MXPA01006240A

MXPA01006240A - Hydroxy diphenyl urea sulfonamides as il-8 receptor antagonists

Info

Publication number: MXPA01006240A
Application number: MXPA/A/2001/006240A
Authority: MX
Inventors: L Widdowson Katherine; Jin Qi; W Mccleland Brent; R Palovich Michael
Original assignee: Smithkline Beecham Corporation
Priority date: 1998-12-16
Filing date: 2001-06-18
Publication date: 2001-12-13

Abstract

The invention relates to novel hydroxy diphenylurea sulfonamides, compositions and intermediates thereof. The hydroxy diphenylurea sulfonamides are useful in the treatment of disease states mediated by the chemokine, Interleukin-8.

Description

SULFONAMIDES OF HYPROXYPIFENILUREA AS ANTAGONISTS PE RECEIVER PE INTERLEUCINE-8 FIELD PE INVENTION The present invention relates to novel diphenylurea compounds substituted with sulfonamide, pharmaceutical compositions, methods for the preparation and use thereof in the treatment of diseases mediated by IL-8, GROa, GROß, GRO ?, NAP-2 and ENA- 78 ANTECEPENTES PE THE INVENTION Many different names have been applied to interleukin-8 (IL-8), such as, for example, protein-1 attractant / neutrophil activation (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activation factor ( NAF) and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant of neutrophils, basophils and a subset of T cells. It is produced by a majority of nucleated cells that include macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1a, IL-1β or LPS, and by the neutrophils themselves when exposed to LPS or chemotactic factors, such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J, Immunol. 144, 2223 (1990); Strieter, et al, Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al, J. Immunol. 148, 3216 (1992). GROa, GROß, GRO? and NAP-2 also belong to the chemokine family. As well as IL-8, these chemokines have also been named under different names. For example, GROa, ß,? have been designated as MGSAa, ß and? respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiolo v. 129, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All chemokines in the family that possess the ELR motif that directly precede the CXC motif bind to the IL-8 B receptor (CXCR2). IL-8, GROa, GROß, GRO ?, NAP-2 and ENA-78 stimulate several functions in vitro. All have been shown to have neutrophil chemoattractant properties, whereas IL-8 and GROa have demonstrated T lymphocytes and basophilic chemotactic activity. In addition I L-8 can induce histamine release from basophils of normal and atopic individuals. In addition, GROa and IL-8 can induce enzymatic release of lysozymes and respiratory burst of neutrophils. IL-8 has also been shown to increase surface expression of Mac-1 (CD11b / CD18) in neutrophils without protein synthesis once again. This may contribute to increase the adhesion of neutrophils to vascular endothelial cells. Many known diseases are characterized by massive infiltration of neutrophils. Since IL-8, GROa, GROß, GRO? and NAP-2 stimulate the accumulation and activation of neutrophils, these chemokines have been related to a wide variety of acute and chronic inflammatory disorders, including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev. Immunol. 12. 17 (1992); Oppenheim et al. Annu. Rev. Immunol. 9. 617 (1991); Seitz et al, J. Clin. Invest. 87, 463 (1991); Miller et al, A. Breathe Dis. 146, 427 (1992); Donnely et al, Lancet 341, 643 (1993). In addition, ELR chemokines (those containing the ELR motif of amino acids just before the CXC motif) have also been related to angiostasis, Strieter, et al, Science 258. 1798 (1992). In vitro, IL-8, GROa, GROß, GRO? and NAP-2 induce the neutrophil figure change, chemotaxis, granular release and respiratory burst by binding to and activation of seven transmembrane receptors, family G-protein linked, in particular by binding to IL-8 receptors , most notably, the IL-8β receptor (CXCR2). 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 family of receptors is unprecedented. For a review see R. Freidinger in: Progress in Drug Research. Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Accordingly, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents. Two human L-8 receptors of high affinity (77% homology) have been characterized: IL-8Ra, which binds only to IL-8 with high affinity, and IL-8Rβ, which has high affinity for IL-8 , as well as for GROa, GROß, GRO? and NAP-2. See Holmes et al, supra; Murphy et al, Science 253, 1280 (1991); Lee et al, J. Biol. Chem. 267, 16283 (1992); LaRosa et al, J. Biol. Chem. 267, 254-2 (1992); and Gayle et al, J. Biol. Chem. 268, 7283 (1993). The need persists for a treatment, in this field, of compounds that have the ability to bind to the IL-8a or β receptor. Therefore, conditions related to an increase in the production of I L-8 (which is responsible for chemotaxis of subsets of neutrophils and T cells at the inflammatory site) would benefit from the compounds, which are inhibitors of receptor binding of IL-8.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method of treating a chemokine-mediated disease, wherein the chemokine is the one that binds to an IL-8 a or b receptor, and that the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokine is IL-8. This invention also relates to a method for inhibiting the binding of IL-8 to its receptors in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of Formula (I).

Also, the present invention provides the novel compounds of Formula (I) and a pharmaceutical carrier or diluent. The compounds of Formula (I) useful in this invention are represented by the structure: wherein: R is independently hydrogen, NReR7, OH, ORa, aryl, C1-5alkyl, C1-4 arylalkyl, C2- arylalkonyl; cycloalkyl, cycloalkylalkyl of C? -5, heteroaryl, heteroarylalkyl of C? -, heteroarylalkenyl of C2-4, heterocyclic, C? -alkyl heterocyclic alkyl, or a C2-4 heterocyclic alkenyl portion, the portions of which can be replaced as an option of one to three times independently by halogen; nitro; C- alkyl substituted with halogen; C-M alkyl; amine substituted with amino, mono or di-alkyl of CM; ORa; C (0) Ra; NRaC (O) ORa; OC (O) NR6R7; hydroxy; NR9C (O) Ra; S (O) m a; C (O) NR6R7; C (O) OH; C (O) ORa; S (O) tNR6R7; NHS (O) tRa. Alternatively, the two Rb substituents can be joined to form a ring of 3-10 elements, optionally substituted and containing, in addition to optionally substituted Cμ alkyl, independently, 1 to 3 portions of NRa, O, S, SO or SO2, which can be optionally unsaturated; Ra is an alkyl, aryl, arylalkyl of C-, heteroaryl, heteroarylalkyl-C 1-4, heterocyclic, COORa ', or an alkyl portion of C-4-heterocyclic portion, the portions of which may be optionally substituted; Ra is an alkyl, aryl, arylC1-4 alkyl, heteroaryl, C1-4 heteroarylalkyl, heterocyclic or a C1-4 heterocyclic alkyl moiety, the portions of which may be optionally substituted; m is an integer that has a value of 1 to 3; m 'is 0, or an integer having a value of 1 or 2; n is an integer that has a value of 1 to 3; q is 0, or an integer that has a value of 1 to 10; t is 0, or an integer that has a value of 1 or 2; s is an integer that has a value of 1 to 3; R-t is independently selected from hydrogen, halogen, nitro, cyano, C-MO alkyl, C-O alkyl substituted with halogen, C2-10 alkenyl. C-MO alkoxy, C-MO alkoxy substituted with halogen, azide, S (O) tR 4, (CR 8 R 8) q S (O) t R 4, hydroxy, C 1 -C 4 alkyl substituted with hydroxy, aryl, C 1-4 arylalkyl, arylalkenyl of C-2-10, aryloxy, C 1 -4 arylalkyloxy, heteroaryl, heteroarylalkyl, C 2-10 heteroarylalkenyl, heteroaryl C 1-4 heteroarylaxy, heterocyclic, heterocyclic C 1-4 alkyl, C 1-4 heterocyclic alkyloxy, C2-10 heterocyclic alkenyl, (CR8R8) qC (O) NR4R5, C2-10 alkenyl - C (O) NR4R5, (CR8R8) qC (O) NR4R? O, S (0) 3R8, (CR8R8) qC (0) R ??, alkenyl of C2-10 - C (0) Rn, C2-10 alkenyl - C (O) ORn, (CR8R8) qC (0) ORn, (CR8R8) qOC (O) Rn, (CR8R8) qNR4C (0) Rn, (CR8R8) qC (NR4) NR4R5, (CR8R8) qNR4C (NR5) Rn, (CR8R8) qNHS (O) tR? 3, (CRsRdJqSÍOJtNR? Rs, or two Ri portions together can form O- (CH) sO or a saturated or unsaturated ring of 5 to 6 elements, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic portions can be optionally substituted; Rs independently are hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted C 1 -C 4 arylalkyl, optionally substituted heteroaryl, optionally substituted C heteroarylamino, heterocyclic, C 1-4 heterocyclic alkyl, or R 4 and Re together with the nitrogen to which they are attached they form a ring of 5 to 7 elements, which can optionally comprise an additional heteroatom selected from O, N and S, Re and R independently are hydrogen, or a C 1-4 alkyl heteroaryl, aryl , alkylaryl, C1-4 alkylheteroalkyl, which may be optionally substituted or Re and R together with the nitrogen to which they are attached form a ring of 5 to 7 elements, which may comprise as an option an additional heteroatom selected from oxygen, nitrogen or sulfur, and which may be optionally substituted; Y is hydrogen, halogen, nitro, cyano, Ci.-io alkyl substituted with halogen, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, C1-10 alkoxy substituted with halogen, azide, ( CR8R8) qS (O) tRa, (CR8R8) qORa, hydroxy, C1-4 alkyl substituted with hydroxy, aryl; arylalkyl of C -? -, aryloxy, arylalkyloxy of C-M, arylalkenyl of C2-10, heteroaryl, heteroarylalkyl, CM heteroarylalkyloxy, C2-10 heteroarylkenyl, heterocyclic, heterocyclic CM alkyl, heterocyclic C2-10 alkenyl, C2-10 alkenyl - C (0) NR4R5, (CR8R8) qC (0) NR4R5, (CR8R8) qC (O) NR4R? 0lS (O) 3R8, (CR8R8) qC (O) Rn, C2- alkenyl 10 - C (O) Rn, (CR8R8) qC (O) ORn, C2-10 alkenyl - C (0) OR,, (CR8R8) qOC (O) Rn, (CR8R8) qNR4C (O) Rn, ( CR8R8) qNHS (O) tRi3, (CR8R8) qS (O) tNR4R5, (CR8R8) qC (NR4) NR4R5, (CR8R8) qNR4C (NR5) Rn, or two portions Y together can form O- (CH2) sO or a saturated or unsaturated ring of 5 to 6 elements, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl may be optionally substituted; R8 is hydrogen or C-alkyl; Rg is hydrogen or CM alkyl; R10 is C (O) 2R8 of C1-10 alkyl; R11 is hydrogen, optionally substituted C-alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C-alkyl; R 13 is suitably C 1 -C 4 alkyl, aryl, C 1 a 4 alkyl, heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclic CH alkyl; or a pharmaceutically acceptable salt thereof.

PETALLAPA PESCRIPTION OF THE INVENTION The compounds of Formula (I) may also be employed in conjunction with the veterinary treatment of mammals, other than humans, that require the inhibition of IL-8 or other chemokines that bind to the IL-8a and β receptors. Diseases mediated by chemokines for the treatment, therapeutically or prophylactically, in mammals include disease states, such as those mentioned herein, in the section corresponding to the methods of treatment. Suitably, Rb is independently hydrogen, NR6R7, OH, ORa, CM alkyl, aryl, arylalkyl of CM, arylalkenyl of C2-4, heteroaryl, heteroarylalkyl of C, heteroarylalkenyl of C2-4, heterocyclic, alkyl of heterocyclic CM, or a portion of alkenyl of C2-4 heterocyclic, the portions of which can be substituted as an option one to three times independently by halogen, nitro, substituted C.sub.1 -C.sub.H alkyl, C.sub.1 -C.sub.4, amino substituted amino, mono- or di.-C.sub.4 -alkyl, cycloalkyl, C.sub.1 -C.sub.alkylalkyl -5, ORa, C (O) Ra, NRaC (O) ORa, OC (O) NR6R7, aryloxy, aryloxy of CM, hydroxy, alkoxy of CM, NR9C (0) Ra, S (O) m-Ra, C (0) NR6R7, C (O) OH, C (O) ORa, S (O) tNR6R7, NHS (O) tRa. Alternatively, the two Rb substituents can be joined to form a ring of 3-10 elements, optionally substituted and containing, in addition to carbon, independently, 1 to 3 portions of NRg, O, S, SO or SO2, which can be optionally replaced.

Suitably, Ra is an alkyl, aryl, arylalkyl portion of CM, heteroaryl, heteroarylalkyl of CM, heterocyclic, or an alkyl portion of heterocyclic CM, which portions may be optionally substituted. Suitably Ri independently is selected from hydrogen, halogen, nitro, cyano, halogen substituted Cwo alkyl, such as CF3, C-MO alkyl, such as methyl, ethyl, isopropyl, or n-propyl, C2-10 alkenyl , C-O alkoxy, such as methoxy, or ethoxy; C1-10 alkoxy substituted with halogen, such as trifluoromethoxy, azide, (CR8R8) qS (O) tR4, wherein t is 0, 1 or 2, hydroxy, hydroxyalkyl of C, such as methanol or ethanol, aryio, such as phenyl or naphthyl , arylalkyl of CM, such as benzyl, aryloxy, such as phenoxy, arylalkyloxy of C 1-4, such as benzyloxy; heteroaryl, heteroarylalkyl, heteroarylalkyloxy of C; C2-10 arylalkenium, C2-10 heteroarylalkenyl, C2-10 heterocyclic alkenyl, (CR8R8) qNR4R5, C2-10 alkenyl - C (O) NR4Rs, (CR8R8) qC (O) NR4R5, (CR8R8) qC ( O) NR4R? O, S (O) 3H, S (0) 3R8, (CR8R8) qC (O) Rn, C2-10 alkenyl - C (O) Rn, C2-10 alkenyl - C (O) ORn, (CRg), (CR8R8) qC (O) ORn, (CR8R8) q0C (O) Rn, (CRßRßJqNFUCÍOJRn, (CR8R8) qC (NR4) NR4R5, (CR8R8) qNR4C (NR5) R11, (CR8R8) qNHS (O) tRi3, (CR8R8) qS (O) tNR4R5 All the aryl, heteroaryl and heterocyclic containing portions can optionally substituted, as defined hereinafter For the use herein, the term "aryl, heteroaryl and heterocyclic containing portions" refers to the ring and the alkyl, or to be included, the alkenyl rings, such as aryl, arylaxy, and arylalkenyl rings. The term "portions" and "rings" can be used interchangeably throughout the text. Suitably, R4 and R5 independently are hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclic, heterocyclic CM alkyl, or R4 and R5 together with the nitrogen to which they are attached form a ring of 5 to 7 elements, which may optionally comprise an additional heteroatom selected from O, N and S. Suitably, Rs is independently hydrogen or alkyl of CM. Suitably, Rg is hydrogen or C-M alkyl. Suitably, q is 0 or an integer having a value of 1 to 10. Suitably, R10 is C (0) 2R8 of C-MO alkyl, such as CH2C (O) 2H or CH2C (O) 2CH3. Suitably, R-n is hydrogen, alkyl of CM, aryl, arylalkyl of CM, heteroaryl, heteroarylalkyl of CM, heterocyclic, or alkyl of heterocyclic CM. Suitably, R 12 is hydrogen, C-MO alkyl, optionally substituted aryl, or optionally substituted arylalkyl.

Suitably, R 13 is CM alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclic CH alkyl, wherein all aryl, heteroaryl and heterocyclic containing moieties can be optionally substituted. Suitably, Y is independently selected from hydrogen, halogen, nitro, cyano, Ci.-io alkyl substituted with halogen, C1-10 alkyl, C2-? Al alkenyl, C1-10 alkoxy, C- alkoxy MO substituted with halogen, azide, (CR8R8) qS (0) tRa, hydroxy, hydroxyalkyl of CM, aryl; CM arylalkyl, aryloxy, arylalkyloxy of CM, heteroaryl, heteroarylalkyl, heteroarylalkyloxy of CM, heterocyclic, C-heterocyclic alkyl, arylalkenyl of C2-10, heteroarylalkenyl of C2-10, alkenyl of C2-10 heterocyclic, (CR8R8) qNR4R5, alkenyl of C2-? o-C (O) NR4R5, (CR8R8) qC (O) NR4R5, (CR8R8) qC (0) NR4R? o, S (O) 3H, S (0) 3R8, (CRsR8) qC (O) R? - ?, alkenyl of C2.?0-C (O) Rn, C2-10 alkenyl C (0) Rn, (CR8R8) qC (O) OR? 2, (CR8R8) qOC (O) Rn, (CR8R8) qC (NR4) NR4R5, (CR8R8) qNR4C (NR5) R ??, (CR8R8) qNR4C (O) Rn, (CR8R8) qNHS (O) tR? 3, or (CRsR8) qS (O) tNR4R5, or two portions Y together can form O- (CH2) sO or a saturated or unsaturated ring of 5 to 6 elements. The aforementioned aryl, heteroaryl and heterocyclic containing portions may be optionally substituted as defined herein. Suitably, s is an integer that has a value of 1 to 3. When Y forms a dioxi bridge, s is preferably 1. When And it forms an additional unsaturated ring, preferably it has 6 elements, which results in a naphthylene ring system. These ring systems can be substituted 1 to 3 times by other Y portions, as defined above. Suitably, Ra is alkyl, aryl, C arylalkyl, heteroaryl, C-M heteroarylalkyl, heterocyclic, or heterocyclic CH alkyl, wherein all of these portions may be optionally substituted. And preferably it is halogen, CM alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR4R5, CM thioalkyl, thioaryl, halogen-substituted alkoxy, optionally substituted C-alkyl, or hydroxyalkyl. Preferably, Y is mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, more preferably, these groups are mono- or di-substituted at the 2'-position or the 2'-position. , 3'. While Y can be substituted in any of the ring positions, n is preferably one. While, R-i and Y can be hydrogen, it is preferred that at least one of the rings be substituted, preferably that both rings are substituted. As used herein, "optionally substituted", unless specifically defined, will mean such groups, such as halogen, such as fluorine, chlorine, bromine or iodine, hydroxy; C1-10 alkyl substituted with hydroxy, C-MO alkoxy, such as methoxy or ethoxy, Ci-10-S (O) m- alkyl, wherein m 'is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; amino, mono and d-substituted, such as in the group NR4R5, NHC (O) R4, C (O) NR4R5, COOR4, S (O) tNR4R5, NHS (O) tR2o, C1.10 alkyl, such as methyl , ethyl, propyl, isopropyl, or t-butyl, C1-10 alkyl substituted with halogen, said CF3, an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocyclic, heterocyclic alkyl optionally substituted, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, wherein these aryl, heteroaryl or heterocyclic portions may be substituted one to two times by halogen; hydroxy; substituted hydroxyalkyl, CMO alkoxy; alkyl of C-O-S (O) m >; alkylamino amino, mono and disubstituted, such as in the group NR4R5; C1-10 alkyl, or C0 alkyl substituted with halogen, such as CF3. R20 is suitably C-M alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclic C-alkyl. Those skilled in the art are well aware of suitable pharmaceutically acceptable salts, and include basic salts of organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, acid tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) also they can be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are known to those skilled in the art and include alkaline, alkaline earth, ammonia and quaternary ammonia cations. The following terms, as used herein, refer to: "halogen" - all halogens, i.e., chlorine, fluorine, bromine and iodine. • "C-MO alkyl" or "alkyl" - the portions of each straight and branched from 1 to 10 carbon atoms, unless the length of the chain, otherwise, is limited, including, but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like. "Cycloalkyl" is used herein to mean a cyclic portion, preferably 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. • "alkenyl" is used herein in all cases in which it occurs to mean a straight or branched chain portion of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like, "aryl" -phenyl and naphthyl; • "heeroaryl" (by itself or in any combination, such as "heteroaryloxy" or "heteroarylalkyl") - an aromatic ring system of 5 to 10 elements, wherein one or more rings contain one or more heteroatoms, selected from the group consists of N, O or S, such as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, soquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, traizole, imidazole, or benzimidazole. • "heterocyclic" (by itself or in any combination, such as "heterocyclic alkyl") - a saturated or partially unsaturated 4-10 element ring system, wherein one or more rings contain one or more heteroatoms selected from the group consisting of of N, O or S; as, but not limited to pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine or imidazolidine. In addition, the sulfur can optionally be oxidized to sulfone or sulfoxide. "Arylalkyl" or "heteroarylalkyl" or "heterocyclic alkyl" is used herein to mean C-MO alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise stated. • "sulfinyl" - the S (O) oxide of the corresponding sulfide, the term "thio" refers to the sulfide and the term "sulfonyl" refers to the completely oxidized S (0) 2 portion. • "wherein two portions R-i (or two portions Y) can together form a saturated or unsaturated ring of 5 or 6 elements" is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl portion having attached a partially saturated or unsaturated ring of 6 elements, such as cycloalkenyl of Ce, ie, hexene, or a cycloalkenyl portion of C5, such as cyclopentene. Illustrative compounds of Formula (I) include: N- (2-Hydroxyl-3-aminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-aminosulfonyl-4-chlorophenyl) -N '- (2,3-dichlorophenyl) urea; N- (2-Hydroxy-3-N "-benzylaminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N" -benzylaminosulfonyl-4-chlorophenyl) - N '- (2,3-dichlorophenol) urea; N- [2-Hydroxy-3- (N ", N" -dimethyl] -aminosulfonyl-4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-Hydroxy-3-N ", N" -d'-methylaminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N "-methylaminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N" -methylaminosulfonyl-4-chlorophenyl) - N- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- [N- (methoxycarbonylmethyl) aminosulfonyl] -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- (N "- (2-methoxycarbonyl) -methyl) -aminosulfonyl-4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3-] [(N "-2-carboxymethyl) -aminosulfonyl] -4-chlorophenyl] -N '- (2,3-dichloro-phenyl) -urea; N- [2-Hydroxy-3- (N "-2-carboxymethyl) -aminosulfonyl-4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3-aminosu-2-phenyl-4-chlorophenyl] -N '- (2-chlorophenyl) urea; N- [2-Hydroxy-3-aminosulfonyl-4-chlorophenyl] -N'-phenylurea; N- (2-Hydroxy-3-aminosulfonyl-4-chlorophenyl) -N '- (2-phenoxyphenyl) urea; N- (2-Hydroxy-3- [N "- (3-carboxyethyl) -aminosulfonyl] -4-chlorophenyl) -N, - (2-bromophene) urea; N- [2-Hydroxy-3- (isopropylaminosulfonyl) - 4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (isopropylaminosulfonyl) -4-chlorophenyl] -N' - (2-chlorophenyl) urea; N - [2-Hydroxy-3- (isopropylaminosulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- (4-chloro-2-hydroxy-3-aminosulfonyl) -N '- (2-methoxyphenyl) urea; N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-methylenedioxyphenyl) urea; N- (2-benzyloxyphenyl) -N '- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) urea; N- [3- (N "-alkylaminosulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [N "- (2-trifluoroethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2,3-dichlorophenyl) -N '- [2-hydroxy-4-methoxy-3-N "- (phenylammonosulfonyl) phenyl] urea; N- (2-bromophenyl) -N '- [2-hydroxy-4-methoxy-3-N "- (phenylammonosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- [ N "- (2-methoxyethyl) aminosulfonyljphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) aminosulfonyl] phenyl] urea; N- (2-bromophenyl) -N' - [4 -chloro-2-hydroxy-3- (4-morpholinylsulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- (4-morfoiinylsulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- [3-tert-butoxycarbonylamino) propy] aminosulfonyl] -4-chloro-2-hydroxyphenyl] - N '- (2,3-dicyorophenyl) urea; N- (2-bromophenyl) -N '- [3- [N "- [3- (tert-butoxycarbonylamino) propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N-trifluoroacetate] "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxy phenyl] -N '- (2-bromophenyl) urea; N- [3- [N "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxyphene] -N'- (2-bromophenyl) urea hydrochloride; N- [3- [N"] trifluoroacetate - (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxy phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosuifonyl] -4-cynor-2-hydroxyphenyl] urea; N- [3- [N" - (2-aminoethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- (2-bromophenyl) -N '- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl] -4-chloro-2-hydroxyphenyl-urea; N- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-cioro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (1-piperazinylsulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (piperazin-1-ylsulfonyl) phenyl] urea trifluoroacetate; N- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfoniI] phenyl] -N '- (2,3-dichloro-phenyl) -urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyl] urea; potassium salt of N- (4-chloro-2-) hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea; N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N' - (2,3-dichlorophenyl) urea sodium salt; N- (2-bromophenyl) -N '- [4-chloro-3- [N ", N" -di- (2-methoxyethyl) aminosulfonyl] -2-hydroxy phenyljurea; N- [4-chloro-3-] [N ", N" -di- (2-methoxyethyl) aminosulfonyl] -2-hydroxyphenyl] -N '- (2,3-dichloro phenyl) urea; N- (2-bromophenyl) -N' - [4] hydrochloride -chloro-3- [N "- [2- (dimethylamino) ethyl] amino sulfonyl] -2-hydroxyphenyl] urea; N- [4-Chloro-3- [N "- [2- (dimethylamino) etiI] aminosulfonyl] -2-hydroxy phenyl] -N '- (2,3-dicyorophenyl) urea hydrochloride; N- [4-chloro] -2-hydroxy-3- [N "- [3- (methylsulfonyl) propyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfonyl) propyl] amino sulfonyljphenyljurea; N- [4-chloro-2-hydroxy] hydrochloride 3- [N "- [2- (morpholinyl) ethyl] aminosulfoni!] Phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] aminosulfoniyl] phenyl] -N '- (2-chlorophenyl) urea hydrochloride; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [2- (4-morpholinyl) ethyl] aminosulfonyl] phenyljurea; N- [4-chloro-2] -hydroxy-3- (4-thiomorpholysulfonyl) phenyl] -N '(2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-2-hydroxy] 3- (4-thiomorpholinylsulfonyl) phenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-3- [N ", N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxy phenyljurea; N- [4-chloro-3- [N ", N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxyphenyl] -N '- (2,3-dichloro phenyl) urea; N- [ 4-chloro-2-hydroxy-3- [N "- [3- (methylsulfinyl) propyl] aminosulfonyl] phenyl] - N, - (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfinyl) propyl] aminosulfonyl] phenolyl] N- (2-bromophenyl) - N '- [3- [N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] amino sulfonyl] -4-cyoro-2-hydroxyphenyl] urea; N- [3- [N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfoniyl] -4-chloro-2-hydroxyphenyl-N '->. S-dicyoropheniurea; N- [4 -chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] -N '- (2,3-dichlorophenol) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] urea; N- [4-Chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] amino] sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate; Hydrochloride of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyl] phenyl] urea; N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; Potassium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxyphenyl-urea; Sodium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxyphenyljurea; N- (2-bromophenyl) -N '- [4-chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl) urea; N- [4-chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- [4-chloro-3- (N "-cycloethaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dicyoropheni) urea; N- (2-bromophenyl) -N' - [4 -chloro-2-hydroxy-3- (N "-propylaminosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxyl-3- (N "-propylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-Chloro-2-hydroxyl-3- (N "-propylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-3-] (N "-ethylaminosulfonyl) -2-hydroxyphenyl] urea; N- [4-chloro-3- (N "-ethiaminosulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenol) urea; N- [4-chloro-3- (N" -ethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [3- [N "- [5-tert-butoxycarbonylamino) -5-carboxylpentyl] amino sulfonyl] -4-cyoro-2-hydroxyphenyl] urea; N- [3- [ N "- [5- (tert-butoxycarbonylamino) -5-carboxylpentyl] aminosulfonyl] -4-chloro-2-hydroxy-phenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxylpentyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) ) -N, - [4-chloro-2-hydroxy-3- [N "- (2-hydroxyethyl) aminosulfonyl] urea; N- (2,3-dichlorophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (2-hydroxyethyl) aminosulfonyl] urea; N- (2-bromophenyl) -N '- [3- [N "- [[(2-bromophenylamino) carboxyl] ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3 - [N "- (2-benzylloxyethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N "-cyclopropylmethylaminosulfonyl) -4-chlorophenyl] -N '- (2,3-dichloro phenyl) urea; N- [2-Hydroxy-3- (N" -cyclopropylmethylaminosulfonyl ) -4-chlorophenyl] -N '- (2-chlorophenyl) urea; N- [2-Hydroxy-3- (N "-cyclopropylmethylaminosulfonyl) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N" -methoxy-N "-methylaminosulfonyl) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N "-methoxy-N" -methylaminosulfonyl) -4-chlorophenyl] -N' - (2-chlorophenyl) urea; N- [2-Hydroxy-3- (N "-methoxy-N" -methylammonosulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- [2-Hydroxy] -3- (N "-pyrrolidinium-sulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenol) urea; N- [2-Hydroxy-3- (N "-pyrrolidinylsulfonyl) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N" -pyrrolidinylsulfonyl) -4-chlorophenyl ] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(4-pyridinylammonosulfonyl) phenol] urea; N- [4-Chloro-2-hydroxy-3 - [(4-pyridinamino-sulfonyl] phenyl] -N '- (2,3-dichlorophenol) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[2- (tetrahydro-2-furanyl) methyl] amino sulfonyl] phenyl] urea; N- [4-Chloro-2-hydroxy-3 - [[[2- (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-c! Oro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) methyl] amino sulfonyl] phenyl] urea; and N- [4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanyl) methyl] amino-sulfonyl-phenyl-urea; N- [4-chloro-2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyl] urea N- [4-chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea, and N- (2-chlorophenyl) -N' - [4-chloro] -2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phen i I urea; N- (2-bromophenyl) -N '[4-chloro-2-hydroxy-3- (N "-isoxazoiidinylaminosulfonyl) phenyl] urea N- [4-chloro-2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-chlorophenyl) -N' - [4-chloro- 2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) phenyl] urea N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyljurea; N- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] -N '- (2,3-dichloro phenyl) urea; N- (2-chlorophenyl) -N' - [4-chloro] -2-hydroxy-3-N "- (tetrahydroisoxazilaminosulfonyl) phenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-lsopropoxyethyl) aminosulfonyl] phenyl] urea; N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfoni!] Phenyl] -N '- (2,3-dichlorophenol) urea; N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] urea; N- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl phenyljurea; N- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonylphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3 - [(2-carboxy) -azetidin-1-yl] sulfonylphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-Bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propyI] aminosulfonyl] phenyl] urea hydrochloride; N- [4-Cioro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propyl] -aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea hydrochloride and N-hydrochloride - [4-chloro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propyl] aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl-sulphonylphenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) pyrrolidin-1-yl] sulfonylphenyljurea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonylphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) -pyrrolidin-1-ylsulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) -pyrrolidin-1-yl] sulfonyl-phenyl] -N '- (2-chlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) -pyrrolidin-1-yl] sulfonylphenii] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (- methoxycarbonyl) pyrrolidin-1-yl] sulfonylphenyljurea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S- (2-carboxy) pyrrolidin-1-yl] sulfonyl] urea N- (2-bromophenyl) -N '- [3- [N "- (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N" - (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- [3- [N "- (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] - N '- (2-chlorophenyl) urea; N- [3- [N "- [5- (tert-butoxycarbonyllamino) -5-carboxypentyl] aminosulfonyl] -4-chloro-2-hydroxy-phenyl] -N '- (2-chlorophenyl) urea; N- [3- [N "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea hydrochloride; N- [3- [ N "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea hydrochloride; N- [4-chloro-3] - (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-3- (1,1-dioxidothiomorpholinesulfonyl) ) -2-hydroxyphenyl] urea, N- [4-chloro-3- (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea N- [3- [N "- [2- (tert-butoxycarbonylamino) etl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [trifluoroacetate] 3- [N "- (2-aminoethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- [3- [N-trifluoroacetate] "- (2-aminoetiI) aminosulfonyl] -4-chloro-2-hydroxyphenyl] - N '- (2-chlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (N ", N" -dimethylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N '- (2-bromo-3-fluorophenyl) urea; N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N '- (2-chloro-3-fluorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylamino sulfonyl] -2-hydroxyphenyl] urea hydrochloride; N- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxy-phenyl] N '- (2,3-dichlorophenyl) urea hydrochloride; N- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxy phenyl] -N '- (2-chlorophenyl) urea hydrochloride; or a pharmaceutically acceptable salt thereof.

