CA2432662A1

CA2432662A1 - Il-8 receptor antagonists

Info

Publication number: CA2432662A1
Application number: CA002432662A
Authority: CA
Inventors: Katherine Louisa Widdowson; Daniel Frank Veber; Anthony Joseph Jurewicz; Melvin Clarence Rutledge Jr.; Robert Philip Hertzberg
Original assignee: Smithkline Beecham Corporation; Katherine Louisa Widdowson; Daniel Frank Veber; Anthony Joseph Jurewicz; Melvin Clarence Rutledge Jr.; Robert Philip Hertzberg
Current assignee: SmithKline Beecham Corp
Priority date: 1995-02-17
Filing date: 1996-08-21
Publication date: 1997-08-21

Abstract

The invention relates to a compound of formula (see Formula I) and the use of such a compound for treating a chemokine mediated disease state in a mammal.

Description

WO 97!29743 PCT/IJS96/13632 s FIELD OF THE INVENTION
This invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL,-8, GROG, GRO~, GROy and NAP-2 mediated diseases and pharmaceutical compositions for use in such therapy.
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL,-8), such as neutrophil attractant/activation protein-1 (NAP-1}, monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, iL-1 a, IL-1 b or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, ( l 989); 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). _ GROG, GRO~i, GROy and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GROa, ~3, y have been referred to as MGSAa, b and g respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 ( 1986) and Chang et al, J. Immunol 148, 451 ( 1992). All of the chemokines of the a-family which possess the ELR motif directly preceding the CXC motif bind to the FL-8 B
receptor.
IL-8, GROa, GRO~i, GROy and NAP-2 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROG have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-a and IL-8 can in addition, induce Iysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CDIIb/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROa, GRO~i, GROy and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEES Lett. 307, 97 (1992); Miller et al, rit R v.
Immunol. I2, 17 (1992); Oppenheim et al, Annu. Rev. Immunol. 9, 617 (1991);
Seitz et al., J. CIin. Invest. 87, 463 ( 1991 ); Miller et al., Am. Rev. Re~pir.
Dis. 146, 427 ( 1992); Donnely et al., Lancet 341, 643 ( 1993). In addition the ELR
chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 ( 1992).
to In vitro, IL-8, GROa, GRO~i, GROy and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem.
266, 14839 ( 1991 ); and Holmes et al., Science 253, 1278 ( 1991 ). The development of non-peptide small molecule antagonists for members of this receptor family has precedent.
For a review see R. Freidinger in: Progress in Drub Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the 1L-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been 2o characterized: TL-8Ra, which binds only IL-8 with high affinity, and IL-8Rb, which has high affinity for IL-8 as well as for GRO-a, GROb, GROg and NAP-2. See Holmes et al.. supra; Murphy et al., Science 253, 1280 (i991); Lee et al., J. Biol.
Che~n. 267, 16283 ( 1992); LaRosa et al., J. Biol. Chem. 267, 25402 ( 1992); and Gayle et al., ~
Biol. Chem. 68, 7283 ( 1993).
There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 a or b receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.

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

This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Compounds of Formula (I) useful in the present invention are represented by the structure:
R
n~Y)~ J,.~ ~ R~)m H H
(I) wherein X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R 1 is independently selected from hydrogen; halogen; vitro; cyano; C 1 _ 10 ~Yl:
halosubstituted'C1_10 alkyl; C2_10 alkenyl; C1-10 alkoxy; halosubstituted Cl-l0~koxy; azide; S(O)tR4; (CRBRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C 1 ~
alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 ~
alkyloxy;
heterocyclic, heterocyclic Cl~alkyl; heterocyclicCl~alkyloxy;
heterocyclicC2_10 alkenyl; (CRBRg)q NR4R5; (CRBRg)q C(O)NR4R5; C2_ l0 aikenyl C(O)NR4R5;
(CRBRg)q C(O)NR4R10; S(O)~H; S(O)3Rg; (CRBRg)q C(O)R11; C2-10 ~kenyl C(O)R11; C2_IO alkenyl C(O)ORI1; (CRBRg)q C{O)OR11; (CRBRg)q OC(O)R11;
(CRBRg)qNR4C(O)R11; (CRBRg)q C(NR4}NR4R5; (CRBRg)q NR4C(NRS)R11 , (CRBRg)q NHS(O)ZR13; (CRBRg)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of i to 3;
R4 and RS are independently hydrogen, optionally substituted C1_4 alkyl, optionally substituted aryl, optionally substituted aryl Cl~alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cl~alkyl, heterocyclic, heterocyclic C 1 ~ alkyl, or R4 and RS together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; vitro; cyano; halosubstituted C 1 _ 10 alkyl; C 1-10 ~Yl~ C2-10 alkenyl; C 1 _ 10 alkoxy; halosubstituted C 1 _ 10 alkoxy; azide;
(CRBRg)qS(O)tR4, (CRBRg)qOR4; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl;
_3_ aryloxy; arylC 1 _q. alkyloxy; aryl C2_ I0 alkenyl; heteroaryl;
heteroarylalkyl;
heteroaryl C 1 ~ alkyioxy; heteroaryl C2_ 10 alkenyl; heterocyclic, heterocyclic C 1 _4alkyi; heterocyclicC2_ 10 alkenyl; (CRgRg)qN'R4R5; CZ_ 10 alkenyl C(O)NR4R5; (CRBRg)qC(O)NR4R5; (CRBRg)q C(O)NR4R10; S(O)3Rg;
(CRBRg)qC(O)R11; C2-10 ~kenylC(O)Rl l; (CRBRg)qC(O)OR11:
C2-l0~kenylC(O)OR11; (CRBRg)qOC(O)Rli; {CRBRg)qNR4C(O)R11:
{CRBRg)qNHS(O)2Rb; (CR8R8)qS(O)ZNRøR5; (CRgRg)qC(NR4)NR4R5;
(CRBRg)q NR4C(NRS)R1 l; or two Y moieties together may form O-(CH~,)s0- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, i0 heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
m is an integer having a value of 1 to 3;
R( and R7 are independently hydrogen or a C 1..4 alkyl group, or R6 and R~
together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
Rg is hydrogen or C 1 ~ alkyl;
R 10 is C 1 _ 10 alkyl C(O)ZRg;
R 1 l is hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 alkyl;
R 12 is hydrogen, C 1 _ 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R 13 is suitably C l~ alkyl, aryl, aryl C 1 alkyl, heteroaryl, heteroarylC 1 alkyl, heterocyclic, or heterocyclicCl_4alkyl;
Rb is NR6R~, alkyl, aryl, aryl C1~ alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 ~ alkyl, heteroarylC2~ alkenyl, heterocyclic, heterocyclic C 1 ~ alkyl, heterocyciic C2~ alkenyl, or camphor, all of which groups may be optionally substituted;
or a pharmaceutically acceptably salt thereof.
Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, as defined herein.

This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (II), as defined herein.
This invention also relates to the novel compounds of Formula (II), or a pharmaceutically acceptable salt thereof, as defined herein.
Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof, as defined herein.
to This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mamma!
an effective amount of a compound of Formula (III), as defined herein.
This invention also relates to the novel compounds of Formula (111), or a pharmaceutically acceptable salt thereof, as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the II,-8 a and b receptors. Chemokine mediated 2o diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
In compounds of Formula (1), R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to '7. Such functional groups include, but are nat limited to, hydroxy, carboxylic acid, thioi, -SR2 -OR2, -NH-C(O)Ra, -C(O)NR(R~, a substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHR~, NHC(X2)NHRb, or a tetrazolyl; wherein X2 is oxygen or sulfur, preferably oxygen.
Preferably, the functional group is other than a sulfonic acid, either directly or as a substituent group on the aryl, heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2. More preferably R is OH, SH, or NHS(O 2Rb.
Suitably, R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.
Suitably, R6 and R~ are independently hydrogen or a C 1..4 alkyl group, or R( and R~ together with the nitrogen to which they are attached form a 5 to 7 member ring -S-WO 97/Z9743 FCTlUS96/13632 which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.
Suitably Ra is an alkyl, aryl, arylC 1 alkyl, heteroaryl, heteroaryIC 1 alkyl, heterocyclic, or a heterocyclic C 1 ~alkyi moiety, all of which may be optionally substituted, as defined herein below.
Suitably, Rb is a NR6R~, alkyl, aryl, aryl Cl~ alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 ~ alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C1~ alkyl, a heterocyclic C2~ alkenyl moiety, or camphor, all of which groups may be optionally substituted one to three times independently by halogen; vitro;
halosubstituted C 1 ~ alkyl, such as CF3; C 1 ~ alkyl, such as methyl; C l~
alkoxy, such as methoxy; aryl; heteroaryl; heterocyclic; NR9C(O)Ra; C(O)NR6R~, S(O)3H, S(O)m~Ra (wherein m' is 0, 1 or 2), or C(O)OC 1 ~ alkyl. When Rb is an aryl or arylalkyl, preferably it is an optionally substituted phenyl, benzyl, or styryl. When Rb is a heteroaryl preferably it is an optionally substituted thiazole, optionally substituted thienyl, optionally substituted quinalinyl or isoquinolyl ring, or pyridyl ring.
R9 is hydrogen or a C 1 ~ alkyl, preferably hydrogen. Suitably, when the substituent group on the Rb moiety is NR9C(O)Ra, then Ra is preferably an alkyl group, such as methyl.
Suitably Rc is hydrogen, alkyl, aryl, arylC 1 alkyl, arylC l~alkenyl, heteroaryl, heteroarylC 1 alkyl, heteroarylC 1 ~alkenyi, heterocyclic, or heterocyclic C 1 alkyl, or a heterocyclic C 1 ~alkenyl moiety, all of which groups may be optionally substituted one to three times independently by halogen, vitro, halosubstituted C 1 ~
alkyl, C 1..4 alkyl, Cl~ alkoxy, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(O)OCI~ alkyl, wherein R9 is hydrogen or a C1~ alkyl. Preferably, Rc is an optionally substituted phenyl.
When R is an ORZ or SRZ moiety it is recognized by one of skill in the art that the aryl ring must, therefore, contain the required ionizable hydrogen. The aryl ring may also be additionally substituted, independently, by one to three groups, which groups may also contain an additional ionizable group, and which include but are not limited to, halogen, vitro, halosubstituted C 1 ~ alkyl, C 1.~ alkyl, C 1 ~
alkoxy, hydroxy, SH, -C(O)NR(R~, -NH-C(O)Ra, -NHS(O)2Rb, S(O)2NR6R~, C(O)ORg~ or a tetrazolyl ring.

WO 97/29'143 PG"T/US96/13632 In compounds of Formula (I), suitably R1 is suitably an electron withdrawing moiety. R 1 may be independently selected from hydrogen; halogen; nitro;
cyano;
halosubstituted C 1 _ 10 alkyl, such as CF3; C 1 _ 10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2_ 10 alkenyl; C 1 _ 1p alkoxy, such as methoxy, or ethoxy;
halosubstituted CI-10 alkoxy, such as trifluoromethoxy; azide; S(O)tR~, wherein t is 0, 1 or 2;
(CRgRg)q S(O)tR4; hydroxy; hydroxy substituted Cl~alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl: aryl C 1 _4 alkyl, such as benzyl;
aryl C2_ I O
alkenyl ; aryloxy, such as phenoxy; aryl C 1 ~ alkyloxy, such as benzyloxy;
heteroaryl;
t0 heteroarylalkyl: heteroaryl C1~ alkyloxy; heteroaryl C2_10 alkenyi;
(CRgRg)qNR4R5;
C2-10 alkenyl-C(O)NR4R5; (CRgRg)qC(O)NR4R5; (CRgRg)qC(O)NR4R10; S(O)3H;
S(O)3Rg; (CRgRg)q C(O)R1 ~, such as trifluromethyl ketone ; C2_10 alkenyl C(O)Rl 1, C2-10 ~enylC{O)OR11; (CRgRg)qC(O)OR11, such as carboxy, methylcarboxyiate or phenylbenzoate; (CRgRg)qC(O)OR12; (CRgRg)qOC(O)R11; (CRgRg)q NR4C(O)R11;
~5 (CRgRg)qNHS(O)2R13; (CRgRg)qS(O)2NR4R5; or two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring; and s is an integer having a value of 1 to 3. The alkyl, aryl, arylalkyl, aryialkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties may all be optionally substituted as defined herein below. Preferably R1 is other than azido 20 or S(O)3Rg. Rg is independently hydrogen or C 1~ alkyl, which may be branched or straight.
When RI forms a dioxybridge, s is preferably 1. When Rl forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system.
25 This naphthylene ring may be substituted independently, 1 to 3 times by the other R1 moieties as defined above.
Suitably, R4 and RS are independently hydrogen, optionally substituted C1~
alkyl, optionally substituted aryl, optionally substituted aryl Cl_4alkyl, optionally 3o substituted heteroaryl, optionally substituted heteroaryl Cl~alkyl, heterocyclic, heterocyclicC 1~ alkyl, or R4 and Rg together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/5. The optionally substituted moieties are as defined herein below.
R10 is suitably C1_10 alkyl C(O)2Rg, such as CH2C(O)2H or CH2C(O)2CH3.

R 11 is suitably hydrogen, optionally substituted C 1 _4 alkyl, optionally substituted aryl, optionally substituted aryl C1_4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1..4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C 1 _q.alkyl. The optionally substituted moieties are as defined herein below.
R 12 is suitably hydrogen, optionally substituted C 1 _ 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl. The optionally substituted moieties are as defined herein below.
to Preferably R1 is halogen, cyano, vitro, CF3, C(O)NR4R5, alkenyl C(O)NR~RS, C(O) R4R 10, alkenyl C(O)OR 12, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably R4 and RS are both hydrogen or one is phenyl. A
preferred ring substitution for R1 is in the 4-position of the phenyl ring.
When R is OH, SH or NS02Rb than R1 is preferably substituted in the 3-position, the 4- position or di-substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably when R is OH, SH or NSOZRb, than R1 is vitro, halogen, cyano, trifluoromethyl group, C(O)NR4R5.
When R is carboxylic acid, than R 1 is preferably hydrogen, or R 1 is preferably substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro.
In compounds of Formula (I), suitably Y is independently selected from hydrogen; halogen; vitro; cyano; halosubstituted C 1 _ 10 alkyl; C 1 _ 10 alkyl; C2_ 10 alkenyl; C 1 _ 10 alkoxy; halosubstituted C 1 _ l p alkoxy; azido;
(CRBRg)qS(O)tR4, wherein q is 0 or an integer having a value of 1 to I0; (CRBRg)qOR4; hydroxy;
hydroxy C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryloxy; arylC 1.4 alkyloxy; aryl C2_ 10 alkenyl; heteroaryi; heteroarylallcyl; heteroaryl C 1 ~. alkyloxy; heteroaryl C2_ 10 3o alkenyl; heterocyclic, heterocyclic C 1 alkyl; heterocyclicC2_ 10 alkenyl;
(CRgR~qNR4Rg; C2_ 10 alkenyl C(O)NR4R5; (CRBRg)qC(O)NR4R5;
(CRBRg)qC(O)NR4R10; S(O)3R8; (~gRg)qC(O)R11; C2-IO alkenyl C(O)R11;
C2-10 ~kenyl C(O)OR11; (CRBRg)q C(O)OR12; (CRBRg)qOC(O)R11;
(CRBRg)qNR4C(O)R11; (CRBRg)q NHS(O)2Rb; (CRBRg)qS(O)2NR4R5;
3s CRBRg)qC(NR4)NR4R5; (CRBRg)q NR4C(NRS)R11, or two Y moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring. When Y forms a dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is _g_ WO 97/29743 PCTlCTS96l13632 preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted 1 to 3 times by another Y moiety, such as defined above.
Additionally ail of the various aryl, heteroaryl and heterocyclic groups noted above, as well as the R4, RS and Rl 1 substituent groups, may be optionally substituted as defined herein in the specification below. Preferably Y is other than azido or S(O)3Rg. Rg is independently hydrogen or C 1 ~ alkyl.
Y is preferably a halogen, C 1 ~ alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryialkoxy, optionally substituted 1o arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5, thioC 1 alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C 1 ~
alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted allcoxy, disubstituted allcoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3'-position.
While Y may be substituted in any of the 5 ring pdsitions, preferably when R
is OH, SH, or NHS02Rb, Y is preferably mono-substituted in the 2'-position or 3'-position, with the 4'- preferably being unsubstituted. If the ring is disubstituted, when R
is OH, SH, or NHS02Rb, substituents are preferably in the 2' or 3' position of a 2o monocyclic ring. While both R1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.
In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen.
2s While not explicitly covered by Formula (n, (Ia-c), (II), {IIa-c), or (11n, another aspect of this invention are the symmetrical bis compounds which are included for each structure.
Compounds exemplified by this bis like structure include:
3o N-{Bis (2-hydroxy-4-vitro phenyl-N'-(dianisdine~iurea 4-Methylene bis(N-(2-chloro phenyl)-N'-(2-hydroxy 4-nitrophenyl)urea) Exemplified compounds of Formula (I) include:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;
35 N-[5-Nitro-2-hydroxyphenyl]-N'-phenyl urea 3-Hydroxy-4-{ [(phenylamino)carbonyl)amino )benzamide N-(z-Hydroxy-4-fluorophenyl)-N'-phenyl urea WO 97/29743 PCT/US96l13632 2- { [(Phenylamino)carbonyl]amino } thiophenol N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea N-(4-Nitro-2-(phenylsulfonylamino)phenyl)-N'-phenyl urea N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea t0 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-nitraphenyl)-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-nitraphenyl)-N'-(2-trifluoromethoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro 6-methyl phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-sulfoxymethyl phenyl) urea N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-{2-bromo phenyl) urea N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea 3o N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-phenyl phenyl) urea N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea N-(2-Hydroxy-4-nitraphenyl) N'-(2,4-dichloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl) N'-(2,4-dibromaphenyl) urea N-(2-Hydroxy-1-napthyl)-N'-(2-bromophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea WO 97/29743 PCT/US96l13632 N-(2-Hydroxy-4-nitrophenyl)-N'-(3-chloro-2-methoxyphenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methyiphenyl) urea N-(4-(Benzylamino)carbonyl-2-hydroxyphenyi)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxyphenyl) urea S N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromophenyl) urea N-(2-Hydroxy-3-napthyl)-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 t0 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylaminophenyl) urea N-(2-Hydroxy-3-carboxyphenyl)-N'-(2-bromophenyl) urea N-(2-Sulfhydryl-4-bromophenyl)-N'-(2-bromophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-iodophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl) thiourea 15 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-Di-methoxyphenylsulfonyl)amino]phenyl)-N'-(2-bromophenyl) urea N-(2-[(4-Acetamidophenylsulfonyl)amino]phenyl)-N'-(2-bromophenyl) urea 20 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-(Aminosulfonyl benzyl) phenyl)-N'-{2-bromophenyl) urea N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea 25 N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenylurea N-(2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyi]urea 30 N-[2-Hydroxy-3,4-diphenyl-phenyl]-N'-[2-bromophenyl]urea N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromopheny1] urea N-[2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea 35 N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyi] 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 t~I-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl} urea N-[2-Hydroxy-4-cyanophenyi]-N'-[2-trifluoromethylphenyi} urea N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-ethylphenyl]-N'-(2-bromophenyl] urea N-(2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-(2-bromophenyl] urea to N-(2-Hydroxy-3-cyano-4-methylphenyl]-N'-[2-bromophenyi] urea N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-[3-Benzyloxy-2-hydroxyphenyi]-N'-[2-bromophenyl] urea (E)-N-[4-[2-(Methoxycarbonyl)ethenyl)-2-hydroxyphenyl]-N'-[2-bromophenyl]urea t5 (E)-N-(3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl}
urea-N'-[2-bromophenyl]urea (E)-N-(3-[2-(Aminocarbonyl)ethenyl}-2-hydroxyphenyl]-N'-(2-bromophenyl]urea-N'-[2-bromopheayl]urea (E)-N-[4-[2-(Aminocarbonyl)ethenyl}-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-2o ' [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-trifluorophenyi)-N'-(2-bromophenyl)urea N-(2-Hydr~xy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea i5 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-(Phenethylsuifonylamino)phenyl]-N'-(2-bromophenyi)urea N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-30 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-methoxyphenyi] urea 35 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 WO 97!29743 PCTILTS96/13632 N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N-(2-Hydroxy-3.4-dichlorophenyl]-N'-[2-methoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-phenylphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyI]-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-bromophenyi)urea N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(2-Benzyl)sulfonylamino]-(S-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 ~5 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 2o 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 25 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 30 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 35 N-(2-(Aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea N-(2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea.
l,1'-{4-Methyl-2-phenylene)bis[2-thio-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-Anisyl)-3-(2-carboxyphenyl)urea 1-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea 1-(2-Carboxyphenyl)-3-(3-chlorophenyl)urea 1-(m-Anisyl)-3-(2-carboxyphneyl)urea 1-(o-Anisyl)-3-(2-carboxyphenyl)urea 1-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea 1-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyl)urea N-[2-[2-(4-Chloro-3-aminophenyl)sulfonylamino]phenyl)-N'-(2-bromophenyl)urea N-[2-(3-Aminophenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-{3-trifluoromethyphenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(2-phenylphenyl)urea 2s N-(2-Hydroxy-3-nitrophenyl)-N'-(2,3dichlorophenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl)urea N-( 2-Hydroxy-3-nitrophenyl)-N'-(2;4-dimethoxyphenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-S-trifluoromethylphenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenylphenyl)urea N-(2-Benzenesuifonylamino-4-cyanophenyl)-N'-(3-trifluoromethylphenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea N-(2-Hydroxy-4-amidinophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3,4-dichloro phenyl) N'( phenyl) urea N-(2-Hydroxy 4-cyano phenyl) N'( phenyl) urea N-(2-Hydroxyphenyl 3-carboxylic acid)N'( phenyl) urea N-(2-Hydroxy-3-nitrophenyl}-N'-phenylurea N-(2-Hydroxy-3-cyano phenyl ) N'(phenyl) urea N-(2-Hydroxy-3-cyano-4-chlorophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea N-(2-Hydroxy-3,4-difluorophenyl)-N'-(phenyl)urea N-[2-(Benzylsulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[2-(Phenylsulfonylamino)-4-trifluoromethylphenyl]-N'-(2,3-dichlorophenyl)urea N-[2-(3-Pyridinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[2-(5-Isoquinolinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-{2-chlorophenyl)urea 1o N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-trifluoromethoxyphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-trifluoromethylphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea 15 N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro phenyl) urea N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-[(2-Pyrid-2-yl)thiophene-5-sulfonylamino-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[(2-Acetamino-4-methyl-5-thiazolesulfonylamino-4-cyanophenyl]-N'-(2,3-2o dichlorophenyl)urea N-((2-Aminosulfonylphenyl) 4-cyano phenyl) N'-(2-methyl 3-chloro phenyl) urea N-(2-Benzenesulfonylamino-3-cyanophenyi)-N'-(2,3dichlorophenyl)urea N-[(Benzylsulfonylamino)-5-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-((2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea 25 N-[(2-Phenylsulfonyiamino)-4-cyanophenyl]-N'-(2-methyl-3-nitrophenyl)urea N-j(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-aminophenyl)urea N-[(2-Phenylsulfonyiamino)-4-cyanophenyl)-N'-(2-aminophenyl)urea N-(2-(2-Pyridinesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Benzenesulfonylamino-3-trifluoromethylphenyl-N'-(2,3-dichlorophenyl)urea -30 N-(4-Benzenesulphonylthiophene-2-sulphonylamino-4-cyanophenyl}-N'-(2,3-dichlorophenyl)urea N-(2-Trifluoromethylbezenesulfonylacnino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2,3-methylenedioxyphenyl)urea N-[2-(2-Nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea 35 N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2-phenylphenyl}urea N-(2-Hydroxy-4-nitrophenyl)-N'~-(2-benzylphenyl)urea WO 97!29743 PCT/C1S96/13632 N-{2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea N-{2-Hydroxy-4-vitro phenyl)-N'-[2-(phenyloxymethyl)phenyl]urea N-{2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylethyl)phenyl]urea N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(4-trifluorophenyl)phenyl]urea N-( 2-Hydroxy-3-trifloromethylphenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-(2-cyanophenylthio)phenyl]urea N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2-chlorophenyl)urea N-(2-Hydroxyethyl)-N'-{2-hydroxy-4-nitrophenyi)urea 1o N-2-(Benzyoxyphenyi)-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(2-Thienylsulfonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyi)urea N-(2-Benzenesulfonylanuno-4-nitrophenyl)-N'-(2-bromophenyl)urea N-(2-Benzylsulfonyiamino-4-nitrophenyl)-N'-(2-bromophenyl)urea ~5 N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichlorophenyl)urea N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydmxy-4-nitrophenyl)urea N-[2-(Methoxycarbonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(Methylsulfonylamino)-4-nitrophenyl]-N'-(2-brornophenyl)urea 20 N-[2-(Propylsulfonylamino)-4-nitrophenyl)-N'-(2-bromophenyl)urea N-[2-(Propylsulfonylamino)-4-nitrophenyl]-N'-(2,3-dichlorophenyl)urea N-[[(2-acetamino-4-methyl-5-thiazolyl)sulforay!amino]-4-nitrophenyl)-N'-{2,3-dichlorophenyl)urea N-[2-(3-Pyridinesulforay!amino)-4-nitrophenyi]-N'-(2,3-dichlorophenyl)urea z5 N-[2-(3-Pyridinesulforay!amino)-4-nitrophenyi]-N'-(2-bromophenyi)urea N-[2-(Methylsulforay!amino)-4-nitrophenyl]-N'-(2,3-dichloropheny!)urea N-(2-Hydroxyeth-1-yloxyphenyl)-N-(2-hydroxy-4-nitrophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea N'-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy-4-nitrophenyl)urea 3o N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-(2-hydroxy-4-nitmpheny!)urea N-[2-(2-Carboxybenzyloxy)phenyl)-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea Additionally exemplified compounds of Formula ()~ include:
35 N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-{2-(2-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2-bromophenyl)urea N-{2-Hydroxy-4-trifluoroacetophenone)-N'-(2,3-dichlorophenyl)urea N-{2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2,3-dichlorophenyl)urea 1o N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2.3-dichlorophenyl)urea Prefered compounds of Formula (n include:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea N-{2-Hydroxy-4-nitrophenyl)-N'-{2-phenylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methylthiophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-{2,3-dichlorophenyl)urea N-(2-hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea N-(2-hydroxy 4-nitro phenyl) N'-{2-phenyloxy phenyl) urea N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3,4-dichlorophenyl)-N'-{2-bromophenyl)urea 3o N-(3-Cyano-2-hydroxyphenyl)-N'-{2-bromophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea N-(2-Hydorxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea N-(3-Trifluoromechyl-2-hydroxyphenyl)-N'-{2-bromophenyl)urea N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy 4-vitro phenyl) N'-(~-iodo phenyl) urea N-(2-hydroxy 4-vitro phenyl) N'(2-bromo phenyl) thiourea N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea (E)-N-[3-((2-Aminocarbonyl)ethenyi]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy,3,4-dichlorophenyi)-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 1o N-(2-Hydroxy-3-cyanophenyl)-N'-(2,3 dichlorophenyl)urea As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as cyano, vitro, fluorine, chlorine, bromine or iodine;
hydroxy; hydroxy substituted C1-l0alkyl; C1-10 alkoxy, such as methoxy or ethoxy;
t5 S(O)m~ C1-10 alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR4R5 group;
NHC(O)R4; C(O)NR4R5; C(~)~R11; S(0)2NR4R5; NHS(O)2R13;,C1-10 alkYh such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted C1-10 ~Yl~
such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such 2o as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl, hetroaryi, or heterocyclic moieties may themselves be optionally substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl;
C1-10 alkoxy; S(C)m~Cl-10 ~Yl: ono, mono & di-substituted amino, such as in the 25 NR4R5 group; C 1-10 aIkYI, or halosubstituted C 1-10 alkyl, such as CF3.
R 13 is suitably C 1 ~ alkyl, halosubstituted C 1 ~ alkyl, aryl, aryl C 1 alkyl, heteroaryl, heteroarylC 1-4alkyl, heterocyclic, or heterocyclicC 1 _4alkyl.
Another aspect of the present invention are the novel compounds of Formula 30 (II), or a pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable diluent or carrier.
Compounds of Formula (II) are also useful for treating a chemokine mediated disease, wherein the 35 chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (lI)-or a pharmaceutically acceptable salt thereof.

