 2-phenylphenyl isocyanate (1 mmol) according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.185 g, 50%). EI-MS m / z 363 (MH) ^- .

&Lt; Example 36 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-dichlorophenyl) urea

Urea was prepared from 2-hydroxy-4-nitroaniline (308 mg, 2 mmol) and 2,3-dichlorophenyl isocyanate (2 mmol) according to general method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.5 g, 73%). EI-MS m / z 342 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 37 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea

Urea was prepared from 2-hydroxy-4-nitroaniline (308 mg, 2 mmol) and 2,4-dichlorophenyl isocyanate (2 mmol) according to general method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.26 g, 38%). EI-MS m / z 342 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 38 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) urea

Urea was prepared from 4-nitro-2-hydroxyaniline (308 mg, 2 mmol) and 2-chlorophenyl isocyanate (2 mmol) according to General Method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.29 g, 47%). EI-MS m / z 308 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 39 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dibromophenyl) urea

Urea was prepared from 4-nitro-2-hydroxyaniline (308 mg, 2 mmol) and 2,4-dibromophenyl isocyanate (2 mmol) according to general method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.34 g, 39%). EI-MS m / z 430 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 40 >

Synthesis of N- (2-hydroxynaphthyl) -N '- (2-bromophenyl) urea

Urea was prepared from 1-amino 2-hydroxy naphthalene (195 mg, 1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to general method B. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.030 g, 8%). EI-MS m / z 357 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 41 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) 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 <0> C with 2.5 M n-butyllithium in hexanes (15 mL, 35 mmol). After the addition was complete, the mixture was stirred under reflux for 1 hour. After cooling to room temperature, the ground solid carbon dioxide was added and after 24 h the residue was treated with 10% aqueous NaHCO ₃ and ether. The alkaline layer was separated, washed with ether, then acidified with cold concentrated HCl and extracted with chloroform. Dry the combined organic layers over MgSO _4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m / z 167 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-ethylenedioxyphenyl) urea

To the solution of 2,3-methylenedioxyphenylcarboxylic acid in toluene was added triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL, 1.5 mmol). The reaction mixture was stirred at 60 &lt; 0 &gt; C for 2 h and then 2-amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was cooled to room temperature and 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 MgSO _4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel (hexane: ethyl acetate; 5: 1) to give the product (200 mg, 42%). EI-MS m / z 318 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 42 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-methoxy-3-chlorophenyl) urea

Urea was prepared from 2-hydroxy4-nitroaniline (308 mg, 2 mmol) and 2-chloro-3-methoxyphenyl isocyanate (2 mmol) according to general method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.48 g, 63%). EI-MS m / z 338 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 43 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-methylphenyl) urea

Urea was prepared from 2-hydroxy-4-nitroaniline (308 mg, 2 mmol) and 2-methylphenyl isocyanate (2 mmol) according to general method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.38 g, 53%). EI-MS m / z 288 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 44 >

Synthesis of N (bis (2-hydroxy-4-nitrophenyl) N '- (dianisidine) diurea

Hydroxy-4-nitroaniline (616 mg, 4 mmol) and dianisidinediisocyanate (2 mmol) were prepared according to General Method B (except for using 2 equivalents instead of 1 equivalent of 4-nitro-2-hydroxyaniline) Urea. The product was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.08 g, 6%). EI-MS m / z 605 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 45 >

Synthesis of 4-methylenebis (N- (2-chlorophenyl) N '- (2-hydroxy4-nitrophenyl) urea

Hydroxy-4-nitroaniline (616 mg, 4 mmol) and 4-methylenebis (N- (2-chlorophenylacetyl) amide) were prepared according to general procedure B (except for using 2 equivalents instead of 1 equivalent of 4-nitro- The title compound (0.10 g, 8%) was obtained by filtration. EI-MS m / z 627 &lt; RTI ID = 0.0 &gt; (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 46 >

Synthesis of N- [2-hydroxy-4- (benzylamino) carbonylphenyl] -N '- (2-bromophenyl) urea

a) Synthesis of N- (2-hydroxy-4-carboxylate phenyl) N '- (2-bromophenyl)

Urea was prepared from 3-hydroxy-4-aminobenzoic acid (3.69 g, 24 mmol) and 2-bromophenyl isocyanate (24 mmol) according to general method B. The DMF solution was diluted with methylene chloride and purified by precipitation with hexane (4.0 g, 48%). EI-MS m / z 351 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [4- (benzylamino) carbonyl-2-hydroxyphenyl] -N '- (2-bromophenyl) urea

To a solution of N- (2-hydroxy-4-carboxylate phenyl) N '- (2-bromophenyl) urea (200 mg, 0.58 mmol) in DMF (15 mL) was added EDC (121.9 mg, 0.58 mmol) , HOBT (156.6 mg, 11.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. Benzylamine (123 mg, 11.6 mmol) was then added. The reaction mixture was stirred at the same temperature for 24 hours. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO _4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel (hexane: ethyl acetate; 1: 1) to give the benzyl amino product (500 mg, 65%). EI-MS m / z 441 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 47 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-hydroxyphenyl) urea

The urea was synthesized by treating 2-phenoxyphenylcarboxylic acid (2 mmol) with diphenylphosphoryl azide (0.475 ml) and triethylamine (0.14 ml) in DMF at 80 ° C, 5-Nitrophenol (1 eq.) Was added. The reaction was heated to 80 &lt; 0 &gt; C for 24 hours. The reaction product was oil-removed with hexane. The residue was dissolved in methanol and the solid was precipitated off with water (180 mg, 24%). EI-MS m / z 366 (MH) ^- .

&Lt; Example 48 >

Synthesis of N- (2-hydroxy-4-fluorophenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2-hydroxy-4-fluoroaniline

3-Fluoro 6-nitrophenol (2 g, 11 mmol) was treated with 10% Pd / C (1 g) at 23 &lt; 0 &gt; C. The reaction mixture was flushed with hydrogen gas, and the reaction was stirred for 12 hours and filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.4 g, 77%). EI-MS m / z 169 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2-hydroxy-4-fluorophenyl) N '- (2-bromophenyl) urea

Urea was prepared from 2-hydroxy-4-fluoroaniline (254 mg, 2 mmol) and 2-bromophenyl isocyanate according to General Method B. Purified by dilution with methylene chloride and precipitation with hexanes (173 mg, 26%). EI-MS m / z 325 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 49 >

Synthesis of N- (2-hydroxy-3,4-difluorophenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2-hydroxy-3,4-difluoroaniline

2,3-Difluoro 6-Nitrophenol (2 g, 11 mmol) was treated with 10% Pd / C (1 g) at 23 &lt; 0 &gt; C. The reaction mixture was flushed with hydrogen gas, and the reaction was stirred for 12 hours and filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.6 g, 97%). EI-MS m / z 146 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2-hydroxy-3,4-difluorophenyl) N '- (2-bromophenyl)

Urea was prepared from 2-hydroxy 3,4-difluoroaniline (0.290 g, 2 mmol) and 2-bromophenyl isocyanate (0.4 g) according to General Method B. Purified by dilution with methylene chloride and precipitation with hexanes (0.254 g, 37%). EI-MS m / z 343 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 50 >

Synthesis of N- (2-hydroxy-3-naphthyl) N '- (2-bromophenyl) urea

Urea was prepared from 3-amino 2-hydroxy naphthalene (0.320 g, 2 mmol) and 2-bromophenyl isocyanate (0.40 g) according to general method B. Purified by dilution with methylene chloride and precipitation with hexane (0.339, 47%). EI-MS m / z 357 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 51 >

Synthesis of N- (2-hydroxy-4-phenylphenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2-nitro-5-phenylphenol

A solution of 3-phenylphenol (2 g, 11 mmol) in acetic acid was treated dropwise with concentrated nitric acid until all of the starting material was reacted. The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted with methylene chloride at least once. 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 give the desired compound (1.2 g, 50%). _{^{1 H NMR (CDCl 3):}} δ 10.65 (s, 1H), 8.18 (d, J = 10.0Hz), 7.65 (d, 2H, J = 6.0Hz), 7.49 (m 3H.), 7.34 (s, 1H ), 7.10 (d, 1H, J = 10.0 Hz).

b) Synthesis of 2-amino 5-phenylphenol

A solution of 2-nitro-5-phenylphenol (1.2 g, 5.5 mmol) in methanol was treated with 10% Pd / C (1.2 g). The reaction mixture was flushed with hydrogen and stirred overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound (1.01 g, 98%). EI-MS m / z 186 (M + H) &lt; ⁺ & gt ^; .

c) Synthesis of N- (2-hydroxy-4-phenylphenyl) N '- (2-bromophenyl) urea

Urea was prepared from 2-hydroxy-4-phenylaniline (0.185 g, 1 mmol) and 2-bromophenyl isocyanate (0.198 g) according to General Method B. The DMF solution was diluted with methylene chloride and purified by precipitation with hexane (215 mg, 56%). EI-MS m / z 383 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 52 >

Synthesis of N- (2-hydroxy-4-methylphenyl) N '- (2-bromophenyl) urea

Urea was prepared from 2-hydroxy-4-methylaniline (0.274 g, 2 mmol) and 2-bromophenyl isocyanate (0.40 g, 2 mmol) according to General Method B. The DMF solution was diluted with methylene chloride and purified by precipitation with hexanes (249 mg, 39%). EI-MS m / z 319 (MH) ^- .

&Lt; Example 53 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-phenylaminophenyl) urea

Urea was synthesized by treating 2-tert-butyldimethylsilyloxy 4-nitrophenyl isocyanate (Example 9a, 0.419 g, 1.5 eq) with 2-anilinoaniline (0.184 g, 1 eq) in THF at 40 & . The desired product was precipitated from the reaction mixture (30 mg, 8%). EI-MS m / z 365 (M + H) &lt; ⁺ & gt ^; .

<Example 54>

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

By the general method B, urea was prepared from 2-hydroxy-3-aminobenzoic acid (300 mg, 2 mmol) and 2-bromophenyl isocyanate. It was purified by diluting with DMF solution with methylene chloride and precipitating with hexane (0.287 g, 41%). EI-MS m / z 351 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 55 >

Synthesis of N- (2-sulfopyridyl 4-bromophenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2-amino-6-bromothiazole

4-Bromoaniline (4.3 g, 25 mmol, 1 eq.) And ammonium thiocyanate (5.7 g, 3 eq.) Were dissolved in acetic acid and treated with bromine (4 g, 1 eq.) At room temperature. After the starting mixture disappeared, the reaction mixture was poured into water and the solid was collected. The solid was used in the next reaction without any purification (3.6 g, 46%). EI-MS m / z 229 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of bis (3-bromo 6-aminophenyl) disulfide

2-Amino-6-bromothiazole hydrobromide (500 mg, 1.6 mmol) in water (5 mL) was treated with KOH (2.5 g) at reflux for 8 h and heated. 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 I ₂ . After stirring at room temperature overnight, the reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was purified by flash chromatography (ethyl acetate / hexane) to give the title compound (230 mg, 34%). EI-MS m / z 405 (M + H) &lt; ⁺ & gt ^; .

c) Synthesis of N- (2-sulfopyridyl 4-bromophenyl) N '- (2-bromophenyl) urea

A solution of (3-bromo 6-aminophenyl) disulfide (201 mg, 0.5 mmol) in DMF was treated with 2-bromophenyl isocyanate (1 mmol) at 80 <0> C overnight. The reaction mixture was diluted with methylene chloride, and the solid was precipitated with hexane. The solution was dissolved in MeOH and treated with NaBH _4. After the gas evolution ceased, the reaction mixture was carefully acidified with 1N HCl and the resulting solid was filtered (52 mg, 13%). EI-MS m / z 399 (MH) ^- .

&Lt; Example 56 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-iodophenyl) urea

Urea was synthesized by treating 2-iodobenzoic acid (5 g, 20 mmol) with diphenylphosphoryl azide (1 equivalent) and triethylamine (1 equivalent) in DMF at 80 ° C, 5-Nitro-2-aminophenol (3 g, 1 eq.) Was added. The reaction was heated at 80 &lt; 0 &gt; C overnight. The reaction mixture was purified by filtration through a plug of silica with methylene chloride. The desired product was precipitated off with hexane. Filtration gave the desired compound (1.08 g, 13%). EI-MS m / z 398 (MH) ^- .

&Lt; Example 57 >

Synthesis of N- (2-hydroxy-4-nitrophenyl) N '- (2-bromophenyl) thiourea

2-tert-Butyldimethylsilyloxy thiourea was synthesized by treating 4-nitrophenylthioisocyanate (see Example 9a, 3.73 mmol) with 2-bromoaniline in toluene at 88 DEG C for 36 hours. The solution was concentrated and the residue was purified by flash chromatography (EtOAc / hexanes). A fraction of rf slightly lower than the starting material contained the compound of interest. This fraction was concentrated and then treated with triethylamine hydrofluoride in acetonitrile at 23 &lt; 0 &gt; C for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate / hexane) to give N- (2-hydroxy-4-nitrophenyl) N &apos;-( 2- bromophenyl) thiourea , 4%). EI-MS m / z 369 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 58 >

Synthesis of N- (2-phenylsulfamido) 4-cyanophenyl N '- (2-bromophenyl) urea

a) Synthesis of 3- (phenylsulfamido) benzonitrile

3- (Phenylsulfamido) benzonitrile was synthesized from 3-cyanoaniline (23.9 g, 0.2 mol) according to General Method C. And purified by recrystallization from EtOH (15.8 g, 31%). _{^{1 H NMR (CDCl 3):}} δ7.95 (s, 1H), 7.84 (d, 2H, J = 8.0Hz), 7.59 (t, 1H, J = 8.0Hz), 7.45 (m, 2H), 7.35 ( m, 4H).

b) Synthesis of 3- (phenylsulfamido) 4-nitrobenzonitrile

3- (Phenylsulfamido) benzonitrile (10 g, 39 mmol) was dissolved in acetic anhydride and treated dropwise with concentrated nitric acid until all starting material was reacted at room temperature. The reaction mixture was then carefully quenched by pouring into sodium bicarbonate and allowed to stand until the gas evolution ceased. It was then partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate and filtered. The reaction mixture was concentrated in vacuo, absorbed onto silica gel and purified by column chromatography (methylene chloride / hexane) to give the title compound (1.7 g, 15%). EI-MS m / z 302 (M + H) &lt; ⁺ & gt ^; .

c) Synthesis of 3- (phenylsulfamido) 4-aminobenzonitrile

3- (Phenylsulfamido) 4-nitrobenzonitrile (1.5 g, 4.9 mmol) was treated with tin chloride dihydrate in EtOH at 80 &lt; 0 &gt; C for 12 h. It was then concentrated and flushed with a silica gel plug of 5% methanol / methylene chloride. The filtrate was taken up on silica gel and purified by flash chromatography (ethyl acetate / hexane) to give the title compound (0.9 g, 60%). EI-MS m / z 274 (M + H) &lt; ⁺ & gt ^; .

d) Synthesis of N- (2-phenylsulfamido) 4-cyanophenyl N '- (2-bromophenyl) urea

Urea was synthesized from 2- (phenylsulfamido) 4-aminobenzonitrile (77 mg, 0.28 mmol) and 2-bromophenyl isocyanate according to General Method C. Purification by column chromatography (ethyl acetate / hexane) gave the title compound (30 mg, 22%). EI-MS m / z 469 (MH) ^- .