Methods of Preparation The compounds of Formulas (I) to (VII) can be obtained by the application of synthetic procedures, some of which are illustrated in the following schemes. The synthesis provided in these schemes is applicable for the production compounds of Formulas (I) to (VII), which have a variety of R groups., R-i and Z, which are reacted using optional substituents that are adequately protected to achieve compatibility with the reactions explained herein. In those cases, the subsequent deprotection then produces compounds of the nature described in general. Once the urea core is established, other compounds of these formulas can be prepared by applying standard techniques for the interconversion of functional groups well known in the art.

SCHEME 1 a) i) NCS, AcOH, H2O, ii NR'R ?, pir b) H2SO, HNO3 c) NaOAc, 18-crown-6 d) H2SO4, MeOH e) Pd / C, H2 f) RCNO, DMF 4 -chloro-N- (3-sulfonamido-2-hydroxyphenyl) -N "-phenylurea desired can be synthesized from commercially available 2,6-dichlorothiophenol, using the procedure elaborated in scheme 1. The thiol can be oxidized to the corresponding sulfonyl halide using a halogenating agent, such as NCS, NBS, Cl2 or Br2, in the presence of a protic solvent, such as water, acetic acid, or an alcohol or combination thereof. of pH, such as sodium or potassium acetate is included in the reaction mixture, and the mixture of The reaction is carried out at or below room temperature. Then, the corresponding sulfonyl halide can be condensed with an amine in the presence of a base, such as pyridine, triethylamine, potassium carbonate or sodium hydride to form the analogous sulfonamide 2 - scheme 1. The dichlorosulfonamide 2-scheme 1 can be nitrated using strong nitrates, such as nitric acid in sulfuric acid to form the aromatic nitro compound 3-scheme 1. Chloro ortho to the nitro group can be selectively hydrolyzed using acetate salt, such as sodium acetate in the presence of an ether crown, as -Cone-6, to form the acetate 4-scheme 1. The acetate group can be hydrolysed under acidic conditions in an alcohol solvent, such as methanol or ethanol with a catalytic amount of acid to form the phenol 5-scheme 1. The nitro can reduced by conditions already known in the art, such as hydrogen and palladium on carbon, tin chloride in methanol, zinc in acetic acid or thiol for ormar the corresponding aniline 5 - scheme 1. The aniline can be coupled with a commercially available isocyanate or tsocyanate to form the desired urea or thiourea. Alternatively, the desired isocyanates can be made by condensation of the amine with triphosphene in the presence of a base (such as potassium carbonate) or by reaction of the carboxylic acid with diphenylphosphorazide in the presence of a base (such as triethylamine).

SCHEME 2 a) NaH, R'X b) NaH R "X If the sulfonamide 1-scheme 2 (3-scheme 1) is non-functional R -R" = H, then it may be functional, as required herein, by means of . The sulfonamide is deprotonated using a base, such as sodium hydride and then alkylated using an alkyl halide, such as benzyl bromide or methyl iodide to form 2-scheme 2. The sulfonamide can be alkylated a second time using sodium hydride and another alkyl halide to form 3-scheme 2. This compound can then be converted to the desired urea using the procedure elaborated in scheme 1.

SCHEME 3 a) i) NCS, AcOH, H2O, ii) NaOH MeOH b) H2SO4, HNO3 c) NaOAc MeOH d) PCI5, POCI3 eJNHR'R ", EtsN An alternative route to 5 - scheme 3 (3-scheme 1) is mentioned previously, in Scheme 3, where the thiol of commercially available 2,6-dichloro can be oxidized to sulfonium halide using a halogenating agent, such as NCS, NBS, chlorine or bromine in the presence of a protic solvent, such as alcohol, acetic acid or water The sulfonyl halide can be hydrolyzed using a metal hydroxide, such as sodium or potassium hydroxide to form the corresponding sulphonic acid salt, then the sulfonic acid salt can be nitrated under nitrate conditions, such as acid nitric acid in a strong acid solvent, such as sulfuric acid to form the nitro phenyl sulphonic acid 3-scheme 3. The sulfonic acid 3-scheme 3 can be converted to the sulfonamide 5-scheme 3 using a three-step process covering the formation of the useful metal salt hoisting a base, such as sodium hydroxide, sodium hydride or sodium carbonate to form 4-scheme 3. The sulfonic acid salt is then converted to the sulfonyl chloride using PCI5 with POCI3 as a solvent. The sulfonyl chloride can be converted to the corresponding sulfonamide using the desired amine HNR'R "in triethylamine at temperatures ranging from -78 ° C to 60 ° C to form the corresponding sulfonamide 5-scheme 3 (3-scheme 1). 5-scheme 3 can also be made by the methods contained in scheme 1. This method is not limited to thiol 2, 6-dichlorophenyl, can also be applied to the thiol of 2,6-difluorophenyl, thiol of 2,6-dibromophenyl and thiol of 2,6-diiodophenyl. The halogens in these compounds can be converted to the corresponding cyano, amino, thiol or alkoxy compounds by nucleophilic displacement reactions using nucleophiles, such as alkylthiolates, alkoxides, amine and cyanides. Halogens can also be made functional by palladium coupling and carbonylation reactions, already known in the art, to form the corresponding substituted amido, carbonyl, alkenyl, alkyl, phenyl and heterocyclic products, as required by Formula (I) a (Vil).

The novel intermediates of the present invention encompass compounds of Formula (II), (III), (IV), (V), (VI) and (VII): (II) (IIO (IV)) (V) (VI) (VID where Ri is not hydrogen) The novel synthetic steps described by the present invention include the conversion of a chloro compound of formula (VII) to the phenol of formula (III) using sodium acetate and 18-C-6, followed by hydrolysis with sulfuric acid and methanol and the same transformation achieved in one step using sodium hydride and water in THF.

A novel synthetic step comprises the nitration of the sulfonic acid or sodium salt of formula (VIII) to the nitro compound of formula (IX) using nitric acid in sulfuric acid. R = H or Na SYNTHETIC EXAMPLES In the following, the invention will be described with reference to the following examples, which are only illustrative and will not constitute a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are of the highest purity available, and all reactions are carried out under anhydrous conditions in an argon atmosphere, unless otherwise indicated. In the examples, all temperatures are in degrees centigrade (° C). The mass spectrum was performed on a VG Zab mass spectrometer using rapid atom bombardment, unless otherwise indicated. The 1 H-NMR spectra (hereinafter "NMR") were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. The multiplicities indicated are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br indicates a broad signal. Sat., indicates a saturated solution, eq indicates the proportion of a molar equivalent of reactive agent relative to the main reagent. The purification, yields and spectral characteristics for each of the compounds are ed below.

EXAMPLE 1 Preparation of sodium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenol) urea and N- (2-bromophenyl) -N' - (4- chloro-2-hydroxy-3-aminosulfonylphenyl) urea 2.6-Dichlorobenzenesulfonyl Chloride In a mixture of 200 milliliters (hereinafter "my") of acetic acid, water and dichloromethane (3/1/4, v / v / v), 2,6-dichlorobenzothiol (10.0 grams) was added (hereinafter "g"), 55.8 millimoles (hereinafter "mmoles"), N-chlorosuccinimide (37.28 g, 279 mmoles) and potassium acetate (2.29 g, 27.9 mmoles) The resulting mixture was stirred at 0 °. C, then warmed to room temperature overnight.The mixture was then diluted with 200 ml of dichloromethane, and washed with water (100 ml x 3) .The organic layer was dried (Na2SO4) and concentrated to give the product desired (11 g, 80%). H NMR (CDCl 3): d 7.57 (d, 2 H), 7.47 (t, 1 H). 2,6-Dichlorobenzenesulfonamide A solution of 2,6-dichlorobenzenesulfonyl chloride (10.50 g, 42.77 mmoles) in 100 ml of pyridine was added dropwise to 100 ml of pyridine, while bubbles were formed in the anhydrous ammonia gas through of the solution. After 4 hours at 0 ° C, the mixture was acidified to pH > 1 with 6N ac. HCl, then extracted with ethyl acetate. The organic layer The mixture was then dried (Na2SO4) and concentrated to give the desired product (8.69 g, 90%). EI-MS (m / z) 225.0, 227.1 (M "). 2. 6-Dichloro-3-nitrobenzenesulfonamide In a solution of 2,6-dichlorobenzenesulfonamide (7.8 g, 34.5 mmoles) in 30 ml of concentrated sulfuric acid at 0 °, nitric acid (1.74 ml, 41.4 mmoles) was added dropwise. The mixture was stirred at 0 ° C for 2 hours, then 200 ml of water was added to produce a precipitate. The resulting mixture was filtered. The white solid was collected, washed with water and dried in vacuo to give the desired product (7.17 g, 76%). 1 H NMR (DMSO-de): d 8.25 (s, 2 H), 8.20 (d, 1 H), 7.92 (d, 1 H). 2-Acetyl-6-chloro-3-nitrobenzenesulfonamide A solution of 2,6-dichloro-3-nitrobenzenesulfonamide (2.04 g, 7.5 mmol), potassium acetate (2.21 g, 22.5 mmol) and 18-crown-6 (5.95 g) , 22.5 mmol) in 50 ml of dimethyl sulfoxide was heated at 45 ° C for 7 days. The mixture was acidified with 1 N aq HCl, and extracted with ethyl acetate. The organic layer was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (50/49/1, v / v / v) gave the desired product (1.67 g, 76%). EI-MS (m / z) 293.1, 295.1 (M "). 6-Chloro-2-hydroxy-3-nitrobenzenesulfonamide A solution of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (1.72 g, 5.83 mmol), chlorotrimethylsilane (2 ml) and fuming sulfuric acid (0.5 ml) in methanol was heated under reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (1.0 g, 68%). EI-MS (m / z) 251.1, 253.2 (M ~). 3-Amino-6-chloro-2-hydroxybenzenesulfonamide To a solution of 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.1 g, 4.36 mmol) in ethyl acetate, 10% Pd / C (500 mg) was added. The mixture was subjected to jets of argon, and then stirred under an atmosphere of hydrogen at balloon pressure for 4 hours at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give the desired product (0.9 g, 93%). EI-MS (m / z) 221.1, 223.1 (M-).

N- (4-chloro-2-hydroxy-3-aminophenylethyl) -N '- (2,3-dichlorophenyl) urea A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.88 g, 3.9 mmol) and 2.3 Dicyl-phenyl-isocyanate (0.62 ml, 4.6 mmol) in 5 ml of N, N-dimethyl-formamide was stirred at room temperature for 20 hours.

The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by gel column chromatography of silica, eluting with ethyl acetate / hexane (30/70 to 50/50, v / v), followed by recrystallization from dichloromethane and hexane, gave the desired product (1.18 g, 74%). Mp 241-242 ° C.

N- (2-bromophenyl) -N '- (4-chloro-2-hydroxy-3-aminosulfonyl-phenyl) urea A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (65 mg, 0.29 mmol) and 2.3 Dichlorophenylisocyanate (45μl, 0.36mmol) in 2ml of N, N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70 to 40/60, v / v), gave the desired product (50 mg, 41%). EI-MS (m / z) 418.2, 420.2, 422.2 (M ").

Sodium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylpheni0-N '- (2,3-dichlorophenyl) urea To a solution of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N' - (2,3-dichlorophenyl) urea (1.47 g, 59 mmol) in 150 ml of acetone was added 2.46 ml of aq NaOH solution (1.45 M) .The mixture was stirred for 16 hours at room temperature and the solvent was added. The residue was recrystallized from acetone and dichloromethane to give the desired product (1.41 g, 91%). 1 H NMR (DMSO-de): d 9.27 (s, 2H), 8.01 (m, 3H), 7.77 ( d, 1H), 7.26 (m, 2H), 6.05 (d, 1H).

EXAMPLES 2 AND 3 Preparation of N- [3- (N "-benzylaminosulfonyl) - - chloro - 2 - hydroxyphenyl] - N '- (2,3-dichlorophenH) urea and N- [3- (N" -benzylaminosulfonyl) -4- chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea N-benzyl-2-acetyl-6-chloro-3-nitro-benzenesulfonamide A mixture of 2-acetyl-6-chloro-3-nitro-benzenesulfonamide (500 mg, 1.69 mmol), potassium carbonate (469 mg, 3.39 mmol) ) and benzyl bromide (0.24 ml, 2.0 mmol) in 20 ml of N, N-dimethylformamide was heated at 75 ° C for 24 hours. The mixture was acidified with 1 N aq HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (50/49/1, v / v / v), gave the desired product (274 mg, 42%). EI-MS (m / z) 383.3, 385.3 (M ").

N-benzyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide A solution of N-benzyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (225 mg, 0.59 mmol), 0.1 ml of chlorotrimethylsilane and drops of fuming sulfuric acid in ethanol was heated under reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (189 mg, 94%). 1 H NMR (DMSO-d 6): d 7.92 (d, 1H), 7.18 (m, 5H), 6.93 (d, 1H), 4.15 (s, 2H).

N-Benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide To a solution of N-benzyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (180 mg, 0.52 mmol) in ethyl acetate was added 10% of Pd / C (70 mg). The mixture was subjected to jets of argon, then stirred under an atmosphere of hydrogen under balloon pressure for 1 hour at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give the desired product (140 mg, 85%). 1 H NMR (DMSO-de): d 8.73 (t, 1H), 7.24 (m, 5H), 6.78 (d, 1 H), 4.09 (d, 2H).

N-r3- (N "-benzylaminosulfonin-4-chloro-2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (54 mg, 0.17 mmoles) and 2,3-dichlorophenylisocyanate (34 μl, 0.26 mmoles) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours.The mixture was diluted with ethyl acetate and washed with water to give the material The purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (60/40, v / v), gave the desired product (10 mg, 12%). EI-MS (m / z) 498.2, 500.1, 502.1 (M-).

N- [3- (N "-benzylammonosulfonyl) -4-chloro-2-hydroxy-phenyl] -N '- (2-bromophenyl) urea A solution of N-benzyl-3-amino-6-chloro-2 -hydroxybenzene sulfonamide (54 mg, 0.17 mmol) and 2,3-dichlorophenylisocyanate (80 mg, 0.26 mmol) and 2-bromophenylisocyanate (47 μl, 0.38 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours The mixture was diluted with ethyl acetate and washed with water to give the crude material, purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70 to 70/30, v / v). ), gave the desired product (80 mg, 61%) EI-MS (m / z) 508.1, 510.2, 512.2 (M ").

EXAMPLES 4 and 5 Preparation of N- [4-chloro-3- (N ". N" -dimethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- (2-bromophenyl) - N'-r4-chloro-3- (N ". N" - dimethylaminosulfonyl) -2-hydroxyphenyl-urea NN-dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide To a mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (300 mg, 1.02 mmol) and sodium hydride (122 mg, 3.06 mmol) in 10 ml. ml of N, N-dimethylformamide was added iodomethane (0.64 ml, 10.2 mmol). The mixture was stirred at room temperature for 20 hours. The resulting mixture was acidified with 1N aq HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Gel column chromatography of silica, eluting with ethyl acetate / hexane / acetic acid (50/49/1, v / v / v), gave the desired product (140 mg, 49%). 1 H NMR (DMSO-d 6): d 8.05 (d, 1 H), 7.03 (d, 1H), 2.87 (s, 6H).

NN-Dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide To a solution of N, N-dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (140 mg, 0.50 mmol) in ethyl acetate was added 10% Pd / C (50 mg). The mixture was subjected to nitrogen jets, then stirred under an atmosphere of hydrogen under balloon pressure for 1.5 hours at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give the desired product (100 mg, 80%) 1 H NMR (DMSO-de): d 6.87 (d, 1H), 6.80 (d, 1H), 2.82 (s, 6H).

N- [4-chloro-3-fN ".N" -dimethalaminosulfonyl-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea A solution of N, N-dimethyl-3-amino- 6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2,3-dichlorophenylisocyanate (50 μl, 0.38 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (20/80, v / v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (63). mg, 45%). 1 H NMR (DMSO-d 6): d 10.51 (s, 1 H), 9.34 (s, 1 H), 9.27 (s, 1 H), 9.27 (s, 1 H), 8.29 (d, 1 H), 7.32 (m, 2H), 7.16 (d, 1H), 2.87 (s, 6H).

N- (2-bromophenyl) -N '- [4-chloro-3- (N ". N" -dimethylaminosulfonyl) -2-hydroxyphenyljurea A solution of N, N-dimethyl-3-amino-6-chloro-2-hydroxybenzene sulfonamide (80 mg, 0.32 mmol) and 2-bromophenylisocyanate (47 μl, 0.38 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (20/80, v / v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (88 mg, 62%). EI-MS (m / z) 446.2, 448.3, 450.3 (M ").

EXAMPLES 6 and 7 Preparation of N- [4-chloro-2-hydroxy-3- (N "-methylaminosulfonyl) phenyl] -N'- (2,3-dichloropropyl) urea and N- (2-bromophenyl) -N ' - [4-chloro-2-hydroxy-3- (N "-methylaminosu! Fonyl) phenyl] urea N-Methyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide To a mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (300 mg, 1.02 mmol) and sodium hydride (53 mg, 1.32 mmol) in 10 g. ml of N, N-dimethylformamide was added iodomethane (70 ml, 1.12 mmol). The mixture stirred at room temperature for 66 hours. The mixture was acidified with 1 N aq HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (50/49/1, v / v / v), gave the desired product (185 mg, 59%). EI-MS (m / z) 307.3, 309.3 (M ").

N-Methyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide A solution of N-methyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (170 mg, 0.55 mmole), 0.5 ml of chlorotrimethylsilane and 3 drops of Fuming sulfuric acid in ethanol was heated under reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO) and concentrated to give the desired product (160 mg,> 100%). EI-MS (m / z) 265.2, 267.2 (M).

N-Methyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide To a solution of N-methyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (140 mg, 0.53 mmol) in ethyl acetate was added 10 g. % of Pd / C (60 mg). The mixture was subjected to jets of argon, then stirred under an atmosphere of hydrogen at balloon pressure for 1.5 hours at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give the desired product (160 mg,> 100%) 1 H NMR (DMSO-de): d 7.95 (bs, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 2.48 ( d, 3H).

N- [4-chloro-2-hydroxy-3- (N "-methylaminosulfonyl) phen.p-N '- (2,3-dichlorophenyl) urea A solution of N-methyl-3-amino-6-chloro-2-hydrox Benzene sulfonamide (70 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (57 μL, 0.44 mmol) in 2 mL of N, N-dimethylformamide was stirred at room temperature for 66 hours.The mixture was diluted with ethyl acetate and it was washed with water to give the crude material, purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), gave the desired product (60 mg, 49%, three steps) EI-MS (m / z) 422.3, 424.3, 426.3 (M-).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-methylaminosulfonyl) phenyljurea A solution of N-methyI-3-amino-6-chloro-2-hydroxybenzene sulfonamide (70 mg, 0.29 mmol) and 2-bromophenylisocyanate (55 μl, 0.44 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 66 hours.The mixture was diluted with ethyl acetate and washed with water to give the crude material Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), gave the desired product (85 mg, 67%, three steps). m / z) 432.3, 434.3, 436.3 (M-).

EXAMPLE 8. 9. 10 and 11 Preparation of N- [4-chloro-2-hydroxy-3- [N "- [2- (methoxycarbonyl) -methinamnosulfonyl] phenyl-N '- (2,3-dichlorophenyl) urea, N- [3- [N "- (2-carboxymethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichloropheniCurea) N- (2-bromophenyl) -N' - [4-chloro- 2-hydroxy-3- [N "- [2- (methoxycarbonyl) methyS] aminosulfonyl] phenyl] urea and N- (2-bromophenyl) -N '- [3- [N" - (2-carboxymethyl) aminosulfonyl] -4-chloro-2-hydroxy-phenyl urea N- [2- (methoxycarbonyl) methyl] -2-acetyl-6-chloro-3-nitrobenzenesulfonamide To a mixture of 2-acetyl-6-cynor-3-nitrobenzenesulfonamide (300 mg, 1.02 mmol) and sodium hydride ( 81 mg, 2.02 mmol) in 10 ml of N, N-dimethylformamide was added methyl bromoacetate (106 μl, 1.12 mmol). The mixture was heated at 80 ° C for 20 hours, followed by the addition of more sodium hydride (81 mg, 2.02 mmol) and stirring at room temperature for 66 hours. The mixture was acidified with 1N aq HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (60/39/1, v / v / v), gave the desired product (350 mg, 95%). 1 H NMR (DMSO-de): d 7.76 (d, 1H), 6.12 (d, 1H), 4.57 (s, 2H), 3.66 (s, 3H), 2.22 (s, 3H).

N- [2- (methoxycarbonyl) methyl-1-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide A solution of N- [2- (methoxycarbonyl) methyl] -2-acetyl-6-chloro-3-nitrobenzenesulfonamide (350 mg , 0.95 mmole), 0.5 ml of chlorotrimethylsilane and 3 drops of fuming sulfuric acid in methanol was heated under reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (182 mg, 59%). EI-MS (m / z) 323.0, 325.0 (M ").

N- [2- (methoxycarbonyl) methyl-3-amine-6-chloro-2-hydroxybenzenesulfonamide To a solution of N- [2- (methoxycarbonyl) methyl] -6-chloro-2-hydroxy-3- Nitrobencenesulfonamide (170 mg, 0.52 mmol) in ethyl acetate, added 10% Pd / C (80 mg). The mixture was subjected to hydrogen jets, then stirred under an atmosphere of hydrogen at balloon pressure for 3 hours at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give a mixture of the desired product and impurity. The mixture was used for the next step without further purification. 1 H NMR (DMSO-de): d 8.68 (m, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 3.83 (s, 2H), 3.53 (s, 3H).

N- [4-chloro-2-hydroxy-3- [N "- [2- (methoxycarbonyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea A solution of N- [2- (methoxycarbonyl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.26 mmol) and 2,3-dichlorophenylisocyanate (41 μl, 0.31 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material, purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (40/60, v / v), gave the desired product. (35 mg, 28% for two steps) EI-MS (m / z) 479.9, 482.0, 483.9 (M-).

N- [3- [N "- (2-carboxymethyl) aminosulfonyl] -4-chloro-2-hydroxyfenp-N '- (2,3-dichlorophenyl) urea A mixture of N- [4-chloro-2- hydroxy-3- [N "- [2- (methoxycarbonyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenol) urea (20 mg, 0.041 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmoles) in 5 ml of methanol (95%) was stirred at room temperature for 20 hours. The mixture was acidified with 1N aq HCl, to produce a white precipitate. The resulting mixture was then filtered, the white solid was collected and dried in vacuo to give the desired product (15 mg, 78%). EI-MS (m / z) 465.9, 467.9, 469.9 (M-).