Compounds of Formula (II) are represented by the structure:
R

Rt)m H
(II) wherein X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R I is independently selected from hydrogen; halogen; vitro; cyano; C I_ IO
~Y1:
halosubstituted C 1 _ 10 ~Yl ~ C2-10 ~kenyl; C I-10 alkoxy; halosubstituted C1_l0alkoxy; azide; S(O)tR,~; (CRBRg)q S(O)tR~; hydroxy; hydroxy substituted C 1 _4alkyl; aryl; aryl C 1 ~ alkyl; aryl C2_ I0 alkenyl; aryloxy; aryl C 1 ~
alkyloxy;
t0 heteroaryl; heteroarylalkyi; heteroaryl C2_10 alkenyl; heteroaryl CI~
alkyloxy;
heterocyclic, heterocyclic C 1 _q.alkyl; heterocyclicC 1 ~.alkyloxy;
heterocyclicC2_ 10 aikenyl; (CRBRg)q NR,4R5; (CRBRg)q C(O)NR4R5; C2_10 alkenyl C(O)NR4R5;
(CRBRg)q C(O)NR4RI0; S(O)3Rg; (CRBRg)q C(O)RI I; C2-10 ~enyl C(O)RI I;
C2-10 ~kenyl C(O)ORI I; (CRBRg)q C(O)OR11; (CRBRg)q OC(O)R11;
(CRBRg)qNR4C(O)RI1: (~8R8)q C(NR4)NR4R5: (CR8R8)q ~4C~5)R11.
(CRBRg)q NHS(O)2R13; (CRBRg)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C L.~ alkyl, optionally substituted aryl, optionally substituted aryl C I alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cl~alkyl, heterocyclic, heterocyclicC 1 _4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; vitro; cyano; halosubstituted C 1_ I0 alkyl: C I-10 ~Yl: C2-10 alkenyl; C 1_ 10 alkoxy; halosubstituted C 1_ 10 alkoxy; azide;
(CR8R8)qS(O)tR4, (CRBRg)qOR~; hydroxy; hydroxy substituted C I alkyl; aryl; aryl C 1 ~ alkyl;
aryloxy; arylC 1 ~ alkyloxy; aryl CZ_ I0 alkenyl; heteroaryl;
heteroarylallryl;
heteroaryl C 1 ~ alkyloxy; heteroaryl C2_ 10 alkenyl; heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC2_ l p alkenyl; (CRBRg)qNR4R5; C2_ 10 alkenyl C(O)NR4R5; (CRgRg)qC(O)NR4Rg; (CRgRg)q C(O)NR4R10: S(O)3R8:

(CRgRg)qC(O)Rl 1; C2-10 ~kenylC(O)R11; (CRgRg)qC(O)OR11;
C2-l0~kenylC(O)OR11; (CRgRg}qOC(O) R11; (CRgRg)qNR4C(O)R11:
(CRgRg)q NHS(O)~Rb; (CRgRg)q S(O)2NR4R5; (CRgRg)qC(NR4)NR4R5;
(CRgRg)q NRq,C(NRS)R 11; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl;
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R6 and R~ are independently hydrogen or a C 1 _4 alkyl group, or R( and R~
together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
Rg is hydrogen or C 1 _4 alkyl;
Rl0 is C1_10 alkyl C(O)2Rg;
R11 is hydrogen, optionally substituted C1~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 ~aikyl;
R 12 is hydrogen, C 1 _ 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably Cl~ alkyl, aryl, aryl C1_4alkyl, heteroaryl, heteroarylCl~alkyl, heterocyclic, or heterocyclicCl~alkyl;
Rb is NR6R~, alkyl, aryl, aryl Ci~ alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 _q. alkyl, heteroarylC2~ alkenyl, heterocyclic, heterocyclic C 1 ~ alkyl, heterocyclic C2~ alkenyl, or camphor, all of which groups may be optionally substituted;
E is optionally selected from O
O ~
; ; R~ , or R~ , the asterix * denoting point of attachment of the ring, with at least one E
being present;
or a pharmaceutically acceptably salt thereof.

Suitably, the variables for Formula (II), such as X, R, R1, R4 , RS, R6, R~, Rg, R9, Y, Ra, Rb, Rc, n, m, and s terms, etc. are as defined in Formula (I) above. The E
ring denoted by its point of attachment through the asterix (*) may optionally be present. If if it is not present the ring is a phenyl moiety which is substituted by the R
and R 1 terms as shown. At least one E ring is necessary. The E ring may be substituted by the R 1 or Y moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
to Another aspect of the present invention are the novel compounds of Formula (IIa), (IIb) and (IIc) which are similar to those described herein for Formulas (Ia), {Ib) and (Ic) but which require one of the two phenyl rings to posses an E ring.
Suitably, for compounds of Formula (IIa-c), the variables are as defined herein for Formulas (I) and (II).
Compounds of Formula (IIa) are represented by the structure:
R
n~Yy ~ R~)m x. ~ /
H H
(IIa) wherein X is oxygen or sulfur;
2o R is -NHS(O)2Rb;
Ra is an alkyl, aryl, arylCl~alkyl, heteroaryl, heteroaryl Cl~alkyl, heterocyclic, or a heterocyclic Cl~alkyl moiety, all of which may be optionally substituted;
Rb is a NR6R7, alkyl, aryl, arylC 1 alkyl, aryl C2~alkenyl, heteroaryl, heteroarylCl~alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclic Cl~alkyl, or a heterocyclic C2~alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; vitro;
halosubstituted C1~ alkyl; C1~ alkyl; C1~ alkoxy; NR9C(O)Ra; S(O)m~Ra, C(~)N1t6R7; S(U)3H, or C(O)OC 1-4 alkyl;
R6 and R~ are independently hydrogen or a C 1 ~ alkyl group, or R( and R~
together 3o with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substitued;
R9 is hydrogen or a C1_4 alkyl, preferably hydrogen;

WO 97129743 PCTlLTS96/13632 R 1 is independently selected from hydrogen; halogen; vitro; cyano; C 1-10 alkyl;
halosubstituted C 1 _ 10 alkyl; CZ_ 10 aikenyl; C 1-10 alkoxy; halosubstituted C1-l0alkoxy; azide; S(O)tR4; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 _4alkyl; aryl; aryl C 1 ~ alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C 1 ~
alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_10 alkenyl; heteroaryl C1~
alkyloxy;
heterocyclic, heterocyclic C 1..4alkyl: heterocyclicC 1 _4alkyloxy;
heterocyclicC2_ 10 alkenyi: (CRgRg)q NR4R5; (CRgRg)q C(O)NR4Rg; C2_ 10 alkenyl C(O)NR.4R5;
(CRgRg)q C(O)NR4R10; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 alkenyl C(O)R11;
C2-10 ~kenyl C(O)OR11; (CRgRg)q C(O)OR11; (CRgRg)q OC(O)R11;
~o (CRgRg)qNR4C(O)R11; (CRgRg)q C(NRq.)NRdRS; {CRgRg)q NR4C(NRS)R11~
(CRgRg)q NHS(O)2R13; (CRgRg)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic mollies may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and RS are independently hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl Cl~aikyl, optionally substituted heteroaryl, optionally substituted heteroaryl C l~alkyl, heterocyclic, heterocyclicC 1~ alkyl, or R4 and RS together with the nitrogen to which they are 2o attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; vitro; cyano; halosubstituted C 1 _ 1 O ~Yl ~ C 1-10 ~Yl: C2-10 alkenyl; C1_10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CRgRg)qS(O)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Cl~.alkyl; aryl; aryl C1~ alkyl;
aryloxy; arylC 1 _4 alkyloxy; aryl C2_ 10 alkenyl; heteroaryI;
heteroarylalkyl;
heteroaryl C 1 ~ alkyloxy; heteroaryl C2_ 10 alkenyl; heterocyclic, heterocyclic C 1 alkyl; heterocyclicC2_ 10 alkenyl; (CRgRg)qNR4R5; C2_ 10 alkenyl C(O)NR4R5: (CRBRg)qC(O)NR4R5: (CRgRg)q C(O)NR4R10~ S(O)3R8~
(CRgRg)qC(O)R11; C2-10 ~kenylC{O)R11; (CRgRg)qC(O)ORII;
3o C2_lpalkenylC(O)OR11; (CRgRg)qOC(O) R11; (CRgRB)qNRq.C(O)R11~
(CRgRgyq NHS(O)2Rb; (CRgRg)q S(O)2NR4R5, (CRgRg)qC(NR4)NR4R5;
(CRgRg)q NR4C(NR5)R11; or two Y moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, aryialkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyciicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;
Rg is hydrogen or C 1 _~ alkyl;
R 10 is C 1-10 alkyl C(O)2Rg;
R 11 is hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl C1-alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl;
R 12 is hydrogen, C 1 _ 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl:
R13 is suitably C1~ alkyl, aryl, aryl Cl~alkyl, heteroaryl, heteroarylCl~alkyl, heterocyclic, or heterocyclicC 1 alkyl;
E is optionally selected from O
*
* ~ ~ ~
l O
. ~ , R' , or Ri the asterix * denoting point of attachment of the ring; with the proviso that at least one E ring being present;
or a pharmaceutically acceptably salt thereof.
Formula (IIb) compounds contain the R functionality of X1R2 wherein R2 is R2 -is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety 2o providing the ionizable hydrogen having a pKa of 10 or less; and the remaining variables as defined ahove for compounds of Formula (I) and (II).
Formula (IIc) compounds contain the R functionality X 1H, wherein X 1 is oxygen or sulfur and the remainder of the variables are as defined in Formula (I) and (II) above.
Exemplified compounds of Formula (In include:
N-[2-hydroxy-S-indanone]-N'-[2-bromophenyl] urea;
N-[1-hydroxyfluorene]-N'-j2-bromophenyl] urea;
3o N-[3-hydroxy-9,10-anthraquinon-2-yl]-N'-[2-bromophenyl] urea WO 97129743 PCTIUS96l13632 Another aspect of the present invention are the novel compounds of Formula (III), or a pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula (III) and a pharmaceutically acceptable diluent or carrier.
Compounds of Formula (III) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof.
i0 Compounds of Formula (III:) are represented by the structure:
(Y)n R
R m S N~ _ H H
wherein X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
t 5 R 1 is independently selected from hydrogen; halogen; vitro; cyano; C I _ 10 alkyl;
halosubstituted C 1 _ 10 alkyl; CZ_ 1p alkenyl; C 1-10 alkoxy; halosubstituted Cl-l0~koxy; azide; S(O)tR4; (CRBRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C 1 ~
allcyloxy;
heteroaryl; heteroarylallcyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 ~
allcyloxy;
20 heterocyclic, heterocyclic C 1 _4alkyi; heterocyclicC 1 ~alkyloxy;
heterocyclicC2_ I O
alkenyl; (CRBRg)q NR4R5; (CRBRg)q C(O)NR4R5; C2_10 alkenyi C(O)NR4R5;
(CRBRg)q C(O)NR4R10; S(O)3Rg; (CRBRg)q C(O)R11; C2-10 ~enyl C(O)R11;
C2-10 ~kenyl C(O)ORI I; (CRBRg)q C(O)OR11; (CRBRg)q OC(O)R11;
(CRgRg)qNR4C(O)R11; (~gRg)q C(1'IR4)NR4R5; (CRgRg)Q NR4C(NRS)R11~ .
25 (CRBRg)q NHS(O)2R13; (CRBRg)q S(O)ZNR~RS, or two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
q is 0 or an integer having a value of 1 to I0;
t is 0, or an integer having a value of 1 or 2;
30 s is an integer having a value of 1 to 3;
R4 and RS are independently hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1 _4alkyl, heterocyclic, heterocyclicCl_4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen: halogen; nitro; cyano; halosubstituted C1-10 ~kYl; C1-10 alkyl;
C2_10 alkenyl; C1_lp alkoxy; halosubstituted C1-10 ~koxY; azide; (CRgRg)qS(O)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Cl~alkyl; aryl; aryl C1~ alkyl;
aryloxy; arylC 1 _4 alkyloxy; aryl C2_ 10 alkenyl; heteroaryl;
heteroarylalkyl;
heteroaryl C 1 ~. alkyloxy; heteroaryl C2_ 10 alkenyl; heterocyclic, heterocyclic 1 o C 1 _4alkyl; heterocyclicC2_ 10 alkenyl; (CRgRg)qNR4R5; C2_ 10 alkenyl C(O)NR4R5; (CRgRg)qC(O)NR4R5; (CRgRg~ C(O)NR4R10; S(O)3Rg;
(CRgRg)qC(O)R 11; C2-10 ~kenylC(O)R 11; (CRgRg)qC(O)OR 11;
C2-l0~enylC(O)OR11; (CRgRg)qOC(O) R11; (CRgRg)qNR4C(O)R11:
(CRgRg)q NHS(O)2Rb; {CRgRg)q S(O)2NR4R5; (CRgRg)qC(NR4)NR~RS;
t5 (CRgRg)q NR4C(NRS)R11; or two Y moieties together may form O-(CH2)s0- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
n is an integer having a value of 1 to 3;
20 m is an integer having a value of 1 to 3;
R6 and R~ are independently hydrogen or a C1_r~ alkyl group, or R6 and R~
together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
25 Rg is hydrogen or C 1 _4 alkyl;
R 1 p is C 1 _ 1 p alkyl C(O)2Rg;
R 11 is hydrogen, optionally substituted C 1..4 alkyl, optionally substituted aryl, optionally substituted aryl C l alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1 _4alkyl, optionally substituted heterocyclic, or optionally 30 substituted heterocyclicCl~alkyl;
R12 is hydrogen, Cl-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R 13 is suitably C 1 _4 alkyl, aryl, aryl C 1 _4alkyl, heteroaryl, heteroarylC
1 alkyl, heterocyclic, or heterocyclicC 1 alkyl;
35 Rb is NR6R~, alkyl, aryl, aryl C1~ alkyl, aryl C2~, alkenyl, heteroaryl, heteroaryl C 1 _4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C 1 ~ alkyl, WO 97!29743 PCT/US96/i3632 heterocyclic C2_4 alkenyl, or camphor, all of which groups may be optionally substituted;
E is optionally selected from O
* \~
* *
Ri, i / ~/
. R~ , or R' the asterix * denoting point of attachment of the ring;
or a pharmaceutically acceptably salt thereof.
Suitably, the variables, etc. for Formula (III) are the same as those defined for Formula (n above, such as for example the R, R1 and Y variables. Suitably the E term is the same as previously defined for Formula (II).
Exemplified 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 aspect of the present invention is the novel compounds of Formula (Ia), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease as defined herein. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ia) and a pharmaceutically acceptable diluent or carrier.
The compounds of Formula (Ia) are represented by the strucuture:
NHS(O)2F~
~~N~N
H H
(Ia) wherein X is oxygen or sulfur;
Ra is an alkyl, aryl, arylC 1 alkyl, heteroaryl, heteroaryl C 1..4allcyl, heterocyclic, or a heterocyclic C 1 alkyl moiety, all of which may be optionally substituted;
Rb is a NR(R~, alkyl, aryl, arylC 1 alkyl, aryl C2~alkenyl, heteroaryi, heteroarylCl~alkyl, heteroarylC2~ alkenyl, heterocyclic, or heterocyclic C1_4alkyl, or a heterocyclic C2_4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; vitro;
halosubstituted C 1 _4 alkyl; C 1 _4 alkyl; C 1 _4 alkoxy; NR9C(O)Ra;
S(O)m~Ra, C(O)NR6R?, S(O)3H, or C(O)OC1_4 alkyl;
R6 and R7 are independently hydrogen, or a C1_4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substitued;
R9 is hydrogen or a C1_4 alkyl, preferably hydrogen;
t o R 1 is independently selected from hydrogen; halogen; vitro; cyano; C 1 _ 10 alkyl;
halosubstituted C 1 _ 10 alkyl; C2_ 10 alkenyl; C 1 _ 10 alkoxy;
halosubstituted C1-l0~koxy; azide; S(O)tR4; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryl C2_ 10 alkenyi; aryloxy; aryl C 1 ~
alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 ~
alkyloxy;
heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC 1 _4aikyloxy;
heterocyciicC2_ 10 alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(O)NR4R5; C2_10 alkenyl C(O)NR4R5;
(CRgRg)q C(O)NR4R10; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 ~enyl C(O)R11;
C2-10 ~kenyl C(O)OR11; (CRgRg)q C(O)OR11; (CRgRg)q OC(O)R11;
(CRgRg)qNR4C(O)R11; (~gRg)q C(~4)NR4R5~ (CRgRg)q NR4C(NR5)R11~
2o (CRgRg)q NHS(O)2R13; (CRgRg)q S(O)2NR4R5, ar two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic mollies may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and RS are independently hydrogen, optionally substituted C1~ alkyl, optionally substituted aryl, optionally substituted aryl C1_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1 alkyl, heterocyclic, heterocyclicC 1 _4 alkyl, or R4 and RS together with the nitrogen to which they are attached form a 5 to ? member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; vitro; cyana; halosubstituted C1_10 ~Yl~ C1-10 ~Yl~ C2-alkenyl; C 1 _ 10 alkoxy; halosubstituted C 1 _ 10 alkoxy; azide;
(CRgRg)qS(O)tR4, (CRgRg)qOR4; hydroxy; hydroxy substituted Cl~alkyl; aryl; aryl C1~ alkyl;
aryloxy; arylC l ~. aikyloxy; aryl C2_ 10 alkenyl; heteroaryl;
heteroarylalkyl;
heteroaryl C 1 ~ alkyloxy; heteroaryl C2_ 10 alkenyl; heterocyclic, heterocyclic C l.~alkyl; heterocyclicC2_ 1p alkenyl; (CRgRg)qNR4R5; C2_ 10 alkenyl C(O)NR4R5; (CRgRg)qC(O)NR4R5; (CRgRg)q C(O)NR4R10; S(O)3Rg;
- 27 _ (CR$Rg)qC(O)RI I; C2-10 ~kenylC(O)RI I; (CRgRg)qC(O)ORI1, C2-10a1kenylC(O)ORI I; (CR$Rg)qOC(O) RI I; (CR$Rg)qNRq.C(O)RI I, (CR$Rg)q NHS(O)2Rb; (CR$Rg)q S(O)2NR4R5; (CR$Rg)qC(NR4)NR4R5;
(CR$Rg)q NR4C(NRS)RI I; or two Y moieties together may form O-(CHZ)s0- or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
Rg is hydrogen or C I ~ alkyl;
RI0 is C I-10 alkyl C(O)ZRg;
RI I is hydrogen, optionally substituted C1~ alkyl, optionally substituted aryl, optionally substituted aryl C I alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC I alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCl~alkyl;
R12 is hydrogen, CI-10 alkyl, optionally substituted aryl or optionally substituted arylalkyi;
R I3 is suitably C I ~ alkyl, aryl, aryl C I~talkyl, heteroaryl, heteroarylC I
alkyl, i0 heterocyclic, or heterocyclicC I-4alkyl;
or a pharmaceutically acceptably salt thereof.
Suitably, the variables for Formula (Ia) are the same as those defined for Formula (I) above, such as for examples the R, RI, and Y variables. A
preferred ring ?5 substitution for the RI variable is monosubstituted in the 3-position, or the 4- position, or di-substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety. Preferably RI is nitro, halogen, cyano, trifluoromethyl group, or C( O)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring 3o with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-preferably being unsubstituted. If the ring is di-substituted, substituents are preferably in the 2'-, 3'- positions of a monocyclic ring. While both RI and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i:e. n amd m are each equal to I or more.
35 Y is more preferably a mono-substituted halogen, disubsdtuted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably these groups are substituted in the 2'- position or 2'-,3'-position.
-2$-Exemplified compounds of Formula (Ia) are N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea N-[(2-Phenyisulfamido) 4-cyanoghenyl]- N'-(2-bromo phenyl) urea N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-{2-{Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea 2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-{Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea l0 N-(2-{Amino sulfonyl (3-tolyl) phenyl) N'-{2-bromo phenyl) urea N-(2-{Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amino sulfonyl benzyl} phenyl) N'-(2-bromo phenyl) urea N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea N-(2-Bromophenyl}-N'-[2-dimethylaminosuifonylamino]phenyl]urea 15 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 20 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-( 1 S)-10-Camphorsulfonyiamino]phenyl]-N.'-(2-bromophenyl)urea N-[[2-( 1 R)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea 25 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-(aminosulfonyl phenyl)-3-aminophenyl] N'-(2-bmmo phenyl) urea 30 N-[2-[2-(4-Chloro-3-aminophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-{3-Aminophenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenylphenyl)urea N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(3-trifluoromethylphenyl)urea 35 N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea N-[2-(Benzylsulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl}urea N-[2-(Phenylsulfonylamino}-4-trifluoromethylphenyl]-N'-(2,3-dichlorophenyl)urea N-(2-(3-Pyridinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[z-(~-Isoquinolinesuifonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl}urea N-(2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-chlorophenyl)urea N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-trifluoromethoxyphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-trifluoromethyiphenyl)urea N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro phenyl) urea 1o N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-[(2-Pyrid-2-yl)thiophene-5-sulfonylamino-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[{2-Acetamino-4-methyl-5-thiazolesulfonylamino-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea 15 N-((2-aminosulfonylphenyl) 4-cyano phenyl) N'-(2-methyl 3-chloro phenyl) urea N-(2-benzenesulfonylamino-3-cyanophenyl)-N'-{2,3dichlorophenyl)urea N-((Benzylsulfonylamino)-5-cyanophenyl]-N'-(2,3-dichlorophenyl)urea N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-nitrophenyl)urea zo N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-aminophenyl)urea N-[(2-Phenylsulfonylamino)-4.-cyanophenyl)-N'-(2-aminophenyl)urea N-(2-(2-pyridinesulfonyiamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Benzenesuifonylamino-3-trifluoromethylphenyl-N'-(2,3-dichlorophenyl)urea N-(4-Benzenesulphonylthiophene-2-sulphonylamino~l-cyanophenyl)-N'-{2,3-25 dichlorophenyl)urea N-(2-Trifluaromethylbezenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichloraphenyl)urea N-[2-(2-Thieny lsulfonylamino}phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea 30 N-{2-Benzylsulfonylamino-4-nitraphenyl)-N'-(2-bromophenyl)urea N-{2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichlorophenyl)urea Another aspect of the present invention is the novel compounds of Formula (Ib), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.
35 This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ib) and a pharmaceutically acceptable diluent or carrier.
The compounds of Formula (Ib) are represented by the structure:

n(Y)~ ~ R~)m H
wherein X is oxygen or sulfur;
X 1 is oxygen or sulfur;
R 1 is independently selected from hydrogen; halogen; vitro; cyano; C 1 _ 10 ~Yl:
halosubstituted C 1 _ 10 alkyl; C2_ 10 alkenyl; C 1 _ 1p alkoxy;
halosubstituted C1_l0alkoxy; azide; S(O)tR~; (CRBRg)q S(O)tRq,; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryl C2-10 alkenyl; aryloxy; aryl C 1 ~
alkyloxy;
to ~ heteroaryl; heteroaryialkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 ~
alkyloxy;
heterocyclic, heterocyclic C1_4alkyl; heterocyclicCl_4alkyloxy;
heterocyclicC2_10 alkenyl; (CRBRg)q NR4R5; (CRBRg)q C(O)NR4R5; C2_ 10 allcenyl C(O)NR4R5;
(CRgRg)q C(O)NR4R10; S(O)3R8; (~gRg)q C(O)R11; C2-10 ~enyl C(O)R11;
C2-10 ~kenyl C(O)OR11; (CRBRg)q C(O)OR11; (CRBRg)q OC(O)R11;
15 (~8R8)q~4C(O)R11; (~8R8)q C(~4)~4R5: (CRgR8)q ~4C(NRS)R 11 (CRBRg)q NHS(O)2R13; (CR8R8)q S(O)2NR4R5; or two R1 moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic mollies may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
2a s is an integer having a value of 1 to 3;
R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
R4 and RS are independently hydrogen, optionally substituted Cl~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 _aalkyl, optionally substituted 25 heteroaryl, optionally substituted heteroaryl C1_4allcyl, heterocyclic, heterocyclicCl~ alkyl, or R4 and RS together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; vitro; cyano; halosubstituted C1-10 ~yl~ Cl-10 a.~Yl;

30 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide;
(CRBRg)qS(O)tR4, (CRBRg)qOR4; hydroxy; hydroxy substituted Cl..~alkyl; aryl; aryl C1~ alkyl;
aryloxy; arylC 1 ~ alkyloxy; aryl C2_ 10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C 1 ~ alkyloxy; heteroary! C2-1 p alkenyl; heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC2_ 10 alkenyl; (CRBRg)qNR4R5; C2_ 10 alkenyl WO 97/29743 PCT/US9b/13632 C(O)NR4R5; (CRgRg)qC(O)NR4R5; (CRgRg)q C(O)NR4Rlp; S(O)3Rg;
(CRgRg)qC(O)R I I ; C2- I O ~kenylC{O)R I 1; (CRgRg)qC(O)OR I 1;
C~_lpalkenylC(O)OR1I; (CRgRg)qOC(O) RI I; (CRgRg)qNR4C(O)RI1;
(CRgRg)q NHS{O)2Rb; (CRgRg)q S(O)2NR4R5; (CRgRg)qC(NR4)NR4R5;
(CRgRg)q NR4C(NRS)R1 I; or two Y moieties together may form O-(CH2)s0- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
to n is an integer having a value of I to 3;
m is an integer having a value of I to 3;
R6 and R~ are independently hydrogen or a C I~ alkyl group, or R( and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
Rg is hydrogen or C 1 _4 alkyl;
R 1 p is C I _ I p alkyl C(O)2Rg;
R I I is hydrogen, optionally substituted C I~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 alkyl, optionally substituted heteroaryl, optionally 2o substituted heteroarylCl~alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _~alkyl;
R12 is hydrogen, CI_10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R I3 is suitably C 1 ~ alkyl, aryl, aryl C I alkyl, heteroaryl, heteroarylC I
alkyl, heterocyclic, or heterocyclicC l..~alkyi;
Rb is NR6R7, alkyl, aryl, aryl CIA alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 ~ alkyl, heteroarylC2~ alkenyl, heterocyclic, heterocyclic C I ~ alkyl, heterocyclic C2~ alkenyl, or camphor, all of which groups may be optionally substituted;
or a pharmaceutically acceptable salt thereof.
Suitably, the variable, etc. for Formula (Ib) are the same as those defined for Formula (I) above, such as for example the functional moieties on the R2 group having an ionizable hydrogen with a pKa of 10 or less. Suitably such functional groups include, but are not limited to, hydroxy, carboxylic acid, thiol, -NH-C(O)Ra, -C(O)NR6R7, substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHRc, NHC(X2)NHRb, or tetrazoyl (as defined for Formula (I).