<Example 59>

Synthesis of N- (2-phenylsulfamido) phenyl N '- (2-bromophenyl) urea

a) Synthesis of 2- (phenylsulfamido) aniline

Sulfonamide was synthesized from phenylsulfonyl chloride (0.01 mmol) and o-phenylenediamine (1.08 g, 0.01 mmol) according to General Method C. Purified by recrystallization from EtOH (1.0 g, 40%). EI-MS m / z 249 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2-phenylsulfamido) phenyl N '- (2-bromophenyl) urea

Urea was synthesized from 2- (phenylsulfamido) aniline (1 mmol) and 2-bromophenyl isocyanate according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.234 g, 52%). EI-MS m / z 446 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 60 >

Synthesis of N- (2-styrylsulfamido) phenyl N '- (2-bromophenyl) urea

a) Synthesis of 2- (Styrylsulfamido) aniline

Sulfonamide was synthesized from styrylsulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) by General Method C. Purification by recrystallization from EtOH (1.2 g, 60%). EI-MS m / z 199 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2- (styrylsulfamido) phenyl) N '- (2-bromophenyl) urea

Urea was synthesized from 2- (styrylsulfamido) aniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.309 g, 65%). EI-MS m / z 472 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 61 >

Synthesis of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenylaniline

Sulfonamides were synthesized from 3,4-dimethoxyphenylsulfonyl chloride (0.01 mol) and o-phenylenediamine by General Method C. Purified by recrystallization from EtOH (0.65 g, 21%). EI-MS m / z 309 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenyl N '- (2-bromophenyl) urea

Urea was synthesized from 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenylaniline (1 mmol) and 2-bromophenyl isocyanate according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.062 g, 12%). EI-MS m / z 504 (MH) ^- .

&Lt; Example 62 >

Synthesis of N- (2 - [(4-acetamidophenyl) sulfonylamino] phenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2 - [(4-acetamidophenyl) sulfonylamino] phenylaniline

Sulfonamides were synthesized from 4-acetamidophenylsulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) by General Method C. Purification by recrystallization from EtOH (1.27 g, 40%). EI-MS m / z 304 (MH) ^- .

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

Urea was synthesized from 2 - [(4-acetamidophenyl) sulfonylamino] phenylaniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.12 g, 24%). EI-MS m / z 501 (MH) ^- .

&Lt; Example 63 >

Synthesis of N- (2- (2-thiophenesulfamidophenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2- (2-thiophenesulfamido) aniline

Sulfonamides were synthesized from 2-thiophenesulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) according to General Method C. Purified by recrystallization from EtOH (0.77 g, 30%). EI-MS m / z 255 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2- (2-thiophenesulfonylaminophenyl) N '- (2-bromophenyl) urea

Urea was synthesized from 2- (2-thiophenesulfonylamino) aniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.29 g, 64%). EI-MS m / z 450 (MH) ^- .

Example 64:

Synthesis of N- (2- (3-tolylsulfonylaminophenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2- (3-tolylsulfonylamino) aniline

Sulfonamide was synthesized from 3-tolylsulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) by General Method C. Purified by recrystallization from EtOH (0.73 g, 28%). EI-MS m / z 263 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2 - ((3-tolylsulfonylamino) phenyl) N '- (2-bromophenyl) urea

Urea was synthesized from 2- (3-tolylsulfonylamino) aniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. And recrystallized twice with EtOH (25 mg, 5%). EI-MS m / z 458 (MH) ^- .

&Lt; Example 65 >

Synthesis of N- (2- (8-quinolinylsulfonylamino) phenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2- (8-quinolinylsulfonylamino) aniline

Sulfonamides were synthesized from 8-quinolinylsulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) according to General Method C. Purified by recrystallization from EtOH (0.82 g, 27%). EI-MS m / z 300 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2 - ((8-quinolinyl) sulfonylamino) phenyl) N '- (2-bromophenyl) urea

Urea was synthesized from 2 - ((8-quinolinylsulfonylamino) aniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.23 g, 46%). EI-MS m / z 495 (MH) ^- .

&Lt; Example 66 >

Synthesis of N- (2- (benzylsulfonylamino) phenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2- (benzylsulfonylamino) aniline

Sulfonamide was synthesized from benzylsulfonyl chloride (0.01 mol) and o-phenylenediamine (0.01 mol) by General Method C. Purification by recrystallization from EtOH (0.87 g, 33%). EI-MS m / z 263 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2- (benzylsulfonylamino) phenyl) N '- (2-bromophenyl) urea

Urea was synthesized from 2- (benzylsulfonylamino) aniline (1 mmol) and 2-bromophenyl isocyanate (1 mmol) according to General Method B. It was purified by diluting with methylene chloride and precipitating with hexane. Filtration afforded the title compound (0.11 g, 23%). EI-MS m / z 460 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 67 >

Synthesis of N- (2-hydroxy-4-azidophenyl) -N '- (2-methoxyphenyl) urea

a) Synthesis of N- (2-hydroxy-4-aminophenyl) -N '- (2-methoxyphenyl)

Palladium on activated charcoal, 10%) (100 mg) was added to a solution of N- (2-hydroxy-4-nitrophenyl) -N '- (2- methoxyphenyl) urea (1.0 g, Was added. The reaction mixture was hydrogenated under a balloon of hydrogen for 18 hours. The solid was filtered off with celite and washed three times with methanol. The filtrate was concentrated under reduced pressure to give the amine compound (0.8 g, 89%). EI-MS m / z 274 (M + H) &lt; ⁺ & gt ^; .

b) Synthesis of N- (2-hydroxy-4-azidophenyl) -N '- (2-methoxyphenyl)

(300 mg, 1.17 mmol) was added to HCl / H ₂ O (1.17 mL / 2.34 mL), and a solution of O (2-hydroxy-4-aminophenyl) -N 'Lt; 0 &gt; C. Sodium nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. Sodium azide (76 mg, 1.17 mmol) was added to the reaction mixture and warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. It was then extracted three times with ethyl acetate. Was chromatographed to give the product on a (125 ㎎, 38%): ;: Combine the organic extracts, dried over MgSO _4, filtered and the resulting solid by concentration under reduced pressure was subjected to silica gel (hexane-ethyl acetate 5). EI-MS m / z 300 (M + H) &lt; ⁺ & gt ^; .

&Lt; 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 (10 g, 61 mmol) in methanol (250 mL) was added 10% Pd / C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the 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 the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (8.0 g, 97%). _{^{1 H NMR (CD 3 OD)}} : δ6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).

b) Preparation of N- [2-hydroxy-5-cyanophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-5-cyanophenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-4-cyanophenol (268 mg, 2.00 mmol) . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (540 mg, 81%). _{^{1 H NMR (CD 3 OD)}} : δ8.10 (d, 1H), 7.87 (d, 1H), 7.43 (d, 1H), 7.20 (t, 1H), 7.09 (d, 1H), 6.86 (t, 1H), &lt; / RTI &gt; 6.77 (d, 1H).

&Lt; 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 (1 g, 6.4 mmol) in methanol (250 mL) was added 10% Pd / C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the 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 the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (650 mg, 80.2%). _{^{1 H NMR (CD 3 OD)}} : δ6.41-6.17 (m, 3H).

b) Preparation of N- [2-hydroxy-3-fluorophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-3-fluorophenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-3-fluorophenol (254 mg, 2.00 mmol) . The product was purified by precipitation from methylene chloride / hexane (1/20) and filtered (500 mg, 77%). _{^{1 H NMR (CD 3 OD)}} : δ8.05 (d, 1H), 7.50 (d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 ( m, 2H).

&Lt; 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, 1.23 mmol) in methanol (250 mL) was added 10% Pd / C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the 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 the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (171 mg, 81.2%). _{^{1 H NMR (CD 3 OD)}} : δ7.60 (d, 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

2- [1-Hydroxyfluorene] -N '- [2-bromophenyl] urea was prepared from 2-amino-1-hydroxyfluorene (170 mg, 0.86 mmol) according to General Method B. The resulting solid was purified by chromatography on silica gel (30% EtOAc / hexanes) to give the desired product (300 mg, 84.5%). _{^{1 H NMR (CD 3 Cl)}} : δ8.04 (d, 1H), 7.66 (d, 1H), 7.49 (t, 2H), 7.35-7.20 (m, 4H), 7.09 (d, 1H), 6.90 ( t, 1 H).

&Lt; Example 71 >

Preparation of N-3- [2-hydroxy-9,10-anthraquinolyl] -N '- [2-bromophenyl] urea

3-aminoanthraquinone (480 mg, 2.00 mmol) was reacted with N-3- [2-hydroxy-9,10-anthraquinolyl] -N '- [2-bromophenyl ] Urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (610 mg, 70%). _{^{1 H NMR (CD 3 OD)}} : δ8.93 (s, 1H), 8.12 (m, 2H), 8.02 (d, 1H), 7.77 (m, 2H), 7.61 (d, 1H), 7.52 (s, 1H), 7.38 (t, 1 H), 7.05 (t, 1 H).

<Example 72>

Preparation of N- [2-hydroxy-3-fluoro-5-bromophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-6-fluoro-4-bromophenol

A mixture of tin (II) chloride (4.78 g, 21.2 mmol) in 4-bromo-2-fluoro 6-nitrophenol (1 g, 4.2 mmol) and ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was slightly acidified (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (710 mg, 82%). _{^{1 H NMR (CD 3 OD)}} : δ6.51-6.40 (m, 2H).

b) Preparation of N- [2-hydroxy-3-fluoro-5-bromophenyl] -N '- [2-bromophenyl] urea

Fluoro-4-bromophenol (254 mg, 2.00 mmol) was reacted with N- [2-hydroxy-3-fluoro-5-bromophenyl] -N '- [ 2-bromophenyl] urea. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (500 mg, 77%). _{^{1 H NMR (CD 3 OD)}} : δ7.98 (s, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.33 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H).

&Lt; Example 73 >

Preparation of N- [2-hydroxy-3-chlorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-3-chlorophenol

A mixture of tin (II) chloride (1.2 g, 5.3 mmol) in 3-chloro-2-nitrophenol (250 mg, 1.4 mmol) and ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was slightly acidified (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (143 mg, 69%). _{^{1 H NMR (CD 3 OD)}} : δ6.75 (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 (143 mg, 1.00 mmol) according to General Method B. The resulting solid was purified by chromatography on silica gel (30% EtOAc / hexanes) to give the desired product (195 mg, 57%). _{^{1 H NMR (CD 3 OD)}} : δ7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.20 (t, 1H), 6.90 (m, 2H), 6.70 (t, 1H).

&Lt; Example 74 >

Preparation of N- [2-hydroxy-3-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-trifluoromethylphenol

2-Trifluoromethylphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.73 g, 20.4 mmol) was added. Sulfuric acid (23 mL / 3M) was then added and sodium nitrite catalyzed was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.48 g, 47%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H).

b) Preparation of 2-amino-6-trifluoromethylphenol

A mixture of tin (II) chloride (6.0 g, 26.2 mmol) in 6-trifluoromethyl-2-nitrophenol (1.84 g, 8.67 mmol) and ethanol (150 mL) was heated to 80 ° C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was made slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.35 g, 88%). _{^{1 H NMR (CD 3 OD)}} : δ6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).

c) Preparation of N- [2-hydroxy-3-trifluoromethylphenyl] -N '- [2-bromophenyl]

Trifluoromethylphenyl] -N '- [2-bromophenyl] urea from 280 mg (1.60 mmol) of 2-amino-6-trifluoromethylphenol . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (390 mg, 65%). _{^{1 H NMR (CD 3 OD)}} : δ7.99 (d, 1H), 7.60 (d, 1H), 7.58 (d, 1H), 7.34 (t, 1H), 7.30 (d, 1H), 7.00 (t, 1H), &lt; / RTI &gt; 6.96 (d, 1H).

&Lt; Example 75 >

Preparation of N- [3,4-diphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

4-diphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea from 50 mg (0.19 mmol) of 2-amino- . The product was precipitated with methylene chloride / hexane (1/20) and purified by filtration (61 mg, 69%). _{^{1 H NMR (CD 3 OD)}} : δ7.97 (d, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.31 (t, 2H), 7.25-7.00 (. M 11H), 6.91 ( d, 1H).

<Example 76>

Preparation of N- [2-hydroxy-3-glycine methyl ester carbonylphenyl] -N '- [2-bromophenyl] urea

2-hydroxy-3-glycine methyl ester carbonylphenyl] -N (2-hydroxyphenyl) -N (2-hydroxyphenyl) propanoic acid was obtained from 6-glycine methyl ester carbonyl-2-aminophenol (50 mg, 0.22 mmol) purchased from University of New Hampshire, - [2-bromophenyl] urea. The product was precipitated with methylene chloride / hexane (1/20) and purified by filtration (65 mg, 69%). _{^{1 H NMR (CD 3 OD)}} : δ8.14 (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).