N- (2-bromophenyl VN '- [4-cioro-2-hydroxy-3- [N "-r2-methoxycarbonyl) met!!] Anesulfonyl] phenyl] urea A solution of N- [2- (methoxycarbonyl ) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.26 mmol) and 2-bromophenylisocyanate (38 μl, 0.31 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours. it was diluted with ethyl acetate and washed with water to give the crude material, purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), gave the desired product ( 40 mg, 31% for two steps) EI-MS (m / z) 489.9, 491.9, 493.9 (M ~).

N- (2-bromophenyl) -N '- [3- [N "- (2-carboxymethyl) aminosulfonyl] -4-c [oro-2-hydroxyphenipiourea A mixture of N- (2-bromophenyl) -N' - [ 4-chloro-2-hydroxy-3- [N "- [2- (methoxycarbonyl) methyl] aminosulfoniI] phenyl] urea (15 mg, 0.03 mmol) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) in 5 ml of methanol (95%) was stirred at room temperature for 20 hours. The mixture was acidified with 1N aq HCl, to produce a white precipitate. The resulting mixture was then filtered, the white solid was collected and dried in vacuo to give the desired product (10 mg, 70%). 476.1, 478.1, 490.1 (M "). With the use of analogous methods to those indicated above, the following additional compound was prepared: EXAMPLE 12 N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2-chlorophenyl) urea A solution of 3-amino-6-chloro-2-hydroxybenzenesuiphenamide (40 mg, 0.18 mmol) and 2-chlorophenylisocyanate (33 mg, 0.22 mmol) in 1 ml of N, N-dimethylformamide was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), followed by recrystallization from acetone and hexane, gave the desired product (30 mg, 44%). EI-MS (m / z) 374.3, 376.1 (M ").

EXAMPLE 13 Preparation of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N'-phenyl) urea Following the general procedure for the formation of urea, described in Example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and phenylisocyanate (32 mg, 0.27 mmol) were coupled to form the desired urea (25 mg, 41%). EI-MS (m / z) 340.3, 342.3 (M ').

EXAMPLE 14 N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2-phenoxyphenyl) urea Following the general procedure for the formation of urea, described in Example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-phenoxyphenylisocyanate (46 mg, 0.22 mmol) were coupled to form the desired urea (41 mg, 52%). 1 H NMR (DMSO-d): d 10.69 (s, 1 H), 9.25 (2, 1 H), 9.11 (s, 1 H), 8.18 (m, 4 H), 7.41 (m, 2 H), 7.04 (m, 8H), 6.84 (d, 1 H).

EXAMPLE 15 and 16 Preparation of sodium salt of N- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) aminosulfonyl] phenyl-N '- (2,3-diclphenyl) urea and N- ( 2- bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) -aminosulfonyl] phenyl] urea The following is the general procedure for the formation of sulfonamides.

N- (2-methoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide In a solution of 2,6-dicyoro-3-nitrobenzenesulfonyl chloride (600 mg, 2.06 mmol) in 15 ml of dichloromethane at -78 ° C was added drop to drop a solution of 2-methoxyethylamine (155 mg, 2.06 mmol) and triethylamine (770 μl, 5.15 mmol) in 10 ml of dichloromethane. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was acidified to pH > 1 with 1N aq HCl, then the combined organic layer was extracted with ethyl acetate, then concentrated to give the crude material. Chromatography on gel, eluting with ethyl acetate / hexane (30/70, v / v), gave the desired product (640 mg, 94%). EI-MS (m / z) 327.1, 329.1 (M-). The following is the general procedure for the hydrolysis of dichlorosulfonamide to phenol.

N- (2-methoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide A mixture of N- (2-methoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide (490 mg, 1.49 mmol), 60% sodium hydride ( 179 mg, 4.47 mmol) was heated to 35 ° C while it was kept under an argon atmosphere for 3 days. The reaction was monitored by 1 H NMR. 0.1 equivalent of water was added to the mixture when the reaction had not been completed. The solvent was evaporated when the almost complete reaction was indicated by 1 H NMR. The residue was diluted with ethyl acetate and washed with 1 N aq HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (40/58/2, v / v / v), gave the desired product (270 mg, 58%) EI-MS (m / z) 309.1, 311.1 (MT).

The following is the general procedure for the hydrogenation of nitro compound to aniline.

N- (2-methoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide To a solution of N- (2-methoxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (260 mg, 0.84 mmol) in ethyl acetate, 10% Pd / C (100 mg) was added. The mixture was subjected to jets of argon, and then stirred under a hydrogen atmosphere at balloon pressure for 3 hours at room temperature. The mixture was filtered through celite and this was washed with methanol. The solvent was evaporated to give the desired product (210 mg, 89%). EI-MS (m / z) 281.1, 283.1 (M ") The following is the general procedure for the formation of urea.

N- [4-chloro-2-hydroxy-3-fN "-f2-methoxyethylaminosuifonyl] phenyl] -N'- (2,3-dichlorophenyl) urea A solution of N- (2-methoxyethyl) -3-amino-6-chloro -2-hydroxybenzenesulfonamide (772 mg, 2.75 mmol) and 2,3-dichlorophenylisocyanate (560 mg, 3.03 mmol) in 2 ml of N, N-dimethylformamide was stirred at room temperature for 18 hours. ethyl acetate and washed with water to give the crude material, purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), followed by recrystallization from acetone and hexane, gave the desired product (720 mg, 56%). Theory of analysis of elements: C 41.00%, H 3.44%, N 8.96%, Found: C 40.77%, H 3.28%, N8.83%. The following is the general procedure for the formation of sodium salt.

Sodium salt of N- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) amino sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea To a solution of N- [4- Chloro-2-hydroxy-3- [N "- (2-methoxyethyl) I) sulfonyl] phenyl] -N '- (2,3-dichlorophenol) urea (307 mg, 0.66 mmol) in 30 ml of acetone were added 1.20 ml of a solution of NaOH aq, (0.54 M). The mixture was stirred for 16 hours at room temperature and the solvent was evaporated. The residue was recrystallized from acetonitrile to give the desired product (288 mg, 89%). 1 H NMR (DMSO-d 6): d 9.31 (s, 1 H), 8.00 (d, 1 H), 7.78 (d, 1 H), 7.26 (m, 2 H), 6.05 (d, 1 H), 3.36 (t , 2H), 3.20 (s, 3H), 2.80 (m, 2H).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) amino sulfonyl] phenyl] urea Following the general procedure for the formation of urea described in the example 15, N- (2-methoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (140 mg, 0.50 mmol) and 2-bromophenylisocyanate (119 mg, 0.60 mmol) were coupled to form the desired urea (174 mg, 72%). EI-MS (m / z) 476.0, 478.0, 479.9 (M ').

EXAMPLE 17 Preparation of N- [4-chloro-2-hydrox8-3- (3-carboxyethylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea a) N-f3-ethoxycarbonylethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.17 mmol), ß-aniline ethyl ester (0.95 ml, 6.2 mmol) and triethylamine (1.8 ml, 12.9 mmol) were reacted to form the desired product (1.8 g, 94%). EI-MS m / z 370 (M-H) '. b) N- (3-carboxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (3-ethoxycarbonylethyl) -2,6-dichloro-3-nitrobenzenesulfonamide (1.82 g, 4.9 mmole), NaH (60%, 588 mg, 14.7 mmole) and water (106 mg, 5.88 mmole) were reacted to form the desired product (1.0 g, 63%). EI-MS m / z 323.5 (M-H) \ c) N- (3-carboxymethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- (3-carboxyethyl) -6-chloro-2-hydroxy -3-nitrobenzenesulfonamide (100 g, 0.3 mmol) was reduced with hydrogen and Pd / C (100 mg) to form the desired product (62 g, 68%). EI-MS m / z 293.5 (M-H) \ d) N- [4-chloro-2-hydroxy-3- (3-carboxyethylaminosulfonyl) phenyl] -N '- (2-bromopheniDurea) Following the general procedure for the formation of urea described in Example 15, N- (3- carboxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (62 mg, 021 mmol) and 2-bromophenylisocyanate (42 mg, 0.21 mmol) were coupled to form the desired urea (35 mg, 34%).

EI-MS m / z 491.7 (M-H) ".

EXAMPLE 18, 19 and 20 Preparation of N- (2-bromophenyl) sr- [4-chloro-2-hydroxy-3- (isopropylaminosulfonyl) phenyl] urea. N- [4-chloro-2-hydroxy-3- (isopropylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea and N- [4-chloro-2-hydroxy-3- (isopropylaminosuifonyl) phenyl] -N' - (2,3-dichlorophenyl) urea a) N-isopropyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.17 mmol), isopropylamine (0.44) m, 5.17 mmole) and triethylamine (1.08 ml, 7.76 mmole) were reacted to form the desired product (1.3 g, 81%). EI-MS m / z 312 (M-H) ". b) N-isopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general procedure of hydrolysis described in example 15, N-isopropyl-2,6-dichloro-3-nitrobenzene sulfonamide (1.3 g, 4.15 mmol), NaH (60%, 500 mg, 12.45 mmol) and water (89 mg, 4.98 mmol) were reacted to form the desired product (0.7 g, 57%). EI-MS m / z 293.5 (M-H) -. c) N-isopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N-isopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.7 g, 2.38 mmol. ) was reduced with hydrogen and Pd / C (0.7 g) to form the desired product (0.62 g, 98%). EI-MS m / z 263.5 (M-H) ". d) N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (isopropylaminosulfonyl) phenyljurea Following the general procedure for the formation of urea described in Example 15, N-isopropyl-3 -amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.88 mmol) and 2-bromophenylisocyanate (174 mg, 0.88 mmol) were coupled to form the desired urea (110 mg, 29%). EI-MS m / z 461.7 (M-H) ". e) N- [4-Chloro-2-hydroxy-3- (isopropylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea described in Example 15, N-isopropyl-3 -amino-6-c! gold-2-hydroxybenzenesulfonamide (188 mg, 0.75 mmol) and 2,3-dichiorophenylisocyanate (141 mg, 0.75 mmol) were coupled to form the desired urea (104 mg, 32%). El-EM m / z 451. 7 (M-H) -. f) N- [4-chloro-2-hydroxy-3- (isopropylaminosulfonyl) phenyl] -N'-f2-chlorophenyl) urea Following the general procedure for the formation of urea described in Example 15, N-isopropyl-3- amino-6-chloro-2-hydroxybenzene sulfonamide (220 mg, 0.88 mmol) and 2-chlorophenylisocyanate (135 mg, 0.88 mmol) were coupled to form the desired urea (110 mg, 32%). El-MS m / z 417.1 (M-H) -.

EXAMPLE 21 N- (4-chloro-2-hydroxy-3-aminosulfonylpheni) -N '- (2-methoxyphenyl) urea Following the general procedure for the formation of urea described in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-methoxyphenylisocyanate (33 mg, 0.22 mmol) were coupled to form the desired urea (23 mg, 34%). El-MS m / z 370.3, 372.1 (M-H) -.

EXAMPLE 22 N- (4-Cioro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-methylenedioxyphenyl) urea 2.3- (methylenedioxy) benzoic acid A solution of benzaldehyde of 2,3- (methylenedioxy) (160 mg, 1.06 mmol), potassium carbonate (960 mg, 6.9 mmol) and 2.4 ml of hydrogen peroxide (30-32%) weight of solution in water) in 10 ml of methanol was stirred for 16 hours at room temperature. The mixture was washed with diethyl ether. The water layer was acidified with 1N aq HCl, at pH > 1, then extracted with ethyl acetate. The organic layer was dried over MgSO4, then concentrated to give the desired product (170 mg, 96%). El-MS m / z 164.8 (M ").

N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-methylenedioxyphenyl) urea A mixture of 2,3- (methylenedioxy) benzoic acid (170 mg, 1.02 mmol), diphenylphosphoryl azide (338 mg, 1.23 mmole) and triethylamine (0.17 ml, 1. 23 mmole) was stirred at room temperature for 3 days. The mixture was concentrated. To the residue in 1 ml of N, N-dimethylformamide was added 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, o.18 mmol). The resulting mixture it was stirred at room temperature for 16 hours. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (50/50, v / v), gave the desired product (40 mg, 10%). EMI (m / z) 386.2, 388.2 (M ").

EXAMPLE 23 N- (2-benzyloxyphenyl) -N '- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) urea Following the general procedure for the formation of urea described in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (52 mg, 0.23 mmol) and 2-benzyloxyphenylisocyanate (40 mg, 0.17 mmol) were coupled to form urea desired (20 mg, 26%). El-EM m / z 446.2, 448.3, 450. 2 (M-).

EXAMPLE 24 N-f3- (N "-alkylaminosulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea N-allyl-2-acetyl-6-chloro-3-nitro-benzenesulfonamide A mixture of 2-acetyl-6-chloro-3-nitrobenzene sulfonamide (150 mg, 0.51 mmol), potassium carbonate (84 mg, 0.61 mmol) and Allyl bromide (0.18 ml, 2.0 mmol) in 3 ml of N, N-dimethylformamide was heated at 60 ° C for 4 days. The mixture was acidified with 1N aq HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. The column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (50/49/1, v / v / v), gave the desired product (40 mg, 12%). EMI (m / z) 333.3, 335.2 (M ").

N-allyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide A solution of N-ali! -2-acetyl-6-chloro-3-nitrobenzenesulfonamide (30 mg, 0.09 mmol), 0.1 ml of chlorotrimethylsilane and 2 drops of Fuming sulfuric acid in ethanol was heated under reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was dried (Na 2 S 4) and concentrated to give the desired product (26 mg, 100%). 1 H NMR (MeOD-d 4): d 8.01 (d, 1 H), 7.20 (d, 1 H), 5.70 (m, 1 H), 5.16 (m, 1 H), 5.05 (m, 1 H), 3.62 (m , 2H).

N-allyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide A solution of N-allyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (25 mg, 0.09 mmol) and tin (II) chloride dehydrated ( 101 mg, 0.44 mmol) in 5 ml of ethanol was stirred at room temperature. The mixture was concentrated, the residue was diluted with ethyl acetate and 10% aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the desired product (20 mg) which was carried out in the next step without purification. EMI (m / z) 263.1, 265.2 (M ").

N- [3- (N "-arylaminosulfonyl-V-4-chloro-2-hydroxyphenyl] -N '- (; 2,3-dichloropheni-Durea) A solution of N-allyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (20 mg) and 2,3-dichlorophenylisocyanate (12 μl, 0.09 mmol) in 1 ml of N, N-dimethylformamide was stirred at room temperature for 20 hours.The mixture was diluted with ethyl acetate and washed with water to give the crude material. purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (30/70, v / v), gave the desired product (10 mg, 29% for two steps) .The-MS (m / z) 450.2, 452.2, 454.1 (M ").

EXAMPLE 25 Preparation of N- [4-chloro-2-hydroxy-3- [N "- (2-trifluoroethyl) aminosulfonyl] phenyl-N '- (2,3-dichlorophenyl) urea 2,6-Dichloro-3-nitrobenzenesulfonic acid Lithium hydroxide hydrate (12.64 g, 0.301 mmol) was added to a solution of 2,6-dichlorobenzenesulfonyl chloride (35.53 g, 0.146 mmol in MeOH (600 mL) and the reaction the mixture was allowed to stir at room temperature for 3 hours, the reaction mixture was filtered to remove the suspended solids and then concentrated.The resulting solid was dried in vacuo overnight to remove any residual MeOH.The solid was dissolved in H2SO4 (300 ml) and cooled in an ice bath A solution of H2SO4 (35 ml) and HNO3 (13.2 ml) was added slowly to the above reaction for 90 minutes.

The reaction was allowed to warm to room temperature overnight and then poured slowly into ice water (1200 ml) and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to yield 2,6-dichloro-3-nitrobenzenesulfonic acid (44.35 g, 99%) as the dihydrate. El-MS (m / z) 270 (M-H) ". 2,6-Dichloro-3-Nitrobenzenesulfonyl Chloride Potassium hydroxide (12.07g, 0.215 mmol) was added to a solution of 2,6-dichloro-3-nitrobenzenesulfonic acid dihydrate (44.35b, 0.144 mmol) in MeOH (850 mi) and the reaction was allowed to stir at room temperature for 14 hours. The reaction mixture was concentrated and the resulting solid was dried in vacuo overnight. To this was added PCI5 (30.00g, 0.144 mmol) followed by POCI3 (475 ml) and the mixture was refluxed overnight. The reaction was then cooled to room temperature and concentrated. The resulting mixture was taken up in EtOAc and cooled in an ice bath. Chunks of ice were slowly added to the reaction mixture to quench any remaining PCI5. When the formation of bubbles was stopped, water was added and the reaction mixture was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to yield 2,6-dichloro-3-nitrobenzenesulfonyl chloride (40.42 g, 97%). 1 H NMR (DMSO-de): d 7.88 (d, 1 H), 7.75 (d, 1 H).

N- (2-trifluoroethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (560 mg, 1.93 mmol), hydrochloride of 2-trifluoroethylamine (261 mg, 1.93 mmole) and triethylamine (0.89 ml, 5.79 mmole) were reacted to form the desired product (490 mg, 72%). The-MS (m / z) 351. 1, 353.1 (M ").

N- (2-trifluoroethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide To a solution of N- (2-trifluoroethyl) -2,6-dichloro-3-nitrobenzenesulfonamide (130 mg, 0.36 mmole) in 5 ml of tetrahydrofuran was added 60% NaH (43 mg, 1.08 mmol) and methanol (15 μl, 0.36 mmol). The mixture was stirred for 16 hours at room temperature. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (49/50/1, v / v / v), gave the desired product (44 mg, 33%). EMI (m / z) 333.1, 335.1 (M ").

N- (2-trifluoroethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- (2-trifluoroethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (40 mg, 0.12 mmol) was reduced with hydrogen and 10% Pd / C (20 mg) to form the desired product (36 mg, 100%). EMI (m / z) 303.1, 305.1 (M ").

N- [4-chloro-2-hydroxy-3- [N "- (2-trifluoroethyl) aminosulfonyl-1-phenyl-1 - N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea described in Example 15, N- (2-trifluoroethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (36 mg, 0.12 mmol) and 2,3-dichlorophenylisocyanate (27 mg, 0.14 mmol) were coupled to form the desired urea (23 mg 38%). 1 H NMR (MeOD-d 4): d 8.28 (d, 1H), 8.05 (m, 1H), 7.24 (m, 2H), 7.05 (d, 1H), 3.79 (m, 2H).

EXAMPLE 26 and 27 Preparation of N- (2,3-dichlorophenyl) -N'-r 2 -hydroxy-4-methoxy-3- (N "-phenylamino-S-sulfonyl) -phenylurea and N- (2-bromophenyl) -N '- [2 -hydroxy-4-methoxy-3- (N "-phenylaminosulfonyl) phenyl] urea N-phenyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (540 mg, 1.85 mmol), aniline (173 mg, 1.85 mmole) and triethylamine (0.61 ml, 5.55 mmole) were reacted to form the desired product (130 mg, 20%). 1 H NMR (MeOD-d 4): d 7.65 (d, 1 H), 7.58 (d, 1 H), 7.40 (t, 2 H), 7.15 (m, 3 H).

N-Phenylt-2-hydroxy-6-methoxy-3-nitrobenzenesulfonamide Following the hydrolysis procedure described in the example , N-phenyl-2,6-dichloro-3-nitrobenzenesulfonamide (130 mg, 0.37 mmol), 60% NaH (44 mg, 1.11 mmol) and methanol (15 μl, 0.37 mmol) were reacted. The crude mixture (70 mg) was continued in the next step without purification.

N-Phenyl-3-amino-2-hydroxy-6-methoxybenzenesulfonamide Following the general hydrogenation procedure described in example 15, crude N-phenyl-2-hydroxy-6-methoxy-3-nitrobenzenesulfonamide (70 mg) was reduced with hydrogen and 10% Pd / C (35 mg). The crude mixture was continued to the next step without purification.

N- (2,3-dichlorophenyl VN '- [2-hydroxy-4-methoxy-3-fN "-phenylamino sulfonyl) -phenyl] urea Following the general procedure for the formation of urea, described in Example 15, N-phenyl-3 Crude-amino-2-hydroxy-6-methoxybenzene sulphonamide and 2,3-dichlorophenylisocyanate (43 mg, 0.23 mmol) were coupled to form the desired urea (3.5 mg, 4% for 3 steps) .The-MS (m / z) ) 480.2, 482.1 (M ").

N- (2-bromophenyl) -N '- [2-hydroxy-4-methoxy-3- (N "-phenylaminosulfonyl) -phenyljurea Following the general procedure for the formation of urea, described in Example 15, N-phenyl- Crude 3-amino-2-hydroxy-6-methoxybenzene sulphonamide and 2-bromophenylisocyanate (46 mg, 0.23 mmol) were coupled to form the desired urea (5.0 mg, 5.6%). The MS (m / z) 490.1, 492.1 (M ").

EXAMPLE 30 and 31 Preparation of N- (2-bromophenH) -N '- [4-chloro-2-hydroxy-3- (4-morpholinylsulfonyl) phenyl] urea and N- [4-chloro-2-hydroxy-3-] (4- morpholinysulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea 2. 6-dichloro-1- (4-morpholinyl sulfonyl) -3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol. ), morpholine (150 mg, 1.72 mmole) and triethylamine (479 μL, 3.44 mmole) were reacted to form the desired product (430 mg, 73%). CC-MS (m / z) 341.0 (M "). 6-Chloro-2-hydroxy-1- (4-morpholinylsulfonyl) -3-nitrobenzene Following the general hydrolysis procedure described in Example 15, 2,6-dichloro-1- (4-morpholinosulfonyl) -3-nitrobenzene (410 mg, 1.20 mmoles), 60% NaH (144 mg, 3.6 mmol) and water (26 μl, 1.44 mmol) were reacted to form the desired product (220 mg, 57%). EMI (m / z) 321.1, 323.1 (M "). 4-Chloro-2-hydroxy-3- (4-morpholinylsulfonyl) aniline Following the general hydrogenation procedure described in Example 15, 6-chloro-2-hydroxy-1- (4-morpholinylsulfonyl) -3-nitrobenzene (210 mg , 0.65 mmole) was reduced with hydrogen and Pd / C (100 mg) to form the desired product (180 mg, 95%). 1 H NMR (MeOD-d 4): d 6.28 (m, 2 H), 3.68 (t, 4 H), 3.30 (t, 4 H).

N- (2-BrQophenyl) -N '- [4-chloro-2-hydroxy-3- (4-morpholinylsulfonyl) phenyl] urea Following the general procedure for the formation of urea described in Example 15, 4-chloro-2 -hydroxy-3- (4-morpholinylsulfonyl) aniline (90 mg, 0.31 mmol) and 2-bromophenylisocyanate (46 μl, 0.37 mmol) were coupled to form the desired urea (81 mg, 53%). El-MS (m / z) 487.76, 489.75, 491. 74 (M ").

N-f4-chloro-2-hydroxy-3- (4-morpholinyl-sulfonyl-phenyl] -N'-r2.3-dichloro-phenyl) urea Following the general procedure for the formation of urea described in example 15, 4 -chloro-2-hydroxy-3- (4-morfoinnylsulfonyl) aniine (90 mg, 0.31 mmol) and 2,3-dichlorophenylisocyanate (70 μl, 0.37 mmol) were coupled to form the desired urea (77 mg, 52%). El-MS (m / z) 477.68, 479.72, 481.63 (M ").

EXAMPLE 32 AND 36 Preparation of N- [3- [N "- [3- (tert-butoxycarbonylamino) -propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and trifluoroacetate of N- [3- [N "- (3-aminopropyl) aminosulfonH] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea N- [3- (tert-butoxycarbonylamino) propyl] -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmole), t-butyl N- (3-aminopropyl) carbamate (0.60 mg, 3.44 mmol) and triethylamine (960 μl, 6.88 mmol) were reacted to form the desired product (1.44 g, 98%). EI-MS (m / z) 426.1, 428.1, 430.1 (M-H) -.

N- [3- (tert-butoxycarbonylamino) propyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [3- (tert-butoxycarbonylamino) propyl] -2 , 6-dichloro-3-nitrobenzene Sulfonamide (450 mg, 1.05 mmol), 60% NaH (168 mg, 4.2 mmol) and water (21 μL, 1.15 mmol) were reacted to form the desired product (250 mg, 58%). EMI (m / z) 408.1, 410.1 (M-H) '.

N- [3- (tert-butoxycarbonylamino) propyl] -3-amino-6-chloro-2-hydroxynitrobenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- [3- (tert-butoxycarbonylamino) propyl] -6 -chloro-2-hydroxy-3-nitrobenzenesulfonamide (250 mg, 0.61 mmol) was reduced with hydrogen and 10% Pd / C (100 mg) to form the desired product (220 mg, 95%). 1 H NMR (MeOD-d 4): d 6.82 (m, 2 H), 3.06 (t, 2 H), 2.92 (t, 2 h), 1.60 (m, 2 H), 1.41 (s, 9 H).

N- [3- [N "- [3- (tert-butoxycarbonyllamino) -propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea described in example 15, N- [3- (tert-butoxycarbonylamino) propyI] -3-amino-6-chloro-2-hydroxybenzene-sulfonamide (110 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (65 mg, 0.35) mmoles) were coupled to form the desired urea (90 mg, 55%) MS-MS (m / z) 565.64, 567.74, 569.60 (M ') The following is the general procedure for Boc deprotection.

N- [3- [N "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate A solution of N- [3- [N" - [ 3- (tert-butoxycarbonylamino) propyl] aminosulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea (33 mg, 0.058 mmol) in 1 ml of trifluoroacetic acid was stirred room temperature for 30 minutes. The solvent was concentrated. The residue was diluted with methanol, then concentrated. The procedure was repeated twice to give the raw material. Recrystallization from methanol and water produced the desired product (23 mg, 68%). EMI (m / z) 466.7, 468.8, 470.8 (M ").

EXAMPLE 33. 34 and 35 Preparation of N- (2-bromofrisyl) -N'-f3-fN "-f3- (tert-butoxycarbonylamino) propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea N-trifluoroacetate [3- [N "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea and N- [3- [N" - (3-aminopropyl) aminosulfon hydrochloride] ? l] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea N- (2-bromophenyl) -N '- [3- [N "- [3- (tert-butoxycarbonylamino) propyl aminosulfonyl] -4-chloro-2-hydroxyphenyl-urea Following the general procedure for the formation of urea described in the example 15, N- [3- (tert-butoxycarbonyl-amino) propyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (110 mg, 0.29 mmol) and 2- bromophenylisocyanate (69 mg, 0.35 mmol) were coupled to form the desired urea (140 mg, 84%). EMI (m / z) 575.53, 577.61, 579.62 (M ").

N- [3- [N "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl-N '- (2-bromophenyl) urea trifluoroacetate Following the general procedure for deprotection of Boc described in the example 36, N- (2-bromophenyl) -N '- [3- [N "- [3- (t-butoxycarbonylamino) propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea (21 mg, 0.036 mmol) is stirred in 1 ml of trifluoroacetic acid to form the desired product (16 mg, 75%). 1 H NMR (MeOD-d 4): d 8.28 (d, 1 H), 7.80 (d, 1 H), 7.59 (d, 1 H), 7.33 (t, 1 H), 7.07 (d, 1 H), 7.02 (d, 1 H) ), 3.05 (m, 4H), 1.87 (m, 2H).

N- [3- [N "- (3-aminopropyaminesulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea hydrochloride A solution of N- (2-bromophenyl) -N'- [3- [N "- [3- (tert-butoxycarbonyl amino) propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea (59 mg, 0.102 mmol) in 1 ml of 4.0 M HCl in 1,4-dioxane was stirred at room temperature during minutes. The solvent was concentrated. Recrystallization from acetone and hexane yielded the desired product (45 mg, 85%). CC-MS 477.0 (M +).