Suitably for compounds of Formula (Ib), a preferred ring substitution for R1 is in the 3-position, the 4- position or is preferably di substituted in the 3,4-position. The substituent group is suitably an electron withdrawing moiety. Preferably R 1 is vitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R1 and Y can both be hydrogen, 0 it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
Suitably for compounds of Formula (/b), Y is more preferably disubstituted halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, methylenedioxy, aryl, or alkyl, preferably in the 2'position or 2',3'-position.
IS
Another aspect of the present invention is the novel compounds of Formula (Ic), a subset of compounds of Formula (n useful for treating a chemokine mediated disease.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ic) and a pharmaceutically acceptable diluent or carrier. The compounds 20 of Formula (Ic) are represented by the strucuture:
X~H
n (Y) y ~ \~ -.~( R, )m ~ N N--J
H H
(Ic) wherein X is oxygen or sulfur;
X 1 is oxygen or sulfur;
25 R1 is independently selected from hydrogen; halogen; vitro; cyano; C1-10 ~Yl;
halosubstituted C 1-10 ~Yl; C2-10 ~enyl; C 1-10 foxy; halosubstituted C 1-l0~oxy; azide; S(O)tR4; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 alkyl; aryl; aryl C 1 ~ alkyl; aryl CZ_ 10 alkenyl; aryloxy; aryl C 1 ~
alkyloxy;
heteroaryl; heteroaryialkyl; heteroaryl C2-10 alkenyl; heteroaryl C1~
alkyloxy;
3o heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC 1 ~alkyioxy;
heterocyclicC2-10 alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(O)NR4R5; C2_ 10 ~enyl C(O)NR4R5;
(CRgRg)q C(O)NR4Rlp; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 ~enyl C(O)R11;
C2-10 ~kenyl C(O)OR11; (CRgRg)q C(O)OR11; (CRgRg)q OC(O)R11;
(CRgRg)qNR4C(O)R11; (CRgRg)q C(NR4)NR4R5; (CRgRg)q NR4C(NRS)R11, WO 97!29743 PCT/I1S96/13632 (CRBRg)q NHS(O)2R13; (CRBRg)q S(O)2NR4R5, or two RI moieties together may form O-(CH2)s0- or a 5 to 6 rnembered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic rnoities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R~ and RS are independently hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1 ~ alkyl, heterocyclic, heterocyclic CI_4 alkyl, or R4 and RS together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O!N/S;
Y is hydrogen; halogen; vitro; cyano; halosubstituted CI_10 ~Yl: C1-10 ~Yl~ C2-alkenyl; CI_ !p alkoxy: halosubstituted C 1-10 alkoxy; azide;
(CRgRg)qS(O)tR,~, (CRBRg)qOR4; hydroxy; hydroxy substituted Cl~alkyl; aryl; aryl C1~ alkyl;
t5 aryloxy; arylCl_4 alkyloxy; aryl C2_IO alkenyl; heteroaryl;
heteroarylalkyl;
heteroaryl C 1 ~ alkyloxy; heteroaryl CZ_ 10 alkenyl; heterocyclic, heterocyclic Cl~alkyl; heterocyclicC2_i0 alkenyl; (CRBRg)qNR4R5; C2_10 alkenyl C{O)N~S: (CRgRg)qC(O)NR.4R5: (CRBRg)9 C{O)NR4R10; S(O)3R8:
(CRBRg)qC(O)R11; C2-IO ~enylC(O)RI1; (CR8R8)qC(O)OR11:
2o C2-l0~kenylC{O)OR11; (CRgRg}qOC{O) RI l; (CRgRg)qNR4C(O)R119 (CRBRg)q NHS(O)2Rb; (CR8R8)q S(O)2NR4R5{CRSR8)qC(NR4}NR4R5:
(CRBRg)q NR4C(NRg)R11; or two Y moieties together may form O-(CH2)s0- or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally 25 substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1. to 3;
R6 and R~ are independently hydrogen or a C 1 ~ alkyl group, or R6 and R~
together 30 with the nitrogen to which they are attached form a 5 to ~ member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
Rg is hydrogen or CIA alkyl;
R I O is C 1 _ 1 p alkyl C(O)2Rg;
35 R 11 is hydrogen, optionally substituted C 1 ~ alkyl, optionally substituted aryl, optionally substituted aryl C 1 ~talkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4alkyl, optionally substituted heterocycIic, or optionally substituted heterocyclicC 1 _rlalkyl:
R 12 is hydrogen, C 1-10 ~kYl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably Cl~ alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylCl~alkyl, heterocyclic, or heterocyclicCl-4alkyl;
Rb is NR6R~, alkyl, aryl, aryl CI_4 alkyl, aryl C2_q. alkenyl, heteroaryl, heteroaryl Cl_4 alkyl, heteroarylC2-q, alkenyl, heterocyclic, heterocyclic C1~ alkyl, heterocyclic CZ_4 alkenyl, or camphor, all of which groups may be optionally t o substituted; provided that when n =1 than Y is substituted in the 2- or 3- position;
when n =2 than Y is di-substituted in the 2'- 3'- position, the 2'-5'-position, the 2'-6' position, the 3'-5' or the 3'-6' position;
when n = 3 than Y is trisubstituted in the 2'-3'-5' or the 2'-3'-6'-positions;
further provided that when X1 is O, m=2, R1 is 2-t-butyl, 4-methyl, and n=3 than Y is not 2'-OH,3'-t-butyl, 5'-methyl;
when XI is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2'-OH, 5'-methyl;
when Xl is O, m=l, R1 is hydrogen, and n=2 than Y is not 2'-6'-diethyl;
2o when X1 is O, m=l, RI is 6-OH, and n=2 than Y is not 2'-5'-methyl;
when Xl is S, m=1, RI is 4-ethyl, and n=1 than Y is vat 2-methoxy;
or a pharmaceutically acceptably salt thereof.
Suitably, the variables, etc. for Formula (Ic) are the same as those defined for Formula (I) above unless indicated.
Suitably for compounds of Formula (Ic), a preferred ring substitution for Rl is in the 3-position, the 4- position or dl substituted in the 3,4- position.
Preferably RI is other than hydrogen. The substituent group is suitably an electron withdrawing moiety.
Preferably R I is vitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-greferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Rl and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.

Suitably for compounds of Formula (Ic), Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'position or 2,3-position.
Exemplified compounds of Formula (Ic) are:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;
N-[2-Hydroxy-5-vitro-phenyl]-N'-phenyl urea N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea to N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea 15 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 2o 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 25 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 3o N-{2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea N-(2-Hydroxy-4-nitro-phenyl) N'-(2-chloro 6-methyl phenyl) urea N-(2-Hydroxy-4-vitro-phenyl) N'-(2-sulfoxymethyl phenyl) urea N-(2-Hydroxy-4-trifluoromethyl phenyl)-N-(2-bromo phenyl) urea N-(2-Hydroxy-4-trifluoromethyl phenyl)-N'-(2-phenyl phenyl) urea 35 N-(2-Hydroxy-4-carbomethoxy phenyl)-N'-(2-phenyl phenyl) urea N-{2-Hydroxy-4-nitrophenyl)-N'-(2,3-dichloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dichloro phenyl) urea WO 97/29743 PCT/CTS96i13632 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro phenyl) urea N-{2-Hydroxy-4-nitrophenyl)-N'-(2,4-dibromo phenyl) urea N-{2-Hydroxy-1-napthyl)-N'-(2-bromo phenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl}urea N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea N-[2-Hydroxy-4-(Benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-vitro phenyl)-N'-(2-phenoxy phenyl) urea N-{2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea N-{2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea to N-(2-Hydroxy 4-phenyl phenyl) N'-(;2-bromo phenyl) urea N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea N-(2-Hydroxy-4-vitro phenyl)-N'-(2-phenylamino phenyl) urea N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo ghenyl) urea N-(2-Sulfhydryl-4-bromo phenyl)-N'-(2-bromo phenyl) urea t 5 N-(2-Hydroxy 4-vitro phenyl)-N'-(2-iodo phenyl) urea N-(2-Hydroxy 4-vitro phenyl)-N'-(2-bromo phenyl) thiourea N-{2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-fluorophenyl]-N'-[~-bromophenyl] urea 2o N-(2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-chlorophenyl]-N'-(2-bromophenyl] urea N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea N-[2-hydroxy-3,4-diphenyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromopheny1] urea 25 N-(2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea 3o 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 35 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 WO 97/19743 PCTlUS96/13632 N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenylJ urea N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-cyano-4-methyiphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-(2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea {E)-N-[4-[2-{Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]
urea (E)-N-[3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-[2-bromophenyl] urea {E)-N-[3-[2-(Aminocarbonyl~thenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-[2-bromophenyl] urea {E)-N-[4-[2-{Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-aminocarbonyl phenyl]-N'-[2-bromophenyl] urea N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea 2o N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-(2-methoxyphenylJ urea N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea N-(2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea 3o 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 WO 97129743 PCTlUS96113632 N-[Z-Hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-phenylphenyi) urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichlorophenyll 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-methoxyphenyi] 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-dichlorophenyi) 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-trifluvromethylphenyl] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-{benzyl] urea ~5 N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] 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-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-5-naphthalenesulfonic acid)-N'-{2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalenesulfonic acid)-N'-(2-bromophenyl) urea;
N-(2-Hydroxy 3-napthyl} N'-(2-bromo phenyl} urea;
N-(2-Hydroxy-I-napthyl)-N'-(2-bromo phenyl) urea;
N-(2-Hydroxy-4-nitrophenyl)-N'-( 1-naphthyi)urea;
N-(2-Hydroxy-3-nitrophenyl}-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea N-(2-Hydroxy-3-nitropheny!)-N'-(3-trifluoromethyphenyl}urea 3o N-(2-Hydroxy-3-nitrophenyl)-N'-(2-phenylphenyl}urea N-(2-Hydroxy-3-nitrophenyl~N'-(2,3dichlorophenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl)urea N-(2-Hydroxy-3-nitrophenyl}-N'-(2,4-dimethoxyghenyl)urea N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-4-amidinopheny!)-N'-{2-bromophenyl)urea N-(2-Hydroxy-3,4-dichloro phenyl} N'( phenyl} urea N-(2-Hydroxy-4-cyano phenyl) N'( phenyl) urea W4 97!29743 PCT1US96/13632 N-{2-Hydroxyphenyl-3-carboxylic acid)N'( phenyl) urea N-(2-Hydroxy-3-nitrophenyl)-N'-phenylurea N-(2-Hydroxy-3-cyanophenyl ) N'(phenyl) urea N-(2-Hydroxy-3-cyano-4-chlorophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea N-(2-Hydroxy-3,4-difluorophenyl)~-N'-(phenyl)urea N-{2-Hydroxy-4.-cyanophenyl)-N'-f.2,3-methylenedioxyphenyl)urea N-[2-(2-nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-{2-hydroxy-3-trifluoromethylphenyl)-N'-(2,3-dichiorophenyl)urea N-{2-hydroxy-3-trifluoromethylphenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-benrylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea N-(2-Hydroxy-4-nitro phenyl)-N'-[2-(phenyloxymethyl)phenyl]urea N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylethyl)phenyl]urea ~5 N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(4-trifluorophenyl)phenyl]urea N-(2-Hydroxy-3-trifloromethylphenyl)-N'-(2-methoxyphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyl)urea N-{2-Hydroxy-4-nitrophenyl)-N'-[2-(2-cyanophenylthio)phenyl]urea N-(2-hydroxy-3-trifluoromethy!phenyl)-N'-(2-chlorophenyl)urea N-(2-Hydroxyethyl)-N'-(2-hydroxy-4-nitrophenyl)urea N-2-{Benzyoxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea N-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-niuophenyl)urea N-[2-(2-Methoxycarbonylbenzyloxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea i5 N-[2-(2-Carboxybenzyloxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea N-[2-(Methoxycarbonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea 3o N-(2-Hydroxyeth-1-yloxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea N-(2-Hydroxy-4-cyanophenyl~N'-(2-benzylaminophenyl)urea N'-[2-(2-Pyridylmethoxy)phenylJ-N'-(2-Hydroxy-4-nitrophenyl)urea N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-{2-hydroxy-4-nitrophenyl)urea N-[2-(2-Carboxybenzyloxy)phenyl)-N'-(2-hydroxy-4-nitrophenyl)urea 35 N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea Additionally exemplified compounds of Formula (Ic) include:

WO 9?!29743 PCT/US96/13632 N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(2-pyridylmethyloxy}phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-trifluorosulfony!phenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2-bromophenyl)urea t0 N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2,3-dichlorophenyl)nrea N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2,3-dichlorophenyl)urea Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
~ "halo" - all halogens, that is chloro, fluoro, bromo and iodo.
~ "C1_lpalkyl" or "alkyl" - both straight and branched chain radicals of 1 to carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, ten butyl, n-pentyl and the like.
~ The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

~ The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-progenyl, 1-butenyl, 2-butenyl and the like.
~ "aryl" - phenyl and naphthyl;
~ "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazale, furan, thiophene, quinoline, isoquinoline, 1o quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
~ "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatorns selected from the group consisting of N, O, or S;
t 5 such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
~ The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean C 1 _ 10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
2o ~ "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio"
refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety.
The term "wherein two R1 moieties (or two Y moieties) may together form a or 6 membered unsaturated ring" is used herein to mean tile formation of a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring 25 such as a C6 cycloalkenyl, i.e hexene, or a CS cyloalkenyl moiety, cyclopentene.
The compounds of Formula (1), (Ia), (Ib), (Ic), (II, (IIa ), (IIb), (IIc), and (III) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the 3o producing compounds of Formula (1), (Ia), (Ib), (Ic), (II, (IIa ), (IIb), (IIc), and (III) having a variety of different R, Rl, and Ar groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been 35 established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the WO 97!29743 PCT/US96I13632 schemes are shown with compounds only of Formula {17 this is merely for illustration purposes only.
Scheme t R a ~ \ R O
s NH2 / N' _ N

R=NH2, OH, COZH, SH a)PhNCO

Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard conditions involving the condensation of commercially available ortho substituted aniline(Aldrich Chemical Co., Milwaukee, Wi) with the commercially available optionally substituted aryl isocyanate (Aldrich Chemical Co., Milwaukee, Wi) to in an aprotic solvent (DMF, toluene). When the 1-{RS02NH)2-{NH2)Ph is not commercially available it can be made by treating the commercially available with the cooresponding 2-phenylene diamine in the presence of an base like triethyl amine or NaH in an aprotic solvent (like methylene chloride or DMF).
S~;heme 2 R» R. R.
\ ~ ~ \ -b /

R'=OH, NH2, NHS02R a)HNO3, 23 °C b)SnC4~, EtOH
If the desired 2-substituted aniline 5-scheme 2. is not commercially available the corresponding vitro compound can be prepared from 3-scheme 2, under standard nitration conditions (using HN03 or BF4N03) at 23 °C. The vitro compound is then 2o reduced to the corresponding aniline using SnCl2 in EtOH(or alternately H2JPd or LiAlH4).

ch m N SH
> ~ / %~' NHp ~
NH2 a S b NH2 6_ 7 $
a)NH4SCN, Br2 b)NaOH EtOH
If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3.
This thiazole can then be hydrolyzed to the desired 2-amino benzeneihiol 8-scheme 3 with a suong base like NaOH in a erotic solvent (i.e., EtOH).
Scheme 4 OzN ~ OH O~ OTBS
a,b \ X
NH2 . ~ / N It c 021'1 ~ \ OH X /
N~ N
X=S, O
a)TBSCI, imid, DMF b)i)CICXCI, NaHCog, ii)PhNH2 c)Et3N~HF, CH3CN
In the case where the thioisocyanate or phenyl isocyanate is not commercially available, the thiourea or urea 11-scheme 4 may be prepared from the commercially lo available ortho substituted aniline. This compound is first protected with a protecting group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art(see Greene, T Protecting Gmups in Organic Synthesis. Wiley&Sons, New York, 1981).
This protected aniline is then reacted, in the presence of a base(like triethyl amine or sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic solvent (ie. DMF, toluene), followed by aniline to produce the protected thiourea or urea respectively. The corresponding urea or thiourea is then deprotected, using conditions standard in the art, to form the desired thiourea or urea 11-scheme 4.

hem 5 a. b /~ ~ /

12 1~ X
a)(Ph0)2PON3,Et3N b)PhXNH2 X=OH, NHS02R. SH
Alternately the urea can be formed using a Curtius rearrangement from the corresponding aromatic or thiophene carboxylic acid 12-scheme 5. The carboxylic acid is submitted to standard Curtius conditions ((Ph0)2PON3, Et3N or CICOCOCI
followed by NaN3) and the intermediate isocyanate is trapped by an appropriately substituted aniline.
Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
Another aspect of the present invention is the novel synthesis of cyano nitrophenol intermediates. Numerous conversions of aryl halides to aryl cyano derivatives with copper (I) cyanide have been published. However, no examples of an t5 aryl ring with a hydroxy group present were mentioned. Several attempts to obtain a cyano phenol moiety with published results failed. Using known conditions of elevated temperatures, greater than 170°C, such as from 180 to 210° did not yield displacment of the halogen to a cyano moiety. Standard bases, such as DMF and pyridine further provided no desired product. Intermediates such as 2-amino-5-fluorophenol, 2-vitro-5-fluorophenol, 2-vitro-5-methyl-6-bromophenol were tried with a change of halogens, from fluorine to chlorine to bromine, and with use of copper (n cyanide. The use of a bmmine derivative, such as 2-vitro-5-methyl-6-bromophenol, with dimethylformamide~
and using triethylamine with a catalytic amount of dimethylamino pyridine and copper (I) cyanide at reduced temperatures,. i.e. <100° C, preferably 60 to about 80° C for reduced times from strandarized procedures, i.e., < 18 hours, preferably about 4 to 6 hours yielded the desired products.
Therefore one aspect of the invention is to a process for producing a cyano phenol derivative of the formula:

H
W, c-N
J
wherein R 1 is as defined for Formula (I) above, which method comprises reacting a compound of the fotznula:
H
X
~J
R' wherein X is halogen with copper (1) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.
Preferably, the process is run at reduced temperatures of about 60 to about 80° C.
Preferably X is bromine.
In the Examples, ail temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, 1o unless otherwise indicated. 1H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively.
Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, equiv.
indicates the proportion of a molar equivalent of reagent relative to the principal reactant_ 15 Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh).
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of 2o the present invention. All temperatures are given in degrees centigrade, all solvents used herein are of the highest available purity and all reactions are run under anhydrous conditions in an argon atmosphere unless otherwise indicated.
General Method A: Synthesis of N, N'- phenyl urea To a solution of substituted 25 phenyl isocyanate { 1.0 equiv.) in toluene (5 miliLiters (hereinafter "mL")) the corresponding aniline {1.0 equiv.) was added. The reaction mixture was stirred at about 80°C until complete (24-48 hours (hereinafter "hrs" or "h")), then cooled to room temperature. The purifications, yields and spectral characteristics for each individual compound are listed below.

WO 97!29743 PCTIUS96/13632 General Method B: Synthesis of N, N'~ phenyl urea To a solution of phenyl isocyanate ( 1.0 equiv. ) in dimethyl .formamide ( 1 mL) the corresponding aniline ( 1.0 equiv.) was added. The reaction mixture was stirred at about 80 C until complete (24-48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics for each individual compound are listed below.
General Method C:Synthesis of sulfonamide The ortho substituted aniline (1 equiv.), triethyl amine ( 1 equiv.) and the desired sulfonyl chloride ( I equiv.) were combined in methylene chloride and allowed to stir at about 23 °C until complete ( 12-36 h). The t0 reaction mixture was partitioned between water and methylene chloride. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The purifications of each compound are listed below.
xam !e 1 Prevaration of ~-I2-Hvdroxv-4-lmethoxvcarbonvl)v~envll N'-nhenvl urea N-{2-Hydroxy-4-(methoxycarbonyi)phenyl]-N'-phenyl urea was prepared from methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate ( 1.19 mmol) according to the procedure noted above in General Method A. The product was purified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp: 188.4-188.8°C; 1H NMR (CD30D/CDC13): d 8.15 (d, 1H, J =
8.25 Hz), 7.70 (s, 1H), 7.51 (d, 1H, J = 8.25 Hz), ?.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, 3 =
8.25 Hz), 7.01 (t, 1H, J = 8.25 Hz), 3.87 (s, 3H); BI-MS m/z 286 (M+H)+; Anal.
(C 15H 14N204) C, H, N.
am Ie 2 Prevaration of N-L5-vitro-2-hvdroxyphen !v 1-N'-phenyl urea The N-{5-vitro-2-hydroxyphenyl]-N'-phenyl urea was prepared from the S-vitro 2-hydroxy aniline and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (100 mg, 30%). 1H NMR (CD30D): d 9.48 (s, IH, NH), 9.07 (d,1=
1.56 Hz, NH), 8.55 (s, 1H), 7.80 (dd, 1H, J = 6.25 Hz and J = 1.56 Hz), 7.50 (d, 2H, J =

6.25. Hz), 7.30 (t, 2H, J = 6.25 Hz), 7.01 (m, 2H). EI-MS mlz 273 (M+H)+.
x 3 Preparation of 3-hydroxy-4-{ flphenvlaminolcarbonvllaminolbenzamide a)Pteparation of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents WO 97/29743 PCTlUS96113632 To a suspension of the appropriate hydrochloride (0.02 mole (hereinafter "mol")) in dry toluene (20 mL) at about 0°C, was slowly added a solution of (2M, 10 mL) of trimethyl aluminum in toluene. After the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for about I-2 hours until gas evolution has ceased.
b)Preparation of 3-hydroxy-4-{[(phenylamino)carbonyl]amino}benzamide To a solution of the N-[2-hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea (60 miligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mL) was added aluminum amide reagent (0.9 mL, 0.67M). The reaction mixture was stirred at reflux for about 12 1o hours. The reaction mixture was cooled to room temperature and was carefully quenched with 5% HCI. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (ethyl acetate) gave the desired amide (28 mg, 49%). mp:
106.8-107.1°C; 1H NMR (CD30DICDC13): d 7.98 (d, 1H, J = 8.25 Hz), ?.35 (d, 2H, J
= 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (t, 2H, J = 8.25 Hz), 6.91 (t, 1H, J = 8.25 Hz); EI-MS tn/z 271 (M+H)+; Anal. (C I4H 13N303) C, H, N.
Example 4 'reparation of N-l2-hydroxy-4-fluorophen 1v 1-1V_-,phenyl urea a)Preparation of 2-amino-5-fluoro phenol A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 nzmol) and tin (II) chloride ( 1.76 g, 9.2 mmol) in ethanol ( 10 mL) was heated at 80°C under argon.
After 30 min, the starting material had disappeared and the solution was showed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8), by addition of 5%
aqueous sodium bicarbonate, before being extracted with ethyl acetate.-The organic phase was washed with brine, dried over MgS04 and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). /H NMR (CD30D/CDCl3): d 6.6 (m, 1H), 6.38 (dd, IH. J = 8.3 Hz and J = 2.8 Hz), 6.29 (m, IH).
b)Preparation of N-(2-hydroxy-4-fluorophenyl)-N'-phenyl urea N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91 %). mp: 195.5-195.7°C; 1H NMR
(CD30D/CDC13): d 7.70 (m, 1H), 7.3 (d, 2H, J = 8.25 Hz), 7.15 (t, 2H, J = 8.25 Hz), 6.89 (t, 1H, J = 8.25 Hz), 6.50 - 6.38 (m, 2H); EI-MS mlz 246 (M+H)+; Anal.
(C 13H11N202 F) C, H, N.