&Lt; Example 77 >

Preparation of N- [2-hydroxy-3-glycine carbonylphenyl] -N '- [2-bromophenyl] urea

-N- [2-bromophenyl] urea (50 mg, 0.12 mmol) by stirring in a 3/1 ratio of methanol / water (10 mL) ) To give N- [2-hydroxy-3-glycine carbonylphenyl] -N '- [2-bromophenyl] urea. One equivalent of lithium hydroxide was added and stirring was continued until the starting material disappeared (45 mg, 92%). The product was purified by chromatography on silica gel (9/1 / 0.1 CH ₂ Cl ₂ / MeOH / AcOH) to give the desired product (195 mg, 57%). _{^{1 H NMR (CD 3 OD)}} : δ8.14 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.34 (t, 1H), 7.04 (t, 1H), &lt; / RTI &gt; 6.82 (t, 1H), 3.96 (2H).

&Lt; 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 (1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol (50 mL) was heated to 80 ° C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was made slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (685 mg, 80%). _{^{1 H NMR (CD 3 OD)}} : δ6.75 (s, 1H), 6.61 (s, 1H).

b) Preparation of N- [2-hydroxy-3,5-dichlorophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-3,5-dichlorophenyl] -N '- [2-bromophenyl] urea was obtained from 2-amino-4,6-dichlorophenol (143 mg, . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (660 mg, 88%). _{^{1 H NMR (CD 3 OD)}} : δ7.96 (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] urea

N- [2-hydroxy-3-nitrophenyl] -N '- [2-bromophenyl] urea was prepared from 2-hydroxy-3-nitroaniline (1.25 g, 8.1 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (2.4 g, 84%). _{^{1 H NMR (CD 3 OD)}} : δ8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.01 (m, 2H).

&Lt; Example 80 >

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

1-amino-2-hydroxy-4-naphthalenesulfonic acid (0.48 g, 2.0 mmol) was reacted with 1 ml of triethylamine according to General Method B to give N- [2-hydroxy-4-naphthalenesulfonic acid] [2-bromophenyl] urea was prepared. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (690 mg, 79%). _{^{1 H NMR (CD 3 OD)}} : δ8.14 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 ( t, 1 H).

&Lt; Example 81 >

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

N-3- [2-hydroxy-5-naphthalenesulfonic acid] -N (2-amino-3-hydroxy-6-naphthalenesulfonic acid) - [2-bromophenyl] urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (715 mg, 82%). _{^{1 H NMR (CD 3 OD)}} : δ8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 (s, 1H), 7.04 ( m, 2H).

&Lt; 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 (3.26 g, 20 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.88 g, 22 mmol) was added. Sulfuric acid (20 mL / 3M) was then added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.8 g, 44%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.04 (d, 1H), 7.15 (d, 1H).

b) Preparation of 2-amino-5,6-dichlorophenol

A mixture of tin (II) chloride (5.8 g, 26.1 mmol) in 5,6-dichloro-2-nitrophenol (1.8 g, 8.7 mmol) and ethanol (50 mL) was heated to 80 ° C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was made slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.4 mg, 90%). _{^{1 H NMR (CD 3 OD)}} : δ6.71 (d, 1H), 6.45 (d, 1H).

c) Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-3,4-dichlorophenyl] -N '- [2-bromophenyl] urea was obtained from 2-amino-5,6-dichlorophenol (350 mg, 2.00 mmol) . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (670 mg, 89%). _{^{1 H NMR (CD 3 OD)}} : δ7.90 (d, 1H), 7.85 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 6.99 (t, 1H), 6.96 (d, 1H).

&Lt; Example 83 >

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-cyanophenol

2-Cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.88 g, 22 mmol) was added. Sulfuric acid (20 mL / 3M) was then added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.4 g, 42%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.47 (d, 1H), 8.15 (d, 1H), 7.30 (t, 1H).

b) Preparation of 2-amino-6-cyanophenol

A mixture of tin (II) chloride (3.2 g, 14.4 mmol) in 6-cyano-2-nitrophenol (600 mg, 1.0 mmol) and acetic acid (50 mL) was heated to 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was made slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (365 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ6.92 (d, 1H), 6.85-6.69 (m, 2H).

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

[2-Hydroxy-3-cyanophenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-6-cyanophenol (134 mg, 1.00 mmol) according to general method B . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (260 mg, 78%). _{^{1 H NMR (CD 3 OD)}} : δ7.98 (d, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.30 (t, 1H), 7.22 (d, 1H,), 6.98 (t , &Lt; / RTI &gt; 1H), 6.94 (t, 1H).

&Lt; Example 84 >

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-cyanophenol

3-Cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.88 g, 22 mmol) was added. Sulfuric acid (20 mL / 3M) was then added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (910 mg, 28%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.30 (d, 1H), 7.67 (s, 1H), 7.49 (d, 1H).

b) Preparation of 2-amino-5-cyanophenol

A mixture of tin (II) chloride (3.2 g, 14.4 mmol) in 5-cyano-2-nitrophenol (250 mg, 1.5 mmol) and ethanol (50 mL) was heated to 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was made slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (175 mg, 86%). _{^{1 H NMR (CD 3 OD)}} : δ7.00 (d, 1H), 6.88 (s, 1H), 6.69 (d, 1H).

c) Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-4-cyanophenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-5-cyanophenol (170 mg, 1.27 mmol) according to General Method B . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (310 mg, 74%). _{^{1 H NMR (CD 3 OD)}} : δ8.25 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (s, 1H), &lt; / RTI &gt; 7.01 (t, 1H).

&Lt; Example 85 >

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

[2-hydroxy-4-cyanophenyl] -N '- [4-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) according to general method B . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (110 mg, 86%). ¹ H NMR (CD ₃ OD):? 8.23 (d, 1H), 7.61-7.51 (m, 2H), 7.32 s, 1H).

&Lt; Example 86 >

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

[2-hydroxy-4-cyanophenyl] -N '- [2-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (170 mg, 1.27 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (150 mg, 85%). _{^{1 H NMR (CD 3 OD)}} : δ8.20 (d, 1H), 7.73 (d, 1H), 7.51-7.20 (m, 8H), 7.13 (d, 1H), 7.01 (s, 1H).

&Lt; Example 87 >

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

[2-Hydroxy-4-cyanophenyl] -N '- [2-methylphenyl] urea was prepared from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (90 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ8.25 (d, 1H), 7.59 (d, 1H), 7.26-7.00 (m, 5H), 2.30 (s, 3H).

&Lt; Example 88 >

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-trifluoromethylphenyl] urea

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-trifluoromethylphenyl] urea from 2-amino-5-cyanophenol (60 mg, Respectively. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (110 mg, 76%). _{^{1 H NMR (CD 3 OD)}} : δ8.25 (d, 1H), 7.81 (d, 1H), 7.68 (d, 1H), 7.61 (t, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, 1 H).

<Example 89>

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [3-trifluoromethylphenyl] urea

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [3-trifluoromethylphenyl] urea from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) Respectively. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (114 mg, 79%). _{^{1 H NMR (CD 3 OD)}} : δ8.30 (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, 1 H).

<Example 90>

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [4-trifluoromethylphenyl] urea

4-cyanophenyl] -N '- [4-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) according to General Method B Respectively. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (108 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ8.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H), 7.20 (dd, 1H), 7.07 (s, 1H).

&Lt; Example 91 >

Preparation of N- [2-hydroxy-3-n-propylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-n-propylphenol

2-n-propylphenol (5.00 g, 36.8 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (3.43 g, 40.5 mmol) was added. Sulfuric acid (45 mL / 3M) was added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (3.2 mg, 48%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ7.99 (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 (2 g, 11.0 mmol) in methanol (100 mL) was added 10% Pd / C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the 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 the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.50 g, 80.2%). _{^{1 H NMR (CD 3 OD)}} : δ6.65 (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

[2-hydroxy-3-n-propylphenyl] -N '- [2-bromophenyl] urea was obtained from 2-amino-6-n-propylphenol (302 mg, 2.00 mmol) . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (640 mg, 92%). _{^{1 H NMR (CD 3 OD)}} : δ8.00 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, 1H), &lt; / RTI &gt; 6.78 (d, 1H).

&Lt; Example 92 >

Preparation of N- [2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-ethylphenol

3-Ethylphenol (5.00 g, 41 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (3.83 g, 45 mmol) was added. Sulfuric acid (50 mL / 3M) was added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.7 g, 25%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.02 (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 (1 g, 6.4 mmol) in methanol (250 mL) was added 10% Pd / C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the 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 the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (750 mg, 91%). _{^{1 H NMR (CD 3 OD)}} : δ6.41-6.17 (m, 3H).

c) Preparation of N- [2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-5-ethylphenol (274 mg, 2.00 mmol) according to General Method B. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (520 mg, 77%). _{^{1 H NMR (CD 3 OD)}} : δ7.96 (d, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), &lt; / RTI &gt; 6.76 (d, 1H).

&Lt; Example 93 >

Preparation of N- [2-hydroxy-3-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-phenylaminocarbonylphenol

2-Phenylaminocarbonylphenol (5.00 g, 23 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (2.20 g, 25.5 mmol) was added. Sulfuric acid (30 mL / 3M) was added and sodium nitrite catalytic amount was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (2.50 g, 42%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.15 (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 (1 g, 4.0 mmol) in methanol (250 mL) was added 10% Pd / C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (800 mg, 91%). _{^{1 H NMR (CD 3 OD)}} : δ7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H ).

c) Preparation of N- [2-hydroxy-3-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-3-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] -4,5- Urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (800 mg, 94%). ¹ H NMR (CD ₃ OD):? 8.25 (d, 1H), 7.94 (d, 1H), 7.75-7.57 (m, 4H), 7.48-7.30 7.02 (dd, 1 H), 6.92 (t, 1 H).

&Lt; Example 94 >

Preparation of N- [2-hydroxy-3-cyano-4-methylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-methyl-6-bromophenol

A solution of t-butylamine (6.88 mL, 4.79 g, 2 eq) in methylene chloride was treated with bromine (1.67 mL, 5.2 g, 1 eq) at -20 < The flask was then cooled to-78 C and added dropwise with vigorous stirring with 2-nitro-5-methyl 6-bromophenol (5 g, 1 eq in methylene chloride). The reaction mixture was slowly warmed to-30 C for 1 h and then warmed to -10 C for 2 h. The reaction mixture was then partitioned between methylene chloride and 5% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (ethyl acetate / hexane) to remove the dibromide species. The 2-nitro-4-bromo-5-methylphenol was then selectively precipitated from methylene chloride. The final isomer was obtained in 90% purity by a final silica gel column (5% ethyl acetate / hexanes) (1.05 g, 14%). ¹ H NMR (CDCl ₃ ):? 7.95 (d, 1H, J = 10.0 Hz), 6.91 (d, 1H, J = 10.0 Hz), 2.52 (s, 3H).

b) Preparation of 2-nitro-5-methyl-6-cyanophenol

2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethylformamide (2 mL) followed by the addition of triethylamine (0.175 g, 1.73 mmol). Subsequently, a dimethylaminopyridine catalyst was added followed by copper (I) cyanide (155 mg, 1.73 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 4 hours. The solvent was evaporated and the resulting solid was chromatographed on silica gel (2% MeOH / CH ₂ Cl ₂ ) to give the desired product (70 mg, 91%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.30 (d, 1H), 7.15 (d, 1H), 2.61 (s, 3H).

c) Preparation of 2-amino-5-methyl 6-cyanophenol

A mixture of 5-cyano-2-nitrophenol (70 mg, 0.39 mmol) and tin (II) chloride (265 mg, 1.18 mmol) in ethanol (20 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (175 mg, 86%). _{^{1 H NMR (CD 3 OD)}} : δ6.87 (d, 1H), 6.75 (d, 1H), 6.32 (s, 3H).

d) Preparation of N- [2-hydroxy-3-cyano-4-methylphenyl] -N '- [2-bromophenyl] urea

Methyl-6-cyanophenol (50 mg, 0.34 mmol) was reacted with N- [2-hydroxy-3-cyano- Bromophenyl] urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (70 mg, 60%). _{^{1 H NMR (CD 3 OD)}} : δ7.92 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.62 (t, 1H), &lt; / RTI &gt; 2.49 (s, 3H).

&Lt; Example 95 >

Preparation of N- [2-hydroxy-4-carboxyphenylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 4-nitro-3-hydroxybenzophenone

3-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.42 g, 16.7 mmol) was added. Sulfuric acid (25 mL / 3M) was added followed by the sodium nitrite catalytic amount. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.10 g, 30%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.25 (d, 1H), 7.86 (d, 1H), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd , 1H).

b) Preparation of 4-amino-3-hydroxybenzophenone

A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7 mmol) and tin (II) chloride (2.5 g, 11.1 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. When the starting material disappeared, the solution was cooled and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (685 mg, 87%). _{^{1 H NMR (CD 3 OD)}} : δ7.65 (d, 2H), 7.55 (d, 1H), 7.49 (t, 2H), 7.26 (s, 1H), 7.16 (dd, 1H), 6.68 (d, 1H).

c) Preparation of N- [4-carboxyphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

[4-carboxyphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea was prepared from 4-amino-3-hydroxybenzophenone (330 mg, Respectively. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (490 mg, 79%). _{^{1 H NMR (CD 3 OD)}} : δ8.40 (d, 1H), 8.09 (d, 1H), 7.83 (d, 2H), 7.65-7.60 (m, 4H), 7.48 (s, 1H), 7.43 ( d, 1 H), 7.35 (d, 1 H), 7.10 (t, 1 H).

&Lt; Example 96 >

Preparation of N- [2-hydroxy-3-carboxyphenylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 3-nitro-2-hydroxybenzophenone

2-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.42 g, 16.7 mmol) was added. Sulfuric acid (25 ml / 3M) was added, followed by catalytic addition of sodium nitrite. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.60 g, 44%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.30 (d, 1H), 7.86 (m, 3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd, 2H), 7.24 (t , 1H).

b) Preparation of 3-amino-2-hydroxybenzophenone

A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5 mmol) and tin (II) chloride (1.7 g, 7.5 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (490 mg, 92%). _{^{1 H NMR (CD 3 OD)}} : δ7.65-7.40 (m, 5H), 6.98 (d, 1H), 6.86 (d, 1H), 6.67 (t, 1H).

c) Preparation of N- [2-hydroxy-3-carboxyphenylphenyl] -N '- [2-bromophenyl] urea

Preparation of N- [2-hydroxy-3-carboxyphenylphenyl] -N '- [2-bromophenyl] urea from 3-amino-2-hydroxybenzophenone (250 mg, 1.20 mmol) Respectively. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (200 mg, 78%). _{^{1 H NMR (CD 3 OD)}} : δ8.35 (d, 1H), 7.96 (d, 1H), 7.72 (d, 2H), 7.65-7.50 (m, 4H), 7.35 (d, 1H), 7.30 ( d, 1 H), 7.01 (dd, 1 H), 6.92 (t, 1 H).