EXAMPLE 37 and 38 Preparation of N-f2-bromophen-8) -N '-? R3- [N "-f3- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea and N- [3- [N "- (2-aminoethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl-N '- (2-bromophenyl) urea t-butyl N- (2-aminoethyl) carbamate A solution of ethylenediamine (3.0 g, 49.9 mmol), di-tert-butyl-dicarbonate (3.63 g, 16.6 mmol) and triethylamine (6.95 mL, 49.9 mmol) in 100 mL of dichloromethane was stirred at room temperature for 16 hours. The mixture was filtered to remove the solid produced during the reaction. The filtrate was washed with water, dried over MgSO 4, concentrated and dried in vacuo to give the desired product (1.79 g, 67%). CC-MS 160.97 (M +).

N- [2- (tert-butoxycarbonylamino) ethyl 1-2.6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g) , 3.44 mmole), t-butyl N- (2-aminoethyl) carbamate (0.5 g, 3.44 mmole) and triethylamine (0.72 ml, 5.16 mmole) were reacted to form the desired product (1.29 g, 90%). 1 H NMR (MeOD-d 4): d 7.93 (d, 1 H), 7.78 (d, 1 H), 3.12 (m, 4 H), 1.41 (s, 9 H).

N- [2- (tert-butoxycarbonylamino) ethyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [2- (tert-butoxycarbonylamino) etl. ] -2,6-dichloro-3-nitrobenzenesulfonamide (1.63 g, 3.94 mmol), 60% NaH (630 mg, 15.8 mmol) and water (71 μL, 3.94 mmol) were reacted to form the desired product (200 mg, 13%). 1 H NMR (MeOD-d 4): d 8.10 (d, 1 H), 7.21 (d, 1 H), 3.15 (t, 2 H), 3.08 (t, 2 H), 1.41 (s, 9 H).

N- [2- (tert-butoxycarbonylamino) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- [2- (tert-butoxycarbonylamino) ethyl] - 6-Chloro-2-hydroxy-3-nitrobenzenesulfonamide (200 mg, 0.51 mmol) was reduced with hydrogen and 10% Pd / C (100 mg) to form the desired product (170 mg, 92%). 1 H NMR (MeOD-d 4): d 6.84 (m, 2 H), 3.15 (t, 2 H), 2.95 (t, 2 H), 1.42 (s, 9 H).

N - (- bromophenyl) -N '[3- [N "- [2- (tert-butoxycarbonylamino) ethyl] -amino sulfonyl] -4-chloro-2-hydroxyphenyl-urea Following the general hydrogenation procedure described in example 15, N- [2- (tert-butoxycarbonylamino) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (170 mg, 0.47 mmol) and 2-bromophenylisocyanate (92 mg, 0.47 mmol) were coupled to form the desired urea (120 mg, 49%). CC-MS 565.0 (M +).

N- [3- [N "- (2-aminoethyl) aminosulfonyl] -4-chloro-2-hydroxy-phenyl] -N '- (2-bromophenyl) urea trifluoroacetate Following the general procedure for deprotection of Boc described in Example 36, N- (2-bromophenyl) -N '- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] 4-chloro-2-hydroxyphenyl] urea (80 mg, 0.14 mmol) is stirred in trifluoroacetic acid to form the desired product (22mg, 34%). CC-MS 465.0 (M +).

EXAMPLE 39 and 42 Preparation of N- (2-bromophenyl) -N '- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl] -4-chloro-2-hydroxyphenyl] urea and trifluoroacetate N- (2-bromophenyl-N '- [4-chloro-2-hydroxy-3- (piperazin-1-yl) sulfonylphenyl] urea 1- [4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-2,6-dichloro-3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-Chloride -nitrobenzenesulfonyl (500 mg, 1.72 mmol), tert-butyl 1-piperazinecarboxylate (320 mg, 1.72 mmol) and triethylamine (479 μl, 3.44 mmol) were made react to form the desired product (650 mg, 84%). CC-MS (m / z) 440.2 (M +). 1-f4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene Following the general hydrolysis procedure described in Example 15, 1 - [4- (tert-butoxycarbonyl) piperazin-1-ylsulfonyl-2,6-dichloro-3-nitrobenzene (200mg, 0.45 mmol), 60% NaH (54mg, 1.35 mmol) and water (8mL, 0.45 mmol) were reacted to form the desired product (60mg, 32%). EI-MS (m / z) 420.1, 422.1 (M +). 3-f4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxyaniline Following the general procedure of hydrogenation, described in example 15, 1- [4- (tert-butoxycarbonyl) piperazine-1 -I-Sulphonyl-6-chloro-2-hydroxy-3-nitrobenzene (256 mg, 0.061 mmol) was reduced with hydrogen and 10% Pd / C (120 mg) to form the desired product (220 mg, 93%). 1H NMR (MeOD-d4): d 6.84 (m, 2H), 3.45 (m, 4H), 3.27 (M, 4H), 1.43 (s, 9H).

N- (2-Bromophenyl VN'-f3- [r4-fter-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxyphenyl] urea Following the general procedure for the formation of urea, described in example 15, 3- [4- (tert-butoxycarbonyl) piperazin-1-yl] suphonyl-4-chloro- 2-hydroxyaniline (11 Omg, 0.28 mmol) and 2-bromophenylisocyanate (67 mg, 0.34 mmol) were coupled to form the desired urea (60 mg, 36%). Theory of analysis of elements: C 44.80%, H 4.44%, N 9.50%, Found: C 44.65%, H 4.15%, N 9.20%.

N-C2-bromophenyl VN'-f4-chloro-2-hydroxy-3- (piperazin-1-yl) sulfonylphenyl] urea trifluoroacetate Following the general procedure for deprotection of Boc, described in Example 36, N- (2-bromophenyl) ) -N '- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxyphenyl] urea (1 Omg, 0. 019 mmol) was stirred in trifluoroacetic acid to form the desired product (5mg, 49%). 1 H NMR (MeOD-d 4): d 8.28 (d, 1 H), 7.91 (d, 1 H), 7.60 (d, 1 H), 7.33 (t, 1 H), 7.14 (d, 1 H), 7.02 (d, 1 H) 3.64 (t, 4H) 3.33 (m, 4H).

EXAMPLE 40 and 41 Preparation of N- [3-f4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxyphenyl-Nil- (2,3-dichlorophenyl) urea and N- [4-] trifluoroacetate chloro-2-hydroxy-3- (piperazin-1-yl) sulfonylphenyl] -N '- (2,3-dichlorophenyl) urea N- [3- [4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 3- [4- (tert-butoxycarbonii) piperazin-1-yl] sulfonyl-4-chloro- 2-hydroxyaniline (110 mg, 0.28 mmol) and 2,3-dichlorophenylisocyanate (64 mg, 0.34 mmol) were coupled to form the desired urea (34 mg, 25%). EI-MS (m / z) 576.65, 578.65, 580.67 (M ").

N- [4-Chloro-2-hydroxy-3- (piperazin-1-yl) sulfonyl-phenyl] -N '- (2,3-dichlorophenol) urea trifluoroacetate Following the general procedure for deprotection of Boc, described in Example 36, N- [3- [4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl-4-chloro-2-hydroxy-phenyl-N '- (2,3-dichlorophenyl) urea (20 mg, 0.034 mmol ) was stirred in trifluoroacetic acid to form the desired product (13.5 mg, 66%). EI-MS (m / z) 481.7, 483.7, 485.7 (M +).

EXAMPLE 43. 51 and 60 Preparation of N- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea N- [ 4-chloro-2-hydroxy-3- [N "- [3- (mathylsulfonyl) propylaminosulfonyl] phenyl-1 - N, - (2,3-dichlorophenyljurea and N- [4-chloro-2-hydroxy-3- [N" - [ 3- (Methylsulfonyl) propyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea N- (3-methylthiopropyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2g, 6.88 mmol), - (methylthio) propylamine (0.72 g, 6. 88mmol) and triethylamine (1.92mL, 13.76mmol) were reacted to form the desired product (2.07g, 82%). 1 H NMR (MeOD-d 4): d 7.93 (d, 1 H), 7.79 (d, 1 H), 3.16 (t, 2 H), 2.47 (t, 2 H), 2.00 (s, 3 H), 1.76 (m, 2 H) ).

N- (3-methylthiopropyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (3-methylthiopropyl) -2,6-dichloro-3-nitrobenzenesulfonamide ( 1.0g, 2.78mmol), 60% NaH (330mg, 8.13mmol) and water (59mL, 3.25mmol) were reacted to form the desired product (650mg, 69%). EI-MS (m / z) 339.86, 341.84 (M ").

N- (3-methylthiopropyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- (3-methylthiopropyl) -6-chloro-2-hydroxy- 3-Nitrobenzene Suifonamide (300 mg, 0.88 mmol) was reduced with hydrogen and 10% Pd / C (150mg) to form the desired product (250mg, 91%). 1 H NMR (MeOD-d 4): d 6.84 (d, 1 H), 6.77 (d, 1 H), 2.93 (t, 2H), 2. 40 (t, 2H), 1.89 (s, 3H), 1.63 (m, 2H).

N- [4-chloro-2-hydroxy-3- [N "-f3-methylthiopropylaminosulfonyljphenyl] -N'- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N- (3 -methylthiopropyl) -3-amino-6-chloro-3- Hydroxybenzenesulfonamide (250mg, O.dOmmoles) and 2,3-dichlorophenylisocyanate (182mg, 0.97mmol) were coupled to form the desired urea (278mg, 70%). H NMR (MeOD-d4): d 8.29 (d, 1H), 8.06 (d, 1H), 7.24 (m, 2H), 7.05 (d, 1 H), 3.07 (t, 2H), 2.48 (t, 2H) ), 1.98 (s, 3H) 1.74 (m, 2H).

N- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfonyl) propyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea A solution of N- [4-cioro-2] -hydroxy-3- [N "- [3- (methylthiopropyl] aminosulfonp] phenyl] -N, - (2,3-dichlorophenyl) urea (50mg, O.IOmmoles) and oxone (93mg, 0.15mmol) in acetonitrile (13mL) and water (7mL) was stirred for 3 days at room temperature, the mixture was diluted with ethyl acetate and washed with water to give the crude material, purification by column chromatography on silica gel, eluting with acetate ethyl acetate / hexane / acetic acid (49/50/1, v / v / v), followed by recrystallization from acetone and hexane, gave the desired product (46mg, 87%) EI-MS (m / z) 527.53, 529.57, 531.55 (M +).

N- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfinyl) propyl] aminosulfonyl] f eni? -N '- (2,3-didorof nil) urea A solution of N- [4-chloro -2-hydroxy-3- [N "- [3- (methylthiopropyl] aminosulfonyl] -phenyl] -N '- (2,3-dicyorophenyl) urea (50mg, O.Ommoles) and sodium periodate (26 mg, 0.12 mmol) in acetonitrile (6 ml) and water (2 ml) was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Recrystallization from acetone and hexane gave the desired product (42mg, 81%). 1 H NMR (DMSO-d 6): d 9.32 (S, 1 H), 9.27 (S, 1 H), 8.59 (s, 1 H), 8.29 (d, 1 H), 8.07 (m, 1 H), 7.33 (m, 2 H) ), 7.13 (d, 1 H), 3.00 (m, 2H), 2.75 (m, 1H), 2.65 (m, 1H), 2.47 (s, 3H), 1.79 (m, 2H).

EXAMPLE 44. 52 and 61 Preparation of N- (2-bromophenyl) -N'-f4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyl] urea NC-bromophene-N '- ^ - chloro-S-hydroxy-3-rN "-r3- (methylsulfonyl) propyp-aminosulfon-pfen-purea and N- (2-bromophenyl) -N'-r4-chloro-2-hydroxy-3-fN "-r3- (methylsulfonyl) propyl] aminosulfonyl] phenylurea N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopyrin amynesurfonyl] phenyl] urea Following the general procedure for the formation of urea, described in Example 15, N- (3-methylthiopropyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (250 mg, O.dOmmoles) and 2-bromophenylscyanate (191mg, 0.97mmol) were coupled to form the desired urea (300mg, 74%). 1 H NMR (MeOD-d 4): d 8.28 (d, 1 H), 7.91 (d, 1 H), 7.58 (d, 1 H), 7.33 (t, 1 H), 7.05 (d, 1 H), 7.00 (t, 1 H) ), 3.08 (t, 2H), 2.48 (t, 2H), 1.98 (s, 3H), 1.74 (m, 2H).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3-fN "- [3- (methylsulfonyl) propyl] -aminosulfonyl] phenyl] urea Following the oxidation procedure described in example 51 , N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyljurea (50 mg, O.Ommoles) and oxone (91 mg, 0.15 mmol) ) were reacted to give the desired product (41 mg, 77%). Found analysis of elements: C 37.58%, H 3.37%, N 7.59%, Theory: C 37.75%, H 3.54%, N 7.77%.

N- (2-Bromophenyl VN '- [4-chloro-2-hydroxy-3- [N "-r3- (methylsulfonyl) propyl] -aminosulfonyl] phenol] urea Following the oxidation procedure described in the example 61, N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyljurea (50mg, O.Ommoles) and sodium periodate (25 mg, 0.12 mmol) were reacted to give the desired product (8 mg, 16%) CC-MS 526.0 (M +).

EXAMPLE 47. 58. 48 and 59 Preparation of N- (2-bromophenyl) -N'-r4-chloro-3-fN ". N" -di- (2-methoxyethyl) aminosulfonyl] -2-hydroxyphenyl] urea. N- (2-bromophenyl) -N '- [4-chloro-3- [N ". N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxyphenyl] urea. N- [4-chloro-3-fN ".N" -di- (2-methoxyethyl) -aminosulfonyl-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-chloro-3-] [N ".N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea NN-di- (2-methoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.82g, 6.26mmol) ), b1s (2-methoxyethyl) amine (830mg, 6.26mmol and triethylamine (1.7mL, 12.52mmol) were reacted to form the desired product (2.16, 89%). CC-MS (m / z) 387.2 ( M +).

NN-di- (2-methoxyethyl) -6-chloro-2-hydroxy-3-n-tetrabenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N, N-di- (2-methoxyethyl) - 2,6-dichloro-3-nitrobenzenesulfonamide (800mg, 2.07mmol), 60% NaH (248mg, 6.21mmol) and water (45mL, 2.48mmol) were reacted to form the desired product (420mg, 55%) EI-MS (m / z) 366.89, 368.81 (M ").

NN-di- (2-methoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N, N-di- (2-methoxyethyl) -6-chloro -2-hydroxy-3-nitrobenzenesulfonamide (100 mg, 0.27 mmol) is reduced with hydrogen and 10% Pd / C (50 mg) to form the desired product (80 mg, 87%). 1 H NMR (MeOD-d 4): d 6.85 (m, 2 H), 3.58 (t, 4 H), 3.47 (t, 4 H), 3.21 (s, 6 H).

N- (2-bromophenin-N'-r4-chloro-3- [N ". N" -di- (2-methoxyethyl) amino-sulfonyl] -2-hydroxyphenyl] urea Following the general procedure for the formation of urea, described in Example 15, N, N-di- (2-methoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.12 mmol) and 2-bromophenylisocyanate (23 mg, 0.12 mmol) were coupled to form urea desired (39mg, 61%) EI-MS (m / z) 534.6, 536.6 (M ").

N- (2-bromophenin-N'-f4-chloro-3-rN ".N" -di-f2-hydroxy-vinyl-sulphonyl] -2-hydroxyphenyl] urea A solution of N- (2 -bromophenyl) -N '- [4-chloro-3- [N ", N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxyphenyl] urea (9.9mg, 0.018mmol) and aluminum bromide (4.2mg , 0.018 mmol) in 2 ml of ethanol was stirred for 16 hours at room temperature, the mixture was concentrated, the residue was diluted with ethyl acetate, then washed with 1N aq HCl, the organic layer was dried over MgSO4 and concentrated. Recrystallization from acetone and methanol gave the desired product (4mg, 44%). 1 H NMR (MeOD-d 4): d 8.30 (d, 1H), 7.92 (d, 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.07 (d, 1H), 7.01 (t, 1H) 3.68 (t, 4H), 3.51 (m, 4H).

N- [4-chloro-3- [N ". N" -di- (2-methoxyethyl) -aminosulfonyl] -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in example 15, N, N-di- (2-methoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.12 mmol) and 2,3-dichlorophenylisocyanate (22 mg, 0.12 mmol) they were coupled to form the desired urea (55mg, 87%). 1 H NMR (MeOD-d 4): d 8.27 (m, 1 H), 8.03 (m, 1 H), 7.23 (m, 2 H), 7.03 (m, 1 H), 3.61 (m, 4 H), 3.45 (m; 4H), 3.23 (s, 6H).

N- [4-chloro-3-fN ".N" -di- (2-hydroxyethyl) amynesulfonyl] -2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea Following the deprotection procedure, described in example 58, N- [4-chloro-3- [N ", N" -di- (2-methoxyethyl) -aminosu-ionyl] -2-hydroxyphenyl] -N '- (2,3, -dichlorophenyl) urea (15mg) , 0.028 mmol) and aluminum bromide (18.7mg, 0.07mmol) were reacted to give the desired product (2mg, 14%). CC-MS 500.0 (M +).

EXAMPLE 49 AND 50 Preparation of N-2- (bromophenyl) -N'-f4-chloro-3-fN "- [2- (dimethylamino) ethyl] amynesulfonyl] -2-hydroxy-phenyl] urea hydrochloride and hydrochloride of N- [4- chloro-3- [N "- [2- (dimethylammono) ethyl] -aminosulfonyl] 2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea N- [2- (dimethylamino) ethyl] -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for sulfonamide formation, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (400 mg, 1.38 mmoles), N, N-dimethylethylenediamine (121 mg, 1.38 moles) and triethylamine (0.39 ml, 2.76 mmoles) were reacted to form the crude product (480 mg) which was carried out in the hydrolysis without purification.

El-MS (m / z) 341.88 (M ").

N- [2- (dimethylamino) ethyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [2- (dimethylamine) ethyl] -2.6 crude dichloro-3-nitrobenzenesulfonamide (480 mg), 60% NaH (168 mg, 4.2 mmol) and water (25 μl, 1.4 mmol) were reacted. The crude product (80 mg) was carried out in the next step without purification. EI-MS (m / z) 321.98, 323.96 (M ").

N- [2- (dimethylamino) ethyl] -3-amino-6-chloro-2-hydroxybenzene sulfonamide Following the general hydrogenation procedure described in Example 15, N- [2- (dimethylamino) ethyl] -6-chloro- Crude 2-hydroxy-3-nitrobenzenesulfonamide (80mg) was reduced with hydrogen and 10% Pd / C (40mg) to form the crude product (70mg) which is continued to form the urea without purification.

N-2- (bromophenyl) -N'-r4-chloro-3-rN "-r2-fdimethyl-amino) ethyl] aminosulfunyl-3-2-hydroxyphenyl] urea hydrochloride Following the general procedure for the formation of urea, described in the example 15, Crude N- [2- (di-methylamino) ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (35mg) and 2-bromophenylisocyanate (28mg, 0. 14mmol) were coupled to form the desired urea (12mg, 20% for four steps). El-MS (m / z) 490.7, 494.7 (M +).

N-r4-chloro-3-yN "-r2- (dimethylamino) et p-aminosulfonyl] 2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in example 15, crude N- [2- (dimethylamino) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (35mg) and 2,3-dichlorophenylisocyanate (26mg, 0. 14mmol) were coupled to form the desired urea (5.8mg, 10% for four steps). El-MS (m / z) 482.80, 484.78 (M +).

EXAMPLE 53. 54 and 55 Preparation of N- [4-chloro-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] aminosulfonyl] phenyl] -N '- (2.3-d) hydrochloride chlorophenol) urea N-f4-chloro-2-hydroxy-3-rN "- [2- (morpholinyl) etl1-am8-sulphonophenip-N '- (2-chlorophenyl) urea hydrochloride and N ^ -bromofeniQ-N '- ^ - chloro ^ -hydroxy-S-rN "- ^^ - morpholinyl) ethyl] aminosulfonyl] phenyl]? Rea N- [2- (morpholinyl) ethyl] -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nltrobenzenesulfonyl chloride (600 mg, 2.07 mmol) ), 4- (2-aminoethyl) morpholine (269mg, 2. 07 mmol) and triethylamine (0.58 mL, 4.13 mmol) were made-reacted to form the desired product (593 mg, 75%). CC-MS (M / z) 384.0 (M +).

N- [2- (morpholinyl) ethyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [2- (morpholinyl) etii] -2.6 - dichloro-3-nitrobenzenesulfonamide (400 mg, 1.04 mmol), 60% NaH (125 mg, 3.12 mmol) and water (23 μl, 1.25 mmol) were reacted to form the crude product (600 mg) which is continued in the hydrogenation without purification. El-MS (m / z) 363.95, 365.94 (M ").

N- [2- (morpholinyl) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- [2- (morpholinyl) ethyl] Crude crude 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg) was reduced with hydrogen and to form the crude product (300 mg) which was continued to the urea passage without purification. El-MS (m / z) 338.93, 340.98 (M +).

N- [4-cyclo-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] amino sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in Example 15, crude N- [2- (morpholinyl) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (150mg) and 2,3-dichlorophenylisocyanate (49mg, 0. 26 mmol) were coupled to form the desired urea (23 mg, 15% for 3 steps). El-MS (m / z) 522.72, 524.65, 526.70 (M +).

N- [4-chloro-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] -aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in example 15, crude N- [2- (morpholinyl) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (183mg) and 2-chlorophenylisocyanate (40mg, 0. 26mmol) were coupled to form the desired urea (50mg, 39% for 3 steps). CC-MS 489.2 (M +).

N-r2-bromophenyl VN '- [4-chloro-2-hydroxy-3-rN "-r2- (4-morpholinyl) ethyl] aminosulfonyl-3-phenyl] urea Following the general procedure for the formation of urea, described in example 15, N- [2- (morpholinyl) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg) and 2-bromophenylisocyanate (51 mg, 0. 26mmol) were coupled to form the desired urea 10mg, 7% for 3 steps). El-MS (m / z) 535.64, 537.56, 539.61 (M +).

EXAMPLE 56 AND 57 Preparation of N- [4-chloro-2-hydroxy-3- (4-thiomorpholinylsulfonyl) phenyl] -N'- (2,3-dichlorophenyl) urea v N-f2-bromophenyl) -N '- [4- chloro-2-hydrox8-3- (4-thiomorpholinylsulfonyl) phenyl]? rea 2. 6-dichloro-3-nitro-1- (4-thiomorpholinylsulfonyl) benzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0g, 6.88mmol) , thiomorpholine (71 Omg, 6.88 mmol) and triethylamine (1.92 mL, 13.76 mmol) were reacted to form the desired product (2.30 g, 94%). 1 H NMR (MeOD-d 4): d 7.95 (d, 1 H), 7.85 (d, 1 H), 3.68 (t, 4 H), 2. 69 (t, 4H). 6-Chloro-2-hydroxy-3-nitro-1- (4-thiomorpholinylsulfonyl) benzene Following the general hydrolysis procedure described in Example 15, 2,6-dichloro-3-nitro-1- (4-thiomorpholinylsulfonyl) ) benzene (1.04 g, 2.91 mmol), 60% NaH (349 mg, 8.73 mmol) and water (63 μL, 3.50 mmol) were reacted to form the desired product (330 mg, 33%). The MS (m / z) 336.89, 338.93 (M "). 4-Chloro-2-hydroxy-3- (4-thiomorpholinylsulfonyl) aniline Following the general procedure of hydrogenation, described in Example 15, 6-cyclo-2-hydroxy-3-nitro-1- (4-thiomorpholinylsulfonyl) benzene ( 330 mg, 0.97 mmol) was reduced with hydrogen and 10% Pd / C (150 mg) to form the desired product (240 mg, 80%). 1 H NMR (MeOD-d 4): d 7.08 (d, 1 H), 6.98 (d, 1 H), 3.59 (t, 4 H), 2.68 (t, 4 H).

N- [4-Chloro-2-hydroxy-3- (4-thiomorpholinylsulfonyl) phenyl] -N '- (2,3-dichloro-phenyl) Following the general procedure for the formation of urea, described in Example 15, 4-chloro-2- hydroxy-3- (4-thiomorpholinylsulfonyl) aniline (120mg, 0.36mmoies) and 2,3-dichlorophenylisocyanate (68mg, 0.36mmol) were coupled to form the desired urea (50mg, 28%). 1H NMR (MeOD-d4): d 8.31 (m, 1 H), 8.05 (m, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 3.61 (m, 4H), 2.69 (m, 4H).

N- [2-Bromophenyl) -N '- [4-chloro-2-hydroxy-3- (4-thiomorpholinylsulfonyl) -pheniurea Following the general procedure for the formation of urea, described in Example 15, 4-chloro-2 -hydroxy-3- (4-thiomorpholysulfonyl) aniline (120 mg, 0.26 mmol) and 2-bromophenylisocyanate (72 mg, 0.36 mmol) were coupled to form the desired urea (110 mg, 60%). 1 H NMR (DMSO-de): d 9.25 (S, 1 H), 8.98 (S, 1 H), 8.34 (d, 1 H), 7.92 (d, 1 H), 7.65 (d, 1 H), 7.35 (t, 1H), 7.19 (d, 1H), 7.01 (t, 1 H), 3.54 (t, 4H), 2.67 (t, 4H).

EXAMPLE 45 Potassium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea The general procedure described in Example 15 was followed to give sa! of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea potassium. 1 H NMR (DMSO-de): d 9.27 (s, 2H), 8.01 (m, 3H), 7.81 (d, 1 H), 7.26 (m, 2H), 6.15 (m, 1H).

EXAMPLE 46 Sodium salt of N - ^ - chloro-S-hydroxy-S-aminosulfonylpheniQ-N'-tert.S-dichlorophenyl) urea The general procedure described in Example 15 was followed to give sodium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea. 1 H NMR (DMSO-de): d 9.27 (s, 2H), 8.01 (m, 3H), 7.77 (d, 1H), 7.26 (m, 2H), 6.05 (d, 1H).

EXAMPLE 62. 67. 63 AND 66 Preparation of N- (2-bromophenyl) -N '- [3-N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2- hydroxyphenyl urea, N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyl-1-phenyl] -urea hydrochloride. N- [3- [N "- [(tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-] trifluoroacetate chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyl} phenyl] -N '- (2,3-dichlorophenyl) urea N - [(1-tert-butoxycarbonylpiperidin-4-iPmethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-chloride - Nitrobenzenesulfonyl (1.2g, 4.13mmol), N- (tert-butoxycarbonyl) -4-aminomethyl piperidine (0.88g, 4.13mmol) and triethylamine (0.86mL, 6.20mmol) were reacted to form the desired product (1.52g, 79 %). CC-MS (m / z) 468.2 (M +).

N - [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N - [(1-tert-butoxycarbonylpiperidine -4-yl) methyl] -2,6-dichloro-3-nitrobenzenesulfonamide (800mg, 1.89mmol), 60% NaH (227mg, 5.67mmol) and water (41mL, 2.27mmol) were reacted to form the desired product (495mg, 58%). El-MS (m / z) 447.92, 449.84 (M ").

N - [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N - [(1-ter -butoxycarbonylpiperidin-4-yl) methyl] -6-cyclo-2-hydroxy-3-nitrobenzenesulfonamide (480 mg, 1.07 mmol) was reduced with hydrogen and % Pd / C (240mg). The crude product (460 mg) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 6.86 (m, 2 H), 4.00 (d, 2 H), 2.83 (m, 2 H), 2.78 (m, 2 H), 1.60 (m, 3 H), 1.44 (s, 9 H) , 1.00 (m, 2H).