Example S
Preparation of 2-( ffohenylaminolcarbonyllamino~hiophenol 2-}[(Phenylamino)carbonyl)amino}thiophenol was prepared from2-aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85 %). mp: 194.5°C; 1H
NMR
(CD30D/CDC13): d 7.48 - 7.26 (m, 4H), 7.25 - 7.10 (m, 3H), 7.04 - 6.79 (m, 2H); EI-MS mJz 244 (M+H)+; Anal. (C13H12N2OS) C, H, N.
to ExamRle 6 Preparation of N-l2-Carboxy"-4-hydroxw-phenyl)-N'=phenvl~ea N-{2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-S-hydroxy benzoic acid ( 1 g, 6.53 mmol) according to the procedure in General Method B. The reaction mixture was partitianed between ethyl acetate and water. The organic phase was washed with brine, dried aver MgS04 and filtered. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate, 1:1 to 100% ethyl acetate) gave the titled compound ( 1.5 g, 84%). 1 H NMR
(CD30D/CDC13): d 8.36 (d, 1H, I = 8.25 Hz), 7.63 (m, 4H), 7.48 (t, 2H, J =
8.25 Hz), 7.20 (m, 1 H); EI-MS m/z 272 (M+H)+; Anal. (C 14H 12N204) C, H, N.
am 1e 7 Preparation of N - f2 - h~droxy,- 4- ftr'r,~'Iuorometh~~Rheny~ - N' - ~het~ 1v urea a)Preparation of 2-vitro-5-trifluoromethylphenol 2-Nitro-S-trifluoromethylphenol was prepared by adding concentrated HN03 (6 mL) drop-wise to a,a,a-trifluoro-m-cresol (5g, 30.8 mmol) at room temperature.
After the addition was complete the reaction was quenched with saturated ammonium acetate and extracted with EtOAc. The organic was separated, dried over sodium sulfate and filtered. Concentration of the solution in vacuo afforded an oil which was purified by column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to afford the titled compound as an oil(1.7 g, 27%). 1H NMR (CDCI3): 10.6 (s, 1H, OH), 8.26(d, 1H, J = 7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H, J= 7.8 Hz) b)Preparation of 2-amino-S-trifluoromethylphenol 2-Amino-S-trifluoromethylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of 5nC12(3.Sg, mmol) in EtOH at 23 °C for 12h. The mixture was concentrated to 50 mL and adjusted to pH 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H20 9?43 PCT/US96/13632 and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification.
1H NMR (CDCl3}: 7.6 (s, 1H), 7.39(d, 1H, J = 8.5 Hz), 7.08(d, 1H, J= 8.5 Hz) c)Preparation of N - [2 - hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea N - [2 - Hydroxy - 4- (trifluaromethyl) phenyl] - N' - phenyl urea was prepared from 2-amino-5-trifiuoromethylphenol ( 150 mg, 1.09 mmol) and phenyl isocyanate( 1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to afford the titled 1o compound ( 230 mg, 87% ), mp: °C; 1H NMR (DMSO-d6): d 9.45 (s, 1H, NH), 8.50 (s, 1 H, NH), 8.31 (d, 1 H, J = I0.0 Hz), 7.45 (d, 2H, J = 10.0 Hz), 7.29 (t, 2H, J = 6.67 Hz), 7.10 (m, 2H), 6.99 (t, IH, J = 6.67 Hz). EI-MS m/z 296 (M+). Anal.
(C 14H 11 N202F3)C, H, N.
is Example 88 Preparation of N-l2-hvdro_xy-4-nitro~enyl)-N'-(2-hyd~xy-4-nitrovhenvll urea a}Preparation of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline To a solution of 2-amino-5-nitrophenol ( I g, 6.49 mmol) and imidazole (0.88 g, 20 12.3 mmol) in DMF ( 15 mL), tert -butyldimethylsilyl chloride ( 11.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction mixture was partitioned between 0.1 % HCl and ethyl acetate. The combined organic _ phase was washed with brine, dried over MgS04 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl 25 acetate; 5:1) gave the titled compound (1.7 g, 98 %). 1H NMR (CDC13): d 7.78 (dd, 1 H, 3 = 6.7 Hz and J = 2.7 Hz), 7.61 (d, 1 H, J = 2.7 Hz), 6.7 (d, 1 H, J =
8.8 Hz), 1.0 (s, 9H), 0.28 (s, 6H).
b)Preparation of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N-[(2-tert-butyldimethylsiloxy)-4- nitrophenyl] urea 3o To a solution of 2-(ten-butyldimethylsilyloxy)-4-nitroaniline(200 mg, 0.75 mmol) in toluene (10 mL) triethylamine (0.I3 mL, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours, then cooled to room temperature. Then more 2-(tent -butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70°C for 35 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgS04 and filtered. Removal of solvent at reduced pressure and WO 97129743 PG"T/US96/I3632 chromatography of the resulting oil on silica gel (hexane : ethyl acetate, 10:1 ) gave the titled compound( 130 mg, 31%). 1H NMR (CDCl3): d 8.36 (d, 2H, J = 8.3 Hz), 7.90 (dd. 2H, J = 8.3 Hz and J = 2.8 Hz), 7.71 (d, 2H, J = 2.8 Hz), 7.22 (s, 2H), 1.02 (s, 18H), 0.35 (s, 12H).
c)Preparation of N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea To a solution of N-[(2-ten-butyldimethylsilyloxy)-4-nitrophenyl]-N'-[(2-tert-butyldimethylsilyloxy)-4- nitrophenyl] urea(50 mg, 0.089 mmol) in THF (2 mL), tetrabutylammonium fluoride ( 1 M, 0.09 mL, 0.089 mmol) was added at 0°C. The reaction mixture was stirred at 23°C. After 1 hour, the starting material had to disappeared. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was dried over MgS04 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl acetate; 1:1 to 100% ethyl acetate) gave the titled compound(24 mg, 81%). 1H
NMR
(CD30D/CDCl3):, d 8.32 (d, 2H, J = 8.25 Hz), 7.80 (dd, 2H, J = 8.25 Hz and J =
2.06 t5 Hz), 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H)+. Anal. (C 13H 10N407) C, H, N.
Exa Preparation of N-l2-hydroxv-4-nitro~henyl)-N'-Rhen"yl-thiourea a)Preparation of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea 2o N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared by treating a biphasic solution of 2-tent-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHC03 in CHC13:H20(2.5:1, 7mL) with thiophosgene at 0°C. The solution was allowed to warm to 23°C and the reaction was continued overnight. The CHC13 layer was separated and dried over sodium sulfate. The solution was 25 concentrated in vacuo and the residue was dissolved in toluene and treated with aniline ( 100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography ( 10% EtOAc/hexanes) to afford the titled compound as a yellow solid ( 120.8 mg, 98%) mp: 144-145°C;1H NMR (CD30D/CDCl3):
d 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H), 30 7.10 (m, 1 H).
b)Preparation of N-(2-hydroxy-4-nitrophenyl}-N'-phenyl-thiourea N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tent-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea ( 100 mg, 0.248 mmoi) in CH3CN ( 1 mL) with Et3N~HF ( 100uL, 0.62 mmol) in acetonitrile for 35 10 minutes at 23°C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%).

mp: 144-145°C;1H NMR (CD30DlCDCI3): d 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J
= 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Example 10 Preparation of N-l4- nitro 2-lphenylsulfonvlamino)phen~il-N'-phen~,rl urea a) Preparation of 4-vitro 2-(phenylsulfonylamino) aniline A solution of 4-vitro 1,2-phenylene diamine(I.53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride( 1.76 g, 10.0 mmol) and triethyl amine( 1.01 g) in DMF for 12 h at 23 °C. The reaction mixture was partitioned between saturated NH4C1 and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrysiallized (EtOH) to afford desired (0.2?5 g, 9%). 1H NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74{d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,lH, J=2Hz), 6.79 (d, 1H, J=8Hz), 6.5(s, 2H, br) t5 b)Preparation of N-(4- vitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea was prepared from 4- vitro 2-(phenylsulfonyiamino) aniline(82 mg) and phenyl isocyanate(33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9:1 methylene chloride and methanol. The organic phase was dried over 2o magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford desired(30.8 mg, 26%).
EI-MS mlz 413(M+H)+
Exam 1 25 Preparation of N-f2-hvdroxy-5-nitro~henyll-N'-l3-methoxy-2-thien 1)y urea a)Preparation of 3-methoxy-2-thienylcarboxlic acid To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at -78°C, butyllithium ( 17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78°C for 1 hour, then it was warmed to 0 °C for 3 hours. After to recooling -78°C
30 the reaction mixture was poured into a beaker filled with crushed dry ice ( 14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice ( 10 g) to which conc. HCI (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96 %). EI-MS mlz 169 (M+H)+.
35 b)Preparation of N-{2-hydroxy-5-nitrophenyl)-N'-{3-methoxy-2-thienyl)urea To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg, 1.27 mmol) in benzene, (Ph0)2PON3 (0.33 mL), 2-amino-4-nitrophenol ( 195.7 mg, 1.27 mmol) and triethylamine ( 1.1 equiv., 0.25 mL) were added. The reaction mixture was stirred at reflux overnight. The reaction nuxture was partitioned between Solo citric acid and ethyl acetate. The organic layer was separated and-the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate; l : l ) gave a solid product ( 160 mg, 41 %). mp:
172.6-173.0°C; 1H NMR (CD30D/CDC13): d 8.96 (d, 1H, J = 2.5 Hz), 7.74 (dd, 1H, J
t0 =5.0 Hz and J = 1.25 Hz), 6.82 (d, 1H, J =7.5 Hz), 6.76 (s, 2H), 3.80 (s, 3H); EI-MS
m/z 309 (M+H)+; Anal. (C 12H 11N305S) C, H, N.
Example 12 Prgparation of N-(2-hxdroxy-4-nitrophenyI)-N'-(3-methoxy-2-thien~l)urea t5 To a solution of 3-methoxy-2-thiophene carboxylic acid (example l la, 200 mg, 1.27 mmol) in toluene, (Ph0)2PON3 (0.33 mL) and triethylamine ( 1.1 equiv., 0.25 mL) were added. The reaction mixture was stirred at 70°C for 2 hours and cooled down to room temperature then 2-amino-S-nitrophenol was added. The reaction mixture was stirred at 70°C overnight. The reaction mixture was partitioned between 5% citric acid 20 and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane:ethyl acetate; l : l ) gave the product ( 190 mg, 48%). 1 H NMR
(CD30D/CDCI3): d 8.38 (d, 1H, J = 5.0 Hz), 7.85 (dd, 1H, J = 5.0 Hz and J =
1.25 Hz), 25 7.76 (d, 1H, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS mlz 309 (M+H}+;
Anal.
(C12H11N305S} C, H, N.
Example 13 Preparation of N-l2-hvdroxv-4-nitrophenvl)-N'-l3-methoxyphenyDurea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2=
30 hydroxy 4-vitro aniline ( 154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 140 mg, 46%). EI-MS m/z 302(M-H) -35 Example 14 P~paration of N-f2-hydroxv-4-nitrophen~rll-N'-(2-methoxy~he_nvllurea WO 97129743 PGTlUS96/13632 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-vitro aniline ( 154 mg, l _0 mmol) and 2-methoxy phenyl isocyanate( mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg, 27%). EI-MS m/z 302(M-H)-~xamnle 1 S
Preparation of N 12-h~o_xy-4-nitrophen~l-N'-(3-trifluoromethYl_phenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-to hydroxy 4-vitro aniline ( 154 mg, 1.0 mmol) and 3-trifluoromethyl phenyl isocyanate ( 1 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 180 mg, 52%). EI-MS m/z 342(M+H) +
l~xamp",~e 16 15 Preparatior~of N-(2-hy~roxv-4-nitro~h_envll-N'-l2-trifluorometh; lphen llurea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea was prepared from 2-hydraxy 4-vitro aniline ( 154 mg, 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes.
20 - Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H) +
Example 1?
Preparation of N-l2-h~~v-4-nitrophenyll-N'-l4-trifluorometh~nhenyllurea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea was prepared 25 from 2-hydroxy 4-vitro aniline ( 154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes.
Filtering afforded the title compound ( 111 mg, 32%). EI-MS m/z 340(M-H)-Example 18 30 Preparation of N-t2-hydroxy-4-nitro~henyl)-N'-f2-bromoph~yl_lurea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the 35 title compound(530 mg, 47%). EI-MS m/z 350(M-H) ' Example 19 Preparation of N-E2-hvdroxv-4-nitrophen~rll-N'-f 3-bromophenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol)according to the procedure in General Method B. The product was purified by s dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.96g, 87%). EI-MS m/z 350(M-H) -Example 20 Preparation of N-(2-hydroxy-4-nitrophenyt)-N'-f4-bromo hen 1Y lurga 1o N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromo pheny!)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.41 g, 37%). EI-MS m/z 352(M+H) +
Example 21 l~renaration of N-l2-hvdroxy-4-nitrophenyl)-N'-(2-phenvl~hen 1)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.22 g, 19%). EI-MS m/z 350(M+H) +
Example 22 Pre~araticZn of N-l~.-ll,~rdroxv-4-nitrophenyl)-N'-t1-naphth 1)urea N-(2-Hydroxy-4-nitrophenyl)-N'-( 1-naphthyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol;) and 1-naphthyl isocyanate (3.24 mmol) according to the procedure in General Methad B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1:3 triethyl ' amine:methylene chloride. The filterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1N HCI in water.
The desired product precipitated from solution and was collected by filtration(0.1 1g, 10%).
EI-MS m/z 324(M+H) +
E ample 23 Preparation of N-(2-t~ydrox~-4-nitro~henyl)-N'-(2-nitro~henvl)urea N-(2-Hydroxy-4-nitrophenyl)-N°-(2-vitro phenyl)urea was prepared from 2-hydroxy 4-vitro aniline {500 mg, 3.24 mmol) and 2-vitro phenyl isocyanate {3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 44%). EI-MS m/z 319(M+H) +
Example 24 Preparation of N-l2-hydroxy-4-nitrophen~,~)-N'-l2-fluorophenyllurea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methyiene chloride and precipitation with hexanes. Filtering afforded the title compound(0.59 g, 31%). EI-MS m/z 292(M+H) +
Examp1~25 Preparau~gn of N-(2-hydrox~!-4-nitrophenyl)-N'-(2.6-difluorophenvl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-{2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro phenyl isocyanate(3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.91 g, 91 %). EI-MS m/z 308(M-H) °
Example 26 Preparation of N-(2-hxdrox~-4-nitrophenvl)-1V'-(2-ethoxYphenyllurea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-ethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with rnethylene chloride and precipitation with hexanes. Filtering afforded the title compound{0.84 g, 81%). EI-MS m/z 318(M+H) +
Exam 1~ a 27 Preparation of N- 2-hydroxy-4-nitro~henyll-N'-l2-ethylphenyl urea 3o N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H) +
Example 28 Preparation of N-l2-hydroxv-4-vitro phenyll-N'-(2-t 'fluoromethoxyphetl, llv urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-vitro aniline (500 tng, 3_24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B.
The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H) +
Example 29 Synthesis of N-l2-h~drox~-4-vitro phenyl) N'-(2-methvlthio~hen l~rea The urea was prepared from 2-hydroxy 4-vitro aniline (500 mg , 3.24 mmol) t0 and 2-methylthio phenyl isocyanate(3.24 nnmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes.
Filtering afforded the title compound(0.63 g, 61 %). EI-MS m/z 320(M+H) +
Exam a 30 15 Synthesis of N-(2-hvdro~y-4-vitro phenyl) N'-(2-chloro 6-met_iiyl phenyl) urea The urea was prepared from 2-hydroxy 4-vitro aniline (500 mg, 3.24 mmol) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). El-MS m/z 322(M+H) +
Exam )p a 31 Synthesis of N-(2-h~~-4-vitro phenyl) N'-(2- meth3rl sulfoxYphenyl) urea The urea was synthesized by treatment of N-( 2-hydroxy 4-vitro phenyl) N'-(2-methyl thio phenyl) urea(example 28, 100 mg) with sodium periodate( 100 mg) in t-butanollwater for 12 hours at 23 °C. The product precipitated from the reaction mixture(30 mg, 29%). EI-MS m/z 336(M+H) +
Exam"Rle 32 Synthesis of N-(2-hydroxy 4-trifluorometh~~henyll N'-(2-byomo nhen,1~ urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aailine(example 7a, 0.171g, mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54%). EI-MS m/z 375(M+H) +
xa 33 Synthesis of N-(2-hydroxy 4-carbomethoxy phenyl) N'-(2-bromo enyl) urea The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol} and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H) -Example 34 Synthesis of N-f2-h~droxv 4-trifluQromethyl phenyl) N'-l2-phgnxl phenyl) urea The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was t0 purified by dilution with methylene chloride and precipitation with hexane.
Filtering afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H)+
Example 35 Synthesis ofN-(2-hydroxy 4-carbomethoxy phen~rl, N'-l2~henyl nhenyrl) urea The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-phenyl phenyl isocyanate( l mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.185 g, 50%). EI-MS m/z 363(M-H) Example 36 Synthesis of N-l2-hvdroxv 4-nitro~henvll N'-(2.3-dic oro hen~)u_r~a The urea was prepared from 2-hydroxy 4-vitro aniline(308 mg, 2 mmol) and 2,3-dichloro phenyl isocyanate(2 mmoI) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.5 g, 73%). EI-MS m/z 342(M+H) +
Example 37 Synthesis of N-f2-h~droxv 4-vitro phenyll N'-(2.4-dichloro ~yll urea The urea was prepared from 2-hydroxy 4-vitro aniline(308 mg, 2 mmol) and 2,4-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.26 g, 38%). EI-MS m/z 342 (M+H) +
Example 38 Synthesis ol~N-l2-hy, roxy-4-nitro,phenyl) N'-(2-chloro Rhe~Srl) urea _5g_ The urea was prepared from 4-vitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g, 47%). EI-MS m/z 308(M+H) +
Example 39 Synthesis of N-12-hvdroxv-4-nitroahenvl) N'-(2.4-dibromo Qhen~l~ urea The urea was prepared from 4-vitro 2-hydroxy aniline(308 mg, 2 mmoi) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g, 39%). EI-MS m/z 430(M+H) +
Exam 1~ 40 S~thesis of 1-~(2-hydroxynapthyl~ N'-(2-bromo phenXll urea The urea was prepared from 1-amino 2-hydroxy napthalene( 195 mg, 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.030 g, 8%). EI-MS m/z 357(M+H) +
Example 41 Synthesis of N-(2-h~roxy-4-nitrophenyl)-N'-(2.3-methylenedioxy~heny~,lurea a)Preparation of 2,3-methylenedioxyphenylcarboxylic acid A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10°C with 2.5 M n-butyllithium ( 15 mL, 35 mmol) in hexane.
When the addition was complete, the mixture was stirred under reflux fvr one hour.
After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq. NaHC03 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure (1.1 g, 20 %). EI-MS mJz 167 (M+H)+
b)Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea To a solution of the 2,3-methylenedioxyphenylcarboxylic acid in toluene, triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL, 1.5 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours, then 2-amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred WO 97/29743 PCT/i1S96/13632 at 100°C for 18 hours. After the reaction mixture was cooled to room temperature, it was partitioned between 5 % citric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate.
The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5:1 ) gave product (200 mg, 42 %). EI-MS m/z 318 (M+H)+
Example 42 ~nthesis of N-(2-hydro~ 4-vitro phenyl) N'-(2-method 3-chloro phenyl? urea The urea was prepared from 2-hydroxy 4-vitro aniline(308 mg, 2 mmol) and 2-chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48 g, 63%). EI-MS mlz 338(M+H) +
Example 43 ~nthesis of N-l2-hydroxx4-vitro phenyll N'-(2-methyl ~enyl urea The urea was prepared from 2-hydroxy 4-vitro aniline(308 mg, 2 mmol) and 2-methyl phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title 2o compound(0.38 g, 53%). EI-MS m/z 288(M+H) +
Example 44 Synthesis of N(bis (2-hydroxv 4-vitro phenyl) N'-(dianisdine diurea The urea was prepared from 2-hydroxy 4-vitro aniline(616 mg, 4 mmol) and dianidisdine diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-vitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound( 0.08 g, 6%).EI-MS m/z 605(M+H) +
Example 45 ~nthesis of 4-methylene bis(N-(2-chloro phenvI~ N'-(2-h3rdroxy 4-nitr~henyll urea) The urea was prepared from 2-hydroxy 4-vitro aniline(616 mg, 4 mmol) and 4-methylene bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-vitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane.
Filtering afforded the title compound(0.10 g, 8%). EI-MS mlz 627(M+H) +
_60_ Example 46 Synthesis of N-f 2-hydroxy 4-(benzylaminolcarbonyl phenyll-N'-(2-bromophenyl urea a)Synthesis of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) area The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%). EI-MS m/z 351(M+H) +
t0 b)Preparation of N-(4-(benzyiamino)carbonyl-2-hydroxyphenylJ-N'-(2-bromophenyI)urea To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.58 mmol) in DMF ( 15 mL), EDC ( 121.9 mg, 0.58 mmol), HOBT ( 156.6 mg, 11.6 mmol) were added . The reaction mixture was stirred at room temperature for 16 hours. Then the benzyl amine ( 123 mg, 11.6 mmol) was t 5 added. The reaction mixture was stirred at same temperature for 24 hours.
Then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate.
The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl 2o acetate; 1:1 ) gave benzylamino product (500 mg, 65 %). EI-MS m/z 441 (M+H)+
Example 47 Synthesis of N-(2-hvdrox~4-n~r_o ~henvl) N'-(2-nhenoxv nhenvl) urea The urea was synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol,) with 25 diphenyl phosphoryl azide(0.475 mL) and triethyl amine(.14 mL) in DMF at 80 °C after 24 hours the 2-amino 5-vitro phenol ( 1 equiv.) was added. The reaction was heated for 24 hours at 80°C. The reaction product was oiled out with hexane. The residue was dissolved in methanol and the solid was precipitated out with water.( 180 mg, 24%) EI-MS m/z 364{M-H) example 4~
S~rnthesis of N-(2-hydrox~-4-fluoro ~enyll N'-(2-bromo phen, I~u_re_a a)Synthesis of 2-hydroxy 4-fluoro aniline 3-fluoro 6-vitro phenol (2 g, I 1 mmol} was treated with I0%PdlC(1 g) at 23 °C.
The reaction mixture was flushed with hydrogen gas and the reaction was allowed to WO 97/29743 PCTlI1S96/13632 stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afford the title compound {1.4 g, 77%). EI-MS mlz 169(M+H) +
b)Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane( 173 mg, 26%). EI-MS m/z 325 (M+H) +
Example 49 S~rnthesis of N-( 2-h~rdroxy 3.4-difluoro phen l~'-,~2-bromo_~henyl) urea a)Synthesis of 2-hydroxy 3,4-difluoro aniline 2,3 difluoro 6-vitro phenol (2 g, 11 mmol) was treated with 10%Pd/C( 1 g) at °C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title compound ( 1.6 g, 97%). EI-MS m/z I46(M+H)+
b)Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. it was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS mlz ' 343(M+H) +
Example 50 ~nthesis of N-(2-by oxy 3-napthyll N'-l2-bromo phenyll urea The urea was prepared from 3-amino 2-hydroxy napthaiene(0.320 g, 2 mmol) and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339, 47%).EI-MS
nn/z 357(M+H)+
Exam l ~;~,nthesis of N-(2-hydroxv 4-den r~l phenyl) N'-(2-bromo ~envl) urea a)Synthesis of 2-vitro 5-phenyl phenol A solution of 3-phenyl phenol(2 g, 11 mmol) in acetic acid was treated with concentrated nitric acid drop-wise until all starting material was consumed.
The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography(ethyl acetate/hexanes) to afford desired ( 1.2 g, 50%).1H NMR (CDC13): d 10.65(s, 1H), 8.18 (d, 1H, J =
10.0 Hz), 7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J=10.0Hz).
b)Synthesis of 2-amino 5-phenyl phenol A solution of 2-vitro 5-phenyl phenol( 1.2 g, 5.5 mmol) in methanol was treated with 10% Pd/C( 1.28). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired ( 1.01 g, 98%).EI-MS m/z 186(M+H)+
c)Synthesis of N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and 2-bromo phenyl isocyanate(0.198 g} by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56%).EI-MS m/z 383(M+H) +
Example 52 Synthesis of N-(2-hvdrox~ethvl nhenyl) N'-(2-bromo ahenvl) urea The urea was prepared from 2-hydroxy 4-methyl aniline(.274g, 2 mmol) and 2-bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with 2o hexane(249 mg, 39%). EI-MS m/z 319(M-H) Example 53 Synthesis of N(2-hydroxy 4-vitro ~yl) N'-(2-phenvlamino phen~ll ureaThe urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-vitro phenyl isocyanate(example 9a, 0.4198, 1.5 equiv.) with 2-anilino aniline(0.184 g, 1 equiv.) in THF overnight at 40 °C. The desired product precipitated out of the reaction mixture(30 mg, 8%). EI-MS m/z 365(M+H) +
Example 54 Synthesis of N-l2-h~droxy 3-carbox 1v ate phenyl) N'-(2-bromo phenyll urea The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilation of the DMF solution with methylene chloride and precipitation with hexane(.287 g, 41 %). EI-MS m/z 351(M+H) +
Exam 1p a 55 Synthesis of Nf2-sulfh~rvl 4-bromo phenyl) N'-l2-bromo.phenyll ureaa)Synthesis of 2-amino 6-bromo thiazole 4-Bromo aniline(4.3 g, 25 mmol, 1 equiv.) and ammonium th.iocyanate(5.7 g, 3equiv.) was dissolved in acetic acid and treated with bromine(4 g, lequiv.) at room temperature. After complete disappearance of starting material the reaction mixture was poured into water and the solid was collected. The solid was used in the next step without any purification(3.6 g, 46%). EI-MS m/z 229(M+H) +
b)Synthesis of bis (3-bromo 6-amino phenyl) disulfide The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in 1o water(SmL) was treated with KOH (2.5 g) was heated at reflux for 8 h at reflux. The reaction mixture was then acidified to ph 4 with acetic acid and extracted with methylene chloride. The methylene chloride mixture was concentrated in vacuo.
The residue was dissolved in DMSO and treated with I2. After stirring overnight at room temperature the reaction mixture was partitioned between methylene chloride and t5 saturated sodium bicarbonate. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The resulting solid was purified by flash chromatography(ethyl acetatelhexane) to afford the title compound (230 mg, 34%). EI-MS m/z 405(M+H) +
c)Synthesis of N(2-sulfhydryl 4-bromo phenyl) N'-{2-bromo phenyl) urea Zo A solution of (3-bromo b-amino phenyl) disulfide(201 mg, .5 mmol) in DMF
was treated with 2-bromo phenyl isocyanate( 1 mmol) at 80 °C overnight.
The reaction mixture was diluted with methylene chloride and a solid was precipitated out with hexanes. The solution was dissolved in MeOH and treated with NaBH4. After gas evolution ceased the reaction mixture was carefully acidified with 1N HCI and the 25 resulting solid was filtered(52 mg, 13%). EI-MS m/z 399 (M-H) E_~Dle 56 Synthesis of N-l2-h day 4-vitro phenyl) N'-(2-iodo~henyll urea The urea was synthesized by the treatment of 2-iodo benzoic acid(5 g, 20 mmoi) 3o with diphenyl phosphoryI azide( 1 equiv.) and triethyl amine ( 1 equiv.) in DMF at 80 °C after gas evolution ceased the 5-vitro 2-amino phenol (3 g, I
equiv.) was added. 'The reaction was heated overnight at 80°C. The reaction mixture was purified by filtering through a plug of silica with methylene chloride. The desired product was then precipitated out with hexane. Filtering afforded the desired compound(1.08 g, 13%).
35 EI-MS m/z 398(M-H) Example 57 Synthesis of N-(2-hvdroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea The thiourea was synthesized by treatment of the 2-tert-butyldimethylsilyloxy nitro phenyl thioisocyanate(see example 9a , 3.73 mmol) with 2-bromo aniline in toluene at 88°C over 36 h. The solution was concentrated and the residue was purified by flash chromatography(EtOAc/Hexanes). The fraction slightly lower rf than starting material contained the desired compound. This fraction was concentrated and then treated with triethyl amine hydrofluoride in acetonitrile for 15 minutes at 23 °C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash 1o chromatography(ethyl actate/hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea(52 mg, 4%;1. EI-MS m/z 369(M+H) +
Example 58 ~nthesis of N-(2-vhenvlsulfamido) 4-cyanop~en_3r1 N'-(2-bromo phenyll urea t 5 a)Synthesis of 3-(phenylsulfamido) benzonitrile The of 3-(phenylsulfamido) benzonitrile was synthesized from the 3-cyano aniline (23.9 g, .2 mol) by Method C. It was purified by recrystalization from EtOH(15.8 g, 31%).1H NMR (CDC13): d 7.95(s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.45 (m, 2H), 7.35 (m, 4H).
2o b)Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile The 3-(phenylsulfamido) benzonitrile(10 g, 39 mmol) was dissolved in acetic anhydride and treated with concentrated nitric acid dropwise at room temperature until all the starting material had been consumed. The reaction mixture was then quenched by carefully pouring it into sodium bicarbonate and left to sit until all gas evolution had 25 subsided. 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 afford the title compound ( 1.7g, 15%).
EI-MS mlz 302(M+H) +
30 c)Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile The 3-(phenylsulfamido) 4-nitro benzonitrile(1.5 g, 4.9 rnmol) was treated with tin chloride dihydrate in EtOH at 80 °C for 12h. It was then concentrated and flushed through a plug of silica gel with 5% methanol/methylene chloride. The filterate was absorbed onto silica gel and purified by flash chromatography(ethyl acetatelhexane) to 35 afford the title compound (0.9 g, 60%). EI-MS m/z 274 (M+H) +
d)Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl) urea The urea was synthesized from 2-(phenylsulfamido) 4-amino benzonitrile(77 mg, 0.28 mmol) and 2-bromo phenyl isocyanate by general Method C. It was purified by column chromatography(ethyl acetate/hexane) to afford the title compound (30 mg, 22%). EI-MS m/z 469(M-H) Example 59 Synthesis of N-(2-(phenyl sulfamidol phenvll N'-(2-bromophenvl) urea a)Synthesis of 2-( phenyl sulfamido) aniline The sulfonamide was synthesized from phenyl sulfonyl chloride(0.01 mmol) and to o-phenylene diamine( 1.08 g, 0.01 mmol) by general Method C. it was purified by recrystallization from EtOH(1.0 g, 40%).EI-MS m/z 249(M+H) +
b)Synthesis of N-(2-(phenyl suifamido) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized Z-(phenyl sulfamido) aniline( 1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with 15 methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.234 g, 52%).EI-MS m/z 446(M+H) +
Example 60 Synthesis of N-(2-( styrvi sulfamido) phenvll N'-(2-bromo phenyll urea 20 a)Synthesis of 2-( styryl sulfamido) aniline The sulfonamide was synthesized from styryl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH( 1.2 g, 60%)EI-MS m/z 199(M+H) +
b)Synthesis of N-(2-(styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea 25 The urea was synthesized from 2-(styryl sulfamido) aniline( 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.309 g, 65%). EI-MS m/z 472(M+H} +
30 Example 61 Synthesis of 2-ff3.4 dimethoxyphenvl)sulfonyl arninol nhenvll N'-(2-bromo phen~
urea a)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl 35 chloride(0.01 mol) and o-phenylene diamine by general Method C. It was purifed by recrystallization from EtOH(0.65 g, 21%). EI-MS m/z 309(M+H) +