<Example 97>

Preparation of N- [2-hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-benzyloxyphenol

2-Benzyloxyphenol (5.00 g, 25.0 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (2.30 g, 27.5 mmol) was added. Sulfuric acid (31 ml / 3M) was added, followed by catalytic addition of sodium nitrite. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (2.6 g, 43%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ7.70 (d, 1H), 7.50-7.28 (m, 5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 (s, 2H).

b) Preparation of 2-amino-6-benzyloxyphenol

A mixture of 2-nitro-6-benzyloxyphenol (1.00 g, 4.10 mmol) and tin (II) chloride (2.75 g, 12.2 mmol) in ethanol (150 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.35 g, 88%). ¹ H NMR (CD ₃ OD):? 7.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, 1H), 6.40 (d,

b) Preparation of N- [2-hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea

[3-benzyloxy-2-hydroxyphenyl] -N '- [2-bromophenyl] urea was prepared from 2-nitro-6-benzyloxyphenol (430 mg, 2.00 mmol) according to General Method B . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (630 mg, 76%). _{^{1 H NMR (CD 3 OD)}} : δ7.93 (d, 1H), 7.58 (d, 1H), 7.54-7.42 (m, 3H), 7.40-7.25 (m, 4H), 7.00 (t, 1H), 6.69 (d, 2 H), 5.16 (s, 2 H).

&Lt; Example 98 >

Preparation of N-3- [2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea

a) Preparation of 2-hydroxy-3-nitro-5-indanone

2-hydroxy-5-indanone (3.00 g, 20.0 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.95 g, 21.0 mmol) was added. Sulfuric acid (25 ml / 3M) was added, followed by catalytic addition of sodium nitrite. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.5 g, 39%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ7.70 (d, 1H), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H).

b) Preparation of 3-amino-2-hydroxy-5-indanone

A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80 mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol (150 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.00 g, 79%). _{^{1 H NMR (CD 3 OD)}} : δ6.85 (d, 1H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).

c) Preparation of N-3- [2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea

[2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea from 326 mg (2.00 mmol) of 3-amino- . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (610 mg, 85%). _{^{1 H NMR (CD 3 OD)}} : δ7.92 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 7.09 (t, 1H), 7.00 (d, 1H), 2.90 (d, 2H), 2.66 (d, 2H).

&Lt; Example 99 >

Preparation of (E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 4-nitro-3-hydroxycinnamic acid

3-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.70 g, 26.1 mmol) was added. Sulfuric acid (25 ml / 3M) was added, followed by catalytic addition of sodium nitrite. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.0 g, 26%). ¹ H NMR (CD ₃ COCD ₃ ):? 8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H), 7.46 (d, 2H), 6.75

b) Preparation of 4-nitro-3-hydroxymethylcinnamate

4-Nitro-3-hydroxycinnamic acid was stirred with excess catalytic amount of sulfuric acid in methanol. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.0 g, 94%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.17 (d, 1H), 7.69 (d, 1H), 7.52 (s, 1H), 7.45 (d, 2H), 6.75 (d, 1H), 3.80 (s , 3H).

c) Preparation of 4-amino-3-hydroxymethylcinnamate

A mixture of 4-nitro-3-hydroxymethylcinnamate (1.0 g, 4.50 mmol) and tin (II) chloride (3.0 g, 13.4 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (650 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ7.50 (d, 1H), 6.94 (s, 1H), 6.89 (d, 1H), 6.68 (d, 1H), 6.18 (d, 1H), 3.74 (s, 3H).

d) Preparation of (E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

(E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl) piperidine was prepared from 4-amino-3-hydroxymethylcinnamate (250 mg, ] -N '- [2-bromophenyl] urea. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (300 mg, 59%). _{^{1 H NMR (CD 3 OD)}} : δ8.24 (d, 1H), 8.05 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.21 (s, 1H), 7.19 (d, IH), 7.10 (t, IH), 6.45 (d, IH), 3.81 (s, 3H).

&Lt; Example 100 >

Preparation of (E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2- bromophenyl] urea

a) Preparation of 3-nitro-2-hydroxycinnamic acid

2-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (2.21 g, 26.1 mmol) was added. Sulfuric acid (30 ml / 3M) was added, followed by catalytic addition of sodium nitrite. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (2.0 g, 52%). ¹ H NMR (CD ₃ COCD ₃ ):? 8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72

b) Preparation of 3-nitro-2-hydroxymethylcinnamate

3-Nitro-2-hydroxycinnamic acid was stirred in an excess of methanol together with a sulfuric acid catalyst. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.0 g, 94%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.25 (d, 1H), 8.15 (d, 1H), 8.06 (s, 1H), 7.20 (t, 2H), 6.76 (d, 1H), 3.80 (s , 3H).

c) Preparation of 3-amino-2-hydroxymethylcinnamate

A mixture of 3-nitro-2-hydroxymethyl cinnamate (1.0 g, 4.5 mmol) and tin (II) chloride (3.0 g, 13.4 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (700 mg, 81%). _{^{1 H NMR (CD 3 OD)}} : δ8.04 (d, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 6.71 (t, 1H), 6.43 (d, 1H), 3.72 (s, 3H).

d) Preparation of (E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

(E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl) piperidine was prepared in accordance with General Procedure B from 3-amino-2-hydroxymethylcinnamate (100 mg, ] -N '- [2-bromophenyl] urea. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (150 mg, 74%). _{^{1 H NMR (CD 3 OD)}} : δ8.10 (d, 1H), 8.00 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.38 (t, 1H), 7.32 (d, IH), 7.05 (t, IH), 6.55 (d, IH), 3.81 (s, 3H).

&Lt; Example 101 >

(E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2- bromophenyl] urea-N' Production of urea

a) Preparation of 2-hydroxycinnamide

2-Hydroxycinnamic acid (2.00 g, 12.3 mmol) was dissolved in dimethyl formamide (10 mL) and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (5.4 g, 12.3 mmol) and triethylamine (1.7 mL, 12.3 mmol). The reaction mixture was bubbled with ammonia gas for 30 minutes. The mixture was stirred for 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.5 g, 75%).

b) Preparation of 3-nitro-2-hydroxycinnamide

2-Hydroxyne cinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (430 mg, 5.1 mmol) was added. Sulfuric acid (7 mL / 3M) was added followed by the addition of sodium nitrite catalyst. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (350 mg, 36%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.19 (d, 1H), 8.02 (d, 1H), 7.88 (d, 1H), 7.15 (t, 1H), 6.84 (d, 1H).

c) Preparation of 3-amino-2-hydroxycinnamide

A mixture of 3-nitro-2-hydroxymethylcinnamate (350 mg, 1.7 mmol) and tin (II) chloride (3.0 g, 13.4 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (244 mg, 80%).

d) Preparation of (E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

(E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] - piperidine-1- carboxylic acid was prepared from 3-amino-2-hydroxyne cinnamide (100 mg, 0.56 mmol) N ' - [2-bromophenyl] urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (110 mg, 52%). _{^{1 H NMR (CD 3 OD)}} : δ8.00 (d, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.35 (m, 2H), 7.05 (t, 1H), 6.95 (t, IH), 6.70 (d, IH).

&Lt; Example 102 >

Preparation of (E) -N- [4- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2- bromophenyl] urea

a) Preparation of 3-hydroxycinnamide

3-Hydroxycinnamic acid (2.00 g, 12.3 mmol) was dissolved in dimethylformamide (10 mL) and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (5.4 g, 12.3 mmol ) And triethylamine (1.7 mL, 12.3 mmol). Ammonia gas was bubbled into the reaction mixture for 30 minutes. The mixture was stirred for 24 h and the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.3 g, 65%).

b) Preparation of 4-nitro-3-hydroxycinnamide

3-Hydroxyne cinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (430 mg, 5.1 mmol) was added. Sulfuric acid (7 mL / 3M) was added followed by the addition of sodium nitrite catalyst. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (240 mg, 25%). ¹ H NMR (CD ₃ COCD ₃ ):? 8.09 (d, IH), 7.49 (d, IH), 7.26 (s, IH), 7.16 (d,

c) Preparation of 4-amino-2-hydroxycinnamide

A mixture of 4-nitro-3-hydroxymethylcinnamate (300 mg, 1.40 mmol) and tin (II) chloride (980 mg, 4.30 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (200 mg, 74%).

d) Preparation of (E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

(E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] - piperidine was prepared from 4-amino-2-hydroxyne cinnamide (100 mg, N ' - [2-bromophenyl] urea. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (125 mg, 54%). _{^{1 H NMR (CD 3 OD)}} : δ8.05 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.05 (m, 2H), 6.50 (d, 1 H).

&Lt; Example 103 >

Preparation of N- [2-hydroxy-4- (phenylaminocarboxy) phenyl] -N '- [2-bromophenyl] urea

Preparation of N- [2-hydroxy-4- (phenylaminocarboxy) phenyl] -N '- [2-bromophenyl] urea from 5- (phenylaminocarboxy) Respectively. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (150 mg, 70%). _{^{1 H NMR (CD 3 OD)}} : δ8.25 (d, 1H), 8.00 (d, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.50 (d, 2H), 7.41 (m, 3H), 7.16 (t, IH), 7.05 (t, IH).

<Example 104>

Preparation of N- [4-aminocarbonyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

Aminocarbonyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea was obtained from 5-aminocarbonyl-2-aminophenol (304 mg, 0.50 mmol) . The product was purified from methylene chloride / hexane (1/20) and purified by filtration (440 mg, 62%). _{^{1 H NMR (CD 3 OD)}} : δ8.09 (d, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.45 (m, 3H), 7.00 (d, 1H).

&Lt; Example 105 >

Preparation of N- (2-hydroxy-3,5,6-trifluorophenyl) -N '- [2-bromophenyl] urea

(83 mg, 0.51 mmol) and 2- (bromophenyl) isocyanate (100 mg, 0.53 mmol) were reacted with N- [2-hydroxypyridine -3,5,6-trifluorophenyl) -N '- (2-bromophenyl) urea. The product was purified by preparative thin layer chromatography. EI-MS m / z 359 (MH) ^- .

&Lt; Example 106 >

Preparation of N- (2-hydroxy-3-fluoro-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea

(2- (4-fluorophenyl) isoxazole-2-carboxylic acid ethyl ester was prepared from 4- (trifluoromethyl) -3-fluoro-2-hydroxyaniline (239 mg, 1.2 mmol) and 2- Hydroxy-3-fluoro-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea. The solvent was removed under reduced pressure and the resulting solid was chromatographed on silica gel (hexane: ethyl acetate) to give the title compound (20 mg, 4%). EI-MS m / z 391 (MH) ^- .

&Lt; Example 107 >

Preparation of N- (2-hydroxy-3-iodophenyl) -N '- (2-bromophenyl) urea

(2-hydroxy-3-iodo-3-iodo-4-methoxyphenyl) isocyanurate was obtained from 3- iodo-2-hydroxyaniline (200 mg, 0.85 mmol) and 2- (bromophenyl) isocyanate (169 mg, Phenyl) -N '- (2-bromophenyl) urea. The solvent was removed under reduced pressure and the resulting solid was chromatographed on silica gel (hexane: ether) to give the title compound (40 mg, 11%). ^{1 H NMR (DMSO): δ9.45} (s, 1H), 9.15 (s, 1H), 8.8 (s, 1H), 7.95 (d, 1H), 7.8 (d, 1H), 7.65 (d, 1H) , 7.4 (d, IH), 7.3 (t, IH), 7.0 (t, IH), 6.65 (t, IH).

&Lt; Example 108 >

Preparation of N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [2- [2- (trifluoromethyl) phenyl] (sulfonamido) aniline]

The title compound was prepared according to General Method C using 2- (trifluoromethyl) benzenesulfonyl chloride (1 eq.). The product was purified by chromatography on silica gel (methylene chloride: methanol) (1.04 g, 33%). EI-MS m / z 317 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl-N'- (2-bromophenyl) urea

The title compound was prepared from [2- [2- (trifluoromethyl) phenyl] sulfonamido] aniline (1.04 g, 3.2 mmol) and 2- (bromophenyl) isocyanate (652 mg, 3.2 mmol) according to General Method B . The solvent was evaporated and the desired urea (1.03 g, 61%) was obtained. EI-MS m / z 514 (M + H) &lt; ⁺ & gt ^; .

<Example 109>

Preparation of N- (2-bromophenyl) -N '- [2-dimethylaminosulfonylamino] phenyl] urea

a) Preparation of [2- [1,1- (dimethylamino)] sulfonamidoaniline]

The title compound was prepared according to General Procedure C using dimethylsulfamoyl chloride (1 eq.). The product was purified by chromatography over silica gel (methylene chloride: methanol). EI-MS m / z 216 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- (2-bromophenyl) -N '- [2- (dimethylaminosulfonylamino] phenyl] urea

The title compound was prepared according to General Procedure B from [2- [1,1- (dimethylamino) sulfonamidoaniline (137 mg, 0.6 mmol) and 2- (bromophenyl) isocyanate (126 mg, 0.6 mmol). The solvent was evaporated and chromatographed on silica gel (ethyl acetate: hexanes) to give the desired urea. EI-MS m / z 413 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 110 >

Preparation of N- [2- (phenethylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea

(Example 60, 300 mg, 1.09 mmol) was placed in a Parr shaker bottle containing palladium (180 mg) under an argon atmosphere. Methanol (150 mL) was added and the vessel was placed on a Parr shaker (55 psi) for several hours. The reaction mixture was filtered through celite and the filtrate was evaporated to give the desired aniline (269 mg, 90%). EI-MS m / z 277 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2- (phenethylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared according to General Method B from [2- (phenethylsulfonamido) aniline] (269 mg, 0.97 mmol) and 2- (bromophenyl) isocyanate (193 mg, 0.97 mmol). Purified urea was precipitated from toluene / hexane (384 mg, 78%). EI-MS m / z 472 (MH) ^- .