N- (2-bromophenyl) -N '- [3-N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenylurea Following the general procedure for the formation of urea, described in Example 15, crude N - [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (230 mg) and 2-bromophenylisocyanate (129mg, 0.65mmol) were coupled to form the desired urea (110mg, 30% for two steps). CC-MS (m / z) 619.0 (M +).

N-C2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyljphenyl] urea hydrochloride A solution of N- (2-bromophenyl) -N '- [3-N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl urea (27mg, 0.044mmol) in 1.0mL of 4.0N HCl in 1,4-dioxane was stirred at room temperature for 10 minutes. The mixture was concentrated. Recrystallization from acetone and hexane gave the desired product (16mg, 65%). CC-MS (m / z) 519.2 (M +).

N- [3- [N "- [(tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for Urea formation, described in Example 15, crude N - [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (230 mg) and 2.3- dichlorophenylisocyanate (122mg, 0.65mmol) were coupled to form the desired urea (100mg, 29% for two steps). 1 H NMR (MeOD-d 4): d 8.29 (d, 1 H), 8.05 (m, 1 H), 7.25 (m, 2 H), 7.06 (d, 1 H), 4.35 (d, 2 H), 2.83 (m, 2 H) ), 2.49 (m, 2H), 1.69 (m, 3H), 1.43 (s, 9H), 1.00 (m, 2H).

N- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate Following the general procedure of Boc deprotection described in Example 36, N- [3- [N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2, 3-dicyorophenyl) urea (20 mg, 0. 033 mmole) was stirred in trifluoroacetic acid to form the desired product (9 mg, 44%). CC-MS (m / z) 509.0 (M +).

EXAMPLE 64. 140. 65 and 141 Preparation of N-f4-chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl-1 - N '- (2,3-dichlorophenol) urea. sodium salt of N-f4-chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] -N '- (2,3-d8-chlorophenyl) urea. N- (2-bromophenyl) -N '- [4-cioro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] urea and N - ^ - chloro-S-hydroxy-S ^ -oxidothiomorpholinosulfonyljphenill-N' ^ S- chlorophenyl) urea 6-Chloro-2-hydroxy-3-nithro-1- (1-oxydotiomorpholinesulfonyl) benzene A solution of 6-chloro-2-hydroxy-3-nitro-1- (4-thiomorpholyl) sulfonyl) benzene ( 100 mg, 0.30 mmol) and sodium periodate (95 mg, 0.44 mmol) in acetonitrile (10 ml) and water (2 ml) was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate and washed with water, dried over MgSO4 and concentrated to give the desired product (106 mg, 100%). El-MS (m / z) 352.89, 354.87 (M-). 4-Chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) aniline Following the general hydrogenation procedure described in Example 15, 6-chloro-2-hydroxy-3-nitro-1- (1-oxidothiomorpholinosulfonyl) benzene (103 mg, 0.29 mmol) was reduced with hydrogen and 10% Pd / C (59 mg) to form the desired product (89 mg, 95%). CC-MS (m / z) 325.0 (M +).

N-4-chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl)) phenyl] -N '(2,3-dicyrophenolurea) Following the general procedure for the formation of urea, described in example 15, 4-chloro-2-hydroxy -3- (1-oxidothiomorphorylinosulfonyl) aniline (117 mg, 0.35 mmoies) and 2,3-dichlorophenylisocyanate (72 mg, 0.38 mmoies) were coupled to form the desired urea (79mg, 44%). 1H NMR (DMSO-de) : d 9.34 (s, 1 H), 9.27 (s, 1H), 8.28 (d, 1 H), 8.05 (m, 1H), 7.32 (m, 2H), 7.21 (d, 1 H), 3.75 (m , 2H), 3.65 (m, 2H), 2.89, (m, 4H).

Sodium salt of N- [4-chloro-2-hydroxy-3- (1-oxidothiomorpholino sulfonyl) enylj-N '- (2,3-dichlorophenyl) urea Following the general procedure for salt formation, described in example 15, N- [4-Chloro-2-hydroxy-3- (1-oxidothiomorpholino sulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea (275 mg, 0.53 mmol) and 0.50 N ac NaOH (1.06 ml, 0.53 mmoles) was reacted to give the desired sodium salt (250 mg, 87%). 1 H NMR (DMSO-d 6): d 9.30 (s, 2H), 8.00 (d, 1H), 7.67 (D, 1H), 7.25 (m, 2H), 5.89 (d, 1 H), 3.68 (m, 4H), 2.90 (t, 2H), 2.75 (t, 3H).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (1-oxidothiomorpholino-sulfonyl) -phenyl] urea Following the general procedure for the formation of urea, described in Example 15, 4- chloro-2-hydroxy-3- (1-oxidotomorpholinosulfonyl) aniline (88 mg, 0.27 mmol) and 2-bromophenylisocyanate (65 mg, 0.33 mmol) they were coupled to form the desired urea (65 mg, 46%). CC-MS (m / z) 524.2 (M +).

N- [4-Chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] -N '- (2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 4-chloro- 2-hydroxy-3- (1-oxidothiomorpholinosuiphenyl) aniline (117 mg, 0.35 mmol) and 2-chlorophenylisocyanate (58 mg, 0.28 mmol) were coupled to form the desired urea (58 mg, 35%). CC-MS (m / z) 478.0 (M +).

EXAMPLE 68. 69 and 70 Preparation of N-f3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) N- [3- (1-azetidinylsulfonyl) -4- chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea and N- [3- (1-azetidin-lysulfonyl) -4-chloro-2-hydroxyphenyl-N' - (2,3-dichlorophenyl) urea 1- (azetidin-1-yl) sulfonyl-2,6-dichloro-3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmole), azetidine hydrochloride (320 mg, 3.44 mmol) and triethylamine (1.44 ml, 10.32 mmol) were reacted form the desired product (51 Omg, 48%). 1 H NMR (MeOD-d 4): d 7.94 (d, 1 H), 7.79 (d, 1 H), 4.16 (t, 4 H), 2.29 (m, 2 H). 1 - . 1-diazetidin-1-l) sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene Following the general hydrolysis procedure described in example 15, 1- (azetidin-1-yl) sulfonyl-2,6-dichloro 3-Nitrobenzene (510 mg, 1.64 mmol), 60% NaH (197 mg, 4.92 mmol) and water (35 μL, 1.97 mmol) were reacted to form the desired product (240 mg, 50%). 1 H NMR (MeOD-d 4): d 8.09 (d, 1 H), 7.25 (d, 1 H), 4.15 (t, 4 H), 2.29 (M, 2 H). 3- (azetidin-1-yl) sulfonyl-4-chloro-2-hydroxyaniline Following the general procedure of hydrogenation, described in example 15, 1- (azetidin-1-yl) sulfonyl-6-chloro-2-hydroxy 3-Nitrobenzene (240 mg, 0.82 mmol) was reduced with hydrogen and 10% Pd / C (110 mg) to form the desired product (215MG, 100%). 1 H NMR (MeOD-d 4): d 6.91 (m, 2 H), 4.01 (t, 4 H), 2.23 (m, 2 H).N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] N '- (2-bromophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 3- (azetidin-1) -yl) sulfonyl-4-chloro-2-hydroxyaniline (215 mg, 0.82 mmol) and 2-bromophenylisocyanate (195 mg, 0.98 mmol) were coupled to form the desired urea (69 mg, 18%). CC-MS 462.0 (M +).

N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] N '- (2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 3- (azetidin-1) -ii) Sulfonyl-4-chloro-2-hydroxyaniiine (235 mg, 0.9 mmol) and 2-chlorophenylisocyanate (134 mg, 0.9 mmol) were coupled to form the desired urea (200 mg, 54%). CC-MS 416.0 (M +).

N- [3-p-azetidinylsulfonin-4-chloro-2-hydroxyphenyl] N '- (2,3-dichlorophenol urea) Following the general procedure for the formation of urea, described in example 15, 3 - (azetidin-1-yl) sulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.9 mmol) and 2,3-dichlorophenylisocyanate (169 mg, 0.9 mmol) were coupled to form the desired urea (160 mg, 40% CC-MS 450.0 (M +).

EXAMPLE 71 Potassium salt of N- (2-bromophenyl) -N'-r4-chloro-3- (N ". N" - dimethylaminosu! Fonyl) -2-hydroxyphenyl] urea The general procedure described in Example 15 was followed to give potassium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxyphenyl] urea; 1 HNMR (DMSO-d6): d 9.20 (s, 1H), 8.99 (S, 1H), 7. 82 (D, 1H), 7.66 (D, 1H), 7.57 (D, 1H), 7.29 (t, 1 H), 6.95 (T, 1h), 5.93 (D, 1H), 2.83 (s, 6H).

EXAMPLE 72 Sodium salt of N-2-bromophenyl) -N, - [4-chloro-3- (N ". N" -dimethylaminosulfonyl) -2-hydroxyphenyl] urea The general procedure described in Example 15 was followed to give sodium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxyphenyl] urea; elementary analysis theory (1.25 eq., water): C 36.53%, h3.37%, N 8.52%, Na 4.66%, Found: C 36.32%, H 3.34%, N 8.38%, NA 4.69%.

EXAMPLE 73. 74 and 75 Preparation of N -bromopheni-N '- ^ - chloro-S ^ N "- cycloprop-Silaminosulfonyl) -2-hydroxyphenyl) urea N- [4-chloro-3- (N" -cycloethaminosulfonyl) ) -2hydroxyphenyl] -N '- (2-chlorophenyl) urea and N- [4-chloro-3- (N "-cyclopropylammonosulfonyl) -2-hydroxyphenyl] -N' - (2,3-dichlorophenyl) urea N-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dicyoro-3-nitrobenzenesulfonyl chloride (1.39 g, 4.78 mmol), cyclopropylamine (273 mg , 4.78 mmole) and triethylamine (1.0 ml, 7.17 mmole) were reacted to form the desired product (1.15g, 77%). 1 H NMR (MeOD-d 4): d 7.72 (d, 1 H), 7.65 (d, 1 H), 2.34 (m, 1 H), 0. 75 (m, 4H).

N-cyclopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide? Following the general hydrolysis procedure, described in Example 15, N-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.15 g, 3.70 mmol), 60% NaH (444 mg, 11.1 mmol) and water ( 67μl, 3.70mmol) were reacted to form the desired product (740mg, 68%). 1 H NMR (MeOD-d 4): d 8.06 (D, 1 H), 7.24 (d, 1 H), 2.29 (m, 1 H), 0.06 (m, 4 H).

N-cyclopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N-cyclopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (740 mg, 2.53 g. mmoles) was reduced with hydrogen and 10% Pd / C (350 mg) to form the desired product (660mg, 99%). H NMR (MeOD-D4): d6.83 (m, 2H), 2.20 (m, 1H), 0.56 (m, 4H).

N- (2-bromophenyl) -N '- [4-chloro-3- (N "-cyclopropylammonosulfonyl) -2-hydroxyphenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-cyclopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-bromophenyl isocyanate (199 mg, 1.01 mmol) were coupled to form the desired urea (135 mg, 35%). CC-MS (m / z) 462.0 (M +).

N- [4-Chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl] -N'-2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-cyclopropyl-3 -amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-chlorophenylisocyanate (155 mg, 1.01 mmol) were coupled to form the desired urea (150 mg, 43%). CC-MS (m /) 416.2 (M +).

N- [4-chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-cyclopropyl-3 -amino-6-cyoro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2,3-dichlorophenylisocyanate (190 mg, 1.01 mmol) were coupled to form the desired urea (176 mg, 46%). LC-MS (m / z) 452.0 (M +).

EXAMPLE 76. 77 and 78 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-propylaminosulfonyl) phenyl] urea N- [4-chloro-2-hydroxy] -3- (N "-propy! Aminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-chloro-2-hydroxyl-3- (N" -propylaminosulfonyl) phenyl} . -N '- (2-chlorophenyl) urea N-propyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.3 g, 4.48 mmol), propylamine (264 mg , 4.48 mmole) and triethylamine (0.94 ml, 6.72 mmole) were reacted to form the desired product (1.0g, 71%). 1 H NMR (MeOD-d 4): d 7.92 (d, 1 H), 7.78 (D, 1 H), 3.00 (t, 2 H), 1.50 (m, 2 H), 0.88 (t, 3 H).

N-propyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N-propyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.0g, 3.19 mmoles), % NaH (393 mg, 3.19 mmol) and water (58 μl, 3.19 mmol) were reacted to form the desired product (650 mg, 69%). LC-MS (m / z) 295.0 (M +).

N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N-propyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (650 mg, 2.2 mmol) it was reduced with hydrogen and 10% Pd / C (320 mg) to form the desired product (560mg, 96%). 1 H NMR (MeOD-d 4): d 6.83 (m, 1 H), 2.86 (t, 2 H), 1.50 (m, 2 H), 0. 87 (t, 3H).

N- (2-bromophenyl) -N '- [4-chloro-3- (N "-propylaminosulfonyl) phenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-propyl-3-amino -6-Cioro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-bromophenylisocyanate (140 mg, 0.71 mmol) were coupled to form the desired urea (149 mg, 46%) LC-MS (m / z) 464.0 ( M +).

N- [4-Chloro-2-hydroxy-3- (N "-propylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-propyl 3-amino-6-cyclo-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2,3-dichlorophenylisocyanate (133 mg, 0.71 mmol) were coupled to form the desired urea (259 mg, 81%). (m / z) 452.0 (M +).

N- [4-Chloro-2-hydroxy-3- (N "-propylaminosulfonyl) phenyl] -N '- (2-chlorophenyl irea Following the general procedure for the formation of urea, described in Example 15, N-propyl- 3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-chlorophenylisocyanate (108 mg, 0.71 mmol) were coupled to form the desired urea (148 mg, 50%). (m / z) 418.2 (M +).

EXAMPLE 79. 80 and 81 Preparation of N- (2-bromophenyl) -N '[4-chloro-3- (N "-ethylaminosulfonyl]) - 2-hydroxyphenyl] urea N- [4-chloro-3- (N "-ethylaminosulfonyl]) - 2-hydroxyphenyl] -N '- (2-chloroenhydride) and N- [4-chloro-3- (N" -ethylaminosulfonyl]) - 2-hydroxyphenyl] -N'- (2,3-dichlorophenyl) urea N-ethyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (800 g, 2.75 mmol), ethylamine ( 4.13 ml, 8.26 mmole) and triethylamine (1.15 ml, 8.36 mmole) were reacted to form the desired product (61 Omg, 74%). 1 H NMR (MeOD-d 4): d 7.92 (d, 1H), 7.78 (D, 1 H), 3.08 (q, 2H), 1.11 (T, 3H).

N-ethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N-ethyl-2,6-d-chloro-3-nitrobenzenesulfonamide (1.16 g, 3.88 mmol) , 60% NaH (466 mg, 11.64 mmol) and water (70 μl, 3.88 mmol) were reacted. The crude product (1.34) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 8.07 (d, 1 H), 7.25 (D, 1 H), 3.05 (q, 2 H), 1. 12 (t, 3H).

N-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, crude N-ethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.34 g) was reduced with hydrogen and 10% Pd / C (400 mg) to form the desired product (800 mg, 82% for two steps). 1 H NMR (MeOD-d 4): d 6.85 (d, 1 H), 6.78 (d, 1 H), 2.85 (q, 2 H), 0. 95 (t, 3H).

N- (2-bromophenyl) -N '- [4-chloro-3- (N "-ethylaminosulfonyl) -2-hydroxyphenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-et l-3-amino-6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2-bromophenylisocyanate (211 mg, 1.06 mmol) are coupled to form the desired urea (211 mg, 44%). CC-MS (m / z) 450.0 (M +).

N- [4-chloro-3- (N "-ethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-ethyl- 3-amino-6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2-chlorophenylisocyanate (163 mg, 1.06 mmol) were coupled to form the desired urea (142 mg, 33%). CC-MS (m / ) 04.0 (M +).

N-f4-chloro-3- (N "-ethylaminosulfonyl-V2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N-ethyl-3-amino 6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2,3-dichlorophenylisocyanate (200 mg, 1.06 mmol) were coupled to form the desired urea (193 mg, 41%) LC-MS (m / z) 440.0 (M +).

EXAMPLE 82 AND 136 Preparation of N- (2-bromophenyl) -N '- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxyl] pentyl] anesulfonyl] -4-chloro-2- hydroxyphenyl] urea and N- [3- [N "- (5-amino-5-carboxypentyl) -aminosulfonyl] -4-chloro-2-hydroxyphenyl-N '(2-bromophenyl) urea trifluoroacetate N- [5- (tert-butoxycarbonylamino) -5-methoxycarbonylpentyl] -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), Boc-Lys-Ome acetate (2,206 g, 6. 88 mmol) and triethylamine (2.4 ml, 17.2 mmol) were reacted to form e! desired product (1.25g, 35%). 1 H NMR (MeOD-d 4): d 7.93 (d, 1 H), 7.78 (D, 1 H), 4.02 (m, 1 H), 3.70 (s, 3 H), 3.04 (t, 2 H), 1.69 (m , 2H), 1.50 (m, 4H), 1.43 (s, 9H).

N- [5- (tert-butoxycarbonyllamino) -5-carboxypentyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [5- (ter- butoxycarbonylamino) -5-methoxycarbonylpentyl] -2,6-dichloro-3-nitrobenzenesulfonamide (1.2 g, 2.33 mmol), 60% NaH (379 mg, 9.32 mmol) and water (84 μl, 4.66 mmol) were reacted to form the desired product (850mg, 76%). 1 H NMR (MeOD-d 4): d 8.05 (d, 1 H), 7.22 (d, 1 H), 4.00 (m, 1 H), 3.01 (t, 2 H), 1.72 (m, 2 H), 1.50-1.65 ( m, 4H), 1.44 (s, 9H).

N- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- [5- (tert-butoxycarbonylamino) no) -5-carboxypentyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (204 mg, 0.42 mmol) was reduced with hydrogen and 10% Pd / C (100 mg) to form the desired product (189 mg , 100%). 1 H NMR (MeOD-d 4): d 6.84 (m, 1 H), 4.08 (m, 1 H), 2.92 (t, 2 H), 1.75 (m, 2 H), 1.55 (M, 4 H), 1.44 (s, 9 H ).

N- (2-bromophenyl) -N '- [3- [N "- [5- (tert-butoxycarbonylamino) -5-ca-rboxi-pentyl] -aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea Following the procedure General for the formation of urea, described in Example 15, N- [5- (tert-butoxycarbonylamino) -5-carboxypentiyl] -3-amino-6-cyoro-2-hydroxybenzenesulfonamide (189 mg, 0.42 mmol) and 2- bromophenylisocyanate (84 mg, 0.42 mmol) were coupled to form the desired urea (20 mg, 7%) CC-MS (m / z) 651.2 (M +).

N- [3- [N "- (5-amino-5-carboxypentyl) amino sulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea trifluoroacetate Following the general procedure for Boc deprotection in Example 36, N- (2-bromophenyl-N '- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] -aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea (108 mg) , 0.17 mmole) was stirred in 1 ml of trifluoroacetic acid to form the desired product (75 mg, 66%) CC-MS (m / z) 551.2 (M +).

EXAMPLE 83 AND 137 Preparation of N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- [3-fN "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxy-phenyl] -N '- (2,3-dicylophenyl) urea hydrochloride N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl-amino-sulfonyl-1- (4-chloro-2-hydroxyphenyl) -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea , described in Example 15, N- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (233 mg, 0.518 mmol) and 2,3-dichlorophenylisocyanate (98 mg, 0.518 mmol) were coupled to form the desired urea (100 mg, 30%). CC-MS (m / z) 641.2 (M +).

N- [3- [N "- (5-amino-5-carboxypentyl amino sulfonylj-4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate Following the general procedure for deprotection of Boc in the example 36, N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea (100 mg, 0.16 mmol) was stirred in 1 ml of trifluoroacetic acid to form the desired product (78 mg, 74%) CC-MS (m / z) 541.0 (M +).

EXAMPLE 84 and 85 Preparation of N- (2-bromophenyl) -N'-f4-chloro-2-h8droxy-3-rN "- (2-hydroxyethyl) amine-sulfonyl-urea and N- (2-bromophenyl) -N '- [3- [N "-ff (2-bromophenylamino) carboxy] ethyl] -aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea 2-benzyloxyethylamine To a solution of ethanolamine (5 g, 81.8 mmol) in 100 ml of Dry THF was added 60% NaH (3.27g, 81.8 mmol) at room temperature. The mixture was heated under reflux for 30 minutes, then benzyl chloride (9.32 g, 73.6 mmol) was added. The resulting mixture was passed under reflux for 3 hours. The mixture was concentrated, the residue was diluted with 1N aq HCl, extracted with dichloromethane. The aqueous layer was adjusted to pH > 14 with 10% NaOH aq, extracted with dichloromethane. The organic layer was dried over MgSO 4, concentrated to give the desired product (10.11g, 82%). 1 H NMR (CDCl 3): d 7.34 (m, 5 H), 4.54 (s, 2 H), 3.54 (t, 2 H), 2.93 (t, 2H).

N- (2-benzyloxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-benzyloxylethalamine (1.04g, 6.88 mmole) and triethylamine (1.92 ml, 13.76 mmole) were reacted to form the desired product (2.31 g, 83%). H NMR (MeOD-d4): d 7.69 (d, 1 H), 7.53 (d, 1 H), 7.25 (m, 3H), 7.14 (d, 2H), 4.26 (s, 2H), 3.45 (t, 2H), 3.36 (t, 2H).

N- (2-benzyloxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (2-benzyloxyethyl) -2,6-dichloro- 3-nitrobenzenesulfonamide (2.31 g, . 71 mmoles), 60% NaH (683 mg, 17.1 mmol) and water (103 μl, 5.72 mmol) were reacted to form the desired product (1.70G, 77%). CC-MS (m / z) 387.5 (M +).

N- (2-hydroxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N- (2-benzyloxyethyl) -6-cyoro-2-hydroxy-3- Nitrobenzene sulfonamide (366 mg, 0.95 mmol) was reduced with hydrogen and 10% Pd / C (170 mg). The crude product (265 mg) was continued to the next step without purification.

N- (2-bromophenin-N '- [4-chloro-2-hydroxy-3- [N "- (2-hydroxyethylaminosulfonyljurea and N- (2-bromophenyl) -N' - [3- [N "- [[(2-Bromophenylamino) carboxy] ethyl] aminosulfonylj-4-chloro-2-hydroxyphenyl] urea Following the general procedure for the formation of urea, described in Example 15, N- (2-hydroxyethyl) -3- amino-6-chloro-2-hydroxybenzenesulfonamide (265 mg) and 2-bromophenylisocyanate (187 mg, 0.95 mmol) were coupled to form the desired urea 84 (54 mg, 12% for two steps) CC-MS (m / z) ) 4.66.0 (M +), and urea 85 (10 mg, 1.6% for two steps) CC-MS (m / z) 663.0 (M +).

EXAMPLE 86 and 149 Preparation of N- [3- [N "- (2-benzyloxyethyl) -aminosulfonyl] -4-chloro-2-hydroxyphenip-N'-ff.S-dichlorophenipyrate and N-f3-fN" - (2 - hydroxyethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N - (2,3-dichlorophenyl) urea N- (2-Benzylloxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide A mixture of N- (2-benzyloxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (157 mg, 0.41 mmol) ) in THF (15 ml) and 5% aq NaHCO3 (10 ml) was stirred at room temperature, sodium dithionite (1.5 g) was added in 0. 2 g of potion. The mixture was acidified with 1N aq HCl, extracted with acetate of ethyl. The organic layer was dried over MgSO 4 and concentrated to give the desired product (120 mg, 82%). CC-MS (m / z) 357.0 (M +).

N- [3- [N "- (2-benzyloxyethyl) -amynesulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of a urea, described in example 15, N- (2-benzyloxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (119 mg, 0.33 mmol) and 2,3-dichlorophenylisocyanate (44 mg, 0.23 mmol) were coupled to form urea desired (94 mg, 75%). CC-MS (m / z) 546.0 (M +).

N- [3- [N "- (2-hydroxyethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea To a solution of N- [3- [N" - (2 -benzyloxyethyl) -aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dic! orophenyl) urea (46 mg, 0.08 mmol) in 3 ml of dichloromethane was added iodotrimethylsilane (38 mg, 0.19 mmol) ). The mixture was stirred for 16 hours at room temperature. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (60/40, v / v), gave the desired product (14mg, 37%). CC-MS (m / z) 455.8 (M +).

EXAMPLE 87. 88 and 89 Preparation of N- (2-bromophenyl) -N '- [4-chloro-3- (N "-cyclopropylmethylaminosulfonyl) -2-hydroxyphenyl] urea N- [4-Cioro-3- (N "- cyclopropylmethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea. Y N- [4-chloro-3- (N "-cyclopropylmethylaminosulfonyl) -2-hydroxy] phenyl] -N, - (2-chloropheni-Qurea) N-cyclopropylmethyl-2,6-dichloro-3-nitrobenzenesulfanamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), aminomethyl cyclopropane hydrochloride ( 0.56 g, 5.2 mmol) and triethylamine (1.8 ml, 12.9 mmol) were reacted to form the desired product (1.28 g, 84%). CC-MS m / z 325 (M +). 6-Chloro-N-cyclopropylmethyl-2-hydroxy-3-nitrobenzenesulfonamide Following the general procedure of hydrolysis, described in Example 15, N, -cyclopropylmethyl-2,6-dicyoro-3-nitrobenzenesulfonamide (0.85 g, 2. 6 mmole), 80% NaH (0.23 g, 9.8 mmol) and water (56 μl, 3.1 mmol) were reacted to form the desired product (0.58 g, 72%). CC-MS m / z 307 (M +). 3-amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, 6-chloro-N-cyclopropylmethyl-2-hydroxy-3-nitrobenzenesulfonamide (0.1 g, 3.2 mmol) it was reduced with hydrogen and 10% Pd / C (0.1g) to form the desired product (0.08g, 89%) CC-MS m / z 277 (M +).

N- (2-bromophenyl) -N '- [4-chloro-3- (N "-cyclopropylmethylaminosulfonylV 2 -hydroxyphenii] urea Following the general procedure for the formation of urea, described in Example 15, 3-amino-6- Chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77 mmol) and 2-bromophenyl isocyanate (100 μl, 0.81 mmol) were coupled to form the desired urea (0.19 g, 52%). CC-MS m / z 474 (M +).

N- [4-Chloro-3- (N "-cyclopropylmethylaminosulfonyl) -2-hydroxyphenyl] -N'- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 3-amino-6 -chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77 mmol) and 2,3-dichloropheniisocyanate (100 μl, 0.76 mmol) were coupled to form the desired urea (0.19 g, 53%). CC-MS m / z 464 (M +).

N- [4-chloro-3- (N "-cyclopropylmethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 3- amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77 mmol) and 2-chlorophenyl isocyanate (95 μl, 0.79 mmol) were coupled to form the desired urea (0.07 g, 21%). z 430 (M +).

EXAMPLE 90. 91 AND 92 Preparation of N- (2-bromophenyl) -N, - [4-chloro-2-hydroxy-3-rN "-methoxy-N" -methylaminosulfonidene-phenyliphenyl. N- [4-chloro-2-hydroxy-3- (N "-methoxy-N" methylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea. and N- (2-chlorophenyl) -N'- [4-chloro-2-hydroxy-3- (N "-methoxy-N" -methiaminosulfonyl) phenyl] urea (N-methoxy N-methyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g. mmoles), N, O-dimethylhydroxyl amine hydrochloride (0.52 g, 5.3 mmol) and triethylamine (2.0 ml, 14.3 mmol) were reacted to form the desired product (1.04 g, 63%). CC-MS m / z 315 (M +).