b)Synthesis of 2-((3,4-dimethoxyphenyl)sulfonylamino] phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline( 1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.062 g, 12%).EI-MS m/z 504(M-H) -Exam~e 62 ~nthesis of N-f2-f(4-acetamidophenvllsulfonvlam'no7 phenyl) N'-(2-bromo phe~rl) urea a)Synthesis of 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline The sulfonamide was synthesized from 4-acetamidophenyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH( 1.27 g,40%)EI-MS m/z 304(M-H) .
b)Synthesis of N-(2-[(4-acetamidophenyisulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylanuno]phenyl aniline( 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane.
Filtering afforded the desired compound(0.12 g, 24%). EI-MS m/z 501 (M-H) -Example 63 S~rnthesis of N-f2-(2-thio~hene sulfamido phenvll N'-(2-bromo phenyll urea a)Synthesis of 2-(2-thiophene sulfamido) aniline The sulfonamide was synthesized from 2-thiophene sulfonyi chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.77 g, 30%). EI-MS m/z 255 (M+H)+
b)Synthesis of N-{2-(2-thiophene sulfonyl amino phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-( 2-thiophene sulfonyl amino) aniline( 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.29 g, 64%). EI-MS m/z 450(M-H) Exam,~le 64 Synthesis of N-(2-(3-told sulfon~amino ~henyll N'-l2-bromo phenyll urea a)Synthesis of 2-( 3-tolyl sulfonyl amino) aniline The sulfonamide was synthesized from 3-tolyl suifonyl chloride(O.OI mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.73g, 28%}.EI-MS m/z 263 (M+H)+
b)Synthesis of N-{2-((3-tolyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-{3-tolyl sulfonyl amino) aniline( 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexanes. It was recrysallized two times with EtOH(25 mg, 5%). EI-MS m/z 458(M-H) 1o Example 65 S~rnthesis of N-l2-(8-auinolinyl sulfonXl aminol phenyl) N'-(2-brQ,mo hen ) urea a)Synthesis of 2-(8-quinoiinyl sulfonyl amino) aniline The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol;1 by general Method C. It was purified by recrystallization from EtOH(0.82 g, 27%).EI-MS mlz 300 (M+H) +
b)Synthesis of N-(2-( (8-quinolinyl) sulfonyI amino) phenyl) N'-{2-bromo phenyl) urea The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) aniline( 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded 2o the desired compound(0.23 g, 46%).EI-MS m/z 495(M-H) Example 66 S, nY these of N-(2-( benzyl sulfon'rl aminol phen Il N'- 2-bromo phenyll urea a)Synthesis of 2-(benzyl sulfonyl amino) aniline The sulfonamide was synthesized from benzyl sulfonyl chloride(0.01 moi) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+.
b)Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-{ benzyl sulfonyl amino} aniline( 1 mmol) 3o and 2-bromo phenyl isocyanate(lmmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.11 g, 23%). EI-MS m!z 460 (M+H)+
Example 67 Svnthes~s o~jV-(2-h~droxx-4-azidoghenxll-N'-~2-methoxyphen_vllurea a)Synthesis of N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea To a solution of N-(2-hydroxy-4-nitro phenyl)-N'-(2-methoxyphenyl)urea( 1.0 g, example IS) in methanol, palladium (on activated carbon, 10%) (100 mg) was added.
Then the reaction mixture was hydrogenated under a hydrogen balloon for 18 hours.
The solid was filtered off by celite and washed three times by methanol. The filtrate was concentrated under reduced pressure to give amine compound (0.8 g, 89%). EI-MS
m/z 2?4 (M+H)+
b)Synthesis of N-(2-hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea The N-{2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg, 1. I7 mmol) was added to HCI/H20 ( 1.17 mLJ2.34 mL), cooled to 0°C. Sodium nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate.
The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gei (hexane ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+
Example 68 Preparation of N-f2-hvdroxy-5-c~anophen 1y_ 1-N'-'~2-bromophen 11 urea a)Preparation of 2-amino-4-cyanophenol To a solution of 2-nitro-4-cyanophenol(lOg, 61mmo1) in methanol(250mL) was added 10% PdIC ( l g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(8.0 g, 97%).
1H NMR (CD30D): d 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).
b)Preparation of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea .
N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (540mg,81%). 1H NMR (CD30D): d 8.10 (d, 1H), 7.87 (d, 1H}, 7.43 (d, 1H), 7.20 (t, 1H), 7.09 (d, 1H), 6.86 (t, 1H), 6.77 (d, 1H).
Example 69 Pre,~aration of N-f 2-hydroxy-3-fluoro~Yll-N'-~?-bromophen 11 urea a)Preparation of 2-amino-3-fluorophenol To a solution of 2-nitro-3-fluorophenol( 1 g, 6.4mmol) in methanol(250mL) was added 10% Pd/C (1g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH! CH2C12) gave the desired product{650 mg, 80.2 %). IH NMR (CD30D): d 6.41-6.1? (m, 3H).
b)Preparation of N-(2-hydroxy-3-fluorophenyl]-N°-(2-bromophenyl] urea to N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amino-3-fluorophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1l20) and filtering. {500 mg, 77%). 1H NMR (CD30D): d 8.05 (d, 1H), 7.50 (d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 (m, 2H).
Exam~nle 7-0 Preparation of N-2-f I-hydroxyfluorenel-N'-f2-bromophen 1Y-1 urea a)Preparation of 2-amino-1-hydroxyfluorene To a solution of I-hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in 2o methanol(250mL) was added 10% Pd/C ( l g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(171 mg, 81.2 96). 1H NIviR (CD30D): d 7.60 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H).
b)Preparation of N-2-[1-hydroxyfluorene]-N'-[2-bromophenyl] urea N-2-[1-hydroxyfluorene]-N'-[2-bromo phenyl] urea was prepared from 2- .
amino-1- hydroxyfluorene ( 170mg, 0.86 mmol) according to the procedure in General 3o Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). 1H NMR
(CD3C1): d 8.04 (d, 1H), 7.66 (d, 1H), 7.49 (t, 2H), 7.35-7.20 (m, 4H), 7.09 (d, 1H), 6.90 (t, 1H).
Example 71 R'O 97!29743 PCTIUS96/13632 Preparation of N-3-f2-hydroxy-9.10-anthraquinonvll-N'-f2-bromophenyl] urea N-3-[2-Hydroxy-9.10-anihraquinonyl]-N'-[2-bromophenyl] urea was prepared from 2-hydroxy-3-aminoanthraquinone(480mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride!
hexane(1120) and filtering. (610mg, 70%). 1H NMR (CD30D): d 8.93 (s,lH), 8.12 (m, 2H), 8.02 (d> 1H), 7.77 (m, ZH), 7.61 (d, 1H), 7.52 (s, 1H), 7.38 (t, 1H), 7.05 (t, 1 H).
Example 72 t0 Preparation of N-f2-hydroxv-3-fluoro-5-bromophenyll-N'-f2-bromophenyl_]
urea a)Preparation of 2-amino-6-fluoro-4-bromophenol A mixture of 4-bromo-2-fluoro 6-nitrophenol( 1 g, 4.2mmo1) and tin (II) chloride (4.78 g, 21.2mmol) in ethanol(SOmL) was heated at 80°C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(710 mg, 82 %). 1H NMR (CD30D}: d f.51-6.40 (m, 2H).
2o b)Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl]
urea N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1120} and filtering. (500 mg, 77%). 1H NMR (CD30D): d 7.98 (s, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.:33 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H).
Example 73 PreRa~ation of N-f2-h~droxv-3-chlorophenvll-N'-f2-bromophen !v_! urea a)Preparation of 2-amino-3-chlorophenol A mixture of 3-chloro-2-nitrophenol(250 mg, l.4mmoi) and tin (I17 chloride ( 1.2 g, 5.3mmol) in ethanol(SOmL) was heated at 80~C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the -?1 resulting solid on silica gel (4%MeOHI CH2CI2) gave the desired product(143 mg, 69 %). IH NMR (CD30D): d 6.75 (t"IH), 6.70 (d, 1H), 6.65 (d, 1H).
b)Preparation of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-3-chlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product(195mg, 57%). 1H NMR
(CD30D): d 7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.20 (t, IH), 6.90 (m, 2H), 6.70 (t. 1H).
lo Example 74 Preparation of N-t2-h~~3-trifluoromethyiphenyll-N'-f2-bromo henxll ureaa)Preparation of 2-vitro-6-trifluoromethylphenol 2-trifluoromethylphenol (3.40g, lB.Smmo1) was dissolved in methylene 15 chloride(40mL) followed by the addition of sodium nitrate ( I .73g, 20.4mmol). The addition of sulfuric acid (23 mIJ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.
The organic layer was dried over MgS04 and filtered. The solvent was evaporated and 20 chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.84 g, 47 %). IH NMR (CD3COCD3): d 8.35 (d,lH), 7.95 (d, IH), 7.13 (t, IH).
b)Preparation of 2-amino-6- trifluoromethylphenol A mixture of 6-trifluoromethyl-2-nitrophenol( 1.84 g, 8.67mmol) and tin (In 25 chloride (6.0 g, 26.2 mmol} in ethanol( 1 SOmL) was heated at 80°C
under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography 30 of the resulting solid on silica gel (4~vMeOH/ CH2Cl2) gave the desired product( 1.35 g, 88 %). 1H NMR (CD30D): d 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).
c)Preparation of N-[2-hydroxy-3- trifluoromethylphenyl]-N'-[2-bromophenyl]
urea N-[2-hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-trifluoromethylphenol (280mg, 1.60 mmol) according to the procedure 35 in General Method B. The product was purified by precipitation from methylene chloride/ hexane( I/20) and filtering. (390mg, 65%). /H NMR {CD30D): d 7.99 (d, 1H), 7.60 (d, 1H), 7.58 (d, 1H), 7.34 (t, 1H), 7.30 (d, 1H), 7.00 (t, 1H), 6.96 (d, 1H).
Example 75 Preparation of N-f3.4 diphenyl-2-h'rdroxyphenyll-N'-[2-bromophen~~llurea N-[3,4 diphenyi-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(II20) and filtering (6lmg, 69%). /H NMR (CD30D): d 7.97 (d, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.31 (t, 1H), 7.25-7.00 (m, 11H), 6.91 (d, 1H).
Exam , Ip a 76 Preparation of N-f2-hvdroxv-3-~Ivcinemethvlestercarbon~~yll-N' j2-bromonhenvll urea N-[2-hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromopheny1] urea was prepared from 6-glycinemethylestercarbonyl-2-aminophenol (50mg, 0.22 mmol), purchased from the University of New Hampshire, according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering (b5mg, 69%). 1H NMR (CD30D): d 8.14 (d, 1H), 7.96 (d, 2o IH). 7.49 (d, 1H), 7.24 (t, 2H), 6.89 (dd, 1H), 6.81 (t, 1H), 4.10 (s,2H), 3.74 (s,3H).
Exam 1p a ?7 Preparation of N-f2-hydroxv-3-glvcinecarbon r~iphen~rl]-N'l2-bromopheny[Lurea N-[2-Hydroxy-3-glycinecarbonylphenyi]-N'-[2-bromophenyl] urea was prepared from N-[2-hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea(SOmg, 0.12 mmol) by stirring in a 3/1 ratio of methanol/water ( 10 mL). Addition of 1 equiv. of lithium hydroxide was added and stirring continued until the starting material had disappeared. (45mg, 92%). The product was purified by chromatography of the resulting solid on silica gel (9/1/0.1 CH2C12/ MeOH/ AcOH) to give the desired product(195mg, 57%). 1H NMR (CD30D): d 8.14 (d, IH), 7.92 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.34 (t, 1H), 7.04 (t, 1H), 6.82 (t, IH), 3.96 {2H).
Example 78 Preparation of N-f2-hydroxv-3.5-dichlorophen~]-N'-(2-bromopheny, urea a)Preparation of 2-amino-4,6-dichlorophenol A mixture of 4,6-dichloro-2-nitrophenol( 1 g, 4.8mmo1) and tin (II) chloride (3.2 g, 14.4mmol) in ethanol(SOmL) was heated at 80° C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH.
before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(685 mg, 80 %). 1H NMR (CD30D): d 6.75 (s,lH), 6.61 (s, 1H).
b)Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea to N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-4,6-dichlorophenol (143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (660mg, 88%). 1H NMR (CD30D): d 7.96 (s, 1H), 7.89 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.00 (t, 1H), 6.95 (dd, 1H).

Example 79 Prep anon of N-f2-hvdroxv-3-nitro~henjrll-N'-f2-bromonhen 1~1 ureaN-[2-Hydroxy-nitrophenyl]-N'-[2-bromophenyl] urea was prepared from 2-hydroxy-3-nitroaniline { 1.25g, 8.1 mmol) according to the procedure in General Method B. The product was 20 purified by precipitation from methylene chloride/ hexane( 1120) and filtering. (2.4g, 84%). 1H NMR (CD30D): d 8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.01 (m, 2H).
Example 80 25 Preparation of N-f 2-h r~droxv-4-nanhthalenesulfonic acidl-N'-f 2-bromonheavll urea N-[2-hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea was prepared from 1-amino-2-hydroxy-4-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the procedure in General Method B and the addition of 1mL of triethylamine The product was purified by precipitation from methylene chloride/
30 hexane( 1/20) and filtering. (690 mg, 79%). 1 H NMR (CD30D): d 8.14 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 (t, 1H).
Exa~n~le 81 Preparation of N-f2-hvdroxy 5-na~hthalenesulfonic acidl-N'-f2-brQmophenyll urea 35 N-3-[2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromophenyl] urea was prepared from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol) WO 97!29743 PCTIUS96/i3632 according to the procedure in General Method B and the addition of 1mL of triethylamine The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (715 mg, 82%). 1H NMR (CD30D): d 8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 (s, 1H), 7.04 (m, 2H).
Example 82 Preparation of N-f 2-hvdroxy-3.4-diehlorophen~]-N'-f 2-bromophe X11 urea a)Preparation of 2-vitro-5,6 dichlorophenol 2,3-dichlorophenol (3.26g, ZOmmoi) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol).
The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(1.8 g, 44 %). 1H NMR (CD3COCD3): d 8.04 (d,lH), 7.15 (d, 1H).
b)Preparation of 2-amino-5,6 dichlarophenol A mixture of 5,6-dichloro-2-nitrophenol( 1.8 g, 8.7mmol) and tin (II) chloride (5.8 g, 26.1mmol) in ethanol(50mL) was heated at 80_C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.4 mg, 90 %). 1H NMR (CD30D): d 6.71 {d, 1H), 6.45 (d, 1H).
c)Preparation of N-[2-hydroxy-3,4-dichlorophenyi]-N'-[2-bromophenyi] urea N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (670mg, 89%). 1H NMR {CD30D): d 7.90 (d, 1H), 7.85 (d, 1H), 7.59 (d, 1H), 7.3I (t, 1H), 6.99 (t, 1H), 6.96 (d, (1H).
Example 83 Preparation of N12-h d~--rox_y-3-c~anopheny_1]-N'-f2-bromophen 11 urea a)Preparation of 2-vitro-6-cyanophenol _75_ 2-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol}. The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOHI CH2Cl2) gave the desired product( 1.4 g, 42 %).
1H NMR (CD3COCD3): d 8.47 (d,lH), 8.15 (d, 1H), 7.30 {t, 1H).
b)Preparation of 2-amino-6-cyanophenol 1o A mixture of 6-cyano-2-nitrophenol(600 mg, l.Ommo1) and tin (II) chloride (3.2 g, 14.4mmol) in acetic acid(SOmL) was heated at 80_C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOHI CH2C12) gave the desired product(365 mg, 75 %). 1H NMR (CD30D): d 6.92 (d, IH}, 6.85-6.69 (m,2H).
c)Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[2-bromophenylj urea N-[2-Hydroxy-3-cyanophenyi]-N'-[2-bromophenyl] urea was prepared from 2-2o amino-6-cyanophenol ( I34mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1J20) and filtering. (260mg, 78%). IH NMR (CD30D): d 7.98 (d, 1H), 7.74 (d, 1H), 7.57 (d, IH), 7.30 (t, 1H), 7.22 (d, 1H), 6.98 (t, 1H), 6.94 (t, (1H).
Exam 1p a 84_ Preparation of N-f2-h dy roxy-4-cyanophenyrll-N'-f2-bromophenyl] urea a)Preparation of 2-nitro-5-cyanophenol 3-cyanophenol (2.388, 20mmo1) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmo1). The addition of sulfuric acid (20mL 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methyiene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(910 mg, 28 %}. 1H NMR (CD3COCD3): d 8.30 (d,lH), 7.67 (s,lH), 7.49 (d, IH).
b)Preparation of 2-amino-5-cyanophenol _76_ A mixture of 5-cyano-2-nitrophenol(250 mg, l.Smmo1) and tin (II) chloride {3.2 g, 14.4mmol) in ethanol(SOmL) was heated at 80_C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product( 175 mg, 86 %). 1H NMR (CD30D): d 7.00 (d, 1H), 6.88 (s,lH), 6.69 (d, 1H).
c)Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea t0 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenylJ urea was prepared from 2-amino-5-cyanophenol ( 170mg, 1.27 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering (310mg, 74%). 1H NMR (CD30D): d 8.25 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (s, 1H), 7.01 (t, (1H).
Example 85 Preparation of N-(2-h~droxy-4-c~phenyll N'-L4-methoxyPhen, 1i urea N-[2-Hydroxy-4-cyanophenyl]-N'-(4-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General 2o Method B. The product was purified by precipitation from methyiene chloride/
hexane(1/20) and filtering. ( 110mg,86%). 1H NMR (CD30D): d 8.23 (d, 1H), 7.61-7.51 (m, 2H), 7.32 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H).
Example 86 Preparation of N-f2-hydroxy-4-c~phen~]-N'-f2-phen l~nhenyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-(2-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol ( 170 mg, 1.27 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloridel hexane(1/20) and filtering. (150mg, 85%). 1H NMR (CD3OD): d 8.20 (d, 1H), 7.73 (d, 1H), 7.51-7.20 (m, 8H), 7.13 (d, 1 H), 7.01 (s, ( 1 H).
xa 7 Preparation of N-f2-hvdroxv-4-cvanoohenvll-N'-f2-methvlt~l envll urea N-[2-Hydroxy-4-cyanophenyl]-N'-(2-methylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
_77_ hexane( 1/20) and filtering. (90mg, 75%). 1H NMR (CD30D): d 8.25 (d, IH), 7.59 (d, 1H). 7.26-7.00 (m, SH), 2.30 (s, 3H).
Example 88 Preparation of N-f2-hYdroxy-4-c~anophenyll-N'-f2-trifluoromethyl~henvll urea N-{2-Hydroxy-4-cyanophenylJ-N'-[2-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. ( 1 lOmg, 76%). 1 H NMR (CD30D): d 8.25 (d, 1H), 7.81 to (d, 1H), 7.68 (d, 1H), 7.6I (t, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, (1H).
Exam~1~89 Preparation of N-f2-hvdroxv-4-cvanonhenvll-N'-f3-trifluoromethvlQhenvll urea N-[2-hydroxy-4-cyanophenyl)-N'-[3-trifluoromethyiphenyl] urea was prepared is from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (114mg, 79%). 1H NMR (CD30D): d 8.30 (d, 1H), 7.92 (s, 1H), 7.60 (d, 1H), 7.47 (t, 1H), 7.29 (d, IH), 7.18 (dd, IH), 7.06 (s, 1H).
2o Example 90 Preparation of N-f2-hydroxy-4-c,~phenvll-N'-f4-trifluoromethyl~nyll urea N-[2-Hydroxy-4-cyanophenylJ-N'-[4-trifluoromethylphenylJ urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
25 hexane(1/20) and filtering. (108mg, 75%). 1H NMR (CD30D): d 8.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H), 7.20 (dd, 1H), 7.07 (s, 1H).
Example 91 P~,eparation of N-f 2-hydroxk 3-n-propylphenyll-N'-f2-bromo hr ~~envll urea 3o a)Preparation of 2-nitro-6-n-propylphenol 2-n-propylphenol (5.00g, 36.8mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (3.438, 40.Smmo1).
The addition of sulfuric acid (45mL13M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction 35 mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and _78_ chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(3.2 mg, 48 %). 1H NMR (CD3COCD3): d 7.99 (d,lH), 7.46 dd, 1H), 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H).
b)Preparation of 2-amino-6-n-propylphenol To a solution of 2-vitro-6-n-propylphenol(2g, 11.Ommo1) in methanol( 100mL) was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography to of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product( I.50 g, 80.2 %). 1H NMR (CD30D): d 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H).
c)Preparation of N-[2-hydroxy-3-n-propyiphenyi]-N'-[2-bromophenyl] urea N-[2-Hydroxy-3-n-propyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2- amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (640mg,92%). 1H NMR (CD30D): d 8.00 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, IH), 6.78 (d, 1H).
2o Example 92 Preparation of N-f2-hydroxY-4-ethvlphenyll-N'-f2-bromophe,~,~ll urea a)Preparation of 2-vitro-5-ethylphenol 3-ethylphenol (S.OOg, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric acid (SOmL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( I .7 g, 25 %).