&Lt; Example 111 >

Preparation of N- [2 - [(2-acetamido-4-methylthiazol-5-yl) sulfonylamino] phenyl] -N'- (2-bromophenyl) urea

a) Preparation of [2 - [(2-acetamido-4-methyl-5-thiazole) sulfonamido] aniline]

The title compound, was prepared in accordance with the general method C using 2-Acetamido-4-methyl-5-thiazole sulfonyl chloride (1 eq.). The solid was precipitated from the reaction mixture and filtered to give the desired aniline (1.68 g, 52%). EI-MS m / z 327 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2 - [(2-acetamido-4-methylthiazol-5-yl) sulfonylamino] phenyl] -N'- (2-bromophenyl) urea

(1.68 g, 5.14 mmol) and 2- (bromophenyl) isocyanate (1.02 g, 5.14 &lt; RTI ID = 0.0 & mmol). &lt; / RTI &gt; The product was precipitated from ethyl acetate / hexane (220 mg, 8%). EI-MS m / z 524 (M + H) &lt; ⁺ & gt ^; .

Example 112:

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

[2-hydroxy-4-cyanophenyl] -N '- [4-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (135 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ8.33 (d, 1H), 7.71-7.29 (m, 9H), 7.25 (d, 1H), 7.12 (s, 1H).

&Lt; Example 113 >

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2,3-dichlorophenyl] urea

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2,3-dichlorophenyl] urea from 2-amino-5-cyanophenol (60 mg, 0.45 mmol) Respectively. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (125 mg, 86%). ¹ H NMR (CD ₃ OD):? 8.27 (d, 1H), 8.15 (m, 1H), 7.39-7.20 (m, 2H), 7.16 (d,

&Lt; Example 114 >

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

N- [2-hydroxy-4-cyanophenyl] -N '- [2-methoxyphenyl] urea was prepared from 2- amino-5-cyanophenol (60 mg, 0.45 mmol) . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (105 mg, 83%). _{^{1 H NMR (CD 3 OD)}} : δ8.26 (d, 1H), 8.02 (d, 1H), 7.14 (d, 1H), 7.05 (s, 1H), 7.00-6.83 (m, 3H), 3.84 ( s, 3H).

&Lt; Example 115 >

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [3-methoxyphenyl] urea

N- [2-hydroxy-4-cyanophenyl] -N '- [3-methoxyphenyl] urea was prepared from 2- amino-5-cyanophenol (60 mg, 0.45 mmol) . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (102 mg, 80%). _{^{1 H NMR (CD 3 OD)}} : δ8.25 (d, 1H), 7.25-7.08 (m, 3H), 7.04 (s, 1H), 6.90 (t, 1H), 6.58 (d, 1H).

&Lt; Example 116 >

Preparation of N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-4-fluorophenol

A mixture of 4-fluoro-2-nitrophenol (1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (622 mg, 85%). _{^{1 H NMR (CD 3 OD)}} : δ6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).

b) Preparation of N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea

[2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea was prepared from 2-amino-6-fluorophenol (254 mg, 2.00 mmol) according to general method B . The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (520 mg, 80%). _{^{1 H NMR (CD 3 OD)}} : δ7.88 (d, 1H), 7.79 (dd, 1H), 7.57 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.76 (dd, 1H), &lt; / RTI &gt; 6.57 (ddd, 1H).

&Lt; Example 117 >

Preparation of N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-4-trifluoromethylphenol

A mixture of 4-trifluoromethyl-2-nitrophenol (1.0 g, 4.8 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol (150 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was cooled and poured into ice. The pH was slightly basic (pH 7-8) by adding solid NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (708 mg, 83%). _{^{1 H NMR (CD 3 OD)}} : δ6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).

b) Preparation of N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

2-amino-4-trifluoromethylphenol (354 mg, 2.00 mmol) was reacted with N- [2-hydroxy-5-trifluoromethylphenyl] -N ' . The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (490 mg, 65%). _{^{1 H NMR (CD 3 OD)}} : δ8.40 (s, 1H), 7.94 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.18 (d, 1H), 7.03 (t, 1H), &lt; / RTI &gt; 6.95 (d, 1H).

&Lt; Example 118 >

Preparation of N- [2-hydroxyphenyl] -N '- [2-bromophenyl] urea

N- [2-hydroxyphenyl] -N '- [2-bromophenyl] urea was prepared from 2-aminophenol (141 mg, 1.30 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (300 mg, 75%). _{^{1 H NMR (CD 3 OD)}} : δ8.05 (d, 1H), 7.49 (d, 1H), 7.25 (t, 2H), 6.96 (t, 1H), 6.90 (t, 2H), 6.68 (t, 1H).

&Lt; Example 119 >

Preparation of N- [trans-3-styr-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of trans-6-styr-2-nitrophenol

The trans-2-stilphenol (500 mg, 2.55 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrite (240 mg, 2.81 mmol) was added. Sulfuric acid (3 mL, 3M) was then added, and a catalytic amount of sodium nitrite was added. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (200 mg, 36%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.05 (d, 1H), 7.90 (d, 2H), 7.65-7.20 (m, 7H), 7.00 (t, 1H).

b) Preparation of trans-6-styr-2-aminophenol

A mixture of trans-6-styr-2-nitrophenol (200 mg, 0.83 mmol) and tin (II) chloride (560 mg, 2.60 mmol) in ethanol (50 mL) was heated at 80 <0> C under argon. After 2 hours, when the starting material disappeared, the solution was allowed to cool and poured into ice. Solid NaOH was added to bring the pH to slightly basic (pH 7-8) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (50 mg, 29%). _{^{1 H NMR (CD 3 OD)}} : δ7.51 (m, 3H), 7.29 (m, 3H), 7.11 (t, 1H), 7.00 (m, 2H), 6.69 (m, 2H).

c) Preparation of N- [trans-3-styr-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

[Trans-3-styr-2-hydroxyphenyl] -N '- [2-bromophenyl] Urea. The product was purified from methylene chloride / hexane (1/20) and purified by filtration (36 mg, 53%). _{^{1 H NMR (CD 3 OD)}} : δ7.97 (d, 1H), 7.62-7.48 (m, 4H), 7.45-7.26 (m, 5H), 7.25 (t, 1H), 7.15 (d, 1H), 7.01 (t, 1 H), 6.88 (t, 2 H).

&Lt; Example 120 >

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-methoxyphenyl] urea

N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-methoxypyridin-2-yl] -methanone was prepared in accordance with General Method B from 2-amino-5,6-dichlorophenol (80 mg, 0.50 mmol, Phenyl] urea. The product was precipitated from methylene chloride / hexane (1/20) and purified by filtration (125 mg, 77%). _{^{1 H NMR (CD 3 OD)}} : δ8.02 (d, 1H), 7.79 (d, 1H), 7.05-6.86 (m, 4H), 3.92 (s, 3H).

&Lt; Example 121 >

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [4-methoxyphenyl] urea

4-dichlorophenyl] -N ' - [4-methoxypyridin-2-yl] -propionic acid was prepared from 2- amino-5,6-dichlorophenol (80 mg, 0.50 mmol, Phenyl] urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (120 mg, 74%). _{^{1 H NMR (CD 3 OD)}} : δ7.89 (d, 1H), 7.35 (d, 2H), 6.99 (d, 1H), 6.90 (dd, 2H), 3.80 (s, 3H).

&Lt; Example 122 >

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [3-trifluoromethylphenyl] urea

4-dichlorophenyl] -N ' - [3-trifluoro (4-fluorophenyl) Methylphenyl] urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (130 mg, 71%). _{^{1 H NMR (CD 3 OD)}} : δ7.96 (d, 2H), 7.60 (d, 1H), 7.48 (t, 1H), 7.30 (d, 1H), 7.00 (d, 1H).

&Lt; Example 123 >

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-phenylphenyl] urea

2-amino-5,6-dichlorophenol (80 mg, 0.50 mmol, Example 82b) was reacted with N- [2-hydroxy-3,4- ] Urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (110 mg, 59%). _{^{1 H NMR (CD 3 OD)}} : δ7.77 (d, 1H), 7.73 (d, 1H), 7.53-7.14 (m, 8H), 6.95 (d, 1H).

&Lt; Example 124 >

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2,3-dichlorophenyl] urea

N- [2-hydroxy-3,4-dichlorophenyl] -N'- [2,3-d] pyrimidine was obtained from 2-amino-5,6-dichlorophenol (80 mg, 0.50 mmol, Dichlorophenyl] urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (130 mg, 71%). _{^{1 H NMR (CD 3 OD)}} : δ8.06 (dd, 1H), 7.91 (d, 1H), 7.25 (m, 2H), 7.00 (d, 1H).

&Lt; Example 125 >

Preparation of N- [2-hydroxy-4-isopropylphenyl] -N '- [3-trifluoromethylphenyl] urea

a) Preparation of 2-nitro-5-isopropylphenol

3-Isopropylphenol (3.00 g, 22 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (2.06 g, 24 mmol) was added. Sulfuric acid (25 mL / 3M) was added followed by the sodium nitrite catalytic amount. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (1.09 g, 27%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ7.95 (d, 1H), 7.62 (d, 1H), 7.11 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).

b) Preparation of 2-amino-5-isopropylphenol

To a solution of 2-nitro-5-isopropylphenol (1 g, 6.4 mmol) in methanol (50 mL) was added 10% Pd / C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the hydrogen atmosphere was maintained at the balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (775 mg, 93%). _{^{1 H NMR (CD 3 OD)}} : δ6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d, 6H).

c) Preparation of N- [2-hydroxy-4-isopropylphenyl] -N '- [3-trifluoromethylphenyl] urea

Preparation of N- [2-hydroxy-4-isopropylphenyl] -N '- [3-trifluoromethylphenyl] urea from 2-amino-5-isopropylphenol (75 mg, 0.50 mmol) Respectively. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (140 mg, 83%). _{^{1 H NMR (CD 3 OD)}} : δ7.91 (d, 2H), 7.62 (d, 1H), 7.47 (t, 1H), 7.39 (d, 1H), 6.75 (s, 1H), 6.72 (d, 1H), 2.80 (m, 1H), 1.21 (d, 6H).

Example 126:

Preparation of N- [2-hydroxy-3-naphthyl] -N '- [2,3-dichlorophenyl] urea

[2-hydroxy-3-naphthyl] -N '- [2,3-dichlorophenyl] urea was prepared from 3-amino-2-naphthol (160 mg, 1.00 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (285 mg, 82%). _{^{1 H NMR (CD 3 OD)}} : δ8.48 (s, 1H), 8.10 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.40-7.23 (m, 4H), 7.18 ( d, 1H).

&Lt; Example 127 >

Preparation of N- [2 - [(2,3-dichlorothien-5-yl)] sulfonylamino] phenyl] -N'- (2- bromophenyl) urea

a) Preparation of [2 - [(2,3-dichlorothien-5-yl)] sulfonylaminoaniline]

The title compound was prepared according to General Method C using 2,3-dichlorothiophene-5-sulfonyl chloride (1 eq.). The product was purified by flash chromatography on silica gel (ethyl acetate / hexane 20/80 - methylene chloride: methanol 90/10) (1.25 g, 39%). EI-MS m / z 321 (MH) ^- .

b) Preparation of N- [2 - [(2,3-dichlorothen-5-yl)] sulfonylamino] phenyl] -N'- (2- bromophenyl) urea

Sulfonylaminoaniline (1.25 g, 3.9 mmol) and 2- (bromophenyl) isocyanate (768 mg, 3.9 mmol) according to General Method B Lt; / RTI &gt; The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (272 mg, 13%). EI-MS m / z 520 (MH) ^- .

&Lt; Example 128 >

Preparation of N- [2 - [(3,5-bistrifluoromethylphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [2 - [(3,5-bistrifluoromethylphenyl)] sulfonylaminoaniline]

The title compound was prepared according to General Procedure C using 3,5- (bistrifluoromethyl) phenylsulfonyl chloride (1.28 g, 4.1 mmol) and o-phenylenediamine (441 mg, 4.1 mmol). The product was purified by flash chromatography on silica gel (methylene chloride: methanol 95/5) (611 mg, 39%). EI-MS m / z 383 (MH) ^- .

b) Preparation of N- [2 - [(3,5-bistrifluoromethylphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared according to General Procedure B from [2- (3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenyl isocyanate (305 mg, 1.5 mmol). The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (10 mg, 1%). EI-MS m / z 580 (MH) ^- .

&Lt; Example 129 >

Preparation of N- [2 - [(2-benzyl) sulfonylamino] - (5-trifluoromethyl) phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [(4-benzylsulfonylamino) - (3-nitro) -benzotrifluoride]

4-Amino-3-nitro-benzotrifluoride (1.0 g, 4.85 mmol) was mixed in DMF and the reaction mixture was cooled to 0 &lt; 0 &gt; C. Sodium hydride (175 mg, 7.28 mmol) was added to the cooled mixture and left to mix for 10 min (a dark red color was found). Toluene sulfonyl chloride (925 mg, 4.85 mmol) was added (reaction color changed to yellow) and the reaction was stirred at room temperature for 16 hours. The reaction was quenched into NH ₄ Cl and extracted with ethyl acetate: hexane (1: 1). The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (878 mg, 52%). EI-MS m / z 359 (MH) ^- .

b) Preparation of [(4-benzylsulfonylamino) - (3-amino) -benzotrifluoride]

[(4-benzylsulfonylamino) - (3-nitro) -benzotrifluoride (230 mg, 0.64 mmol) was mixed in methanol and poured into Parr bottle. Palladium / carbon (15 mg) was added under an argon stream. The reaction mixture was left in a Parr shaker (55 psi, H ₂ ) for several hours. The reaction mixture was filtered through celite to give the title compound (210 mg, 99%). EI-MS m / z 329 (MH) ^- .

c) Preparation of N- [2 - [(2-benzyl) sulfonylamino] - (5-trifluoromethyl) phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared from [(4-benzylsulfonylamino) - (3-amino) -benzotrifluoride (210 mg, 0.64 mmol) and 2- bromophenyl isocyanate (126 mg, 0.64 mmol) according to General Method B Respectively. The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (70 mg, 21%). EI-MS m / z 526 (MH) ^- .