(N-methoxy-N-methyl) -6-dichloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general procedure of hydrolysis, described in Example 15, (N-methoxy, N-methyl) -2,6-dichloro- 3-nitrobenzenesulfonamide (1.0 g, 3. 2 mmol), 80% NaH (0.30 g, 9.6 mmol) and water (58 μl, 3.2 mmol) were reacted to form the desired product (0.66 g, 69%). CC-MS m / z 297 (M +).

(N-methoxy-N-methyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, (N "-methoxy-N" -methyl) -6-chloro- 2-hydroxy-3-nitrobenzenesulfonamide (0.66 g, 2.2 mmol) was reduced with hydrogen and 10% Pd / C (0.66 g) to form the desired product (0.50 g, 85%). CC-MS m / z 266.d (M +).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3-rN "-methoxy-N" -methylaminosulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in example 15 , (N "-methoxy-N" -methyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15g, 0.56 mmole) and 2-bromophenylisocyanate (69 μl, 0.56 mmole) were coupled to form the desired urea ( 0.12 g, 45%). CC-MS m / z 464 (M +).

N-f4-chloro-2-hydroxy-3- (N "-methoxy-N" methylaminosulfonyl) phen.p-N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, (N "-methoxy-N" -methyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15g, 0.56mmol) and 2,3-dichlorophenylisocyanate (74mL, 0.56mmol) were coupled to form the desired urea (0.086g, 34%). CC-MS m / z 454 (M +).

N-C2-chlorophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-methoxy-N" -methylaminosulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in example 15 , (N "-methoxy-N" -methyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.56 mmol) and 2-chlorophenyl isocyanate (63 μl, 0. 56 mmoles) were coupled to form the desired urea (0.077 g, 33%). CC-MS m / z 420 (M +).

EXAMPLE 93. 94 and 95 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-pyrroidinylaminosulfonyl) phenyl] urea N- [4-chloro-2-hydroxy] -3- (N "-pyrroidinylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea. and N- (2-chlorophenyl) - N '- [4-chloro-2-hydroxy-3- (N "-pyrrolidinylammonosulfonyl) phenyl] urea (N-pyrrolidinyl) -2,6 dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.51 g, 5.2 mmol), pyrrolidine (435 μl, 5.2 mmol) and triethylamine (1.1 ml, 7.3 mmol) were reacted to form the desired product (1.16 g, 68%). CC-MS m / z 325 (M +).

(N-pyrrolidinyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, (N-pyrrolidinyl) -2,6-dichloro-3-nitrobenzenesulfonamide (1.12 g, 3.4 mmoles) ), 80% NaH (0.31 g, 10.3 mmol) and water (74 μl, 4.1 mmol) were reacted to form the desired product (0.94 g, 69%). CC-MS m / z 307 (M +).

(N-pyrrolidinyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, (N-pyrrolidinyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.73g, 2.4 mmoles) was reduced with hydrogen and 10% Pd / C (0.73g) to form the desired product (0.69 g, crude). MS m / z (M + H) 276.9, 278.89, 279.8d.

N- (2-Bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-pyrrolidinylamino-sulfonin-phenyl-urea) Following the general procedure for the formation of urea, described in Example 15, (N-pyrrolidinyl) - 3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.23 g, 0.33 mmoles) and 2-bromophenylisocyanate (102 μl, 0.83 mmoles) were coupled to form the desired urea (0.1 g, 26%). z 476 (M +).

N- [4-Chloro-2-hydroxy-3- (N "-pyrrolidinylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, ( N-pyrrolidinyl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide (0.23 g, 0.83 mmol) and 2,3-dichlorophenylisocyanate (110 μl, 0.83 mmol) were coupled to form the desired urea (0.10 g, 26%) CC-MS m / z 464 (M +).

N- (2-chlorophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-pyrrolidinylaminosulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in example 15, (N -pyrrolidinyl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide (0.23 g, 0.83 mmol) and 2-chlorophenylisocyanate (100 μi, 0.83 mmol) were coupled to form the desired urea (0.1 g, 28%). MS m / z 420 (M +).

EXAMPLE 96 AND 97 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-h8droxy-3 - [(4-pyridinyl] -minosulfonyl] phenyl] -urea and N- [4-chloro] -2-hydroxy-3 - [(4-pyridinylaminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea N- (4-Pyridinyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 g, 1.72 mmol), 4-aminopyridine (165mg, 1.75mmol) and triethylamine (0.36ml, 2.58mmol) were reacted to form the desired product (446mg, 76%). El-MS m / z 346 (M-H) \ N- (4-Pyridinip-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide) Following the general hydrolysis procedure described in Example 15, N- (4-pyrrolidinyl) -2,6-dichloro-3-nitrobenzenesulfonamide ( 540 mg, 1. 55 mmole), 80% NaH (217 mg, 7.25 mmole) and water (0.045 ml, 2.46 mmole) were reacted to form the desired product (170 mg, 33%). El-MS m / z 328 (M-H) \ N- (4-Pyridinyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N- (4-pyrrolidinyl) -2-hydroxy-3-nitrobenzenesuifonamide (22.0 mg , 0.066 mmole), was reduced with hydrogen and Pd / C (10.3 mg) to form the desired product (18.0 mg, 90%). El-MS m / z 298 (M-H). " N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(4-pyridinylaminosulfonyl] phenylaurea Following the general procedure for the formation of urea, described in Example 15, N- (4- Pyridinyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (52.6 g, 0.17 mmol) and 2-bromophenylisocyanate (0.0216 ml, 0.17 mmol) were coupled to form the desired urea (66.5 mg, 76%). m / z 496 (MH) '.

N- [4-Chloro-2-hydroxy-3 - [(4-pyridinylaminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl irea Following the general procedure for the formation of urea, described in Example 15, N- (4-Pyridinyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (52.6 g, 0.17 mmol) and 2,3-dichloropheniisocyanate (0.023 ml, 0.17 mmole) were coupled to form the desired urea (62.8 mg, 73%). El-MS m / z 485 (M-H) '.

EXAMPLE 98 AND 99 N- (2-Bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[2- (tetrahydro-2-furanyl) met > l] am8nosulfonii] phenyl] urea and N- [4-chloro-2-hydroxy-3 - [[2- (tetrahydro-2-furanyl) methyl] aminosulfonyl '| phenHl-N, - (2,3-dichlorophenyl) urea N- (2-Tetrahydrofurfuryl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (997 mg, 3.43 mmol), 2-tetrahydrofurfurylamine (0.37 ml, 3.58 mmol) and triethylamine (0.72 ml, 5.16 mmol) were reacted to form the desired product (1.04 g, 86%). EI-MS m / z 353 (M-H) ".

N- (2-Tetrahydrofurfuryl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (2-Tetrahydrofurfuryl) -2,6-dichloro-3 -nitrobenzenesulfonamide (660 mg, 1.86 mmol), 80% NaH (169 mg, 5.63 mmol) and water (0.035 ml, 1. 95 mmoles) were reacted to form the desired product (380mg, 61%). El-MS m / z 335 (M-H) ".

N- (2-Tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxy-3-hydroxybenzene sulfonamide Following the general hydrogenation procedure described in Example 15, N- (2-tetrahydrofurfuryl) -6-chloro -2-hydroxy-3-nitrobenzenesulfonamide (340 mg, 1.01 mmol) was reduced with hydrogen and Pd / C (158 mg) to form the desired product (304 mg, 98%). El-MS m / z 305 (M-H). " N- (2-Bromophenyl VN'- 4-chloro-2-hydroxy-3-rr [2-phthatrahydro-2-furanyl) methyl] anesulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in Example 15, N- (2-tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (152 mg, 0.49 mmol) and 2-bromophenylisocyanate (0.061 ml, 0.49 mmol) were coupled to form the desired urea (98 mg , 40%). El-MS m / z 504 (M-H) '.

N- [4-chloro-2-hydroxy-3 - [[[2- (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N- (2-tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (152 mg, 0.49 mmol) and 2,3-dichlorophenylisocyanate (0.065 ml, 0.49 mmol) were coupled to form the desired urea (184 mg, 76%). El-MS m / z 492 (M-H) '.

EXAMPLE 100 AND 101 N- (2-Bromophenyl) -N, -f4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] urea and N - [4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) met8l] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea N - ((2R) -Tetrahydrofurfuryl) -2,6-dichloro-3-n-tetrabenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (993 mg, 3.41 mmol), (2R) -tetrahydrofurfunylamine (0.36 ml, 3.49 mmol) and triethylamine (0.72 ml, 5.17 mmol) were reacted to form the desired product (1.17 g, 97%). El-MS m / z 353 (M-H) \ N - ((2R) -Tetrahydrofurfuryl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N - ((2R) -tetrahydrofurfuryl) -2.6- dichloro-3-nitrobenzenesulfonamide (1.17g, 3.29 mmol), 80% NaH (303 mg, 10.1 mmoies) and water (0.063 ml, 3. 49 mmole) were reacted to form the desired product (690mg, 63%). El-MS m / z 335 (M-H) ".

N - ((2R) -Tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide Following the general hydrogenation procedure described in Example 15, N - ((2R) -tetrahydrofurfuryl) -6-chloro-2- hydroxy-3-nitrobenzenesulfonamide (660mg, 1.96moles), reduced with hydrogen and Pd / C 303mg) to form the desired product (563mg, 94%). El-MS m / z 305 (M-H). " Nf-bromopheni [VN '- [4-chloro-2-hydroxy-3 - [[[(2R - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in Example 15, N - ((2R) -tetrahydrofurfuryl) -3-amino-6-chloro-3-hydroxybenzenesulfonamide (260mg, O.ddmmoles) and 2-bromophenylisocyanate (0.11mL, O.ddmmoles) were coupled to form the desired urea (127mg, 30%). El-MS m / z 504 (M-H). " N- [4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanipmethyl] amino sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N - ((2R) -tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (260 mg, 0.85 mmol) and 2,3-dichlorophenylisocyanate (0.11mL, O.ddmmoles) were coupled to form the desired urea (306mg, 75%). El-MS m / z 492 (M-H) " EXAMPLE 102 AND 103 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] urea and N- [4-chloro-2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanii) methyl-1-amino-sulfonyl-1-phen, - (2, 3-dichlorophenyl) uria.

N - ((2S) -Tetrahydrofururyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dicyoro-3-nitromencene sulfonyl chloride (1.00g, 3.44mmol), (2S) -tetrahydrofurfuryl amine (0.33mL, 3.20mmol) and triethylamine (0.72mL, 5.17mmol) were reacted to form the desired product (1.12g, 99%). El-MS m / z 353 (M-H). " Nf 2S) -tetrahydrofurfuryl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N - ((2S) -Tetrahydrofurfuryl) -2,6-dichloro- 3-nitrobenzenesulfonamide (1.12g, 3.15mmol), 30% NaH (2d4mg, 9.47mmol) and water (0.057mL, 3.16mmol) were reacted to form the desired product (280mg, 26%). El-MS m / z 335 (M-H) \ N - ((2S) -Tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide Following the general procedure of hydrogenation, described in Example 15, N - ((2S) -Tetrahydrofurfuryl) -3-amino-6 -chloro-2-hydroxybenzene sulfonamide (270mg, O.dOmmoles), was reduced with hydrogen and Pd / C (140mg) to form the desired product (226mg, 94%). El-MS m / z 305 (M-H) \ N- (2-bromophenyl) -N'-f4-chloro-2-hydroxy-3-rrr (2SV etrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in Example 15, N - ((2S) -Tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide (113mg, 0.37mmol) and 2-bromophenylisisocyanate (0.45mL, 0.37mmol) were coupled to form the desired urea ( 143mg, 77%). El-MS m / z 504 (M-H) \ N- [4-chloro-2-hydroxy-3- [f [f2SV (tetrahydro-2-furanyl ') methyl] amino sulfonyl] phenyl] -N' - (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N - ((2S) -Tetrahydrofurfuryl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide (113 mg, 0.37 mmol) and 2,3-dichlorophenylisocyanate (0.049mL, 0.37mmol) were coupled to form the desired urea (52.5mg, 29%). El-MS m / z 492 (M-H) \ EXAMPLE 104. 105 AND 106 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-cyclohexylamino-sulfonyl) -phenyl] -urea N- [4-chloro-2-hydroxy] -3- (N "-cyclopentylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea and N- (2-chlorophenyl) - N' - [4-chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyl] urea" (N-cyclopentyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.6g, 5.5mmol =, Cyclopentylamine (0.54mL, 5.5mmol) and triethylamine (1.1mL, 7.dmmole) were reacted to form the desired product 81.1g, 59%). CC-MS m / z 339 (M +).

(N-cyclopentyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general procedure of hydrolysis, described in Example 15, (N-cyclopentyl) -2,6-dichloro- (3-nitrobenzenesulfonamide (0.76 g, 2.2mmoles), 80% NaH (0.22g, 7.3mmol) and water (45μL, 2.5mmol) were reacted to form the desired product (0.49g, 68%) CC-MS m / z 321 (M +).

(N-cyclopentyl) -3-amino-6-chloro-2-hydroxy-3-benzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, (N-cyclopentyl) -6-chloro-2-hydroxy-3- nitrobenzenesulfonamide (0.54g, 1.7mmol) was reduced with hydrogen and 10% Pd / c (0.54g) were reacted to form the desired product (0.45g, crude). CC-MS m / z 219 (M +).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-cyclopentylamino sulfonylWenylurea Following the general procedure for the formation of urea, described in Example 15, (N-cyclopentyl) - 3-amino-6-chloro-2-hydroxy-3-benzenesulfonamide (0.15 g, 0.52 mmol) and 2-bromophenyl isocyanate 864 μL, 0.52 mmol) were collected to form the desired urea (0.1 g, 39%). / z 43d (M +).

N- [4-Chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea described in Example 15, (N-cyclopentyl) ) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2,3-dichloropheniisocyanate (68 μL, 0.52 mmol) were coupled to form the desired urea (0.1 Og, 40%). m / z 478 (M +).

N- (2-chlorophenyl) -N'-f4-chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyljurea Following the general procedure for the formation of urea described in example 15, (N-cyclopentyl) - 3-amino-6-chloro-2- hydroxybenzenesulfonamide (0.15g, 0.52mmol) and 2-chlorophenylisocyanate (62μL, 0.52mmol) were coupled to form the desired urea (0.1 g, 43%). CC-MS m / z 444 (M +).

EXAMPLE 107. 108 AND 109 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-iSQxazol-J-dinaminosulfonyl) -phenyljurea) N- [4-chloro-2-hydroxy-3] - (N "- soxaz Qlidinilaminosulfonil) phenyl] -N '- (2,3-dichlorophenyl) urea. and N- (2-chlorophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) pheny] urea N- (ethoxycarbonyl) isoxazolidine To a solution of KOH (6.4 g, 0.11 mmol) and hydroxy urethane (12 g, 0.11 mmol) in ethanol (50 mL) was added 1,3-dibromopropane (5.dmL, 0.057). The resulting suspension was heated under reflux for one hour. After the mixture was cooled to room temperature, an additional portion of KOH (3.2g, 0.055 mmol) and dibromopropane (2.9mL, 0.02dmmoles) was added. The mixture was passed under reflux for one hour, cooled to room temperature and the solvent was evaporated. The residue was suspended in ether by boiling 3 times and filtered. The combined filtrates were dried over sodium sulfate, filtered and evaporated. A 3g portion of the crude product was purified by flash column chromatography (EtOAC / Hexane, gradient elution), which yields 1.18 of N- (ethoxycarbonyl) isoxazolidine. 1 H NMR (CDCl 3) d 1.15 (t, 3 H), 2.15 (q, 2 H), 3.55 (t, 2 H), 3.8 (t, 2 H), 4.1 (q, 2 H).

Isoxazolidine hydrochloride N- (ethoxycarbonyl) isoxazolidine (1.1 dg, 9.1 mmol) was dissolved in aqueous HCl (6N, 7ml) and heated under reflux for two hours. After being cooled to room temperature, this solution was washed with ether (3x) and then evaporated to produce crude isoxazolidine hydrochloride which was recrystallized from ethane / ether, yielding 0.79 g (30%) of isoxazolidine hydrochloride. 1 H NMR (CDCl 3, CH 3 OD), d 2.5 (q, 2 H), 3.55 (t, 2 H), 4.2 (t, 2 H).

(N-isoxazolidin) -2,6-dichloro-3-nitrobenzensulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5g, 2.5mmol) ), isoxazolidine hydrochloride (0.56g, 5.2mmol) and triethylamine (2.2mL, 15.5mmol) were reacted to form the desired product (1.2g, 71%). CC-MS m / z 327 (M +).

(N-isoxazolidin) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, (N-isoxazolidinyl) -2,6-dichloro-3-nitrobenzenesulfonamide (1.0dg, 3.3 mmoles), 30% NaH (0.3g, 10Ommoles) and water (72mL, 4mmols) were they reacted to form the desired product (0.79g, 77%). CC-MS m / z 309 (M +).

(N-isoxazolidin) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, (N -oxazolidin) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.84) g, 2.7 mmol) was reduced with hydrogen and 10% Pd / C (0.84) to form the desired product (0.75 g crude). CC-MS m / z 279 (M +).

N- (2-bromophenyl) -N '- [chloro-2-hydroxy-3- (N "-isoxalidinylamino-sulfonyl-phenyl) -Urill following the general procedure for the formation of urea, described in Example 15, (N-isoxazolidinyl) - 3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.25g, 0.90mmol) and 2-bromophenylisocyanate (110mL, 0.90mmol) were coupled to form the desired urea (0.1g, 23%).

CC-MS m / z 476 (M +).

N-f4-chloro-2-hydroxy-3- (N "-isoxalidinylaminosulfoniphenyl) -N'-f2.3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, (N-isoxazolidin) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.25g, 0.90mmol) and 2,3-dichlorophenylisocyanate (120mL, 0.91 mmol) were coupled to form the desired urea (0.1 Og, 24%). CC-MS m / z 466 (M +).

N- (2-chlorophenyl) -N '- [4-chloro-2-hydroxy-3-fN "-isoxazolidinylamine-sulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in Example 15, ( N-isoxazolidin) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.25g, 0.90mmol) and 2-chlorophenylisocyanate (110mL, 0.91mmol) were coupled to form the desired urea (0.1g, 23%). MS m / z 432 (M +).

EXAMPLE 110. 111 AND 112 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] urea, N- [4-chloro-2-hydroxy] -3- (N "-tetrahydroxysoxazylaminosulfonyl) phenyl] -N ^ 2.3-chloro-phenyl) -urea. and N- (2-chlorophenyl) -N'-f4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] urea N- (ethoxycarbonyl) tetrahydroxazine To a KOH solution (3.34 g, 59.6 mmol) and hydroxyurethane (6.1 g, 58. 5 mmole) in ethanol (25 ml) was added 1,4-dibromobutane (3.5 ml, 29.3 mmoles). The resulting suspension was heated under reflux for 1 hour.

After cooling the mixture to room temperature, a portion was added additional KOH (1.65 g, 29.4 mmol) and dibromopropane (1.8 ml, 15 mmol). The mixture was then passed under reflux for 1 hour, cooled to room temperature, and the solvent was evaporated. The residue was suspended in ether boiling three times and filtered. The combined filtrates were dried over sodium sulfate, filtered, and evaporated. A 4g portion of the crude product was purified by flash column chromatography (EtOAC / hexane, gradient elution), yield 1.85g of N- (ethoxycarbonyl) tetrahydroisoxazine. 1 H NMR (CDCl 3) d 1.05 (q, 3 H), 1.45 (dd, 2 H), 1.55 (dd, 2 H), 3.4 (t, 2 H), 3.7 (t, 2 H), 3.95 (q, 2 H).

Tetrahydroisoxazine hydrochloride N- (ethoxycarbonyl) tetrahydroisoxazine (1.35g, 11.6mmol) was dissolved in HCl (6N, 7.dmL) and heated under reflux for 7 hours. After cooling to room temperature, this solution was washed with ether (3x) and then evaporated to yield crude tetraisoxazine hydrochloride, which was recrystallized from ethanol / ether to yield 0.74g (52%) of tetrahydroisoxazine hydrochloride. 1 H NMR (CDCl 3) d 1.35 (dd, 2 H), 1.95 (dd, 2 H), 3.4 (t, 2 H), 4.25 (t, 2 H).

(N-tetrahydroisoxazyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.75 g, 6.0 mmol), tetrahydroisoxazine hydrochloride (0.63 g, 5.1 mmol) and triethylamine (2.2 mL, 15.5 mmol) were reacted to form the desired product (1.32 g, 75%). CC-MS m / z 34 (M +).

(N-tetrahydroisoxazil) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the procedure generated! of hydrolysis, described in Example 15, (N-tetrahydroisoxazyl) -2,6-dichloro-3-nitrobenzenesulfonamide (0.1 g, 0.29 mmol), 30% NaH (26 mg, O.ddmmoles) and water (6.3mL, 0.35 mmol) were they reacted to form the desired product (50mg, 53%). CC-MS m / z 323 (M +).

(N-tetrahydroisoxazyl) -3-amino-6-chloro-2-hydroxybenzene sulfonamide Following the general procedure of hydrogenation, described in Example 15, (N-tetrahydroisoxazyl) -6-chloro-2-hydroxy 3-nitrobenzenesulfonamide (0.76 g) , 2.35 mmol) was reduced with hydrogen and 10% Pd / c (0.76) to form the desired product (0.39g, crude). CC-MS m / z 293 (M +).

Preparation of N- (2-bromophenylVN '- [4-chloro-3-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in example 15, (N-tetrahydroisoxazil -3-amino-6-chloro-2- hydroxybenzenesulfonamide (0.3g, LOmmols) and 2-bromophenylisisocyanate (126mL, LOmmols) were coupled to form the desired urea (0.1g, 20%). CC-MS m / z 490 (M +).

N- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, ( N-tetrahydroisoxazyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.3g, 1. Ominols) and 2,3-dichlorophenylisisocyanate (135mL, LOmmols) were coupled to form the desired urea (0.1 Og, 20%). CC-MS m / z 430 (M +).

N- (2-chlorophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] urea Following the general procedure for the formation of urea, described in Example 15, (N- tetrahydroisoxazyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.3g, LOmmols) and 2-chlorophenylisocyanate (124mL, LOmmoles) were coupled to form the desired urea (0.1g, 22%). CC-MS m / z 446 (M +).

EXAMPLE 113. 114 and 115 N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(: 2-isopropoxyethyl) aminosulfonyl] phen8l] urea.N- [4-chloro-2- hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-chloro-2-hydroxy-3] - [(2-8-Propoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenol) urea N- (2-isopropoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfononamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 16 mmol), -aminoethyl isopropyl ether (0.533g, . 16mmol) and triethylamine (1.42mL, 10.32mmol) were reacted to form the desired product (1.63g, 39%). CC-MS (m / z) 357.0 (M +).

N- (2-isopropoxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (2-isopropoxyethyl) -2,6-dichloro-3- Nitrobenzenesulfonamide (1635g, 4.5dmmoles), 60% NaH (0.41g, 13.74mmol) and water (0.099mL, 5.50mmol) were reacted. The crude product (1.67g) was continued to the next step without purification. CC-MS (m / z) 340 (M-H) +.

N- (2-isopropoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N- (2-isopropoxyethyl) -6-chloro-2-hydroxy-3- Crude nitrobenzenesulfonamide (1.17g) was reduced with hydrogen and Pd / C (350mg). The crude product (1.036 g) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 6.92 (d, 1 H), 6.d 5 (d, 1 H), 3.45 (m, 1 H), 3. 39 (t, 2H), 3.10 (t, 2H), 1.05 (d, 6H).

N- (2-Bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethylV aminosulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in example 15, Crude N- (2-isopropoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (362mg) and 2-bromophenylisocyanate (0.132mL, 1.07mmol) were coupled to form the desired urea (155mg, 29% for 3 steps) CC-MS (m / z) 503 (MH) +.

N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea Following the procedure generated! for the formation of urea, described in Example 15, N- (2-isopropoxyethy) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (362mg) and 2,3-dichlorophenylisocyanate (0.141mL, 1. 07 mmol) were coupled to form the desired urea (264 mg, 50% for 3 steps). CC-MS (m / z) 493 (M-H) +.

N- [4-Chloro-2-hydroxy-3 - [(2-iopropoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenipurea) Following the general procedure for the formation of urea, described in Example 15 , N- (2-isopropoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (362mg) and 2-chlorophenylisocyanate (0.129mL, 1.07mmol) were coupled to form the desired urea (170mg, 34% for 3 steps) CC-MS (m / z) 462 (MH) +.

EXAMPLE 116. 117 and 118 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] urea. N- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-chloro-2-hydroxy-3 - [(2)] -ethoxyethyl) aminosulfonyl] phenyl] -N '- (chlorophenyl) urea N- (2-ethoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.16 mmol), 2-aminoethyl ethyl ether (0.46g, . 16 mmol and triethylamine (1.42 mL, 10.32 mmol) were reacted to form the desired product (1.73 g, 100%). CC-MS (m / z) 345 (M +).

N- (2-ethoxyethyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (2-ethoxyethyl) -2,6-dichloro-3-nitrobenzenesulfonamide ( 1.73g, 5.16mmol), 80% NaH (0.46g, 15.4dmmoles) and water (111mL, 6.20mmol) were reacted. The crude product (1.63g) was continued to the next step without purification CC-MS (m / z) 325.0 (M +).

N- (2-ethoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N- (2-ethoxyethyl) -6-chloro-2-hydroxy-3- Crude nitrobenzenesulfonamide (0.9dg) was reduced with hydrogen and Pd / C (250mg). The crude product (0.01 g) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 6.dd (m, 2H), 3.40 (t, 2H), 3.36 (m, 2H), 3.13 (t, 2H), 1.0d (t, 3H).

N- (2-bromopheni!) - N '- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) -amino sulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in the example 15, N- (2-ethoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (333mg) and 2-bromophenylisocyanate (204mg, 1. 03 mmol) were coupled to form the desired urea (130 mg, 26% for 3 steps). CC-MS (m / z) 494.0 (M-H) +.

N- [4-Chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl-N '- (2,3-dichloropheniurea) Following the general procedure for the formation of urea, described in Example 15, N- (2-ethoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (333mg) and 2,3-dichlorophenylisocyanate (194mg, 1.03mmol) were coupled to form urea 135mg, 37% for 3 steps). CC-MS (m / z) 434.0 (M-H) +.

N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -N '- (2-chloropheniOurea) Following the general procedure for the formation of urea, described in Example 15, N- ( 2-ethoxyethyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (333mg) and 2-chlorophenylisocyanate (15dmg, 1. 03mmoies) were coupled to form the desired urea (133mg, 30% for three steps). CC-MS (m / z) 443.2 (M-H) +.