(CD3COCD3): d 8.02 (d,lH), 6.99 (s,lH), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).
b)Preparation of 2-amino-5-ethylphenol To a solution of 2-vitro-5-ethylphenol(lg, 6.4mmo1) in methanol(250mL) was added 10% PdIC ( I00 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(750 mg, 91 %). 1 H NMR (CD30D): d 6.41-6.17 (m, 3H).
c)Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-ethyIphenyl3-N'-[2-bromo phenyl] urea was prepared from 2-amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (520 mg, 77%}. 1H NMR (CD30D): d 7.96 (d, 1H), 7.62 (s, 1H}, 7.56 (d, 1H), 7.30 (t, 1H}, 6.96 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H).
Example 93 Preparation of N-f2-hvdroxv 3-phenvlaminocarbonYl_phenyll-N'-f2-bromophenvll urea a)Preparation of 2-vitro-6-phenylaminocarbonylphenol 2-Phenylaminocarbonylphenol (S.OOg, 23 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.208, 25.5 mmol).
The addition of sulfuric acid (30mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(2.50 g, 42 %). 1H NMR (CD3COCD3): d 8.15 (d,lH), 8.09 (d,lH), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).
b)Preparation of 2-amino-6-phenylaminocarbonylphenol To a solution of 2-vitro-6-phenylaminocarbonylphenol (1g, 4.0 mmol) in methanol(250mL) was added 10% PdIC ( 100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(800 mg, 91 %). 1H NMR (CD30D): d 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H).
c)Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl]
urea N-[2-hydroxy 3-Phenylaminocarbonyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amino-6-phenylaminocarbonylphenol (456mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (800mg,94%). 1H NMR (CD30D):

WO 97!29743 PCT/US96/13632 1H NMR (CD30D): d 25 (d, 1H), 7.94 (d, 1H), 7.75-7.57 (m, 4H), 7.48-7.30 (m, 3H}, 7.21 (t, 1H), 7.02 (dd, 1H), 6.92 (t, 1H).
Example 94 Preparation of N-f2-hydroxv-3-cvano-4-methvl~ !y 1-N'-(2-bromophe~"vll ureaa) Preparation of the 2-nitro 5-methyl 6-bromo phenol A solution of t-butyl amine(6.88 mL, 4.79 g, 2 equiv.) in methylene chloride was treated with bromine ( 1.67 mL, 5.2 g, 1 equiv.) at -20 °C. The flask was then cooled to -78 °C and the the 2-nitro 5-methyl 6-bromo phenol (5 g, 1 equiv., in to methylene chloride) was added drop-wise with vigrous stirring. The reaction mixture was slowly warmed to -30 °C for I h, then to -10 °C for 2 hours.
The reaction mixture was then partitioned between methylene chloride and 5% aqueous acetic acid.
The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
The reaction mixture was purified by flash chromatography(Ethyl acetate/
hexanes) to remove dibrominated species. The 2-nitro 4-bromo 5-methyl phenol was then selectively crystallized out of methylene chloride. A final silica gel column(5%ethyl acetate/ hexanes) yielded desired isomer in 90% purity.(1.05 g, 14%). 1H NMR
(CDC13): d 7.95 (d, IH, 3 = 10.0 Hz), 6.91 (d, 1H, 3 = 10.0 Hz), 2.52 (s, 3H).
b) Preparation of 2-nitro-5-methyl-6-cyanophenol 2-Nitro-5-methyl-6-bromophenol ( 100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2mL) followed by the addition of triethylamine (0.175g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155mg, 1.73mmol). The mixture was allowed to stir at 80_C for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2%MeOH/ CH2C12) gave the desired product (70 mg, 9I %). 1H NMR (CD3COCD3): d 8.30 (d,lH), 7.15 (d,lH), 2.6I (s, 3H).
c) Preparation of 2-amino-5-methyl 6-cyanophenol A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmo1) and tin (II) chloride .
(265 mg, 1.18mmo1) in ethanol(20mL) was heated at 80_C under argon. After 2 hours, 3o the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product( 175 mg, 86 %). 1H NMR (CD30D): d 6.87 (d, 1H), 6.75 (d,lH), 6.32 (s, 3H).
d) Preparation of N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl]
urea N-[2-hydroxy 3-cyano 4-methyl phenyl)-N'-(2-bromophenyl] urea was prepared from 2-amino-5-methyl-b-cyano phenol (50mg, 0.34 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (70mg, 60%). 1H NMR (CD30D): d 7.92 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.62 (t, 1H), 2.49 (s, (3H).
Example 95 preparation of N-f2-hydroxv 4-Carboxyphenvl phenyli-N'-f2-bromophe~yll ureaa)Preparation of 4-vitro-3-hydroxybenzophenone l0 3-Hydroxybenzophenone (3.00g, 15. Immo1) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.42g, 16.7mmo1).
The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and exuacted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.10 g, 30 %). 1H NMR (CD3COCD3): d 8.25 (d,1H), 7.86 (d,lH), ?.71 (m, 1H), 7.59 (d, 1H}, 7.48 (s, 1H), 7.39 (dd, 1H).
b)Preparation of 4-amino-3-hydroxybenzophenone 2o A mixture of 4-vitro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (I~
chloride (2.5 g, l l.lmmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(685 mg, 87 %). 1H NMR (CD30D): d 7.65 (d, 2H}, 7.55 (d,lH), 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 3o N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 4-amino-3-hydroxybenzophenone (330mg, 1.5 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (490mg, 79%). 1H NMR (CD30D):
d 8.40 (d, 1H), 8.09 (d, 1H), 7.83 (d, 2H), 7.65-7.60 (m, 4H), 7.48 (s, 1H), 7.43 (d, 1H), 7.35 (d, ( 1 H), 7.10 (t, i H).

Example 96 Preparation of N-f2-hydroxy 3-carbox~vhen~ phenyll-N'12-bromophe~ll ureaa}Preparation of 3-vitro-2-hydroxybenzophenone 2-Hydroxybenzophenone (3.00g, lS.Immo1) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.42g, 16.7mmol).
The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and 1o chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( I.60 g, 44 %}. IH NMR (CD3COCD3): d 8.30 (d,lH), 7.86 (m,3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).
b)Preparation of 3-amino-2-hydroxybenzophenone A mixture of 3-vitro-2-hydroxybenzophenone (600 mg, 2.Smmo1) and tin (In chloride ( 1.7 g, 7.Smmol) in ethanol(SOmL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(490 mg, 92 %). 1H NMR (CD30D): d 7.65-7.40 (m, SH), 6.98 (d,lH), 6.86 (d, 1H), 6.67 (t, 1H).
c)Preparation of N-[2-hydroxy 3-carboxyphenyl phenyl]-N'-[2-bromophenyl] urea N-(2-hydroxy 3-carboxyphenyl phenyl]-N'-(2-bromophenyl] urea was prepared from 3-amino-2-hydroxybenzophenone (250mg, 1.20 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloridel hexane(U20) and filtering. (200mg, 78%). 1H NMR (CD30D): d 8.35 (d, 1H), 7.96 (d, 1H), 7.72 (d, 2H), 7.65-7.50 (m, 4H), 7.35 (d, 1H), 7.30 (d, 1H), 7.01 (dd, (1H), 6.92 (t, 1H).
I xample 97 Preparation of N-f2-hydroxv 3-benzvloxy phenvll-N'-f2-bromophenyll urea a)Preparation of 2-vitro-6-benzyloxy phenol 2-Benzyloxyphenol (S.OOg, 25.Ommo1) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.30g, 27.Smmol).
The addition of sulfuric acid (3lmL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried aver MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(2.6 g, 43 %). 1H NMR (CD3COCD3): d 7.70 (d,IH), 7.50-7.28 (m, 5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 (s, 2H).
b)Preparation of 2-amino-6-benzyloxy phenol A mixture of 2-vitro-6-benzyloxy phenol ( 1.00 g, 4. l0mmol) and tin (II) chloride (2.75 g, I2.2 mmol) in ethanol( 150mL) was heated at 80°C
under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the t5 desired product(1.35 g, 88 %). 1H NMR (CD30D): d7.46 (d, 2H), 7.40-7.35 (m, SH), 6.55 (d, 1H), 6.40 (d, 1H), 5.10 (s, 2H).
b)Preparation of N-[2-hydroxy3-benzyloxy phenyl]-N'-[2-bromophenyl] urea N-[3-benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 2-vitro-6-benzyloxy phenol (430mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (630mg, 76%). 1H NMR (CD30D): d 7.93 (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, 2H), 5.16 (s, 2H).
Example 98 Preparation of N-3-f2-hydmxy-5-indanonel-N'-t2-bromophenyll urea a)Preparation of 2-hydroxy-3-vitro-5-indanone 2-Hydroxy-5-indanone(3.OOg, 20.Ommol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.95g, 21.Ommo1).
The .
addition of sulfuric acid (25mLJ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and exuacted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(1.5 g, 39 %). 1H NMR (CD3COCD3): d 7.70 (d,lH), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H).
b)Preparation of 3-amino-2-hydroxy-5-indanone -gq._ A mixture of 2-hydroxy-3-nitro-5-indanone ( 1.50 g, 7.80mmo1) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol( 150mL) was heated at 80° C
under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product( 1.00 g, 79 %). 1 H NMR (CD30D): d 6.85 (d, l H), 6.45 (d, 1 H), 2.95 (d, 2H). 2.60 (d, 2H).
to c) Preparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea N-[2-Hydroxy-5-indanone]-N'-[2-bromophenylJ urea was prepared from 3-amino-2-hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane{1/20) and filtering. .(610mg, 85%). 1H NMR (CD30D): d 7.92 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 7.09 (t, 1H), 7.00 (d, 1H), 2.90 (d, 2H), 2.66 (d, 2H).
Example 99 Preparation of (E)-N-[4-f2-lMethoxycarbonyll ethenyl]-2-hydroxy~hen,~l-N=,L2-bromoohen, i1 urea a) Preparation of 4-nitro-3-hydroxycinnamic acid 3-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.70 g, 26.1 mmol). The addition of sulfuric acid (25 mLJ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.
The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(1.0 g, 26 %). 1H NMR (CD3C4CD3): d 8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,lH).
b) Preparation of 4-nitro-3-hydroxymethylcinnamate 4-Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product( 1.0 g, 94 %}.
1H NMR (CD3COCD3): d 8.17 (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 WO 97129743 PCT/US96Ii3632 A mixture of 4-vitro-3-hydroxymethylcinnamate ( 1.0 g, 4.50mmo1) and tin (II) chloride (3.0 g, 13.4 mmol) in ethanol(50mL) was heated at 80_C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product (650 mg, 75 %). 1H NMR (CD30D): d7.50 (d,lH), 6.94 (s, 1H), 6.89 (d, 1H), 6.68 (d, IH), 6.18 (d, LH), 3.74 (s, 3H).
d)Preparation (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenylj-N'-[2-bromophenyl] urea (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyi]
urea was prepared from 4-amino-3-hydroxymethylcinnamate (250mg, 1.3 mmol) according to the procedure in General Method B. The product was purified by precipitation from methyiene chloride/ hexane(I/20) and filtering. (300mg, 59%). 1H
NMR (CD30D): d 8.24 (d,lH), 8.05 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.21 (s, 1H), 7.19 (d, IH), 7.10 (t, 1H) 6,45 (d,lH) 3.81 (s, 3H).
Example 100 2o Preparation of (E)-N-f3-f2-(Methoxycarbonyi) ethenyll-2-hydrox3r~henXl,]-N'-f2-~omophe~yl] urea N'-f2-bromo~n_yil urea a)Preparation of 3-vitro-2-hydroxycinnamic acid 2-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene chloride(4~mL) followed by the addition of sodium nitrate (2.21 g, 26.1mmo1).
The addition of sulfuric acid (30 mL 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.
The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Ci2) gave the desired product(2.0 g, 52 %). 1H NMR (CD3COCD3): d 8.21 (d, iH), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H) b) Preparation of 3-vitro-Z-hydroxymethylcinnamate 3-vitro-2-hydroxycinnamic acid was stinted in excess methanol with a catalytic amount of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.0 g, 94 %).

1 H NMR (CD3COCD3 ): d 8.25 (d, 1 H), 7.8.15 (d, I H), 8.06 (s, 1 H), 7.20 (t, 2H), 6.76 (d.IH), 3.80 (s, 3H).
c)Preparation of 3-amino-2-hydroxymethylcinnamate A mixture of 3-nitro-2-hydroxymethylcinnamate ( I .0 g, 4.5 mmol) and tin (II) chloride (3.0 g. 13.4 mmol) in ethanol(SOmL) was heated at 80_C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product (700 mg, 81 %). 1H NMR (CD30D): d 8.04 (d, 1H), 6.93 {d, 1H),6.79 (d, 1H), 6.71 (t, 1H), 6.43 (d, IH), 3.72 (s, 3H).
d)Preparation(E)-N-[3-[2-(Methoxycarbonyl) ethenyt]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea i5 (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]
urea was prepared from 3-amino-2-hydroxymethylcinnamate ( 100 mg, 0.52 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1120) and filtering. ( 150mg, 74%).IH
NMR (CD30D): d 8.I0 (d,lH), 8.00 (d, 1H), 7.69 (d, IH), 7.65 (d, 1H), 7.42 (t, 1H), 7.38 (t, 1H), 7.32 (d, IH), 7.05 (t, 1H) 6.55 (d,lH) 3.8I (s, 3H).
Example IOI
Preparation of iEl-N-f3-(2-(Aminocarbon~) ethenvil-2-h' dr roxvnhenvll-N'-I2-bromophen~rll urea N'-[2-bromophenvll urea a)Preparation of 2-hydroxycinnamide 2-Hydroxycinnamic acid (2.00g, 12.3 mmol) was dissolved in dimethyl formamide( IOmL) followed liy the addition of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmoi) and triethylamine ( I.7mL, 12.3mmol). Ammonia gas was bubbled into the reaction 3o mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2C12) gave the desired product( 1.5 g, 75 %).
b)Preparation of 3-nitro-2-hydroxycinnamide -87_ 2-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (430 mg, S.lmmol).
The addition of sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with meLhylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(350 mg, 36 %}. 1H NMR (CD3COCD3): d 8.19 (d, 1H), 8.02 (d, 1H}, 7.88 (d, 1 H), 7.15 (t, 1 H), 6.84 (d, 1 H}
to c)Preparation of 3-amino-2-hydroxycinnamide A mixture of 3-vitro-2-hydroxymethylcinnamate (350 mg, 1.7 mmol) and tin (II) chloride (3.0 g, 13.4 mmol) in ethanol(SOmL) was heated at 80° C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, is before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(244 mg, 80%).
d)Preparation of (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydmxyphenyl]-N'-[2-bromophenyl] urea 20 (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]
urea was prepared from 3-amino-2-hydroxycinnamide ( 100 mg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from -methylene chloride! hexane( 1/20) and filtering. ( 110 mg, 52%).1 H NMR
(CD30D): d 8.00 (d,lH), 7.90 (d, 1H), 7.63 {d, 1H), 7.55 (d, 1H), 7.35 (m, 2H), 7.05 (t, IH), 6.95 25 {t, 1H), 6.70 (d,lH) .
Example 102 Preparation of lE)-N-f4-f2-lAminocarbonvil etheny~]-2-hydrox3rphenv_l]-N'-(~-~romqrhenyll urea N'-f2-bmmophenyll urea 30 a)Preparation of 3-hydroxycinnamide 3-Hydroxycinnamic acid (2.00 g, I2.3 mmol) was dissolved in dimethyl formamide( 10 mL) followed by the addition of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and triethylamine ( 1.7 mL, 12.3mmo1). Ammonia gas was bubbled into the reaction 35 mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic _88_ layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product( 1.3 g, 65 %).
b)Preparation of 4-vitro-3-hydroxycinnamide 3-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (430 mg, S.lmrnol).
The addition of sulfuric acid (7 mI,/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(240 mg, 25 %). 1H NMR (CD3COCD3): d 8.09 (d, 1H), 7.49 (d, 1H), 7.26 (s, 1 H), 7.16 (d, 1 H), 6.71 (d, 1H) c)Preparation of 4-amino-2-hydroxycinnamide A mixture of 4-vitro-3-hydroxymethylcinnamate (300 mg, 1.40 mmol) and tin {II) chloride (980 mg, 4.30 mmol) in ethanol(50 mL) was heated at 80 C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was ?0 washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product (200 mg, 74 %).
d)Preparation(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromopheiiyl] urea (E)-N-[3-(2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenylj urea was prepared from 4-amino-2-hydroxycinnamide ( 100mg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. {125mg, 54%).1H NMR (CD30D):
d 8.05 (d,lH), 7.92 (d, 1H), 7.60 (d, 1H), 7.4 5 (d, 1H), 7.35 (t, 1H), 7.05 (m, 2H), 6.50 (d,lH) .
Example 103 Preparation of N-f2-hydroxx4-(phenyl amino carbox~phenyll-N'-f2-bromophenvll urea N-[2-hydroxy 4-(phenyl amino carboxy) phenyl]-N'-[2-bromophenylj urea was prepared from 5-(phenyl amino carboxy) 2-amino phenol (0.50 mmol) according to the _ 89 -procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 150 mg, 70%). 1 H NMR
(CD30D): d 8.25 (d, 1H), 8.00 (d, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.50 (d, 2H), 7.41 (m, 3H), 7.16 (t, 1H), 7.05 (t, 1H).
Example 104 Preparation of N-f4-aminocarbonyl-2-hydroxvphenyll-N'-f2-bromophenvll urea N-[4-Aminocarbonyl -2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 5-aminocarbonyl-2-amino phenol (304 mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (440 mg, 62%). 1H NMR (CD30D): d 8.09 (d, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.45 (m, 3H). 7.00 (d, 1H).
Example 105 Preparation of N-[2-HYdroxy-3.5.6-trifluorophenyl)-N'-(2-bromophen 1)urea N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea was prepared from 3,5,6-trifluoro-2-hydroxyaniline (83 mg, 0.51 mmol) and 2-(bromophenyl)isocyanate ( mg, 0.53 mmol) according to the procedure in General Method B. The product was purified by preparation thin layer chromatography. EI-MS mlz 359 (M-H) .
Example 106 Preparation of N-(2-Hydroxy-3-fluoro-4-trifluoromethylnhenyll-N'-l2-bromophenxl_lurea N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea was prepared from 4-trifluoromethyI-3-fluoro-2-hydroxyaniline (239 mg, 1.2 mmol) and 2-(bromophenyl)isocyanate (243 mg, 1.2 mmol) according to the procedure in Genera!
Method B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate) gave the title compound (20 mg, 4%).
EI-MS m/z 391 (M-H) .
Example 107 Preparation of N-(2-Hydroxy-3-iodophenyl)-N'-f2-bromophenyl)urea N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-iodo-2-hydroxyaniline (200 mg, 0.85 mmol) and 2-(bromophenyl)isocyanate ( 169 mg, 0.85 mmol) according to the procedure in General Method B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ether) gave the title compound E40 mg, 11%). 1H NMR (DMSO): d 9.45 (s, 1H), 9.15 (s, IH), 8.8 (s, IH}, 7.9~ (d, 1H), 7.8 (d, 1H),7.65 (d, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 7.0 (t, 1H), 6.65(t, 1H).
Example 108 Preparation of N-f2-fff2-ltrifluorometh r~l phenvllsulfonyllaminolphen, 1~~-bromophen I)y urea a)Preparation of [2-[2-(tritluoromethyl)phenyl](sulfonamido)aniline]
The title compound was prepared according to General Method C using 2-(trifluoromethyl)benzenesulfonyl chloride (1 equiv.). The product was purified by chromatography on silica gel (methylene chloride:methanol) ( 1.04 g, 33%). EI-MS m/z 317 (M+H)+.
b)Preparation of N-[2-[[[2-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea The title compound was prepared using[2-[2(trifluoromethyl)phenyl]
(sulfonamido)aniline ( 1.04 g, 3.2 mmol) and 2-(bromophenyl)isocyanate (652 mg, 3.2 mmol) according to General Method B. The solvent was evaporated to give the desired urea ( 1.03 g, 61 %). EI-MS m/z 514 (M+H)+.
2o Example 109 Preparation of N-l2-Bromophenyl)-N'-f2-dimethylaminosulfonvlamino~~envllurea a) Preparation of [2-[1,1-(dimethylamino)]sulfonamidoaniline]
The title compound was prepared according to General Method C using dimethylsulfamoyi chloride ( 1 equiv.). The product was purified by chromatography on silica gel (methylene chloride:methanol). ES-MS m/z 216 (M+H)+
b)Preparation of N-(2-Bromophenyl)-N'-[2-(dimethylaminosulfonylamino]phenyl]urea The title compound was prepared from [2-[ 1,1-(dimethlyamino)sulfonamido-aniline ( 137 mg, 0.6 mmol) and 2-(bromophenyl)isocyanate ( 126 mg, 0.6 mmol) according to General Method B. The solvent was evaporated and chromatography on silica gel (ethyl acetate:hexane) gave the desired urea. EI-MS m/z 413 (M+H)+
Example 110 Preparation of N-[2-fPhenethylsulfonvlaminol phenyl-N'-f2-bromophe~ llurea [2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a Parr shaker bottle containing palladium (180 mg) under an argon stream.
Methanol ( 150 mL) was added and the container placed on a Parr shaker (55 psi) for several hours. The reaction mixture was filtered through Celite and the filtrate was evaporated to give the desired aniline (269 mg, 90%). EI-MS m/z 277 (M+H)+.
b)Preparation of N-[2-(Phenethylsulfonylamino)phenyl]-N'-{2-bromophenyl)urea The title compound was prepared from [2-(phenethyIsulfonamido) aniline] (269 mg, 0.97 mmol) and 2-(bromophenyl)isocyanate ( 193 mg, 0.97 mmol) according to General Method B. The desired urea was precipitated out of toluene/hexane (384 mg, 78%). EI-MS m/z 472 (M-H) .
Exam 1~~
to Preparation of N-f2-jj2-acetamido-4-methylthiazol-5-vl sulfonvlaminolphenyll-N'-f2-~romqphenyl)urea a)Preparation of [2-[(2-acetamido-4-methyl-5-thiazole)sulfonamido]aniline]
The title compound was prepared using 2-acetamido-4-methyl-5-thiazolesuifonyl chloride (1 equiv.) according to General Method C. A solid i5 precipatated from the reaction mixture and was filtered to give the desired aniline (1.68 g, 52%). ES-MS m/z 327 (M+H)+..
b)Preparation of N-[2-[(2-acetamido-4-methylthiazol-5-yl)sulfonylamino)phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-[(2-acetamido-4-methyl-5-2o thiazole)sulfonamido]aniiine] ( 1.68 g,5.14 mmol) and 2-(bromophenyl)isocyanate ( 1.02 g, 5.14 mmol) according to General Method B. The product was precipitated from ethyl acetate/hexane (220 mg, 8%). EI-MS m/z 524 (M+H)+.
Jrxam~ 1e 112 25 Preparation of N-j2-hydrox~~a_nophenvll-N'-f4- h~enyl~h_enyll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (135 mg, 75%). 1H NMR (CD30D): d 8.33 (d, 1H), 7.71-7.29 (m, 9H), 7.25 30 (d, 1H), 7.12 (s, 1H).
Example 113 PreR,aration of,lT j2-~,vdroxv" ~-cyanophenyll-N'-f2.3-dichloroohenvll urea N-{2-Hydroxy-4-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from 35 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/

hexane(1/20) and filtering. (125mg, 86%). 1H NMR (CD30D): d 8.27 (d, 1H), 8.15 (m, 1H), 7.39-7.20 (m, 2H), 7.16 (d, 1H), 7.06 (s, 1H).
Example 114 Preparation of N-f2-hydroxv-4-cvanonhenvll-N'-f2-methoxvohenvll urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering (105mg, 83%). 1H NMR (CD30D): d 8.26 (d, 1H), 8.02 (d, to 1H), 7.14 (d, 1H), 7.05 (s, 1H), 7.00-6.83 (m, 3H}, 3,84 (s, 3H).
Example 115 Preparation of N-f2-hvdroxv-4-c~phenyll-N'-[3-methoxxnhenYlj urea N-[2-Hydroxy-4.-cyanophenyl]-N'-[3-methoxyphenyl] urea was prepared from 2-amino-5-t5 cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1120) and filtering. ( 102mg, 80%). 1 H NMR (CD30D}: d 8.25 (d, 1H), 7.25-7.08 (m, 3H), 7.04 (s, 1H), 6.90 (t, 1H), 6.58 (d, 1H).
20 Exam 116 Preparation of N-f2-hydroxy-5-fluorophenyll-N'-f2-bromophenvl]' urea a)Preparation of 2-amino-4-fluorophenol A mixture of 4-fluoro-2-nitrophenol( 1 g, 4.b4mmol) and tin (II) chloride (5.4 g, 24.2mmol) in ethanol(SOmL) was heated at 80°C under argon. After 2 hours, the z5 starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(622 mg, 85 30 %). 1H NMR (CD30D): d 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).
b)Preparation of N-[2-hydroxy-5-tluorophenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-fluoro phenol (254mg, 2.00 mrnol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
35 hexane(1/20) and filtering. (520mg,80%). 1H NMR (CD30D): d 7.88 (d, 1H), 7.79 (dd, 1H), 7.57 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.76 (dd, 1H), 6.57 (ddd,lH).