&Lt; Example 130 >

Preparation of N- [2- [2- (3-nitrophenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [2 - ((3-nitrophenyl) sulfonylamino) aniline]

The title compound was prepared according to General Method C using 3-nitrobenzenesulfonyl chloride (1 eq.). The product was purified by flash chromatography on silica gel (methylene chloride: methanol 96/4) (1.07 g, 37%). EI-MS m / z 294 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2- [(3-nitrophenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared according to General Method B from [2- (3-nitrophenyl) sulfonylaminoaniline] (590 mg, 2.0 mmol) and 2- (bromophenyl) isocyanate (398 mg, 2.0 mmol). The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (400 mg, 40%). EI-MS m / z 489 (MH) ^- .

&Lt; Example 131 >

Preparation of N- [2- [2- (4-phenoxyphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [2 - ((4-phenoxyphenyl) sulfonylamino) aniline]

The title compound was prepared using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 2.77 mmol) according to General Method C. The reaction mixture was partitioned between water (200 mL) and toluene: methylene chloride (1: 3). The organic phase was collected and the methylene chloride was evaporated to leave toluene. Hexane was added and the product was precipitated from solution (317 mg, 34%). EI-MS m / z 341 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2- [(4-phenoxyphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared according to General Procedure B from [2- (4-phenoxyphenyl) sulfonylaminoaniline] (276 mg, 0.8 mmol) and 2- (bromophenyl) isocyanate (161 mg, 0.8 mmol). The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (240 mg, 55%). EI-MS m / z 536 (MH) ^- .

&Lt; Example 132 >

Preparation of N - [[2- (1S) -10-camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2 - ((1S) -10-camphorsulfonylamino) aniline

The title compound was prepared according to General Procedure C using (1S) (+) - 10-camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6 mmol). The reaction mixture was partitioned between water (200 mL) and toluene: methylene chloride (1: 3). The organic phase was separated and the methylene chloride was evaporated to leave toluene. Hexane was added and the solid was precipitated from the solution (130 mg, 9%). EI-MS m / z 323 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N - [[2- (1S) -10-camphorsulfonylamino] phenyl] -N'- (2-bromophenyl) urea

The title compound was prepared according to General Procedure B from [2- (1S) -10-camphorsulfonylamino] aniline (130 mg, 0.4 mmol) and 2- (bromophenyl) isocyanate (80 mg, 0.4 mmol). The solvent was evaporated and the product was precipitated from methylene chloride: hexane (200 mg, 95%). EI-MS m / z 518 (MH) ^- .

&Lt; Example 133 >

Preparation of N - [[2- (1R) -10-camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2 - ((1 R) -10-camphorsulfonylamino) aniline

The title compound was prepared according to General Procedure C using (1R) (-) - 10-camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6 mmol). The reaction mixture was partitioned between water (200 mL) and toluene: methylene chloride (1: 3). The organic phase was separated and the methylene chloride was evaporated to leave toluene. Hexane was added and the product precipitated from the solution (563 mg, 38%). EI-MS m / z 323 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N - [[2- (1R) -10-camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared according to General Method B from [1- (1R) -10-camphorsulfonylamino] aniline (563 mg, 1.75 mmol) and 2- (bromophenyl) isocyanate (346 mg, 1.75 mmol). The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70) (263 mg, 29%). EI-MS m / z 518 (MH) ^- .

<Example 134>

Preparation of N- [2- [2- (2-nitro- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N'- (2- bromophenyl) urea

a) Preparation of [2 - [(2-nitro) - (4-trifluoromethyl) phenyl] sulfonylamino] aniline]

The title compound was prepared according to General Procedure C using 2-nitro-4- (trifluoromethyl) benzenesulfonyl chloride (1 eq.). The product was purified by flash chromatography on silica gel (methylene chloride: methanol 96/4) (875 mg, 25%). EI-MS m / z 362 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- [2- [2- (2-nitro- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N'- (2- bromophenyl) urea

(740 mg, 2.1 mmol) and 2- (bromophenyl) isocyanate (406 mg, 2.1 &lt; RTI ID = 0.0 &gt; mmol). &lt; / RTI &gt; The product was purified by flash chromatography on silica gel (ethyl acetate: hexane 30/70). The product was further purified by recrystallization in ethyl acetate: hexane (320 mg, 28%). EI-MS m / z 557 (MH) ^- .

Example 135:

Preparation of N- (2-hydroxy-4-azidophenyl) -N '- (2-iodophenyl) urea

a) Preparation of N- (2-hydroxy-4-aminophenyl) -N '- (2-iodophenyl) urea

To a solution of N- (2-hydroxy-4-nitrophenyl) -N '- (2-iodophenyl) urea (220 mg, 0.55 mmol) in ethanol (15 mL) was added tin chloride (522 mg, 2.75 mmol) Was added. The reaction mixture was stirred at reflux temperature for 16 hours and then cooled to room temperature. The reaction mixture was basified to pH 8 with aqueous NaHCO ₃ and extracted three times with ethyl acetate. Combine the organic extracts were dried and filtered over MgSO _4, and concentrated under reduced pressure to give the product (180 ㎎, 89%). EI-MS m / z 370 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- (2-hydroxy-4-azidophenyl) -N '- (2-iodophenyl) urea

(77 mg, 0.21 mmol) was added to HCl / H ₂ O (0.21 mL / 0.42 mL) and treated at 0 &lt; 0 &gt; C Lt; / RTI &gt; Sodium nitrite (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to the reaction mixture and warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. It was then extracted three times with ethyl acetate. And filtered to give the product on a (20 ㎎, 24%): ;: Combine the organic extracts, dry over MgSO ₄ and filtered and the was concentrated under reduced pressure and the resulting solid on silica gel (hexane-ethyl acetate 5). EI-MS m / z 396 (M + H) &lt; ⁺ & gt ^; .

<Example 136>

Preparation of N- (2-hydroxy-3-azidophenyl) -N '- (2-bromophenyl) urea

a) Preparation of N- (2-hydroxy-3-aminophenyl) -N '- (2-bromophenyl)

To a solution of N- (2-hydroxy-3-nitrophenyl) -N '- (2-bromophenyl) urea (300 mg, 0.85 mmol) in ethanol (20 mL) was added tin chloride (958 mg, 4.25 mmol) Was added. The reaction mixture was stirred at reflux temperature for 16 hours and then cooled to room temperature. The reaction mixture was basified to pH 8 with aqueous NaHCO ₃ and extracted three times with ethyl acetate. Combine the organic extracts were dried and filtered over MgSO _4, and concentrated under reduced pressure to give the product (274 ㎎, 99%). EI-MS m / z 323 (M + H) &lt; ⁺ & gt ^; .

b) Preparation of N- (2-hydroxy-3-azidophenyl) -N '- (2-bromophenyl) urea

(274 mg, 0.85 mmol) was added to HCl / H ₂ O (0.85 mL / 1.7 mL) and treated at 0 &lt; 0 &gt; C Lt; / RTI &gt; Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to the reaction mixture and warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. It was then extracted three times with ethyl acetate. Was chromatographed to give the product on a (210 ㎎, 71%): ;: Combine the organic extracts, dry over MgSO ₄ and filtered and the was concentrated under reduced pressure and the resulting solid on silica gel (hexane-ethyl acetate 5). EI-MS m / z 349 (M + H) &lt; ⁺ & gt ^; .

&Lt; Example 137 >

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2-methoxyphenyl] urea

[2-Hydroxy-3-cyanophenyl] -N '- [2-methoxyphenyl] urea was prepared from 2-amino-6-cyanophenol (134 mg, 1.00 mmol) . The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (230 mg, 81%). _{^{1 H NMR (CD 3 OD)}} : δ8.06 (d, 1H), 7.79 (d, 1H), 7.49-7.35 (m, 2H), 7.05-6.87 (m, 3H), 3.95 (s, 3H).

&Lt; Example 138 >

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [3-trifluoromethylphenyl] urea

From 2-amino-6-cyanophenol (134 mg, 1.00 mmol, example 83a) according to general method B to give N- [2-hydroxy-3-cyanophenyl] -N ' ] Urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (280 mg, 87%). ¹ H NMR (CD ₃ OD): δ8.10 (d, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.55-7.25 (m, 3H), 7.01 (t, 1H).

&Lt; Example 139 >

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2-phenylphenyl] urea

[2-Hydroxy-3-cyanophenyl] -N '- [2-phenylphenyl] urea from 134 mg (1.00 mmol, Example 83a) . The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (270 mg, 82%). _{^{1 H NMR (CD 3 OD)}} : δ7.81 (d, 1H), 7.75 (d, 1H), 7.56-7.15 (m, 9H), 6.91 (t, 1H).

&Lt; Example 140 >

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2,3-dichlorophenyl] urea

From 2-amino-6-cyanophenol (134 mg, 1.00 mmol, Example 83a) according to general method B to N- [2-hydroxy-3-cyanophenyl] -N ' ] Urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (300 mg, 93%). _{^{1 H NMR (CD 3 OD)}} : δ8.11 (d, 1H), 8.01 (d, 1H), 7.33-7.25 (m, 3H), 7.00 (t, 1H).

&Lt; Example 141 >

Preparation of N- [2-hydroxy-4-isopropylphenyl] -N '- [2,3-dichlorophenyl] urea

Was prepared from 2-amino-5-isopropylphenol (150 mg, 1.00 mmol, Example 128a) according to General Method B to give N- [2-hydroxy-4-isopropylphenyl] -N ' ] Urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (285 mg, 84%). _{^{1 H NMR (CD 3 OD)}} : δ8.05 (d, 2H), 7.77 (s, 1H), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m, 1H), 1.25 (d, 6H).

&Lt; Example 142 >

Preparation of N- [2-hydroxy-4-isopropylphenyl] -N '- [2-chloro-5-trifluoromethylphenyl] urea

Was prepared from 2-amino-5-isopropylphenol (150 mg, 1.00 mmol, example 128a) according to general method B to give N- [2-hydroxy- Trifluoromethylphenyl] urea. &Lt; / RTI &gt; The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (275 mg, 82%). _{^{1 H NMR (CD 3 OD)}} : δ8.50 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.22 (d, 1H), 6.70 (m, 2H), 6.62 (dd, 1H), 2.76 (m, 1H), 1.16 (d, 6H).

&Lt; Example 143 >

Preparation of N- [2-hydroxy-3-phenylphenyl] -N '- [2,3-dichlorophenyl] urea

a) Preparation of 2-nitro-6-phenylphenol

2-Phenylphenol (3.00 g, 17.6 mmol) was dissolved in methylene chloride (40 mL) and sodium nitrate (1.65 g, 19.4 mmol) was added. Sulfuric acid (25 mL / 3M) was added followed by the sodium nitrite catalytic amount. The mixture was stirred. After 24 h, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (4% MeOH / CH ₂ Cl ₂ ) to give the desired product (900 mg, 24%). ^{_{1 H NMR (CD 3 COCD 3}} ): δ8.19 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t , 1H).

b) Preparation of 2-amino-6-phenylphenol

To a solution of 2-nitro-6-phenylphenol (900 mg, 4.2 mmol) in methanol (50 mL) was added 10% Pd / C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 minutes and the hydrogen atmosphere was maintained at the balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and the resulting solid was chromatographed on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give the desired product (700 mg, 90%). _{^{1 H NMR (CD 3 OD)}} : δ7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H).

c) Preparation of N- [2-hydroxy-3-phenylphenyl] -N '- [2,3-dichlorophenyl] urea

[2-hydroxy-3-phenylphenyl] -N '- [2,3-dichlorophenyl] urea was prepared from 2-amino-6-phenylphenol (92.5 mg, 0.50 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (150 mg, 81%). _{^{1 H NMR (CD 3 OD)}} : δ8.06 (d, 1H), 7.65 (d, 1H), 7.54 (d, 2H), 7.40 (t, 2H), 7.32 (d, 1H), 7.22 (m, 2H), 7.04 - 6.88 (m, 2H).

&Lt; Example 144 >

Preparation of N- [2-hydroxy-5-nitrophenyl] -N '- [2-methoxyphenyl] urea

N- [2-hydroxy-5-nitrophenyl] -N '- [2-methoxyphenyl] urea was prepared from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (270 mg, 89%). ¹ H NMR (CD ₃ OD):? 9.10 (s, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.08-6.88 (m, 4H), 3.96 (s,

&Lt; Example 145 >

Preparation of N- [2-hydroxy-5-nitrophenyl] -N '- [3-trifluoromethylphenyl] urea

N- [2-hydroxy-5-nitrophenyl] -N '- [3-trifluoromethylphenyl] urea was prepared from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (290 mg, 85%). _{^{1 H NMR (CD 3 OD)}} : δ9.12 (s, 1H), 7.89 (d, 1H), 7.68 (d, 1H), 7.55 (m, 2H), 7.45 (d, 1H), 7.00 (d, 1H).

&Lt; Example 146 >

Preparation of N- [2-hydroxy-5-nitrophenyl] -N '- [2-phenylphenyl] urea

N- [2-hydroxy-5-nitrophenyl] -N '- [2-phenylphenyl] urea was prepared from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (285 mg, 81%). _{^{1 H NMR (CD 3 OD)}} : δ8.09 (s, 1H), 7.86 (d, 1H), 7.58-7.20 (m, 9H), 6.95 (d, 1H).

<Example 147>

Preparation of N- [2-hydroxy-5-nitrophenyl] -N '- [2,3-dichlorophenyl] urea

N- [2-hydroxy-5-nitrophenyl] -N '- [2,3-dichlorophenyl] urea was prepared from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to General Method B. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (290 mg, 85%). _{^{1 H NMR (CD 3 OD)}} : δ9.11 (s, 1H), 8.17 (d, 1H), 7.89 (d, 1H), 7.34 (m, 2H), 6.95 (d, 1H).

&Lt; Example 148 >

Preparation of N- [2-hydroxy-5-ethylsulfonylphenyl] -N '- [2,3-dichlorophenyl] urea

2-amino-4- (ethylsulfonyl) phenol (185 mg, 1.00 mmol) was reacted with N- [2-hydroxy-5-ethylsulfonylphenyl] -N ' ] Urea. The product was precipitated from methylene chloride / hexane (1 eq / 20 eq) and purified by filtration (310 mg, 84%). _{^{1 H NMR (CD 3 OD)}} : δ8.65 (s, 1H), 8.18 (d, 1H), 7.45 (d, 1H), 7.26 (m, 2H), 7.00 (d, 1H), 3.33 (q, 2H), 1.24 (t, 3H).