EXAMPLE 119. 120 and 121 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-rtidroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonylphenyl] urea. N- [4-Chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl-phenyl] -N '- (2,3-dichlorophenol) urea and N- [4- chloro-2-hydroxy] -3-f (2-carboxy) -azetidin-1-yl] sulfonylphenyl-N '- (2,3-dichlorophenyl) urea 2-acetoxy-L-azetidine A solution of L-azetidine-carboxylic acid (700 mg, 6.92 mmol) and 1 ml of chlorotrimethylsilane in 10 ml of methanol was heated under reflux overnight. The mixture was concentrated to give the desired product quantitatively (796mg), without purification. H NMR (CCDC! 3); d 9.49 (s, 1 H), 5.20 (m, 2H), 4.27 (m, 1 H), 4.14 (m, 1H), 3.62 (s, 3H), 2.81 (m, 1 H), 2.71 (m, 1 HOUR). 2. 6-dichloro-1 - [Y2-methoxycarbonyl) azetidin-1-yl] sulfonyl-3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.01 g, 6.92 mmol), 2-acetoxy-L-azetidine (796 mg, 6.92 mmol) and triethylamine (1.75 mL, 17.3 mmol) were reacted to form the desired product (1.84 g, 72%). 1 H NMR (CCDCI 3); d 7.68 (d, 1 H), 7.61 (d, 1H), 5.09 (t, 1H), 4.46 (m, 1H), 4.06 (m, 1H), 3.59 (s, 3H), 2.55 (m, 1H) 2.49 (m, 1 H). 6-Chloro-2-hydroxy-1 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl-3-nitrobenzene To a solution of 2,6-dichloro-1 - [(2-methoxycarbonyl) azetidin-1 -yl] -sulfonyl-3-nitrobenzene (1.94g, mmol) at room temperature was added potassium superoxide (946mg, 13.3mmol) in 50 mg of potion. The mixture was stirred for 20 hours. The mixture was acidified with 1N aq HCl, extracted with ethyl acetate. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane / acetic acid (40/58/2, v / v / v), gave the desired product (767mg, 42%). CC-MS (m / z) 351.0 (M +). 6-Chloro-2-hydroxy-1 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonylaniline Following the general procedure of hydrogenation, described in Example 15, 6-chloro-2-hydroxy-1 - [( 2-methoxycarbonyl) azetidin-1-yl] sulfonyl-3-nitrobenzene (742mg, 2.12 mmol) was reduced with hydrogen and 10% Pd / C (250mg) to form the desired product (649mg, 96%). 1 H NMR (MeOD-d 4): d 6.86 (m, 2 H), 4.95 (t, 1 H), 4.17 (m, 1 H), 3.94 (m, 1 H), 3.56 (s, 3 H), 2.45 (m, 2 H) ).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetjdin-1-yl] sulfonyl] phenyl] urea Following the general procedure for the formation of urea, described in Example 15, 6-chloro-2-hydroxy-1 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonylanine (325 mg, 1.01 mmol) and 2-bromophenylisocyanate (201 mg, 1.01 mmol) were coupled to form the desired urea (390mg, 74%). CC-MS (m / z) 520.0 (M +).

N- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl] phenyl] -N '- (2,3-dichlorophenol) urea Following the general procedure for the formation of urea, described in Example 15, 6-chloro-2-hydroxy-1 - [(2-methoxycarbonyl) azetidin-1-ylsulfonilanyl (325 mg, 1.01 mmol) and 2,3-dichlorophenylisocyanate (190 mg, 1. 01 mmoles) were coupled to form the desired urea (479mg, 93%). CC-MS (m / z) 510.0 (M +).

N- [4-chloro-2-hydroxj-3 - [(2-ca rboxi) -azetidin-1-yl] sulfonylphenyl] -N '- (2,3-didorofepil) urea A solution of N- [4-chloro-2] -hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl] phenyl3-N '- (2,3-dichlorophenyl) urea (359mg, 0.71 mmol) and lithium hydroxide monohydrate (296 mg) in methanol (10 ml) and water (1 ml) was stirred at room temperature for 16 hours. The mixture was concentrated, the residue was acidified with 1 N aq HCl. The resulting mixture was filtered, e! solid White was collected and dried in vacuo to give the desired product (323mg, 95%). CC-MS (m / z) 496.0 (M +).

EXAMPLE 122. 123 and 124 Preparation of N-S-Bromopheni-N '- ^ - Chloro-Hydroxy-S- [N "- [3- (4-morpholinyl) propyl] aminosulfonyl] phenyl] urea hydrochloride. N- [4-chloro-2-hydroxy-3- [N "-r3- (4-morpholinyl) propyl] -aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea and N- [4-chloro] chloride -2-hydroxy-3-fN "-f3- (4-morpholinyl) propyl] aminosulfonyl] phenyl-N '^ chloropheniQurea N- [3- (4-morpholinyl) propyl] -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, ß.ddmmoles), 4- (3-aminopropyl) morpholine (993mg, 6.ddmmoles) and triethylamine (1.92mL, 13.76mmol) were reacted to form the desired product (2.04g, 74%). CC-MS (m / z) 398.0 (M +).

N- [3- (4-morpholinyl) propyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- [3- (4-morpholinyl) propyl] -2,6-dichloro-3-nitrobenzenesulfonamide (1.0g, 2.51 mmol), 60% NaH (301 mg, 7.53 mmol and water (54mL, 3.0 mmol) were reacted.The mixture was acidified with 4.0N HCl in 1,4-dioxane and concentrated to give the crude product (1.01g), which was continued to the following steps without purification. CC-MS 330.0 (M +).

N- [3- (4-morpholinyl) propyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N- [3- (4-morpholinyl) propyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.01g) was reduced with hydrogen and 10% Pd / C (250mg). The crude product (390mg) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 6.d6 (m, 2H), 3.67 / m, 4H), 3.15 (m, 6H), 2.98 (t, 2H), 1.92 (m, 2H).

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "-r3- (4-mQrfolinyl) propyl] -aminosulfonyl] phenyljurea hydrochloride Following the general procedure for the formation of urea, described in Example 15, crude N- [3- (4-morpholinyl) propyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (297 g) and 2-bromophenyl isocyanate (166 mg, 0.83 mmol) were coupled to form the desired urea (191mg, 39% for 3 steps) CC-MS (m / z) 549.2 (M +).

N-f4-Chloro-2-hydroxy-3- [N "-f3-f4-morpholinyl) propylammonylsulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in Example 15, N- [3- (4-morpholinyl) propyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (297g) and 2,3-dichlorophenylisocyanate (157mg, 0.83mmol) were coupled to form the desired urea (134mg, 2d% for 3 steps) CC-MS (m / z) 539.2 (M +).

N-4-chloro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propip aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in Example 15, crude N- [3- (4-morpholinyl) propyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (297 g) and 2-chlorophenylisocyanate (127 mg, 0. 83 mmol) were coupled to form the desired urea (133.mg, 29% for 3 steps). CC-MS (m / z) 503.2 (M +).

EXAMPLE 125 AND 126 Preparation of N- (2-bromophenyl) -N'-f4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonylphenyl] urea and N - (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3-fS - (-) - (2-hydroxymethyl) pyrrolidin-1-ylsulfonyl-phenyl] -urea 2. 6-Dichloro-1- [S - (- H2-methoxymethyl) pyrrolidin-1-yl] sulfonyl-3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6- chloride dichloro-3-nitrobenzenesulfonyl (2.0g, 6.88mmol), S - (-) - (2-methoxymethyl) pyrrolidine (793mg, 6.ddmmoles) and triethylamine (1.9mL, 13.76mmol) were reacted to form the desired product ( 2.2mg, 37%). CC-MS (m / z) 369.0 (M +). 6-chloro-2-hydroxy-1- [SfV (2-methoxymethyl) pyrrolidin-1-ylsulfonyl-3-nitrobenzene Following the general hydrolysis procedure described in Example 15, 2,6-dichloro-1- [S-] (-H 2 -methoxymethyl) pyrrolidin-1-yl] sulfonyl-3-nitrobenzene (1.0g, 2.71 mmoles), 60% NaH (325mg, d.13mmol) and water (59mL, 3.3mmol) were reacted. The crude product (1.0 g) was continued to the next step without purification. CC-MS (m / z) 351.0 (M +). 4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonyl aniline Following the general procedure of hydrogenation, described in example 15, 6-chloro-2-hydroxy -1- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonyl-3-nitrobenzene (1.0g) was reduced with hydrogen and 10% Pd / C (320mg). The crude product (0.92g) was continued to the next step without purification. 1 H NMR (MeOD-d): d 6.91 (d, 1H), 6.69 (d, 1H), 4.41 (m, 1H), 3.39 (m, 2H), 3.21 (s, 3H), 1.33-1.97 (m, 6H).

N-ß-bromofep? VN, -r4- oiO-2-hydroxl-3-fS - (-) - (2-methylmethyl) pyrrolidin-1-ylsulfonylphenyljurea Following the general procedure for the formation of urea, described in example 15, 4-chloro-2 Crude -hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-ylsulfonyl aniline (306mg) and 2-bromophenylisocyanate (13dmg, 0.95mmol) were coupled to form the desired urea (170.4mg, 35% for 3 steps). CC-MS (m / z) 520.0 (M +).

N-r2-bromophenyl VN '- [4-chloro-2-hydroxy-3-rS - (- Vr2-methoxymethyl-pyrrolidin-1-yl] sulfonyl-phenyl] -urea To a solution of N- [2-bromophenyl] -N '- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] suphonophenyl] urea (92 mg, O.ldmmoles) in dichloromethane in Ice bath was added boron tribromide 1.0M (0.53mL, 0.53mmol) in dichloromethane. The mixture was stirred for 16 hours. The purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (50/50, v / v), gave the desired product (65mg, 73%). CC-MS (m / z) 506.0 (M +).

EXAMPLE 127 AND 128 N- [4-Chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonylphenyl} -N'- (2,3-dichlorophenyl) urea and N- [4-chloro-2-h8droxy-3-. { S - (-) - (2-hydroxymethyl) -pyrrolidin-1-ylsulphonyl] -phenyl] -N '- (2,3-dichlorophenyl) urea N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonyl-phenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, crude 4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-ylsulfonyl aniline (306mg) and 2,3-dichlorophenylisocyanate ( 179mg, 0.95mmol) were coupled to form the desired urea (218mg, 45% for three steps). CCMS (m / z) 510.2 (M +).

N- [4-chloro-2-hydroxy-3- [S - (- H2-hydroxymethyl) -pyrrolidin-1-yl] sulfonyl] phenyl-N '- (2,3-dichlorophenyl) urea Following the deprotection procedure, described in Example 126, N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) -pyrrolidin-1-ylsulfonyl-phenyl-N '- (2,3-dicyorophenyl) urea (dOmg, 0.16 mmol) and boron tribromide 1.0 M (0.78mL, 0.78mmol) were reacted to form the desired product (50mg, 64%). CC-MS (m / z) 494.0 (M +).

EXAMPLE 129 and 130 N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) -pyrrolidin-1-yl] sulfonyl-phenyl] -N '- (2-chlorophenyl) urea and N-f4-chloro-2-hydroxy-3- [S - (- H2-hydroxymethyl) -pyrrolidin-l-illsulfonylphenir-N '- ^ - chlorophenidae N- [4-Chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonyl] -N '- (2,3-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, crude 4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-ylsulfonyl aniline (306mg) and 2-chlorophenylisocyanate (146mg, 0.96 mmol) were coupled to form the desired urea (129 mg, 29% for 3 steps). CC-MS (m / z) 474.2 (M +).

N- [4-Chloro-2-hydroxy-3- [S - (- H2-hydroxymethyl) -pyrrolidin-1-yl] sulfonyl phenyl] -N '- (2-chlorophenyl) urea Following the deprotection procedure, described in Example 126, N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfoniIfenii] -N '- (2-chlorophenyl) urea (63mg, 0.13 mmol) and boron tribromide 1. 0M (0.65mL, 0.65mmol) were reacted to form the desired product (35mg, 53%). CC-MS (m / z) 460.0 (M +).

EXAMPLE 131 AND 132 Preparation of N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3-FS- (2-methoxycarbonyl!) Pyrrolidin-1-ylsulfonylphenyl] urea and N- (2-bromophenyl) ) -N '- [4- chloro-2-hydroxy-3- [S- (2-carboxy) p8rrolidin-1-yl] sulfonylphenyl] urea 2. 6-dichloro-1- [S- (2-methoxycarbonyl) pyrrolidin-1-yl] sulfonyl-3-nitrobenzene Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-chloride Nitrobenzenesulfonyl (4.79g, 16.5mmol), L-proline methyl ester hydrochloride (2.73g, 16.5mmol) and triethylamine (4.60mL, 33mmol) were reacted to form the desired product (5.02g, 79%). CC-MS (m / z) 333.0 (M +). 6-chloro-2-hydroxy-1- [S- (2-methoxycarbonyl) pyrrolidin-1-ylsulfonyl-3-nitrobenzene To a solution of 2,6-dichloro-1- [S- (2-methoxycarbonyl) pyrrolidin-1 -yl] sulfonyl-3-nitrobenzene (1.0 g, 206 mmol) at room temperature was added potassium superoxide (370 mg, 5.2 mmol) in 50 mg of potion. The mixture was stirred for 16 hours. The mixture was acidified with 1 N aq HCl, extracted with ethyl acetate. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane / acid acetic (50/48/2, v / v / v) gave the desired product (384mg, 40%). CC-MS (m / z) 365.2 (M "). 4-chloro-2-hydroxy-3- [S- (2-methoxycarbonyl) pyrrolidin-1-yl] sulfonyl aniline Following the general hydrogenation procedure described in Example 15, 6-chloro-2-hydroxy-1 - [S- (2-methoxycarbonyl) pyrrolidin-1-yl] sulfonyl-3-nitrobenzene (330mg, 1.04 mmol) was reduced with hydrogen and 10% Pd / C (110mg) to form the desired product (340mg, 93 %). 1 H NMR (MeOD-d 4): d 6.64 (m, 2 H), 4.5 d (m, 1 H), 3.67 (s, 3 H), 2.25 (m, 2 H), 2.10 (m, 2 H), 1.95 (m, 2 H) ).

N-r2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- | "S- (2-methoxycarbonopyrrolidin-1-ylsulfonylphenyl] urea Following the general procedure for the formation of urea, described in Example 15, 4-chloro-2-hydroxy-3- [S- (2-methoxycarbonyl) pyrrolidin-1-ylsulfonyl aniline (339 mg, 1.01 mmol) and 2-bromophenylisocyanate (201 mg, 1.01 mmol) were coupled to form the desired urea (223mg, 41%) CC-MS (m / z) 534.0 (M +) N- [2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S- (2-carboxy) pyrrolidin-1-yl] sulfonylphenyl] urea A solution of N- [2-bromophenyl] - N '- [4-chloro-2-hydroxy-3- [S- (2-methoxycarbonyl) pyrroidin-1-yl] sulfonylphenylurea (40mg, 0.075mmol) and lithium hydroxide monohydrate (40mg) in methanol (10mL) and Water (1 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, the residue was acidified with 1N aq HCl. The resulting mixture was filtered, the white solid was collected and dried in vacuo to give the desired product (39mg, 100%). CC-MS (m / z) 520.0 (M +) EXAMPLE 133. 134 and 135 Preparation of N- (2-bromophenyl) -Ni '- [3- [N "- (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl-urea N- [3- [ N "- (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenity-N '- ^. S-dichlorophenic acid and N- [3- [N2- (tert-butyl) aminosulfonyl] -4-chloro- 2-hydroxyphenyl-N '- (2-chlorophenyl) urea N- (tert-butyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0g, d.ddmmoles), tert-butylamine (503mg, d.ddmmoles) and triethylamine (1.43mL, 10.32mmol) were reacted to form the desired product (1.67g, 75% 9). 1 H NMR (MeOD-d 4): d 7.91 (d, 1 H), 7.73 (d, 1 H), 1.25 (s, 9 H), N- (tert-butyl) -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N- (tert-butyl) -6-chloro-2-hydroxy-3- Nitrobenzenesulfonamide (1.67 g, 5.1 mmol), 60% NaH (61 mg, 15.3 mmol) and water (92 mL), 5.1 mmol) were reacted to form the desired product (1.54 g), which was continued to the next step without purification. 1 H NMR (MeOD-d): d 8.00 (d, 1 H), 7.08 (d, 1 H), 1.24 (s, 9H).

N- (tert-butyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general procedure of hydrogenation, described in Example 15, N- (tert-butyl) -6-chloro-2-hydroxy-3- Crude nitrobenzenesulfonamide (1.54g) was reduced with hydrogen and 10% Pd / C (670mg). The crude product (1.23g) was continued to the next step without purification. 1 H NMR (MeOD-d 4): d 6.d 2 (m, 2 H), 1.22 (s, 9 H).

N- (2-bromophenyl) VN'-f3- | N "- (tert-butylaminosulfonyl-p-4-chloro-2-hydroxyphenyljurea) Following the general procedure for the formation of urea, described in Example 15, N- (ter-butyl) !) - crude 3-amino-6-chloro-2-hydroxybenzenesulfonamide (41 Omg) and 2-bromopheniisocyanate (322mg, 1. 62mmol) were coupled to form the desired urea (228mg, 32% for three steps) .CC-MS (m / z) 478.0 (M +).

N- [3- [N "- (tert-butyl) aminosulfonyl] -4-doro-2-hydroxyphenyl | -N, - (2,3-dichlorophenyl) urea Following the general procedure for the formation of ures, described in Example 15 , Crude N- (tert-butyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide (41 Omg) and 2,3-dichlorophenylisocyanate (304mg, 1.62m moles) were coupled to form the desired urea (336.1 mg, 49%). % for 3 steps) CC-MS (m / z) 468.0 (M +) N- 3- [N "- (tert-butyl) aminosulfonip-4-chloro-2-hydroxyphenyl] -N'-2,3-chlorophenipurea Following the general procedure for the formation of urea, described in Example 15, N- (tert-butyl) -3-amino-6-chloro-2-hydroxybenzenesulfonamide crude (41 Omg) and 2-chlorophenylisocyanate (249mg, 1. 62mmol) were coupled to form the desired urea (243mg, 38% for 3 steps). CC-MS (m / z) 432.0 (M +).

EXAMPLE 138 and 139 Preparation of N- [3-fN "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] aminosulfonyl] - - chloro - 2 - hydroxyphenyl] - N '- (2-chlorophenyl) urea and hydrochloride N- [3- [N "- (5-amino-5-carboxypentyl) amynesulfonyl-4-chloro-2-hydroxy-phenyl-N '- (2-chlorophenyl) urea N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] amino sulfonyl] -4-chloro-2-hydroxyphenyl3-N '- (2-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (233 mg, 0.52 mmol) and 2-dorophenylisocyanate (dOmg, 0.52 mmoles) were coupled to form the desired urea (97mg, 31%) CC-MS (m / z) 605.2 (M +).

N- [3-fN "- (5-amino-5-carboxypentyl) aminosulfonyl-4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea hydrochloride Following the general procedure for deprotection of Boc in the example 36, N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] amine-isophenyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea (104mg, 0.17 mmol) was stirred in 1 ml of trifluoroacetic acid to form the desired product (64mg, 61%). CC-MS (m / z) 505.0 (M +).

EXAMPLE 142. 143 AND 11 Preparation of N- [4-chloro-3- (1,1-dioxidothiomorpholinosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea. n- (2-bromophenyl) -N '- [4-chloro-3- (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyphenyl] urea and N- [4-chloro-3- (1,1-dloxydothiomorpholinosulfonyl) -2-hydroxyphenyl] - N '- (2-chlorophenyl) urea 6-Chloro-1- (1,1-dioxidCtiomorpholinesulfonyl) -2-hydroxy-3-nitrobenzene A solution of 6-chloro-2-hydroxy-3-nitro-1- (4-thiomorpholinylsulfonyl) benzene (563mg, 1.67mmol) and acid m-chloroperbenzoic (1.73g, 5.01 mmol) in dichloromethane (60mL) was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate and washed with water to give the crude product. Purification by column chromatography on silica gel, eluting with ethyl acetate / hexane (49/50/1, v / v / v), gave the desired product (230 mg, 37%). EL-MS (m / s) 363.92, 371.03 (M +) 4-chloro-3- (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyaniline Following the general procedure of hydrogenation, described in example 15, 6-chloro-1- (1,1-dioxydotiomorphino-Inesulfonyl) -2-hydroxy-3- Nitrobenzene (220mg, 0.60 mmol) was reduced with hydrogen and 10% Pd / C (100 mg) to give the desired product (186 mg, 92%). 1 H NMR (MeOD-d 4): d 6.8 d (m, 2 H), 3.35 (t, 4 H), 3.22 (t, 4 H).

N- [4-chloro-3- (1,1-dioxidothiomorpholinosulfonip-2-hydroxyphenyl) -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 4-chloro-3- ( 1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyaniline (62mg, O.ldmmoles) and 2,3-dichlorophenylisocyanate (41 mg, 0. 22mmol) were coupled to form the desired urea (32mg, 34%). CC-MS (m / z) 528 (M +).

N- [2-bromophenyl) -N '- [4-chloro-3- (1,1-dioxidothiomorpholinosulfonyl) -2-hydroxyphenyljurea Following the general procedure for the formation of urea, described in example 15, 4-chloro-3- ( 1, 1-d-oxidothiomorpholinosulfonyl) -2-hydroxyaniline (62mg, O.ldmmoles) and 2-bromophenylisocyanate (44mg, 0. 22mmol) were coupled to form the desired urea (2dMG, 29%). CC-MS (m / z) 539.3 (M +).

N- [4-chloro-3- (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyphenyl] -N '- (2,3-chlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, 4-chloro-3 - (1,1-dioxidothiomorpholinesulfonyl) -2-hydroxyaniline (62mg, O.ldmmoles) and 2-chlorophenylisocyanate (34mg, 0. 22mmol) were coupled to form the desired urea (29mg, 32%). CC-MS (m / z) 496.0 (M +).

EXAMPLE 145 AND 146 Preparation of N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N-trifluoroacetate - [3- N "- (2-aminoethyl) aminosulfonyl] -4-chloro-2-hydroxy-phenyl] -N '- (2,3-dichloropheni-Qurea) N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl3-amino-sulfonyl-1-4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N- [2- (tert-butoxycarbonylamino) etiI] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220mg, O.dOmmoles) and 2,3-dichlorophenylisocyanate (125mg, 0.66mmol) were coupled to form the desired urea (220mg, 66%). CC-MS (m / z) 553.2 (M +).

N- [3- [N "- [2-aminoethyl] aminosulfonyl] -4-chloro-2-hydroxy-phenyl-N '- (2,3-dichlorophenyl) urea trifluoroacetate Following the general procedure for deprotection of Boc, described in Example 36, N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea (56 mg, O.Ommoles) ) was stirred in trifluoroacetic acid to form the desired product (57mg, 100%). CC-MS (m / z) 453.0 (M +).

EXAMPLE 147 AND 148 Preparation of N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl.] 4-chloro-2-hydroxyphenyl} - N '- (2-chlorophenyl) urea and N- [3-fN "- (2-aminoeti aminosulfonyl ^ -chloro ^ -hydroxyphenyl-N '^ -chlorophenyl) urea trifluoroacetate N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyljaminosulfonyl] -4-chloro-2-hydroxyphenyl-N '- (2,3-dichlorophenyl) urea Following the general procedure for the formation of urea, described in Example 15, N- [2- (tert-butoxycarbonylamino) ethyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220mg, O.dOmmoles) and 2-bromophenylisocyanate (101mg, 0.66 mmol) were coupled to form the desired urea (169mg, 54%). CC-MS (m / z) 519.2 (M +).

N- | "3- [N" - [2- (aminoethyl) aminosulfonyl] -4-chloro-2-hydroxy-phen-N'-C2-chloropheniOurea trifluoroacetate Following the general procedure for detection of Boc, described in example 36 , N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea (57 mg, 0.11 mmol) stirred in trifluoroacetic acid to form the desired product (51 mg, 67%). CC-MS (m / z) 419.2 (M +): EXAMPLE 150 Preparation of N- [4-chloro-2-hydroxy-3-N ". N" -dimethylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea a) N-Dimethyl-2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for the formation of sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0g, 6.9mmol), dimethylamine (2.0 M in MeOH, 3.5 mL, 6.9 mmol) and triethylamine (1.44 mL, 10.35 mmol) were reacted to form the desired product (1.45 g, 70.4%). El-MS m / z 293 (M-H) " b) N ".N" -dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N ", N" -dimethyl-2,6-dichloro- 3-Nitrobencenesulfonamide (2.64g, 3.83 mmol), NaH (60%, 1.06 g, 26.5 mmol) and water (191 mg, 10.6 mmol) were reacted to form the desired product (2.3 g, 93%). El-MS m / z 279.5 (M-H) '. c) N ".N" -dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide Following the general hydrogenation procedure described in Example 15, N ", N" -dimethyl-6-chloro-2-hydroxy -3-nitrobenzenesulfonamide (2.3g, 3.2mmol) was reduced with hydrogen and Pd / C (2.3g) to form the desired product (2.0g, 97%). El-MS m / z 246.5 (M-H) ". d) N-4-chloro-2-hydroxy-3-r (N ". N" -dimethylaminosulfonyl) phenyl] -N'-f2-chloropheniDurea Following the general procedure for the formation of urea described in Example 15, N " , N "-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (200mg, O.dmmoles) and 2-chlorophenyl isocyanate (123mg, O.dmmoles) were coupled to form the desired urea (270mg, 83%).

El-MS m / z 403.2 (M-H). " EXAMPLE 151 Preparation of N ^ -chloro-S-hydroxy-S-taminosulfoniQfßnip-N '^ - chloro-S-fluorofeniQurea a) 2-chloro-3-fluoronitrobenzene To a solution at 7d ° C of 3-fluoronitrobenzene (2g, 14.2mmol) in THF (30mL) was added N-chlorosuccinimide (5.69g, 42.6mmol) in THF (20mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below -75 ° C. The resulting mixture was stirred for 30 minutes at -78 ° C. Then it is divided between 5% HCl and ethyl acetate. The combined organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% ethyl acetate / hexane) gave the desired product (231 mg, 9.2%). El-MS m / z 176.5 (M +). b) 2-chloro-3-fluoroaniline To the solution of 2-chloro-3-fluoronitrobenzene (231 mg, 1.32 mmol) in ethanol (10 ml) was added tin (II) chloride (1.4dg, 6.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. NaHC 3 aq was added at pH = 7. It was then extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to give the desired product (136mg, 71%). El-MS m / z 146.5 (M +). c) N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N '- (2-chloro-3-fluoro-phenyl) urea To a solution of 2-chloro-3-fluoroaniline (136 mg, 0.94 mmol!) In toluene (10 mL), triphosgene (111 mg, 0.37 mmol) and triethylamine (0.13 mL, 1.12 mmol) were added. The reaction mixture was stirred at 80 ° C for 4 hours. Then the reaction mixture was concentrated under reduced pressure and then added to 3-amino-6-cyoro-2-hydroxybenzenesulfonamide (104 mg, 0.47 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (30% ethyl acetate / hexane) gave the desired product (80 mg, 43%). El-MS m / z 395.2 (M +).