Example 117 Preparation of N-f2-hvdroxv-5-trifluoromethvln...~-hen lY,l-N'-[2-bromophenvll urea a)Preparation of 2-amino-4- trifluoromethylphenol A mixture of 4-trifluoromethyl-2-nitrophenol{ 1.0 g, 4.8mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol( 150mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(708 mg, 83 %). 1H NMR (CD30D): d 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1 H).
b)Preparation of N-[2-hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea t5 N-[2-hydroxy-5-irifluoromethylphenyl]-N'-[2-bromophenyl) urea was prepared from 2-amino-4-trifluoromethylphenol (354mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (490mg, 65%). 1H NMR (CD30D): d 8.40 (s, 1H), 7.94 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.18 {d, 1H), 7.03 (t, 1H), 6.95 (d, 1H).
Example 118 Preparation of N-f2-hydroxyn, hen~rl]-N'-f2-bromophenyll urea N-[2-hydroxyphenyl]-N'-[2-bromo phenyl] urea was prepared from 2- amino-phenol ( 141mg, 1.30 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1120) and filtering. (300mg,75%). 1H NMR (CD30D): d 8.05 (d, 1H), 7.49 (d, 1H), 7.25 (t, 2H), 6.96 (t, 1H), 6.90 (t, 2H), 6.68 (t, 1H).
Examples 19 Prepara ~n of N-ftrans-3-s;yrl 2-h~drox~ph~ll-N'-f -bromonhenvll ureaa)Preparation of traps-6-styrl-2~-nitrophenol Traps-2-styrlphenol (500 mg, 2.55 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (240 mg, 2.81mmo1).
The addition of sulfuric acid (3 mL of 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.
The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product (200 mg, 36 %). 1H NMR (CD3COCD3): d 8.05 (d, 1H), 7.90 (d, 2H),7.65-7.20 (m,7H),7.00 (t,lH).
b)Preparation of traps-6-styrl-2-aminophenol A mixture of traps-6-styrl-2-nitrophenol (200 mg, 0.83 mmol) and tin (II) chloride (560 mg, 2.60 mmol) in ethanol(50mL) was heated at 80° C under argon.
After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of 14 solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica geI (4%MeOH/ CH2C12) gave the desired product (50 mg, 29 %a). 1H NMR (CD30D): d 7.51 (m, 3H), 7.29 (m, 3H),7.11 (t, 1 H), 7.00 (m, 2~-i), 6.69 (m, 2H).
i5 c)Preparation of N-[traps-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N-[traps-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from traps-6-styrl-2-aminophenol (35mg, 0.17 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1/20) and filtering. (36mg, 53%). 1H NMR (CD3OD): d7.97 (d, 1H), 7.62-20 7.48 (m, 4H), 7.45-7.26 (m, 5H), 7.25 (t, 1H), 7.15 (d, 1H), ?.O1 (t, 1H), 6.88 (t 2H).
Example 120 Preparation of N-f2-hydroxv-3.4-dichlorophen-yll-N'-f2-methoxy~henyl] urea N-[2-hydroxy-3,4-dichiorophenyl]-N'-[2-methoxyphenyl] urea was prepared 25 from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 125mg,77%). 1 H NMR
{CD30D): d 8.02 (d, 1 H), 7.79 (d, 1 H), 7.05-6.86 (m, 4H), 3.92 (s, 3H).
30 Exam 1p a 12l Preparation of N-f2-hvdroxY-3.4-dichloronhenvll-N'-f4-methoxv~henvll urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from 35 methylene chloride/ hexane(lequiv./20equiv.) and filtering. (120mg, 74%).

(CD30D): d 7.89 (d, 1H), 7.35 (d, 2H), 6.99 (d, 1H), 6.90 (dd, 2H), 3.80 (s, 3H).

WO 97/29743 PCTIUS96/i3632 Example 122 Preparation of N-L2-h, d,~r roxy-3.4-dichlorophenvll-N'-j3-trifluoromethvlphenyll urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5,6-dichiorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methyiene chloride/ hexane(lequiv./20equiv.) and filtering. (130mg, 71%). 1H
NMR
(CD30D): d 7.96 (d, 2H), 7.60 (d, 1H), 7.48 (t, 1H), 7.30 (d, IH), 7.00 (d, 1H).
~ca~~le 1~3 Prenaration~N-f2-hvdroxv-3.4-dishloronhenvll-N'-f2-nhenylnhenvll urea N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmoi, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv.J20equiv.) and filtering. (1 IOmg, 59%). 1H
NMR
(CD30D): d 7.77 (d, 1H), 7.73 (d, 1H), 7.53-7.14 (m, 8H), 6.95 (d, 1H).
ExamRle 124 Preparation of N-~,2-hydr~c X 3 4-dichlorophe~rl]-N'-~2 3-dichloro~he~ 1~1 urea N-[2-Hydroxy-3,4-dichlorophenyi]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride! hexane(lequiv./20equiv.) and filtering. (130mg, 71%). 1H
NMR
(CD30D): d 8.06 (dd, IH), 7.91 (d, 1H), 7.25 (m, 2H), 7.00 (d, 1H).
Example 125 Preparation Qf N-12-hvdroxv-4-isonronvhhenvll-N'-C3-trifluoromethvlnhen !y 1 urea a)Preparation of 2-nitro-5-isopropylphenol 3-isopropylphenoi (3.00g, 22 mmol) was dissolved in methylene chloride(40m1) 3o followed by the addition of sodium nitrate (2.06g, 24mmol). The addition of sulfuric acid (25mL 3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride and extracted with v~ater. The organic layer is dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOHI CH2Cl2) gave the desired product(1.09g, 27 %). 1H NMR
(CD3COCD3): d 7.95 (d,IH), 7.62 (d,lH), 7.11 (d, IH), 2.95 (m, 1H), I.24 (d, 6H).

b) Preparation of 2-amino-5-isopropylphenol To a solution of 2-vitro-5-isopropyiphenol(lg, 6.4 mmol) in methanol(50 mL) was added 10% Pd/C ( 100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through ceiite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (S%MeOH/ CH2Cl2) gave the desired product(775 mg, 93 %). 1H NMR (CD30D): d 6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d, 6H).
c) Preparation of N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyi]
urea N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol (75mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (140mg, 83%). 1H
NMR
(CD30D): d 7.91 (d, 2H), 7.62 (d, 1H), 7.47 (t, 1H), 7.39 (d, IH), 6.75 (s, 1H), 6.72 (d, IH), 2.80 (m, 1H), 1.21 (d, 6H).
Example 126 Preparation of N-f2-hvdroxv-3-nanhthvll-N'-f2.3-dichloronhenvll urea N-[2-hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea was prepared from 3 2o amino 2-naphthol ( 160mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (285mg, 82%). 1H NMR (CD30D): d 8.48 (s, 1H), 8.10 (d, IH), 7.68 (d, 1H), 7.57 (d, 1H), 7.40-7.23 (m, 4H), 7.18 (d, 1H).
Example 127 Preparation of N-f2-fj2.3-Dichlorothien-5-y111su1fonYlaminoiphenvll-N'-(2-bromophet~vllurea 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 (M-H)-b)Preparation of N-[2-[(2,3-Dichlorothien-5-yl))sulfonyiamino]phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-[(2,3-dichlorothien-5-yl))sulfonylaminoaniline (1.25 g,3.9 mmol) and 2-(bromophenyl)isocyanate (768 mg, 3.9 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (272 mg, 13 %) EI
~~IS m/z 520 (M-H) g Example 128 Preparation of N-f2-[(3.5-Bistrifluoromethylphenyllsulfgnylamino phenyjl-N'-(2-bromophenyllurea a)Preparation of [2-(3,5-Bistrifluoromethylphenyl)sulfonylaminoaniline]
The title compound was prepared according to General Method 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 chIoride:meihanol 95/5) (61 I mg, 39 %). EI-MS m/z 383 {M-H)-b)Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 mmol) according to General Method B. The product was purified by flash chroma-tography on silica gel (ethyl acetate:hexane 30/70) ( 10 mg, I %).EI-MS m/z 580 (M-H)-2o Exam 1p a 129 Preparation of N-f2-f(2-Benzvllsulfonylami~ol 15-trifluorometh rill h~en~rll-N'-(2-bromophenyllurea a)Preparation of [(4-Benzylsulfonylamino)-{3 -nitro)-benzotrifluoride]
4-Amino-3-nitro-benzotrifluoride ( I.0 g, 4.85 mmol) was mined in DMF and the reaction mixture was cooled to 0°C. Sodium hydride ( 175 mg, 7.28 mmol) was added to the cold mixture and allowed to mix for ten minutes ( a deep red color was noted). Toluenesulfonyl chloride (925 mg, 4.85 mmol) was added ( reaction color changed to yellow) and the reaction was mixed for sixteen hours at room temperature.
The reaction was quenched in NH4C1 and extracted with ethyl acetate:hexane {
1:I).
3o The groduct was purified by flash chromatography on silica gel ( ethyl acetate:hexane 30170) (878 mg, 52 %) EI-MS m/z 359 (M-Hj .
b)Preparation of [(4-Benzylsuifonylamino)-(3-amino)-benzotrifluoride]
[(4-Benzylsuifonylamino)-(3-nitro)-benzotrifluoride (230 mg, 0.64 mmol) was mixed in methanol and poured into a Parr bottle. Palladium on carbon ( 15 mg) was 3s added under an argon stream. The reaction mixture was placed on a Parr shaker ( 55 - 98 _ psi, H2) for several hours. The reaction mixture was filtered through Celite to give the title compound. (210 mg, 99%) EI-MS m/z 329 (M-H) .
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-bromophenylisocyanate ( 126 mg, 0.64 mmol) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel {ethyl acetate:hexane 30/70) {70 mg, 21%) EI-MS
mlz 526 (M-H)-to Example 130 Preparation of N-f2-f2-l3-Nitrophenyl)sulfonvlaminolphen,~rll-N'-(2-bromonhenvl)urea a)Preparation of [2-((3-Nitrophenyl)sulfonylamino)aniline]
The title compound .was prepared according to General Method C using 3-t5 nitrobenzenesulfonyl chloride (1 eq). The product was purified by flash chromatogrphy on silica gel (methylene chloride:methanol 96/4).( 1.07 g, 37 %) EI-MS m/z 294 (M+H)~
b)Preparation of N-[2-[(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoaniline]
(590 mg, 2.0 mmol) and 2-(bromophenyl)isocyanate (398 mg, 2.0 mmol) according to 20 the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (400 mg, 40%). EI-MS m/z 489 (M-Hj Example 131 Preparation of N-f2-f2-(4-Phenoxy~hen_yllsulfonvlaminolphen~rll-N'-l2-bromg~heny1) 25 urea a)Preparation of [2-((4-Phenoxyphenyl)sulfonylamino)aniline]
The title compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and 30 toluene:methylene chloride ( 1:3). 'The organic phase collected and the methyleae chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg, 34 %) EI-MS m/z 341 (M+H)+
b)Preparation of N-[2-[(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea 35 The title compound was prepared from [2-(4-phenoxyphenyl)suifonyl aminoaniline (276 mg, 0.8 mmol) and 2-(bromophenyl)isocyanate ( 161 mg; 0.8 mmol) WO 97!29743 PCT/US96/13632 according to the procedured in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (240 mg, 55 %) EI-MS
m/z 536 (M-H) g Exam lie 132 Preparation of N-([2-llSl-10-Cam orsulfon laminojphenyll-N'-(2-bromophen3rllurea a)Preparation of 2-((1S)-10-Camphorsulfonylamino)aniline The title compound was prepared according to General Method C using ( 1 S)(+) t0 10-Camphorsulfonyl chloride ( 1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6 mmoI). The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride ( 1:3). The organic phase was separated and the methylene chloride evaporated leaving the toluene. Hexane was added and solid precipitated from solution. ( I 30 mg; 9%) EI-MS m/z 323 (M+H)+
i5 b)Preparation of N-[[2-(1S)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea The title compound was prepared from [2-( 1 S)-10-camphorsulfonylamino]aniline ( 130 mg, 0.4 mmol) and 2-(bromophenyl)isocyanate (80 mg, 0.4 mmol) according to the procedure in General Method B. The solvent was 20 evaporated and product was precipitated from methylene chloride:hexane.
(200 mg, 95 %). EI-MS m/z SI8 (M-H)-Example 133 Preparation of N-112-f 1R)-10-Car~phorsulfonylamino henY1_LN'-(2-b~omophenyl)urea a)Preparation of 2-((1R)-10-Camphorsulfonylamino)aniline The title compound was prepared according to General Method C using (1R)(-)-10-camphorsulfony! 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 3o toluene:methylene chloride( 1:3). The organic phase was separated and the methylene chloride evaporated leaving the toluene. Hexane was added and the product precipitated from solution. (563 mg, 38%). EI-MS m1z 323 (M+H)+
b)Preparation of N-[[2-(1R)-10-Camphorsulfonylamino]phenyl)-N'-(2-bromophenyl)urea The title compound was prepared from [I-{IR)-IO-camphorsulfonylaminoaniline] (563 mg, 1.75 mmol) and 2-(bromophenyl)isocyanate (346 mg, 1.75 mmo!) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30170) (263 mg, 29 %) EI-MS m/z 518 (M-H)-Example 134 Preparation of N j2-L2-(2-Nitro-(4-trifluoromethylyhenvllsulfon3rlaminolphenxl-N'-~2-bromophenxl)urea a)Preparation of [2-[(2-Nitro)-(4-trifluoromethyl)phenyl]sulfonylamino]aniline The title compound was prepared according to General Method C using 2-nitro-to 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)+
b)_Preparation of N-[2-[2-{2-Nitro-(4-trifluoromethyl)phenyl)sulfonylaminoJphenyl-N'-(2-bromophenyl)urea t5 The title compound was prepared from [2-[(2-nitro)-(4-trifluoromethyl) phenylJsulfonylamino]aniline (740 mg, 2.1 mmol) and 2-(bromophenyl)isocyanate (406 mg, 2.1 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70). The product was further purified by recrystallization in ethyl acetate:hexane. (320 mg, 28 %) EI-MS
m/z 557 20 (M-H) Exam ip a 135 Preparation of N-l2-hydroxy-4-azidophenyl)-N'-f2-iodophenyllurea 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, 25 0.55 mmol) in ethanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added.
The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl acetate (3x). The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure to give product ( 180 mg, 89%). EI-MS mlz 3a (M+H)+
b)Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyi)urea The N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea(77 mg, 0.21 mmol) was added to HC1/H20 (0.21 mi./0.42 mL), and cooled to 0°C. Sodium nitrate ( 14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 35 0°C for 30 minutes. Sodium azide ( 14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room WO 97/29')43 PCT/US96113632 temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5:1 ) gave product (20 mg, 24%). EI-MS m/z 396 (M+H)+.
s Example 136 Preparation of N-(2-hydroxy-3-azidophenYl-7-N'-l2-bromo henyl)urea a) Preparation of N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea To a solution of N-(2-hydroxy-3-nitrophenyl)-N'-(2-bromophenyl)urea (300 mg, 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl acetate (3x). The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z (M+H)+.
b) Preparation of N(2-hydroxy-3-azidoghenyl)-N'-(2-bramophenyl)urea The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85 mmol) was added to HCl/H20 (0.85 mIJl.7 mL), cooled to 0°C. Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours then it was extracted with three times with ethyl acetate. The organic extracts were combined, dried over MgS04, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate: 5:1) gave product (210 mg, 71°!0). EI-MS m/z 349 (M+H)+.
Exam l~ a 137 Preparation of N-f2-hvd~ox~3-c~ano~henvll-N'-f2-methoxytlhenvll urea N-[2-hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-3o amino-6-cyanophenol ( 134mg, 1.00 rrimol) according to the procedure in General Method B. The product was purified by precipitation from tnethylene chloride) hexane(lequiv./20equiv.) and filtering. (230 mg, 81%). 1H NMR (CD30D): d 8.06 (d, 1H), 7.79 {d, 1H), 7.49-7.35 (m, 2H), 7.05-6,87 (m, 3H), 3.95 (s, 3H).

Example 138 Preparation of N-f2-h~rdroxy-3-cyanophenyl]-N'~(3-trifluoromethyl~henyIl urea N-[2-hydraxy-3-cyanophenyl)-N'-[3-trifluoromethylphenyl) urea was prepared from 2-amino-6-cyanophenol ( 134mg, 1.00 mmoi, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv,) and filtering. (280mg, 87%). 1H
NMR
(CD30D): d 8.10 (d, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.55-7.25 (m, 3H), 7.01 (t, 1H).
Exam L
Preparation of N-f2-hvdroxv-3-cvanonhenylLN'-f2-nhenvLDhenyll a N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-6-cyanophenol ( 134mg, 1.00 mmol, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (270mg, 82%). 1H NMR (CD30D): d 7.81 (d, ~5 1H), 7.75 (d, 1H), 7.56-7.15 (m, 9H), 6.91 (t, 1H).
Example 140 P~paration of N-12-hydroxx-3-cXanophenylLN~2,3-dichlorophen~rll urea N-[2-hydroxy-3-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from 2-amino-cyanophenol ( 134mg, 1.00 mmol, example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride!
hexane( lequiv./20equiv.) and filtering. (300mg, 93%). 1H NMR (CD30D): d 8.11 (d, 1H), 8.01 (d, 1H), 7.33-7.25 (m, 3H), 7.00 (t, 1H).
Example 141 Preaaraeion of N-f2-h~rdroxv-4-isonronvlnhenvll-N'-I2.3-dichloronhenvll urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl) urea was prepared from amino-5-isopropyIphenol ( 150 mg, 1.00 mmol, example 128x) according to the .
procedure in General Method B. The product was purified by precipitation from 3o methylene chloridel hexane(lequiv.l20equiv.) and filtering (285mg, 84%). 1H
NMR
(CD30D): d 8.05 (d, 2H), ?.77 (s, 1H), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m, 1H), 1.25 (d, 6H).

Example 142 Pre aration of N- 2-h dro v-4-i o r 1 hen 1 -N'- 2-chior - -t 'flu ro eth I
hen 1 urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol ( 150mg, I .00 mmol, example 128x) according to the procedure in General Method B. The .product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering.
(275mg, 82%). 1H NMR (CD30D): d 8.50 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.22 (d, 1H), 6.70 (m, 2H), 6.62 (dd, IH), 2.76 (m, (1H), 1.16 (d, 6H).
E,~ample 143 Preparation of N-f2-hydroxv-3-phenylphenyll-N'-f2.3-dichlorophenyl_] urea a)Preparation of 2-nitro-6-phenylphenol 2-phenylphenol (3.00g, 17.6mmo1) was dissolved in methylene chloride(40m1) followed by the addition of sodium nitrate ( 1.65g, 19.4mmol). The addition of sulfuric acid (25m1/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgS04 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C12) gave the desired product(900 mg, 24 %). I
H
NMR (CD3COCD3): d 8.19 (d,lH), 7.79 (d,lH), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t, 1H).
b)Preparation of 2-amino-6-phenyiphenol To.a solution of 2-nitro-6-phenylphenol(900 mg, 4.2mmo1) in methanol(SOmI) was added 10% Pd/C ( 100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for IO min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the ceiite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica get (5%MeOH/ CH2Cl2) gave the desired product(700 mg, 90 %). 1H NMR (CD30D): d 7.55-7.27 (m, SH), 6.77-6.6I (m, 3H) c)Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea N-[2-hydroxy-3-phenylphenyl]-N'-j2,3-dichlorophenyl] urea was prepared from 2- amino-6-phenylphenol (92.Smg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (150mg,81%). IH NMR (CD30D): d 8.06 (d, 1H),7.65 (d, 1H), 7.54 (d, 2H),7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88 Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea b)N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from amino-6-phenylphenol (92.Smg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (150 mg, 81%). 1H NMR (CD30D): d 8.06 (d, IH),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).
Example 144 Preparation of N-12-h~drox_v-5-nitrophenyll-N'-[2-methoxyphenXll urea N-[2-hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-amino-4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( lequiv./20equiv.) and filtering. (270 mg, 89%). 1H NMR (CD30D): d 9.10 (s, 1H), 8.10 (d, 1 H), 7.85 '(d, 1 H), 7.08-b"88 (m, 4H), 3.96 (s, 3H).
Example 145 Preparation of N I2-hvdroxy-S-nitronhenvll-N'-f3-trifluoromethvlnhenvll urea N-[2-hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-4-nitrophenol { 154 rng, 1.00 mmol) according to the procedure in 2o General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv.l20equiv.) and filtering. (290 mg, 85%). 1H NMR (CD30D): d 9.12 (s, IH), 7.89 (d, IH), 7.68 (d, 1H), 7.55 (m, 2H), 7.45 (d, 1H), 7.00 (d, 1H}.
Example 146 Preparation of N-E2-hxdrox, -5-nitro~henyll-N'-I[2-phenyjnhenvll urea N-[2-hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloridel hexane(lequiv./20equiv.) and filtering. (285 mg, 81%). 1H NMR (CD30D): d 8.09 (s, 3o IH}, 7.86 (d, iH), 7.58-7.20 (m, 9H), 6.95 (d, 1H).
Example 147 Preparation of N-L2-hydroxv-5-nitrophenvll-N'-12.3-dichlorophenyll urea N-[2-hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/

hexane{ lequiv./20equiv,) and filtering. (290 mg, 85%). 1H NMR (CD30D): d 9.11 (s, 1H), 8.17 (d, 1H), 7.89 (d, 1H), 7.34 (m, 2H), 6.95 (d, 1H).
Example 148 Pr~aration of N-=j2-h dv roxy-5-ethxlsulfonvIphenyll-N'-f2.3-dichlorophenyl], urea N-[2-hydroxy-5-ethylsulfonylphenyl)-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-{ethylsulfonyl)phenol ( 185 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( lequivJ20equiv.) and filtering. (310 mg, 84%). 1H
NMR
t0 (CD30D): b 8.65 (s, IH), 8.18 (d, IH), 7.45 (d, 1H), 7.26 (m, 2H), 7.00 (d, 1H), 3.33 (q, 2H), 1.24 (t, 3H).
The following compounds of Formula (1) have been prepared in accordance with the examples and schemes as described above:
Example 149 : N-[2-(2-Amino-{4-trifluoromethyl) phenyl) sulfonylamino] phenyl]-N'-(2-bromophenyl)ureaEI-MS m/z 527 (M-H)-.
Example 150 : N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) ureaEI-MS m/z 426 (M+H)+;
Example 15I : N-[2-[2-(4-Chloro-3-aminophenyl)sulfonylamino]phenyl)-N'-(2-2o bromophenyl)urea Example 152 : N-[2-(3-Aminoghenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea Example 153 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyi)urea EI-MS m/z 302.3 (M-H)-.
Example 154 : N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea urea EI-MS
m/z 302.3 (M-H)-.
Example 155 : N-(2-Hydroxy-3-nitrophenyl)-N'-(3-trifluoromethyphenyl)urea urea EI-MS
mlz 340.3 (M-H)-Example 156 : N-(2-Hydroxy-3-nitrophenyi)-N'-(2-phenylphenyl)urea 1H NMR
(DMSO), 8.83(lH,s) 8.63(lH,s), 8.41 (lH,d) 7.79 (lH,d), 7.56 (lH,d) 7.51-7.32 (6H,m) 7.23 (lH,ds) 7.18 ( lH,d) 6.97 ( lH,t) Example 157 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2,3dichlorophenyl) EI-MS m/z 340.3 (M-H)-Example 158 : N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl) EI-MS mlz 348,3 (M-H)-Example 159 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2,4-d.imethoxyphenyl)urea EI-MS
mlz 333.4. (M+H)+;
_ 106 Example 160 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-5-trifluoromethyiphenyl}urea EI-MS m/z 374.2 (M-H)-Example 161 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea EI-MS mlz 421.3 (M-H)-Example 162 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenylphenyl)urea EI-MS mJz 467.3 (M-H)-Example 163 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(3-trifluoromethyiphenyl)urea EI-MS m1z 459.3 (M-H)-Example 164 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea t o EI-MS m/z 461. I (M+H)+;
Exampie 165 : N-(2-Hydroxy-4-amidinophenyl)-N'-(2-bromophenyl)urea 1H NMR
(CD30D): b 8.10( 1 H,8) 7.92( 1 H,8) 7.58 ( i H,b) 7.40-7.25 (3H,m) 7.02 ( 1 H, t); EI-MS mlz 348.0 (M-H)-Example 166 : N-(2-Hydroxy-3,4-dichioro phenyl) N'( phenyl) urea EI-MS m/z 297.0 (M+H)+
Example 167 : N-(2-Hydroxy 4-cyano phenyl) N'( phenyl) urea EI-MS m!z 284.0 (M+H)+
Example 168 : N-(2-Hydroxyphenyl 3-carboxylic acid)N'( phenyl) urea EI-MS m/z 273.0 (M+H)+
Example 169 : N-(2-Hydroxy-3-nitrophenyi)-N'-phenylurea EI-MS m/z 274.0 (M+H)+
z0 Example 170 : N-(2-hydroxy-3-cyano phenyl ) N'(phenyl) urea EI-MS m/z 254.0 (M+H)+
Example 171 : N-{2-Hydroxy-3-cyano-4-chlorophenyl)-N'-{2-bromophenyl)urea EI-MS
m/z 264.2 (M-H)-Example 172 : N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea EI-MS m/z 247.0 (M+H)+
Example 173 : N-(2-Hydroxy-3,4-difluorophenyl)-N'-(phenyl)urea EI-MS m/z 265.0 (M+H)+
Example 174 : N-[2-(Benzylsulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea EI-MS m/z 473.0 (M-H)-Example 175 : N-[2-(Phenylsulfonylamino)-4-trifluoromethylphenyl]-N'-(2,3-dichlorophenyl)urea EI-MS rnlz 502.0 (M-H)-3o Example 176 : N-[2-(3-Pyridinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea 1H NMR (CD30D): 8 8.76(lH,s) 8.70(iH,d), 8.19 (lH,d) 8.00 ( 1 H, dd) 7.92 ( 1 H,dd) 7.54 ( 1 H. dd) 7.54 ( 1 H, dd) 7.45 ( 1 H,dd) 7.19 ( 1 H,d) 7.17 ( 1 H, s) 6.86 (lH,d) Example 178 : N-[2-(5-Isoquinolinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea 1H NMR (CD30D): 8 9.37 (lH,s) 8.51-8.39 (3H,m} 8.29 (lH,d) 8.00 (lH,dd) 7.93 (lH,d) 7.67 (1H, t) 7..50 (lH,dd) 7.25 (lH,d) 7.24 (lH,s) 6.91 (lH,d) Example I79 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-chlorophenyl)urea EI-MS mlz 427.0 (M+H)+
Example 180 : N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea EI-MS
m/z 411.0 (M+H)+
Example l 81 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyl)urea EI-MS m/z 439.0 (M+H)+
Example 182 : N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-trifluoromethoxyphenyl)urea EI-MS m/z 477.0 (M+H)+
Example 183 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl)-N'-(2-trifluoromethylphenyl)urea EI-MS m/z 461.0 (M+H)+
Example 184 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea EI-MS m/z 407.0 (M+H)+
Example 185 : N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro phenyl) urea EI-MS m/z 457.0 (M+H)+
Example 186 : N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea EI-MS ~a~/z 409.0 (M-H)-Example 187 : N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlomphenyl)urea m.p. : 138.5 - 139.2 Example 188 : N-[(2-Pyrid-2-yl)thiophene-5-sulfonylamino-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea ; m.p. : 147.5 - 148.3 2o Example 189 : N-[(2-Acetamino-4-methyl-5-thiazolesulfonylamino-4-cyanophenyl]-N°-(2,3-dichlorophenyl)urea EI-MS m/z 540.4 (M+H)+
Example 190 : N-{(2-aminosulfonyiphenyl) 4-cyano phenyl) N'-(2-methyl-3-chloro phenyl) urea EI-MS nn/z 439.0 (M-H)-Example 191 : N-(2-benzenesulfonylamino-3-cyanophenyl)-N'-(2,3-dichlorophenyi}urea 1H NMR (DMSO): S 10.00 (IH,s) 9.05 (lH,s) 8.93 (lH,s) 8.19 (lH,dd) 8.00 (lH,dd) 7~.72-7.42 (7H,m) 7.35 ( lH,d) 7.32 ( lH,s) Example I92 : N-[(Benzylsulfonyiamino)-5-cyanophenyl]-N'-{2,3-dichlorophenyl)urea EI-MS cn/z 474.0 (M-H)-Example 193 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea EI-MS
mlz 438.0 (M-H)-Example 194 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-nitrophenyl)urea EI-MS m/z 450.0 (M-H)-Example 195 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-aminophenyl)urea EI-MS m/z 422.0 (M+H)+
Example 196 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl)-N-(2-aminophenyl)urea EI-MS m/z 408.0 (M+H)+