Compounds of formula (I) may be prepared according to the above described embodiments and reaction schemes:

&Lt; Example 149 >

N- [2- (2-amino- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N '- (2- bromophenyl) urea EI-MS m / z 527 (MH) ^- .

&Lt; Example 150 >

N- [2- (aminosulfonylphenyl) -3-aminophenyl] -N '- (2-bromophenyl) urea EI-MS m / z 426 (M + H) <^+> .

Compounds of formula (I) may be prepared according to the examples and schemes described above or may be obtained commercially, for example, from sources well known as follows: N- (2-hydroxy-4-nitrophenyl) N'-phenylurea (Aldrich Chemical Company); 1- (2-carboxyphenyl) -3- (3-fluorophenyl) urea, 1- (2-carboxyphenyl) -3- (3-chlorophenyl) urea (Alfred Vader collection of Aldrich Chemical); 1- (2-carboxyphenyl) urea (Galadosch jegerger Company and / or Sigma Al (R) Drake Librae of the Rare Compound); Trifluoromethylbenzoic acid, 2- (4-dichlorophenylcarbonyldiimino) -5-trifluoromethylbenzoic acid, 2- (4-chlorophenylcarbonyldiimino) - (2-carboxyphenyl) urea (Galadose &lt; / RTI &gt; (3-tolyl) thiourea and N- (5-chloro-2-hydroxy-4-nitrophenyl) -N'-phenylurea Maybridge Chemical Company).

Of the compounds of formula I, 1- (m-anyl) -3- (2-carboxyphenyl) urea;

1- (o-anyl) -3- (2-carboxyphenyl) urea;

1- (2-carboxyphenyl) -3- (3,4-dichlorophenyl) urea; And

1- (2-Carboxyphenyl) -3- (2,4-dichlorophenyl) urea may be prepared according to the above examples and reaction schemes, or may be prepared as cited in Chemical Abstracts, respectively.

< Treatment method>

The overexpression of IL-8 cytokines by cells of mammals such as, but not limited to, monocytes and / or macrophages, or other chemokines that bind to IL-8a or &bgr; receptors, also referred to as type I or type II receptors Ia, II, and III, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human or other mammal, Salts can be used.

As used herein, the compounds of formulas I, Ia, Ib, Ic, II, and III all have the same dosage, and as a combination of formula I, the dosage formulations are used interchangeably.

Accordingly, the present invention provides a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, the chemokines are IL-8, GROa, GRObeta, GROg or NAP-2.

The compounds of formula I are administered in an amount sufficient to inhibit cytokine function, particularly IL-8, GROa, GROß, GROy or NAP-2, so that they can be administered to a normal level of physiological function, To improve the disease state. In the context of the present invention, the abnormal levels of, for example, IL-8, GROa, GROß, GROγ or NAP-2 constitute: (i) the level of free IL-8 above 1 picogram / ml; (Ii) IL-8, GRO [alpha], GRO [beta], GRO [gamma] or NAP-2 associated with any cell above normal physiological levels; Or (iii) the presence of IL-8, GROα, GROβ, GROγ or NAP-2 is produced above the basal level of the cell or tissue in IL-8, GROα, GROβ, GROγ or NAP-2, respectively.

There are many disease states in which excessive or unregulated production of IL-8 is associated with deterioration and / or the incidence of the disease. The chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, seizure, septic shock, endotoxic shock, Sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-host response, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis or undesirable hematopoietic stem cell release.

These diseases are characterized primarily by massive neutrophil infiltration, T-cell infiltration, or angiogenic growth and are associated with neutrophil chemotaxis to the inflammatory site or IL-8, GROα, GROβ, GROγ or NAP -2. &Lt; / RTI &gt; In contrast to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8, GROα, GROβ, GROγ or NAP-2 inhibits neutrophil chemotaxis, enzyme release (non- Of course, have unique properties that promote excess oxide formation and activation. Alpha-chemokines acting through IL-8 type I or type II receptors, in particular GRO ?, GRO ?, GRO? Or NAP-2, can promote angiogenesis of tumors by promoting endothelial cell-directed growth. Therefore, inhibition of IL-8 induced chemotaxis or activation will result in a direct reduction of neutrophil infiltration.

The compound of formula I is administered in an amount sufficient to inhibit binding to the IL-8a or &lt; RTI ID = 0.0 &gt; ss receptor, &lt; / RTI &gt; as evidenced by a decrease in neutrophil chemotaxis and activation. The finding that the compounds of formula I are inhibitors of IL-8 binding is based on the effect of the compounds of formula I in the in vitro receptor binding assays described herein. In some cases, the compounds of formula I have been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably, the compound is a single receptor, more preferably a type II inhibitor.

The term " IL-8 mediated disease or disease state ", as used herein, refers to a condition in which IL-8, GROa, GROß, GROγ or NAP-2 is produced by the production of IL-8, GROα, GROß, GROγ or NAP- Refers to any and all disease states that function by IL-8, GRO [alpha], GRO [beta], GRO [gamma] or NAP-2 resulting in the release of other monokines (e.g., IL-1, IL-6 or TNF). Therefore, for example, a disease state in which IL-1 is a major component and its production or action is exacerbated or secreted in response to IL-8 is regarded as a disease mediated by IL-8.

Diseases in which the compounds of the present invention are useful include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, seizures, septic shock, endotoxic shock, Aplastic anemia, Gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-host response, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, There is hematopoietic stem cell release.

The compounds of the present invention may also be used in the treatment of respiratory viruses (including, but not limited to, renoviruses and influenza viruses), herpes viruses (including but not limited to herpes simplex I and II) Hepatitis virus). &Lt; / RTI &gt;

As used herein, the term " chemokine mediated disease or disease state " refers to a condition in which chemokines (such as, but not limited to IL-8, GROa, GRObeta, GROγ or NAP-2) that bind to the IL- &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt; This will include disease states in which IL-8 plays a role by IL-8 itself, or by IL-8, which releases other monokines (non-limiting examples: IL-1, IL-6 or TNF). Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to IL-8 will be regarded as a disease mediated by IL-8.

As used herein, the term " cytokine " refers to any secreted polypeptide that affects the function of the cell and is a molecule that modulates intercellular interactions in an immune, inflammatory or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. For example, monokines generally are produced and secreted by monocytes such as macrophages and / or monocytes. However, many other cells produce monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes. Lymphokines generally produce lymphocyte cells. Non-limiting examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- (TNF-β).

As used herein, the term " chemokine " refers to any secreted polypeptide that affects the function of a cell and that is a molecule that modulates intercellular interactions in an immune, inflammatory or hematopoietic response Lt; / RTI &gt; Chemokines are mainly secreted through the cell dermis, leading to the chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Non-limiting examples of chemokines are IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, IP-10, MIP-1α, MIP-β, PF4 and MCP 1,2, .

In order to use a compound of formula I or a pharmaceutically acceptable salt thereof for therapy, it will be formulated into a pharmaceutical composition according to standard pharmaceutical practice. Therefore, the present invention also relates to a pharmaceutical composition comprising an effective non-toxic amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent.

The compounds of formula I, their pharmaceutically acceptable salts and pharmaceutical compositions incorporating them can be conveniently administered by any route commonly used for drug administration, for example, orally, topically, parenterally or by inhalation &Lt; / RTI &gt; The compounds of formula I can be administered in conventional dosage forms prepared by mixing the compounds of formula I with standard pharmaceutical carriers according to conventional procedures. The compounds of formula I may also be administered in conventional doses with other therapeutically active compounds known in the art. Such processes may include mixing, granulating and compressing or dissolving the components suitable for the desired preparation. It will be appreciated that the form and characteristics of the pharmaceutically acceptable carrier or diluent will be dictated by the amount of active ingredient to be mixed, the route of administration, and other well-known variables. The carrier (s) should be &quot; acceptable &quot; in the sense that they are compatible with the other formulation ingredients and are not harmful to their recipients.

The pharmaceutical carrier used may be, for example, a solid or a liquid. Examples of solid carriers are lactose, white tea, sucrose, talc, gelatin, agar, pectin, gum arabic, masseum stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may comprise a delaying material well known in the art, such as glyceryl monostearate, or glyceryl distearate alone or a mixture of the wax and the glyceryl distearate.

A wide range of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tabletted, or may be in powder or pellet form, or in hard gelatin capsules in the form of troches or lozenges. The amount of solid carrier will vary widely, but will preferably be from about 25 mg to about 1 g. If a liquid carrier is used, the formulation may be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution (e.g. ampoule) or a non-aqueous liquid suspension.

The compounds of formula I may be administered topically, i. E. By non-pro-inflammatory administration. This involves applying the compound of formula I externally to the epidermis or nidus and injecting the compound into the ear, eye and nose so that the compound hardly enters the blood stream. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Suitable formulations for topical administration include liquid or semi-liquid preparations suitable for penetration of the area of inflammation through the skin, such as a dipping agent, lotion, cream, ointment or paste, and a dropping agent suitable for administration to the eye, ear or nose . The active ingredient, for topical administration, may comprise from 0.001% to 10%, such as from 1% to 2% by weight of the combination. However, it may comprise up to about 10% by weight of the formulation, preferably less than 5% by weight, more preferably from 0.1% to 1% by weight.

Lotions according to the present invention include those suitable for application to the skin or eyes. The ophthalmic lotion may optionally comprise a sterile aqueous solution containing a bactericidal agent and may be prepared by a method similar to that for the preparation of a drip agent. Lotions or coatings for application to the skin may also contain a formulation (e.g., alcohol or acetone) and / or a moisturizing agent (e.g., glycerol) or an oil (e. G., Castor oil or peanut oil) that speeds drying and cools the skin .

The cream, ointment or paste according to the invention is a semi-solid formulation of the active ingredient for external application. These may be prepared by mixing the active ingredient, either in fine or powder form, alone or as a solution or suspension in an aqueous or non-aqueous fluid, with an oily or non-inactive base by a suitable machine. The base may include hydrocarbons (e.g., hard, soft or liquid paraffin, glycerol, beeswax, metal soaps); Clot; Oils of natural origin such as almonds, corn, peanuts, castor or olive oil; Bovine bark or its derivatives or fatty acids such as stearic acid or oleic acid and alcohols such as propylene glycol or macrogels. The formulations may incorporate suitable surfactants, for example anionic, cationic or nonionic surfactants, such as sorbitan esters or polyoxyethylene derivatives thereof. Other ingredients such as natural gums, cellulose derivatives or suspending agents such as inorganic substances (e.g. silicic acid silica), and lanolin may also be included.

The dosage form according to the present invention may comprise a sterile aqueous or oily solution or suspension and may be prepared by dissolving the active ingredient in a suitable aqueous solution of the killed bactericide and / or fungicide and / or any suitable preservative, May be prepared by including an active agent. The resulting solution can then be sterilized by filtration, sterilized by transferring it to a suitable container, sealing and autoclaving or holding at 98-100 ° C for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of suitable bactericides and fungicides for inclusion in the drip agent are phenyl mercury nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions are glycerol, dilute alcohol and propylene glycol.

The compounds of formula I may be administered parenterally, i. E., By intravenous, intramuscular, subcutaneous, intranasal, rectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Dosage forms suitable for such administration can be prepared by conventional techniques. The compounds of formula I may also be administered by inhalation, i. E. Intranasal and oral inhalation administration. Dosage forms suitable for such administration, e. G. Aerosol formulations or metered dose inhalers, will be prepared by conventional techniques.

For all methods of use described herein for compounds of formula I, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg / kg total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 80 mg / kg total body weight. The daily daily dose regimen will be from 0.1 mg to 150 mg, preferably from 1 to 4 times, preferably 2 to 3 times per day. The daily inhalation dosage regimen will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. Those skilled in the art will also appreciate that the optimal amount and interval of individual administration of a compound of Formula I or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition to be treated, the mode of administration, route and site of administration, and the particular patient to be treated, It will be appreciated that the conditions can be determined by conventional techniques. It will also be understood by those skilled in the art that the optimal route of treatment, i.e. the number of doses of a given compound of formula I or its pharmaceutically acceptable salt per day for a given number of days, can be ascertained by those skilled in the art using routine routes of treatment determination testing .

The present invention will now be described with reference to the following Biological Embodiments, which merely illustrate the invention and should not be construed as limiting the scope of the invention.

< Biological Example>

The IL-8 and Gro-alpha chemokine inhibitory effects of the compounds of the present invention were determined by in vitro analysis as follows.

Receptor binding assay:

[ ¹²⁵ I] IL-8 (human recombinant) with an activity of 2000 Ci / mmol was obtained from Amersham Corp., Arlington Heights, Ill. GRO-α was obtained from NEN (New England Nuclear). All other chemicals were of analytical grade. High levels of recombinant human IL-8 alpha and beta type receptors were expressed in chinese hamster ovary cells as previously described (Halles et al., Sicence, 1991, 253, 1278). Chiniz hamster ovary membranes were homogenized according to the protocol previously described (Haru et al., J. Biol. Chem., 249, pp. 2195-2205 (1974)) except that the homogenization buffer was replaced with 10 mM Tris- MgSO _4, 0.5mM EDTA. (ethylene-diaminetetraacetic acid), 1mM PMSF (α- toluenesulfonyl fluoride), 0.5 ㎎ / ℓ leupeptin, was changed to pH 7.5 membrane protein concentration of bovine serum albumin as a standard substance use was determined using Pierce Co. Needle (Pierce Co.) Microanalysis kits. all analyzes were performed in 96-well micro plate format. each reaction mixture was _{1.2mM MgSO 4, 0.1mM EDTA, 25mM} NaCl and 0.03 20mM% CHAPS containing bis-tree propane and 0.4mM tris-HCl buffer ^{(pH 8.0) 125 I IL-} 8 (0.25nM) or ¹²⁵ I GRO-α and IL-8Rα film 0.5 ㎍ / ㎖ or IL-8Rβ membranes in 1.0 [mu] g / ml, and the solution was preliminarily dissolved in DMSO to have a final concentration of 0.01 nM to 100 [mu] M On the enemy a drug or compound was added. ¹²⁵ I-IL-8 was added to initiate the analysis by the addition. After 1 hours at room temperature, 1% of a glass fiber filter cut-off to the polyethylenimine /0.5% BSA mat (filtermat) Plates were harvested using a Tomtec 96-well harvester and washed three times with 25 mM NaCl, 10 mM Tris HCl, 1 mM MgSO ₄ , 0.5 mM EDTA, 0.03% CHAPS (pH 7.4) Recombinant IL-8R [alpha] or I-type receptors are also referred to herein as non-permissive receptors, and recombinant IL-8R [beta] or type II receptors are also referred to as permissive receptors.

All exemplary compounds and additionally purchased compounds of Formulas I to III shown in the synthetic chemical moieties (Examples 1 to 150) exhibited an IC ₅₀ of less than about 45 to about 1 μg / ml in an acceptable model of IL-8 receptor inhibition . The compounds tested were also found to be approximately the same level of GRO-alpha binding inhibitors. The compound 1- (2-carboxyphenyl-3- (4-chloro-2-methylphenyl) urea was found to be active at about 75 ug / ml.

The following compounds, which were generally tested to below 45 [mu] g / ml, were found not to exhibit a level of IL-8 receptor antagonism within the above described criteria at the tested dose level:

Trifluoro-3-tolyl) -3- [2- (4-chlorophenyl) thio] -5-chlorophenylurea

Trifluoro-3-tolyl) -3- [2- (4-chlorophenoxy) -5-chlorophenyl] urea

1- (2-mercaptophenyl) -3-phenyl-2-thiourea

1- (2-hydroxyphenyl) -3-phenyl-2-thiourea

3,3 '- (Carbonothioyldiimino) bis [4-hydroxybenzoic acid]

m.m '-( 1,3-thioureylene) di (4-hydroxybenzoic acid)

1- (2-tolyl) -3- (3-chloro-6-hydroxyphenyl) -2-thiourea

1 - [(2-hydroxy-4-aminophenyl)] - (3-phenyl) urea

N- (2-carboxy-4-trifluoromethylphenyl) -N '- (3-chlorophenyl) urea

N- (2-carboxyphenyl) -N '- (2,5-dichlorophenyl) urea

1- (2-Carboxyphenyl) -3- (2-chloro-5-trifluoromethylphenyl) urea

2- [2- [3- (4-bromophenyl) ureido] -4-trifluoromethylphenoxy] benzoic acid

2- [2- [3- (4-chlorophenyl) ureido] phenoxy] benzoic acid

2- [2- [3- (4-Chloro-3- (trifluoromethyl) phenyl) ureido] phenoxy] benzoic acid

N- (2-hydroxyphenyl) -N'-phenylurea

N- [2-hydroxy-5- (methoxycarbonyl) phenyl] -N'-phenylurea

N- [4-carboxy-2-hydroxyphenyl] -n'-phenylurea

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

1- (2-carboxyphenyl) -3- (2,6-xylyl) urea

1- (6-carboxy-2,4-dichlorophenyl) -3- (2,4,6-trichlorophenyl) urea

1- (2-carboxyphenyl) -3- (2,5-dimethoxyphenyl) urea

1- (2-Carboxyphenyl) -3- (2-methylphenyl) urea

1 - [(2-hydroxyphenyl) -3- (2-methyl) -5-nitrophenyl] urea

1- (2,5-Dichlorophenyl) -3- (2-hydroxy-4-nitrophenyl) urea

1- (2-Carboxyphenyl) -3- (4-chloro-2-methylphenyl) urea

N- (2-phenylsulfonylaminophenyl-N'-phenylurea

N- (2-hydroxy-4-nitrophenyl) -N '- (4-ethoxycarbonylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (2-ethoxycarbonylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (3-ethoxycarbonylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (4-phenylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (4-phenoxyphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (4-propylphenyl) urea

N- (4-Trifluoromethyl-2- (4-nitrobenzenesulfonyl) amino] -N'-phenylurea

N- (3-carboxyphenyl) -N '- (2-hydroxy-4-nitrophenyl) urea

N- (4-Trifluoromethyl-2- (methylsulfonyl) amino) -N'-phenylurea

N- (2-hydroxy-4-nitrophenyl) -N '- [2- (isopropyl) phenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (2,6-dimethylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (2-fluoro-5-nitrophenyl) urea

N - (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-4-nitrophenyl) -N '- (2-methoxy-4-nitrophenyl) urea

N- (2-hydroxy-1-naphthyl) -N '- (2-phenylphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (2-bromophenyl) urea

N- (2-hydroxy-3,4-dichlorophenyl) -N '- (4-phenylphenyl) urea

N- (2-hydroxy-3-naphthyl) -N '- (2-methoxyphenyl) urea

N- (2-hydroxy-3-naphthyl) -N '- (2-phenylphenyl) urea

N- (2-hydroxy-3-naphthyl) -N '- (4-methoxyphenyl) urea

N- (2-hydroxy-3-naphthyl) -N '- (3-trifluoromethylphenyl) urea

N- (2-hydroxy-3-naphthyl) -N '- (4-phenylphenyl) urea

N- [2- (2-carboxyphenylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (2-methoxyphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (4-methoxyphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (3-trifluoromethylphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (2-phenylphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (4-phenylphenyl) urea

N- [2 - [(2,5-dichlorothien-3-yl) sulfonylamino] phenyl] -N'- (2- bromophenyl) 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 '- (2,4-dimethoxyphenyl) urea

N - (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-4-isopropylphenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-3-phenylphenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-5-nitrophenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-5-nitrophenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-3-cyanophenyl) -N '- (4-methoxyphenyl) urea

N- (2-hydroxy-3-cyanophenyl) -N '- (4-phenylphenyl) urea

N- (2-hydroxy-3-cyanophenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-3-cyanophenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (2-methoxyphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (4-methoxyphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (3-trifluoromethylphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (2-phenylphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (4-phenylphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (2,3-dichlorophenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-5-phenylphenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (4-methoxyphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (3-trifluoromethylphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (2-phenylphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (4-phenylphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (2,4-dimethoxyphenyl) urea

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea

N- (2-hydroxy-3,4-dichlorophenyl) -N '- [2,4-dimethoxyphenyl] urea

N- (2-hydroxy-3,4-dichlorophenyl) -N '- [2-chloro-5-trifluoromethylphenyl] urea; And

N- (2-hydroxy-3-naphthyl) -N '- [3-trifluoromethylphenyl] urea.

Chemotoxicity analysis:

In vitro inhibition properties of these compounds are described in Current Protocols in Immunology, vol. I, Suppl. 1, Unit 6.12.3], as determined by neutrophil chemotaxis analysis. Neutrophils are described in Current Protocols in Immunology, Vol. I, Suppl. 1, Unit 7.23.1]. The chemoattractants IL-8, GRO- alpha, GRO- beta, GRO-y and NAP-2 were incubated at a concentration of 0.1-100 nM in a 48 well multiwell chamber (Neuro Probe, Cabinn, Chamber. The two chambers are separated by a 5 탆 polycarbonate filter. When testing the compounds of the present invention, they are mixed with cells (0.001-1000 nM) just prior to adding the cells to the upper chamber. The cultivation is carried out in a humidified incubator (about 37 ° C) containing 5% CO ₂ for about 45 to 90 minutes. At the end of the incubation, the polycarbonate membrane was removed and the top surface washed and stained using the Diff Quick dyeing protocol (Baxter Products, McGow Park, Ill., USA). Use a microscope to visually count the cells chemotically expressed on the chemokine. Generally, four zones are counted for each sample, and the number is averaged to obtain the average number of cells migrated. Each sample is tested in triplicate and each compound is repeated at least four times. No compound is added to any cell (positive control cell), and these cells exhibit the maximum chemotactic response of the cell. If voice control (unstimulated) is desired, no chemokine is added to the bottom chamber. The difference between positive control and negative control indicates the chemotactic activity of the cells.

Elastase Release Analysis:

The compounds of the present invention are tested for their ability to prevent the release of elastase from human neutrophils. Neutrophils are described in Current Protocols in Immunology Vol. I, Suppl. 1, Unit 7.23.1]. 0.88 × 10 ⁶ cells of PMN suspended in Ringer's solution (NaCl 118, KCl 4.56, NaHCO ₃ 25, KH ₂ PO ₄ 1.03, glucose 11.1, HEPES 5 mM, pH 7.4) were added to each well of a 96 well plate in a volume of 50 μl . To this plate is added 50 [mu] l of a test compound (0.001-1000 nM), 50 [mu] l volume (20 [mu] g / ml) cytochalasin B and 50 [ These cells are incubated (37 ° C, 5% CO ₂ , 95% RH) for 5 minutes and then IL-8, GROα, GROβ, GROγ or NAP-2 are added to a final concentration of 0.01 to 1000 nM. The reaction is allowed to proceed for 45 minutes, then the 96-well plate is centrifuged (800 x g, 5 minutes) and 100 μl of the supernatant is collected. This supernatant was added to a second 96-well plate and then diluted in phosphate-buffered saline with an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Zolla) is added. Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, Mass.) And analyzed according to Nakajima et al. Biol. Chem. 254 , 4027 (1979)]. The amount of elastase released from the PMN is calculated by measuring the rate of MeOSuc-Ala-Pro-Val-AMC degradation.

The above description fully discloses the present invention including preferred embodiments of the present invention. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the embodiments of the present application are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. Embodiments of the present invention in which a monopoly or exclusive rights are claimed are limited as claimed.

Claims (12)

Comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said malarial is selected from the group consisting of malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, And diseases caused by respiratory viruses, herpes viruses, and hepatitis viruses (including but not limited to hepatitis B and hepatitis C virus), wherein the chemokine is selected from the group consisting of IL- 8 &lt; / RTI &gt; or beta receptor) mediated disease. <Formula I> Wherein X is oxygen or sulfur; R is any functional group having an ionizable hydrogen and a pKa of 10 or less; R &lt; ₁ &gt; is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR &lt; ₄ &gt; C (O) R &lt; _{11 &} gt ;; Or two R ₁ residues together are O- (CH _{2) s} O- or a 5 to 6 membered unsaturated to form a ring; Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy, arylC _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; NR ₄ R ₅ ; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{C (O) NR 4 R 5} ; _{C (O) NR 4 R 10} ; S (O) ₃ H; S (O) ₃ R ₈ ; C _1-10 alkyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; C (O) OR ₁₂ ; OC (O) R ₁₁ ; NR ₄ C (O) R ₁₁ , or two Y moieties together may form O- (CH ₂ ) _s O- or a 5- to 6-membered unsaturated ring; n is an integer from 1 to 3; m is an integer of 1 to 3; t is 0 or an integer of 1 or 2; s is an integer from 1 to 3; R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O / N / S &Lt; / RTI &gt; R ₈ is hydrogen or C _1-4 alkyl; R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ; R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl; R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl. The method of claim 1, wherein the pKa of the ionizable hydrogen is from 3 to 10. The method of claim 2, wherein, R is hydroxy, carboxylic acid, _{thiol, -SR 2, -OR 2, -NH} -C (O) R a, -C (O) NR 6 R 7, -NHS (O) ₂ R _b , -S (O) ₂ NHR _c , NHC (X) NHR _b or tetrazolyl, Wherein R &lt; ₂ &gt; is a substituted aryl, heteroaryl or heterocyclic group having a functional group that provides an ionizable hydrogen whose ring has a pKa of 10 or less; R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group or R ₆ and R ₇ together with the nitrogen to which they are attached form a _5-7 membered ring optionally containing an additional heteroatom selected from oxygen, Form a ring; R _a is alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl group which may all be optionally substituted; R _b are each independently halogen; Nitro; Halo substituted C _1-4 alkyl; C _1-4 alkyl; C _1-4 alkoxy; NR ₉ C (O) R _a ; _{C (O) NR 6 R 7} ; S (O) ₃ H, or C (O) OC _1-4 alkyl with from 1 to 3 times any NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl which may be substituted, Heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl, camphor; R ₉ is hydrogen or C _1-4 alkyl; R _c is independently selected from the group consisting of halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, NR ₉ C (O) R _a , C (O) NR ₆ R ₇ , S (O) ₃ H, or C (O) OC _1-4 alkyl as optionally substituted one to three times be alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, which, heteroaryl, heteroaryl C _{1 -4} alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, a heterocyclic C _2-4 alkenyl group know how. The compound of claim 3, wherein R ₂ is selected from the group consisting of halogen, nitro, halo-substituted C _1-10 alkyl, C _1-10 alkyl, C _1-10 alkoxy, hydroxy, SH, -C (O) NR ₆ R ₇ , (O) R &lt; _a &gt;, -NHS (O) R <_b> , S (O) NR <_6> R <_7> , C (O) OR <_8> or a tetrazolyl ring. The method of claim 3, wherein R is OH, -NHS (O) ₂ R _b or C (O) OH. The method of claim 1, wherein, R ₁ is halogen, cyano, _{nitro, CF 3, C (O)} NR 4 R 5, alkenyl _{C (O) NR 4 R 5} , C (O) R 4 R 10, alkenyl C (O) OR ₁₂ , heteroaryl, heteroarylalkyl, heteroarylalkenyl or S (O) NR ₄ R ₅ . The compound of claim 1, wherein Y is selected from the group _consisting of halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR ₄ R ₅ , thioC _1-4 alkyl, thioaryl, halo substituted alkoxy , Optionally substituted C _1-4 alkyl, hydroxyalkyl. The method according to claim 1, wherein R is OH, SH or NHS (O) _s R _b , wherein R ₁ is substituted in the 3-position, 4-position or in the 3,4-position by an electron withdrawing group . Wherein Y is monosubstituted at the 2 ' -position or 3 ' -position of the monocyclic ring, or disubstituted at the 2 ' - or 3 ' -position. 9. The compound of claim 1, 8 or 9, wherein n and m are each 1 or more. 2. The process of claim 1, wherein R is a carboxylic acid and R &lt; _{1 &gt;} is hydrogen, or R &lt; ₁ &gt; 2. The compound of claim 1, wherein said compound, or a pharmaceutically acceptable salt thereof, 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-nitrophenyl) -N '- (2-chlorophenyl) 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-nitrophenyl) -N '- (2-phenyloxyphenyl) urea; N- (3-chloro-2-hydroxyphenyl) -N '- (bromophenyl) urea; N- (2-hydroxy-3-glycine methyl ester carbonylphenyl) -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; 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-nitrophenyl) -N '- (2-iodophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea; N- (2-phenylsulfonamido) -4-cyanophenyl-N '- (2-bromophenyl) 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) urea; And N- (2-hydroxy-3-cyanophenyl) -N '- (2,3-dichlorophenyl) urea; Or a pharmaceutically acceptable salt thereof.