Example 197 ; N-{2-(2-pyridinesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea 1H NMR (CD30D): 8 8.90 ( lH,d) 8.33 (1H>d) 8.14(2H,m) 7.99 (lH,d) 7.78 (lH,dd) 7.67 ( 1 H,dd) 7.40 ( 1 H,d) 7.39 ( 1 H,s) 7.18 ( I H,s) Example 198 : N-(2-Benzenesulfonylamino-3-trifluoromethylphenyl-N'-(2,3-dichlorophenyl)urea 1H NMR (CD30D): 8 8.0$ (lH,.dd) 7.90 (lH,dd) 7.78 (2H,m) 7.50 (2H,d) 7.41 (3H,m) 7.27 (2H,d) Example 199 . N-(4-benzenesulphonylthiophene-2-sulphonylamino-4-cyanophenyl}-N'-(2,3-dichlorophenyl)urea EI-MS m/z 609.0 (M+H)+
Example 200 : N-(2-trifluoromethylbezenesulfonylamino-4-cyanophenyl)-N'-(2,3-to dichlorophenyl)urea EI-MS m/z 527.1 (M+H)+
Example 201 : N-(2-Hydroxy-4-cyanophenyl)-N'-(2, 3-methylenedioxyphenyl)urea IH
NMR (CD30D): 8 8.22 (lH,d) 7.49 (lH,d) 7.18 (lH.d) 7.08 (lH,s) 6.82 (lH,t) 6.61(IH,d) 6.00 (2H,s) Example 202 : N-[2-(2-nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea; m.p.
204.1 - 205.3 Example 203 : N-{2-hydroxy-3-trifluoromethyiphenyl)-N'-(2,3-dichlorophenyl)urea; m.p.
204.3 - 205.2 Example 204 : N-(2-hydroxy-3-trifluoromethylphenyl}-N'-(2-phenylphenyl)urea m.p. 136.7 - 137.3 2o Example 205 : N-(2-Hydroxy-4-nitrophenyl)-N'-(2-benzylphenyl)urea EI-MS m/z 364.0 (M+H)+
Example 206 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea EI-MS
m/z 394.0 (M-H)-Example 207 : N-(2-Hydroxy-4-vitro phenyl~N'-[2-(phenyloxymethyl)phenyl]urea EI-MS
mlz 378.0 (M-H)-Example 208 : N-(2-Hydroxy-4-nitrvphenyl)-N'-[2-(phenylethyl}phenyl]urea EI-MS
m/z 376.0 (M-H)-Example 209 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(4-trifluorophenyl)phenyl]urea EI-MS
mlz 416.0 (M-H)-Example 210 : N-(2-Hydroxy-3-trifloromethylphenyl~N'-(2-methoxyphenyl)urea EI-MS
mIz 327.3 (M+H)+
Example 211 : N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyl)urea EI-MS m/z 332.0 (M+H)+
Example 212 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(2-cyanophenylthio)phenyl]urea EI-MS
m/z 407.0 (M+H)+

Example 213 : N-(2-hydroxy-3-trifluoromethylphenyl)-N'-(2-chlorophenyl)urea m.p.
179.3°C
Example 214 : N-(2-Hydroxyethyl)-N'-(2-hydroxy-4.-nitrophenyl)urea m.p. 168.2 -168.8°C
Example 215 : N-2-(benzyoxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea m.p. 179.0 -179.6°C
Example 216 : N-[2-(2-thienylsulfonylamino)phenyl]-N°-(2-hydroxy-4-nitrophenyl)urea m.p. 149.0 - 149.6°C
Example 217 : N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyi)urea IH NMR (CD30D): 89.92 (IH,s) 9.68 (iH,s) 9.58 (lH,s) 8.40 (lH,d) 8.14 {IH,dd) 8.00 ( I H,d) 7.76-7.57 (6H,m) 7.38 ( 1 H,dO 7.23 ( 1 H,d) Example 218 : N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea IH
NMR (CD30D): 89.89 (IH,s) 9.51{lH,s) 9.35 (lH,s) 8.41(lH,d) 8.13(lH,dd) 7.87 (lH,d) 7.69-7.57 (6H,m) 7.40 ( 1 H,t) 7.22 ( 1 H,dd) 7.10 ( 1 H,t) Example 219 : N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea IH
35 NMR (CD30D): 8 9.58 (IH,s) 9.30 (IH,s) 9.14 (lH,s) 8.33 (lH,d) 8.13-8.05 (2H,m) 7.88 ( I H,d) 7.69 ( 1 H,d) 7.50 -7.30 (6H,m) 7.08 ( 1 H,t) 4.61 {2H,s) Example 220 : N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichlorophenyl}urea 1H
NMR (CD30D): 8 9.60 ( 1 H,s) 9.42( 1 H,s) 9.40 ( 1 H,s) 8.32 ( I H,d) 8.15( 1 H,dd) 7.45-7.25 (7H,m} 4.62 (2H,s) 2o Example 221 : N-[2-(3-Pyridylmethoxy)phenylJ-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
185.4 - 186.2 Example 222 : N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
189.3 - 189.7 Example 223 : N-[2-{Methoxycarbonylamino)phenyl]-N'-{2-hydroxy-4-nitrophenyl)urea 25 m.p. 199.3 - 199.6 Example 224 : N-[2-(Methylsulfonylamino)-4-nitrophenylJ-N'-(2-bromophenyl)urea Example 225 : N-[2-(Propylsulfonylamino)-4-nitrophenyl)-N'-(2-bromophenyl)urea Example 226 : N-[2-(Propylsulfonylamino)-4-nitrophenyl)-N'-{2,3-dichlorophenyl)urea 30 Example 227 : N-[[(2-acetamino-4-methyl-5-thiazolyl)sulfonylamino]-4-nitrophenyl]-N'-(2,3dichlorophenyl)urea Example 228 : N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl]-N'-(2,3-dichlorophenyl)urea Example 229 : N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl}-N'-(2-35 bromophenyl)urea Example 230 : N-[2-(Methylsulfonylamino)-4-nitrophenyl]-N'-(2,3-dichlorophenyl)urea Example 231 : N-(2-Hydroxyeth-1-yloxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea Example 232 : N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea m.p.:
108.8-109.4 Example 233 : N'-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy-4-nitrophenyl)urea m.p.
193.5-194.0 Example 234 : N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-(2-hydroxy-4-nitrophenyl)urea m.p. 177.2 - 178.0 1o Example 235 : N-[2-(2-Carboxybenzyloxy)phenyl)-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
164.1 Example 236 : N-[2-{Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
188.7- 189.3 ° C
t s The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above:
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyi)urea N-{2-Hydroxy-4-cyanophenyl)-N'-(2-(2-pyridylmethyloxy)phenyl}urea N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyl)urea 2o N-{2-Hydroxy-4-cyanophenyl}-N'-{2-{4-pyridylmethyloxy)phenyl)urea N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-trifluorosulfonylphenyi)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea ?5 N-(2-Hydroxy-3-triflaoromethyl-4-cyanophenyl)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4.-cyanophenyl-3-carboxylic acid)-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2,3-dichlorophenyl)urea N-{2-Hydroxy-4-trifluorosulfonylphenyi)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea 3o N-{2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichiorophenyl)urea N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-{2,3-dichlorophenyl)urea The following compounds of Formula (I) may be prepared in accordance with 35 the examples and schemes as described above, or may also be purchased commercially from well recognized sources. For instance, from Elldrich Chemical Company:
N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurea For instance, from the Alfred Bader Collection of Aldrich Chemical:
1-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea 1-( 2-Carboxyphenyl)-3-( 3-chlorophenyl)urea Available from Gallard Schlesinger Company andlor the Sigma Aldrich Library of Rare Compounds:
1-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea !-(p-Anisyl)-3-(2-carboxyphenyl)urea Available from Gallard Schlisinger Company l0 2-{3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid 2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid N-Phenyl-N'-(2-carboxyphenyl)urea From Maybridge Chemical Company, Cambridge England:
15 I,1'-(4-Methyl-2-phenylene)bis[3-tolyl)]thiourea N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea The following compounds of Formula {I) may be prepared in accordance with the examples and schemes as described above, or as indicated by their respective 2o citations in Chemical Abstracts:
1-(m-Anisyi)-3-{2-carboxyphneyl)urea I -(o-Anisyl)-3-(2-carboxyphenyl)urea I -(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea 1-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea METHOD OF TREATMENT
The compounds of Formula (I), (la), (Ib), {Ic), (II), (IIa), (IIb), (IIc), and (III), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a 3o human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes andlor macrophages, or other chemolcines which bind to the 1L-8 a or b receptor, also referred to as the type I or type II receptor.
For purposes herein, the compounds of Formula (I), {Ia), (Ib), (Ic), (II, (Lia ), (IIb), (IIc), and (III) all have the same dosages, and dosage formulations as that of Formula (I) and are used interchangeably.

WO 97!29743 PCT/US96113632 Accordingly, the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL,-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokines ars IL-8, GROG, GR0~3, GROy or NAP-2.
The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GROa, GROG, GROy or NAP-2 , such that they are biologically regulated down to normal levels of physiological function, or in t0 some case to subnormal levels, so as to ameliorate the disease state.
Abnormal levels of IL-8, GROa, GRO~i, GROy or NAP-2 for instance in the context of the present invention, constitute: (t) levels of free IL-8 greater than or equal to 1 picogram per mL;
(ii) any cell associated IL-8, GROa, GR0~3, GRO~y or NAP-2 above normal physiological levels: or (iii)the presence of IL-8, GROG, GRO~, GRO~y or NAP-2 15 above basal levels in cells or tissues in which IL-8, GROG, GRO~i, GROy or NAP-2respectively, is produced.
There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. Chemokine mediated diseases 20 include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and-renaFreperfusion~ 'r~rtrry,-glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, 25 restinosis, angiogenesis or undesired hematopoietic stem cells release.
These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with increased IL-8 GROa, GRO~3, GROY or NAP-2 productian which is responsible for the chemotaxis of 30 neutrophils into the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-b), IL-8 GROa, GRO~i, GROy or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation. The a-chemokines but particularly, GROG, GRO~, GROy or NAP-2, 35 working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the WO 97!29743 PCTIUS96/13632 inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
The compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds of Farmula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein. The compounds of Formula (I) have been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors.
Preferably the compounds are inhibitors of only one receptor, preferably Type II.
As used herein, the term "IL-8 mediated disease or disease state" refers to any and all disease states in which IL-8, GROa, GRO~i, GROy or NAP-2 plays a role, either by production of IL-8, GROa, GRO~, GROy or NAP-2 themselves, or by IL-8 GROa, GRO~i, GROy or NAP-2 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
As used herein, the term ''chemokine mediated disease or disease state" refers to any and all disease states in which a chemokine which binds to an IL-8 a or b receptor plays a role, such as but not limited to IL-8, GROG, GRO~, GROy or NAP-2. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL-l, IL-6 or TNF. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and Iymphokines, regardless of which cells produce them.
For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes WO 97IZ9743 P(;TIL1S96113632 and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-B).
As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term "cytokine" above. A chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Examples of chemokines include, but are not limited to, IL-8 GROG, GRO~i, GROy, NAP-2, IP-10, MIP-la, MIP-b, PF4, and MCP l, 2, and 3.
In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula (n may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound.
These procedures may involve mixing, granulating and compressing or dissolving the 34 ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryi mono-stearate or glyceryl distearate alone, or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about 1g. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
Compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (n externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001 % to 10% w/w, for instance from 1 % to 2% by weight of the Formulation.
It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

WO 97!29743 PCT/US96/I3632 Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an to anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is 2o then sealed and sterilized by autoclaving or maintaining at 98-100 °C. for half an hour.
Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzallconium chloride (0.01 %) and chlorhexidine acetate (0.01 %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such adminisuation may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (1], the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 1 SO mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of adminisuation, and the particular patient being treated, and that such optimums can be determined by conventional techniques.
It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
The invention will now be described by reference to the following biological examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
BIOLOGICAL EXAMPLES
The IL-8, and Gro-a chemokine inhibitiory effects of compounds of the present invention were determined by the following in vitro assaye Receptor Binding Assays:
~ 125I~ R,_g (human recombinant) was obtained from Amersham Corp., Arlington Heights, 1L, with specific activity 2000 Ci/mmol. Gro-a was obtained from NEN- New England Nuclear. All other chemicals were of analytical grade. High levels of recombinant human IL-8 type a and b receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science,1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)).
Except that the homogenization buffer was changed to lOmM Tris-HCL. 1mM MgS04, 0.5mM EDTA (ethylene-diaminetetra-acetic acid), ImMPMSF (a-toluenesulphonyl fluoride), 0.5 mglL Leupeptin, pH 7.5. Membrane protein concentration was determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard.
All assays were performed in a 96-well micro plate format. Each reaction mixture contained 1251 ~-g (0_25 nM) or 1251 Gro_a and 0.5 pg/mL of IL-8Ra or 1.0 pg/mL of IL-8Rb membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HCl buffers, pH 8.0, containing 1.2 mM MgS04, 0.1 mM EDTA, 25 mM NaC1 and 0.03° CHAPS. In WO 97!29743 PCT/US96/13632 addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM. The assay was initiated by addition of 125I-IL_g. After 1 hour at room temperature the plate was harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1 polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCI> 10 mM TrisHCl, 1 mM MgS04, 0.5 rnM EDTA, 0.03 % CHAPS, gH 7.4. The filter was then dried and counted on the Betaplate liquid scintillation counter. The recombinant IL-8 Ra, or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL,-8 Rb, or Type II, receptor is referred to as the permissive receptor.
All of the exemplified compounds of Formulas (I) to (!in noted herein in the Synthetic Chemistry Section, of Examples 1 to 222 plus the additional purchased compounds demonstrated an IC50 from about 45 to about <1 ~tg/mL in the permissive models for II,-8 receptor inhibition. All of these compounds were also found to be inhibitors of Gro-a binding at about the same level. The compound 1-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea was found to be active at about pg/mL.
The following compounds, generally tested at levels of up to 45 ltg/mL were 2o found to not demonstrate levels of IL-8 receptor antagonism within the criteria set forth above at the dosage levels tested. These compounds are:
1-(4-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-{2-(4-chlorophenyl)thio]-5-chlorophenylurea 1-(6-Chlorv-alpha,alpha,alpha-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-trifluromethylphenyl)-N'-(3-chlorophenyl)urea N-(2-Carboxyphenyl)-N'-(2,5-dichlorophenyl)urea 1-(2-Carboxyphenyl)-3-(2-ChToro-~-trifluoromethylphenyl)urea 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid;
2-{2-[3-(4-Chlorophenyl)ureido]phenoxyJbenozic acid 2-{2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid N- (2-Hydroxyphenyl) -N'-phenyl urea N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N'-phenylurea N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-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-nitropheny!)-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-Trifluromethyl-2-(4-nitrobenzenesulfonyl)amino}-N'-phenylurea 2o N-{3-Carboxyphenyl)-N'-2-hydroxy-4-nitrophenyl)urea N-{4-Trifluromechyl-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-Hydroxy-4-nitrophenyl)-N'-(2-chloro-5-trifluromethylphenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-4-nitrophenyl)urea N-(2-Hydroxy-1-napthyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-bromophenyl)urea N-(2-hydroxy 3,4 dichlorophenyl )-N'-(4-phenylphenyl)urea 3o 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-methoxyphbnyl)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-methoxyphenyi)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(4-methoxyphenyl)urea WO 97!29743 PCTlUS96113632 N-(2-Hydroxy-3-phenylphenyl)-N'-(3-triflouromethylphenyi)urea N-(2-Hydroxy-3-phenylphenyl)-N'-(2-phenylphenyl)urea N-(2-Hydroxy-3-phenylphenyl)-N'-{4-phenylphenyl)urea N-[2-[(2,5-Dichlorothien3-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy,3,4-dichiorophenyl~N'-(2,4 dimethoxyphenyi)urea N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-chloro-5-trifloromethylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(2,4 dimethoxyphenyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-3 phenyiphenyl)-N'-{2,4-dimethoxyphenyl)urea to N-{2-Hydroxy-4-isopropylphenyl)-N'-(2,4-dimethoxyphenyl)urea N-(2-Hydroxy-3-phenylphenyl}-N'-(2-chloro-5-trifluoromethylpheny!)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 t5 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 z0 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-dimethoxypheny!)urea 25 N-(2-Hydroxy-5-phenylphenyl)-N'-(2-chloro-5-trifluoromethylpheny!}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 3o 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 N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea Chemotaxis Assav The in vitro inhibitory properties of these compounds were determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its entirety. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1, whose disclosure is incorporated herein by reference in its entirety. The chemoattractants IL-8, GRO-a, GRO-b, GRO-g and NAP-2 where placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers where separated by a Sum polycarbonate filter. When compounds of this invention were tested, they where mixed with the cells (0.001 - 1000 nM) just prior to the addition of the cells to the upper chamber. Incubation was allowed to proceed for between about 45 and 90 min at about 37oC in a humidified incubator with 5%
C02.
At the end of the incubation period, the polycarbonate membrane was removed and the top side washed, the membrane was then stained using the Diff Quick staining protocol t5 (Baxter Products, McGaw Park, IL, USA). Cell which had chemotaxed to the chemokine were visually counted 'using a microscope. Generally, four fields where counted for each sample, these number where averaged to give the average number of cells which had migrated. Each sample was tested in triplicate and each compound repeated at least four times. To certain cells (positive control cells) no compound was added, these cells represent the maximum chemotactic response of the cells. In the case where a negative control (unstimulated) was desired, no chemokine was added to the bottom chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells.
Elastase Release Assav:
The compounds of this invention where tested for their ability to prevent Elastase release from human neutrophils. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1.
PMNs 0.88 x 106 cells suspended in Ringer's Solution (NaCI 118, KCl 4.56, NaHC03 25, 3o KH2P04 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) where placed in each well of a 96 well plate in a volume of 50 u1. To this plate was added the test compound (0.001 -1000 nM) in a volume of 50 u1, Cytochalasin B in a volume of 50 u1 (20ug/ml) and Ringers buffer in a volume of 50 u!. These cells where allowed to warm (37 oC, 5%
C02, 95% RH) for 5 min before IL-8, GROa, GROb, GROg or NAP-2 at a f nal concentration of 0.01 - 1000 nM was added. The reaction was allowed to proceed for min before the 96 well piate was centrifuged (800 xg 5 min) and 100 u1 of the supernatant removed. This suppernatant was added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochern, La Jolla, CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline.
Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al 3. Biol Chem 254 4027 ( 1979}. The amount of Elastase released from the PMNs was calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-VaI-AMC
degradation.
The above description fully discloses the invention including preferred to embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims.
Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the~Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

1. Use of an effective amount of a compound of formula:

X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl;
halosubstituted C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10alkoxy; azide; S(O)t R4; (CR8R9)q S(O)t R4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl; heterocyclicC1-4alkyloxy; heterocyclicC2-alkenyl; (CR8R9)q NR4R5; (CR8R8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11;
C2-10alkenyl C(O)OR11; (CR8R8)q C(O)OR11; (CR8R8)q OC(O)R11;
(CR8R8)q NR4C(O)R11; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)R11;
(CR8R8)q NHS(O)2R13; (CR8R8)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)s O- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)q S(O)t R4, (CR8R8)q OR4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl;
aryloxy; arylC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic C1-4alkyl; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3R8;

(CR8R8)q C(O)R11; C2-10alkenylC(O)R11; (CR8R8)q C(O)OR11;
C2-10alkenylC(O)OR11; (CR8R8)q OC(O)R11; (CR8R8)q NR4C(O)R11;
(CR8R8)q NHS(O)2R b; (CR8R8)q S(O)2NR4R5; (CR8R8)q C(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11; or two Y moieties together may form O-(CH2)s O- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
R b is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted;
E is optionally selected from the asterix * denoting point of attachment of the ring, with at least one E
being present;
or a pharmaceutically acceptably salt thereof, for treating a chemokine mediated disease state in a mammal, wherein the chemokine binds to an IL-8 .alpha. or .beta. receptor in said mammal.

2. Use of an effective amount of a compound of formula:

X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; vitro; cyano; C1-10 alkyl;
halosubstituted C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10alkoxy; azide; S(O)t R4; (CR8R8)q S(O)t R4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl; heterocyclicC1-4alkyloxy; heterocyclicC2-alkenyl; (CR8R8)q NR4R5; (CR8R8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11;
C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR11; (CR8R8)q OC(O)R11;
(CR8R8)q NR4C(O)R11; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)R11;
(CR8R8)q NHS(O)2R13; (CR8R8)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)s O- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)q S(O)t R4, (CR8R8)q OR4; hydroxy; hydroxy substituted C1-10alkyl; aryl; aryl C1-4 alkyl;
aryloxy; arylC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic C1-4alkyl; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3R8;
(CR8R8)q C(O)R11; C2-10 alkenylC(O)R11; (CR8R8)q C(O)OR11;
C2-10alkenylC(O)OR11; (CR8R8)q OC(O)R11; (CR8R8)q NR4C(O)R11;
(CR8R8)q NHS(O)2R b; (CR8R8)q S(O)2NR4R5; (CR8R8)q C(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11; or two Y moieties together may form O-(CH2)s O- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, optionally substituted C1-4 alkyl; optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
R b is NR6R7, alkyl, aryl, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted;
E is optionally selected from the asterix * denoting point of attachment of the ring, with at least one E
being present;
or a pharmaceutically acceptably salt thereof, in the manufacture of a medicament for treating a chemokine mediated disease state in a mammal, wherein the chemokine binds to an IL-8 .alpha. or .beta. receptor in said mammal.

3. The use of claim 1 or 2 wherein in the compound R is hydroxy, carboxylic acid, thiol, SR2 OR2, NH-C(O)R a, C(O)NR6R7, NHS(O)2R b, S(O)2NHR c, NHC(X)NHR b, or tetrazolyl;
wherein X is oxygen or sulfur;
R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R a is an alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;
R b is a NR6R7 alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; cyano, halosubstituted C1-

4 alkyl;
C1-4 alkyl; C1-4 alkoxy; C1-4 amino, NR9C(O)R a; C(O)NR6R7; S(O)3H; or S(O)m'R a (wherein m' is 0, 1, or 2); or C(O)OC1-4 alkyl;
R9 is hydrogen or a C1-4 alkyl;
R c is alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclicC1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro,cyano, halosubstituted C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, C1-4 amino, NR9C(O)R a, C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl.

4. The use of claim 3 wherein in the compound R is OH, SH, or NHS(O)2R b, and R1 is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.

5. The use according to claim 1 or 2 wherein in the compound Y is halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioC1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4alkyl, or hydroxyalkyl.

6. A compound of formula:

X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl;
halosubstituted C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10alkoxy; azide; S(O)t R4; (CR8R8)q S(O)t R4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl; heterocyclicC1-4alkyloxy; heterocyclicC2-alkenyl; (CR8R8)q NR4R5; (CR8R8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11;
C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR11; (CR8R8)q OC(O)R11;
(CR8R8)q NR4C(O)R11; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)R11;
(CR8R8)q NHS(O)2R13; (CR8R8)q S(O)2NR4R5, or two R1 moieties together may form O-(CH2)s O- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substitutedC1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)q S(O)t R4, (CR8R8)q OR4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl;
aryloxy; arylC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic C1-4alkyl; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4R10; S(O)3R8;
(CR8R8)q C(O)R11; C2-10 alkenylC(O)R11; (CR8R8)q C(O)OR11;
C2-10alkenylC(O)OR11; (CR8R8)q OC(O)R11; (CR8R8)q NR4C(O)R11;
(CR8R8)q NHS(O)2R b; (CR8R8)q S(O)2NR4R5; (CR8R8)q C(NR4)NR4R5;
(CR8R8)q NR4C(NR5)R11; or two Y moieties together may form O-(CH2)s O- or a to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, optionally substituted C1-4alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;

R b is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted;
E is optionally selected from the asterix * denoting point of attachment of the rind, with at least one E
being present;
or a pharmaceutically acceptably salt thereof; wherein the chemokine binds to an IL-8 .alpha. or .beta.
receptor in said mammal.

7. The compound of claim 6 wherein R is hydroxy, carboxylic acid, thiol, SR2 OR2, NH-C(O)R a, C(O)NR6R7, NHS(O)2R b, S(O)2NHR c, NHC(X)NHR b, or tetrazolyl;
wherein X is oxygen or sulfur;
R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R a is an alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;
R b is a NR6R7, alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; cyano, halosubstituted C1-4 alkyl;
C1-4 alkyl; C1-4 alkoxy; C1-4 amino, NR9C(O)R a; C(O)NR6R7; S(O)3H; or S(O)m'R a (wherein m' is 0, 1, or 2); or C(O)OC1-4alkyl;

R9 is hydrogen or a C1-4alkyl;
R c is alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro,cyano, halosubstituted C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, C1-4 amino, NR9C(O)R a, C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl.

8. The compound of claim 7 wherein R is OH, SH, or NHS(O)2R b and R1 is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.

9. The compound of claim 6 wherein Y is halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioC1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4alkyl, or hydroxyalkyl.