EXAMPLE 152 Preparation of N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N '- (2-bromo-3-fluoropheni-Qurea a) 2-chloro-3-fluoronitrobenzene To a solution at -78 ° C of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-bromosuccinimide (7.58 g, 42. mmol) in THF (20 mL) , NaHMDS (1M in THF, 28.4mL, 28.4mmol) was then added dropwise to maintain an internal temperature below -75 ° C. The resulting mixture was stirred for 30 minutes at -73 ° C. Then it was divided between 5% HCL and ethyl acetate. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% ethyl acetate / hexane) gave the desired product (300 mg, 9.6%). El-MS m / z 221 (M +). b 2-chloro-3-fluoroaniline To a solution of 2-bromo-3-fluoronitrobenzene (100 mg, 0.46 mmol) in ethanol (5 ml), tin (II) chloride (520 mg, 2.3 mmol) was added. The mixture was stirred at room temperature for 16 hours, NaHC 3 ac was added at pH = 7. Then it was extracted with ethyl acetate (3x) .The combined organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to give the desired product (80 mg, 93%). EL-MS m / z 191 (M +). c) N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenylj-N '- (2-bromo-3-fluoro-phenylhirea To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.022 mmol) in toluene (5mL), triphosgene (26mg, 0.09mmol) and triethylamine (0.04mL, 0.26mmol) were added.The reaction mixture was stirred at 30 ° C for 4 hours.The reaction mixture was concentrated under reduced pressure and then added to 3-amino-6-chloro-2-hydroxybenzenesulfonamide (44mg, 0.22mmoies) in DMF (1 mL) The reaction mixture was stirred at room temperature for 16 hours, chromatography of the resulting liquid on silica gel (30 mL). % ethyl acetate / hexane) gave the desired product (7 mg, 7%). MS-MS m / z 439.6 (M +).

EXAMPLE 153. 154 and 155 N-f2-bromophenyl) -N'-f4-chloro-3-f (1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxyphenyl] urea hydrochloride. N- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylaminosulfonip-2-hydroxyphenyl] N '- (2,3-dichlorophemethyl) uriane hydrochloride and N- [4-chloro-3-hydrochloride] [(1-ethyl-pyrrolidin-2-methylaminosulfonyl-S-hydroxypheni ^ -N'-t? -chloropheniQurea N - [(1-ethyl-pyrrolidin-2-ipmethyl) -2,6-dichloro-3-nitrobenzenesulfonamide Following the general procedure for sulfonamide formation, described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0g, 6.ddmmoles), 2-aminomethyl-1-ethyl-proline (dd2mg, d.ddmmoles) and triethylamine (1.92mL, 13.76mmol) were reacted. The crude product (2.64%) was continued to the next step without purification. CC-MS (m / z) 382.0 (M +).

(N - [(1-ethyl-pyrrolidin-2-yl) methyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide Following the general hydrolysis procedure described in Example 15, N - [(1-ethyl crude pyrrolidin-2-yl) methyl] -2,6-dichloro-3-n-tetrabenzenesulfonamide (1.50 g), 60% NaH (471 mg, 11.78 mmol) and water (85 mL, 4.72 mmol) were reacted to form the crude product (1.98g), which was continued to the next step without purification CC-MS (m / z) 364.2 (M +).

(N - [(1-ethy1-pyrrolidin-2-yl) methyl] -3-amino-6-chloro-2-hydroxybenzene suifonamide Following the general hydrogenation procedure, described in Example 15, N - [(1 crude -etii-pyrroidin-2-yl) methyl] -6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (2.1dg) was reduced with hydrogen and 10% Pd / C (300mg). The crude product (1.85) was continued in the next step without purification.

N- (2-Bromophenyl N'-r4-doro-3-! T1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl-2-hydroxyphenyl] urea hydrochloride Following the general procedure for the formation of urea described in Example 15, Crude N - [(1-ethyl-pyrrolidin-2-yl) methyl] -3-amino-6-chloro-2-hydroxybenzene sulphonamide (616mg) and 2-bromophenylisocyanate (176mg, 0. d9mmoles) were coupled to form the desired urea (14mg, 3% for four steps). CC-MS (m / z) 533.0 (M +).

N- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylamino sulfonyl] -2-hydroxyphenyl] N'-2,3-dichlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in Example 15, N - [(1-ethy1-pyrrolidin-2-yl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (616mg) and 2,3-dichloropheniisocyanate (167mg, 39 mmol) were coupled to form the desired urea (13 mg, 2.3% for 4 steps). CC-MS (m / z) 523.2 (M +).

N- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylamino sulfonyl] -2-hydroxyphenyl] N'-2-chlorophenyl) urea hydrochloride Following the general procedure for the formation of urea, described in Example 15, N - [(1-ethyl-pyrrolidin-2-yl) methyl] -3-amino-6-chloro-2-hydroxybenzenesulfonamide (41 Omg) and 2-chlorophenylisocyanate (249 mg, 1. 62mmol were coupled to form the desired urea (50mg, 9.6% for 4 steps). CC-MS (m / z) 46720 (M +).

Method of treatment The compounds of the Formula (I), or a pharmaceutically acceptable salt thereof, can be employed in the manufacture of a medicine for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, that is exacerbated. or caused by excessive cytokine production of interleukin-8 or unregulated by the mammalian cell, such as, but not limited to monocytes and / or macrophages, or other chemokines that bind to the αβ receptor of IL-8, also designated as type I or type II receiver. Accordingly, the present invention provides a method for treating a chemokine-mediated disease, wherein the chemokine is one that binds to an α or β receptor, and the method comprises administering an effective amount of a compound of the Formula (I ) or a pharmaceutically acceptable salt thereof. In particular, the chemokines are IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. The compounds of Formula (I) are administered in an amount sufficient to inhibit the function of the cytokine, in particular IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-78, so that they are biologically regulated normal levels of physiological function, or in some cases at subnormal levels, to improve the disease state. The abnormal levels of IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-78, for example in the context of the present invention, constitute: i) levels of free IL-8 greater than or equal to 1 picogram per ml; ii) any cell associated with IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-7d above normal physiological levels; or iii) the presence of IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-78 above the basal levels in cells or tissues, in which IL-8, GROa, GROß, GRO? , NAP-2 or ENA-76, respectively. The compounds of Formula (I) have generally been shown to have a higher t 1/2 improved oral bioavailability over the compounds described in WO 96/25157 and WO 97/29743 whose descriptions are incorporated herein by reference. There are many states in which the excessive or unregulated production of IL-3 is related to the exacerbation and / or cause of the disease. Chemokine-mediated diseases include psoriasis, atopic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, suffocation syndrome in adults, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cerebrovascular accident, septic shock, multiple sclerosis, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac reperfusion injury and renal, glomerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and release of unwanted hematopoietic stem cells and diseases caused by respiratory viruses, herpes viruses and hepatitis viruses, meningitis, herpes encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post-surgical trauma, interstitial pneumonitis, hypersensitivity, crystal-induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, obstruction of airflow, hyper- air response, organized pneumonia bronchiolitis obliterans, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnia, hyperinflation, hypoxemia, hypoxia, reduction of surgical lung volume, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, sarcoidosis, disease of small airways, ventilation-perfusion decoupling, wheezing and lupus. These diseases are characterized mainly by massive neutrophil infiltration, T cell infiltration, or neovascular growth, and are related to an increase in the production of IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-78, which is responsible for neutrophil chemotaxis in the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-76 have a unique property of stimulating neutrophil chemotaxis, enzymatic release which includes, but is not limited to, eiastase release, as well as production and activation of superoxide. The a-chemokines, but in particular GROa, GROß, GRO ?, NAP-2 or ENA-7d, by working through the IL-8 receptor type I or II can stimulate neovascularization of tumors by stimulating the directional growth of endothelial cells. Therefore, the inhibition or activation of chemotaxis induced by IL-d would lead to a direct reduction in neutrophil infiltration. Recent evidence also implicates the role of chemokines in the treatment of HIV infections, Littieman et al, Nature 331 pp. 661 (1996) and Koup et al, Nature 331 pp. 667 (1996). Current evidence also indicates the use of IL-d inhibitors in the treatment of atherosclerosis. The first reference, Boisvert et al, J. Clin. Invest. 1998, 101: 353-363 shows through a bone marrow transplant that the absence of IL-8 receptors in stem cells (and therefore, in monocytes / macrophages) leads to a reduction in the development of atherosclerotic plaques in mice with LDL receptor deficiency. Additional support references are: Apostolopoulos, et al, Aterioscler. Thromb. Vasa Biol. 1996, 16: 1007-1012; Liu, et al, Aterioscler. Thromb. Vasa Biol. 1997, 17: 317-323; Rus, et al, Aterioscler. Thromb. Vasa Biol. 1997, 17: 317-323; Rus, et al, Atherosclerosis. 1996, 127: 263-271; Wang et al,, Biol. Chem. 1996, 271: 8837-3842; Yue, et al, Eur. J. Pharmacol. 1993, 240: 81-84; Koch, et al, Am. J. Pathol. 1993, 142: 1423-1431; Lee, et al, Immunol. Lett. 1996, 53, 109-113; and Terkeltaub et al, Arterioscler. Thromb .. 1994, 14: 47-53. The present invention also provides a means of treatment, in an acute environment, as well as prevention in those individuals prone to CNS lesions, through compounds of chemokine receptor antagonists of the Formula (I).

CNS lesions, as defined herein, include open or penetrating brain trauma, such as by surgery, or a closed head injury, such as by an injury to the brain region.

Ischemic stroke, in particular to the area of the brain, is also included within this definition. Ischemic stroke can be defined as a focal neurological disorder that results from insufficient blood supply to a particular area of the brain, usually a consequence of a local, trophic, or blood vessel athermal obstruction. The role of inflammatory cytokines in this area has been emerging, and the present invention provides a means for the potential treatment of these lesions. There has been relatively little treatment for an acute injury like these. TNF-a is a cytokine with proinflammatory actions, which include expression of endothelial leukocyte adhesion molecules. The leukocytes infiltrate the ischemic cerebral lesions and, consequently, the compounds that inhibit or decrease the levels of TNF would be useful for the treatment of ischemic brain injury. See Liu et al, Stroke. Vol. 25, No. 7, pp. 14d1-d8 (1994), the description of which is incorporated herein by reference. Models of closed brain injuries and treatment with mixed 5-LO / CO agents are discussed in Shohami et al, J. Of Visc & amp; amp;; Clinical Physiology and Pharmacology. Vol. 3, No. 2, pp. 99-107 (1992) whose description is incorporated herein by way of reference. It was discovered that the treatment that reduces the formation of edema improves the functional result in the treated animals. The compounds of Formula (I) are administered in an amount sufficient to prevent IL-8, by binding to the alpha or beta receptors of IL-8, from binding to these receptors, as demonstrated by a reduction in chemotaxis and activation. of neutrophils. The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based on the effects of the compounds of Formula (I) on the in vitro receptor binding assays described herein. It has been shown that the compounds of Formula (I) are inhibitors of type II IL-8 receptors. As used herein, the term "disease status or disease mediated by IL-d" refers to any and all disease states involving IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-7d, either by production of IL-d, GROa, GROß, GRO ?, NAP-2 or ENA-7d, or because IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-7d they cause another monocyte to be released, for example, but not limited to IL-1, IL-6 or TNF. A disease state in which, for example, IL-1 is a major component and whose production or action is exacerbated or secreted in response to IL-8, therefore, would be considered a disease state mediated by IL-8.

As used herein, the term "disease status or chemokine-mediated disease" refers to any and all disease states involving a chemokine that binds to an α or β-receptor of IL-d, such as for example , but not limited to IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. This would include a disease state in which IL-d intervenes, either by production of the IL-d itself, or because IL-d causes another monocyte to be released, such as, but not limited to I L-1 , IL-6 or TNF. A disease state in which, for example, IL-1 is a major component and whose production or action is exacerbated or secreted in response to IL-d, therefore, would be considered a disease state mediated by IL-d. As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule that modulates the interactions between cells in the immune, inflammatory or hemtopoietic response. A cytokine includes, but is not limited to, monocytes and lymphokines, no matter what cells produce them. For example, in general the production and secretion of a monoclin is attributed to a mononuclear cell, such as a macrophage and / or monocyte. However, many other cells also produce monocins, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epithelial keratinocytes and B-lymphocytes. In general, the production of lymphokines is attributed to lymphocyte cells. Examples of cytokines include, but are not limit l-interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (l-8), Tumor-alpha Necrosis Factor (TNF-a) and Tumor-beta Necrosis Factor ( TNF-β). As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule that modulates the interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term "cytokine" previous. A chemokine is secreted mainly 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, GROa, GROß, GRO ?, NAP-2, ENA-76, IP-10, MIP-1a, MlP-β, PF4 and MCP 1, 2 and 3 To employ a compound of the Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will usually be formulated in a pharmaceutical composition in accordance with standard pharmaceutical practice. Therefore, this invention also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. The compounds of Formula (I), the pharmaceutically acceptable salts thereof and the pharmaceutical compositions incorporating them can be conveniently administered by any 132 route used for the administration of drugs, for example, orally, topically, parenterally or by inhalation. The compounds of Formula (I) can be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers, in accordance with conventional procedures. The compounds of Formula (I) can also be administered in conventional doses in combination with a second known therapeutically active compound. These methods may encompass mixing, granulation and compression or dissolution of the ingredients, as appropriate for 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 combined, the route of administration and other known variables. The vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and must not be harmful to the recipient. The pharmaceutical carrier employed can be, for example, solid or liquid. Examples of solid carriers are lactose, alabaster, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the vehicle or diluent may include time-delay material already known in the art, such as glyceryl mono-stearate or glyceryl distearate isolated or with a wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be formed into tablets, placed in a hard gelatin capsule in powder or tablet form or in the form of a troche or lozenge. The amount of solid carrier will vary greatly, but will preferably be from about 25 mg to about 1 g. When using a liquid vehicle, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid, such as a vial or non-aqueous liquid suspension. The compounds of Formula (I) can be administered topically, ie by non-systemic administration. This includes the application of a compound of Formula (I) outside the epidermis or the oral cavity and the instillation of said compound into the ear, eye or nose, so that the compound does not enter the bloodstream significantly. 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% by weight, for example from 1% to 2% by weight of the formulation. However, it can comprise up to 10% by weight, but preferably, it will comprise less than 5% by weight, more preferably from 0.1% to 1% by weight of the formulation. Lotions in accordance with the present invention include those suitable for application to the skin or the eye. An eye lotion can comprise a sterile aqueous solution which as an option contains a bactericide and can 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 accelerate drying and refresh the skin, such as an alcohol or acetone, and / or a humectant such as glycerol or an oil, such as castor oil or peanut oil. The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They can be prepared by mixing the active ingredient in powder or finely divided 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 mucíiago; an oil of natural origin, such as almond, corn, peanut, castor or olive oil; lanolin or its derivatives or a fatty acid, such as spherical or oleic acid together with an alcohol, such as propylene glycol or a macrogel. The formulation can incorporate any suitable surface active agent, such as an anionic, cationic or nonionic surfactant, such as sorbitan ester or a polyethylene derivative thereof. As well Suspending agents may be included, such as natural gums, cellulose derivatives or inorganic materials, such as silicic acid silica and other ingredients, such as lanolin. The drops according to the present invention can comprise sterile aqueous or oily solutions or suspensions and can 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 preference includes an active agent on surfaces. The resulting solution can then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or stored at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the drops are nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of any oil solution include glycerol, dilute alcohol and propylene glycol. The compounds of Formula (I) can be administered parenterally, ie intravenously, intramuscularly, sub-cutaneously, intrarectally, intravaginally or intraperitoneally. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration can be prepared by conventional techniques. The compounds of the Formula (I) can also be administered by inhalation, i.e. administration by intranasal and oral inhalation. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, can be prepared by conventional techniques. For all methods of use described herein for the compounds of the formula (I), the daily oral dose regimen will preferably be from about 0.01 to about 80 mg / kg total body weight; the daily parenteral dose regimen of from about 0.001 to about 80 mg / kg of total body weight; the topical daily dose regimen will preferably be from about 0.1 mg to 150 mg, administered one to four, preferably two to three times a day. The daily inhalation dose regimen will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. Also, a person skilled in the art will recognize that the optimum amount and separation of individual doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and degree of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that said optimum amount can be determined by conventional techniques. One skilled in the art will also appreciate that the optimum course of treatment, ie, 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 determined by the experts in technique using a conventional course of treatment determination tests. The invention will be described below by reference to the following biological examples which are illustrative only and do not constitute a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES The chemokine inhibitory effects of IL-d and GROa of the compounds of the present invention are determined by the following in vitro test: [125l] IL-8 (recombinant human) receptor binding assays are obtained from Amersham Corp., Arlington Heights, IL, with specific activity of 2000 Ci / mmoles. GROa is obtained from NEN-Ne England Nuclear. All other chemicals are of analytical grade. The elevated levels of human recombinant IL-8 type a and β receptors were expressed individually in ovarian cells of Chinese hamsters, as described previously (Holmes et al, Science, 1991, 253, 1273). The ovarian membranes of Chinese hamsters were homogenized according to the protocol described above (Haour, et al, J. Biol. Chem. 249 pp 2195-2205 (1974)). Except that the homogenization pH regulator is changed to 10mM Tris-HCL, 1mM MgSO4, 0.5mM EDTA (ethylenediaminetetraacetic acid), 1mM PMSF (α-toluenesulfonyl fluoride), 0.5mg / L Leupeptin, pH 7.5. The concentration of membrane proteins is determined using a Pierce Co. micro-test kit, which uses bovine serum albumin as a standard. All tests are performed in a 96-well micro plate format. Each reaction mixture contains 125 μl IL-d (0.25 nM) or 25 μl GRO-a and 0.5 μg / ml membranes of IL-dRa or 1.0 μg / ml of IL-dRβ in regulators of 20 mM pH of Bis-Trispropane and 0.4 mM Tris HCl, pH 8.0, containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM Na and 0.03% CHAPS. In addition, the drug or compound of interest, which has been dissolved in DMSO, is added to reach a final concentration between 0.01 nM and 100uM. The test begins with the addition of 125 I-IL-8. After 1 hour at room temperature, the plate was grown using a 96-well Tomtec cultivator in a glass fiber filter blocked with 1% polyethyleneimine / 0.5% BSA and washed 3 times with 25mM NaCl, 10mM TrisHCI, 1mM MgSO4, 0.5mM EDTA, 0.03% CHAPS, pH 7.4. The filter is then dried and counted in the Betaplate liquid scintillation counter. The recombinant IL-8Ra or type I receptor is also transferred as the non-permissive receptor and the recombinant IL-8Rβ receptor, or type II, is termed as the permissive receptor. Representative compounds of Formula (I), Examples 1 to 106 have exhibited positive inhibitory activity in this test at IC50 levels < 30uM. 139 Chemotaxis test The in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay, as described in Current Protocois in Immunology, vol. I, Suppl 1, Unit 6.12.3, the disclosure of which is incorporated herein by reference in its entirety. Neutrophils were isolated from human blood, as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 7.23.1, the disclosure of which is incorporated herein by reference in its entirety. The chemoattractants IL-d, GROa, GROß, GRO? and NAP-2 are placed in a lower chamber of a multicavity 4d chamber (Neuro Probé, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5uM polycarbonate filter. When the compounds of this invention are tested, they are mixed with the cells (0.001-1000 nM) just before the addition of the cells to the upper chamber. The incubation is allowed to proceed between approximately 45 and 90 minutes at about 37 ° C in a humidified incubator with 5% CO2. At the end of the incubation period, the polycarbonate membrane is removed and the top side is washed, the membrane is then stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, IL, E.U.A.). Cells that have undergone chemotaxis to chemokine are counted with the naked eye using a microscope. In general four fields are counted for each sample, these numbers are averaged to give the average number of cells that had migrated. Each sample is tested in triplicate and each compound is repeated at least four times. I dont know adds no compound to certain cells (control positive cells), these cells represent the maximum chemotactic response of the cells. In the case where a negative control is desired (without stimulation), chemokine is not added to the lower chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells.

Elastase release test The compounds of this invention are tested for their ability to prevent the release of elastase from human neutrophils. Neutrophils are isolated from human blood, as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1. PMNs 0.88 x 106 of cells suspended in Ringer's solution (NaCI 118, KCl 4.56, NaHCOβ 25, KH2PO4 1.03, glucose 11.1, 5 mM HEPES, pH 7.4) are placed in each well of a 96-well plate in a volume of 50 ul. To this plate is added the test compound (0.001 - 1000 nM) in a volume of 50 ul, cytochalasin B in a volume of 50 ul (20ug / m!) And Ringer's pH regulator in a volume of 50 ul. These cells are allowed to warm (37 ° C, 5% C02, 95% RH) for 5 minutes before adding IL-3, GROa, GROß, GRO? or NAP-2 at a final concentration of 0.01 - 1000 nM. The reaction is allowed to continue for 45 minutes before centrifugation of the 96-well plate (dOO xg 5 min.) And 100 ul of supernatant is removed. The supernatant is added to a second 96-well plate, followed by an elastase substrate artificial (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) at a final concentration of 6 ug / ml dissolved in phosphate saline with regulated pH. Immediately, the plate is placed in a 96 well plate fluorescent reader (Cytofluor 2350, Millipore, Bedford, MA) and the data are collected at 3 minute intervals, according to the method of Nakajima et al, J. Biol. Chem. 254 4027 (1979). The amount of elastase released from the PMN is calculated by measuring the degradation rate of MeOSuc-Ala-Ala-Pro-Val-AMC.

TNF-a in Traumatic Brain Injury Test This test provides the examination of the expression of tumor necrosis factor mRNA in specific regions of the brain, which follow experimentally, traumatic brain injury (TBI) by percussion of lateral fluid induced in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and subjected to cerebral injury by percussion of moderate lateral fluid (2.4 atm) centered on the left temporal parietal cortex (n = 1d), or "sham" treatment (anesthesia and surgery without injury, n = 1d). The animals are sacrificed by decapitation at 1, 6 and 24 hours after the lesion, the brains are excised and the tissue samples from the left (lesion) parietal (LC) cortex, the corresponding area in the right cortex, are prepared by Northern blot and quantified relative to a positive control RNA of TNF-α (macrophage = 100%). A marked increase in expression is observed of TNF-a mRNA in LH (104 ± 17% positive control, p <0.05 compared with sham), LC (105 ± 21%, p <0.05) and LA (69 + 8%, p <0.01) in the traumatic hemisphere 1 hour after the injury. An increase in TNF-a mRNA expression is also observed in LH (46 ± 8%, p <0.05), LC (30 + 3%, p <0.01) and LA (32 ± 3%, p <0.01). ) to 6 hours, which is determined by 24 hours after the injury. In the contralateral hemisphere, the expression of TNF-a mRNA increases in RH (46 ± 2%, p <0.01), RC (4 + 3%) and RA (22 ± 8%) at 1 hour in RH (28 ± 11%), RC (7 + 5%) and RA (26 + 6%, p <0.05) at 6 hours, but not at 24 hours after the injury. In sham (surgery without injury) or intact animals, no consistent changes in TNF-a mRNA expression are observed in any of the 6 brain areas in any hemisphere at any time. These results indicate that after cerebral injury by parasagittal fluid percussion, the temporal expression of TNF-a mRNA is altered in specific brain regions, including those of the non-traumatized hemisphere. Given that TNF-a has the ability to induce nerve growth factor (NGF) and to stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in the expression of the TNF-a gel plays an important role in the Acute and regenerative response to CNS trauma.

CNS lesion model for IL-1ß mRNA This test characterizes regional expression of interleukin-1β (IL-1ß) mRNA in specific brain regions after injury traumatic brain injury by experimental lateral fluid percussion (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and subjected to cerebral injury by percussion of moderate lateral fluid (2.4 atm) centered on the left temporal parietal cortex (n = 18), or "sham" treatment (anesthesia and surgery without injury). The animals are sacrificed at 1, 6 and 24 hours after the lesion, the brains are excised and tissue samples from the left (left) parietal (lesional) cortex (LC) are prepared, the corresponding area in the contralateral right cortex (RC ), cortex adjacent to the injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH). The total RNA is isolated and hybridization is performed by Northern blot and the amount of IL-1β mRNA from brain tissue is plotted as relative radioactivity percent of positive macrophage RNA of IL-1β that was loaded onto the same gel. One hour after the brain injury, a marked and significant increase in the expression of IL-1β mRNA was observed in LC (20.0 + 0.7% positive control, n = 6, p <0.05 compared to sham), LH (24.5 + 21%, p <0.05) and LA (21.5 + 3.1%, p <0.05) in the injured hemisphere, which remained elevated up to 6 hours after injury in LC (4.0 + 0.4%, n = 6, p < 0.05) and LH (5.0 + 1.3%, p < 0.05). In sham or intact animals, no expression of IL-1 ß mRNA is observed in any of the respective brain areas. These results indicate that after TBI, the temporal expression of IL-1ß mRNA is stimulated by regions in regions specific brain These regional changes in cytokines, such as IL-1ß mRNA, play an important role after the trauma. All publications, including but not limited to patents and patent applications, mentioned in this specification are incorporated herein by reference, as if each individual publication was specifically and individually indicated to be incorporated herein as explains completely. The above description fully explains the invention including the preferred embodiments thereof. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is thought that one skilled in the art, using the above description, can use this invention completely; therefore, the examples herein will be illustrative only and will not constitute a limitation of the scope of the present invention in any way. The embodiments of the invention in which the exclusive privilege and property are claimed are defined below.

Claims

NOVEPAP PE THE INVENTION

REIVINPICATIONS

A compound of the formula (I):

wherein Rb is independently hydrogen, NR6R, OH, ORa, aryl, C -? - alkyl, arylalkyl, C2-4 arylalkenyl; cycloalkyl, cycloalkylalkyl of C 1-5, heteroaryl, heteroarylalkyl of CM, heteroarylalkenyl of C 2-4, heterocyclic, alkyl of heterocyclic CM, or a portion of alkenyl of C 2-4 heterocyclic, whose portions can be replaced as an option one to three times independently by halogen; nitro; 'CM alkyl substituted with halogen; CM alkyl; amine substituted with amino, mono or di-alkyl of C-i-4, ORa; C (O) Ra; NRaC (O) ORa; OC (O) NR6R7; hydroxy; NR9C (O) Ra; S (O) m'Ra; C (O) NR6R7; C (O) OH; C (0) ORa; S (O) tNR6R7; NHS (O) tRa. Alternatively, the two Rb substituents can be joined to form a ring of 3-10 elements, optionally substituted and containing, in addition to optionally substituted CM alkyl, independently, 1 to 3 portions of NRa, O, S, SO or SO2, which may be optionally unsaturated; Ra is an alkyl, aryl, arylalkyl portion of CM, heteroaryl, heteroarylalkyl of C,

heterocyclic, COORa ', or an alkyl portion of heterocyclic CM, which portions may be optionally substituted; Ra 'is an alkyl, aryl, arylalkyl portion of C-M, heteroaryl, heteroarylalkyl of CM, heterocyclic or an alkyl portion of heterocyclic CM, the portions of which may be optionally substituted; m is an integer that has a value of 1 to 3; m 'is 0, or an integer having a value of 1 or 2; n is an integer that has a value of 1 to 3; q is 0, or an integer that has a value of 1 to 10; t is 0, or an integer that has a value of 1 or 2; s is an integer that has a value of 1 to 3; Ri is independently selected from hydrogen, halogen, nitro, cyano, CO alkyl, CMO alkyl substituted with halogen, C2-10 alkenyl, CMO alkoxy, CMO alkoxy substituted with halogen, azide, S (O) tR4, ( CR8R8) S (O) tR4, hydroxy, C-alkyl substituted with hydroxy, aryio, arylalkyl of CM, arylalkenyl of C2-? O, aryloxy, arylalkyloxy of CM, heteroaryl, heteroarylalkyl, heteroarylalkenyl of C2-10, heteroarylalkyloxy of CM , heterocyclic, heterocyclic CM alkyl, heterocyclic CM alkyloxy, C2-? alkenyl or heterocyclic, (CR8R8) qNR4R5, (CR8R8) qC (O) NR R5, C2-10 alkenyl-C (O) NR4R5, (CR8R8 ) qC (O) NR4R10, S (O) 3R8, (CR8R8) qC (O) Rn, C2-10 alkenyl - C (O) Rn, C2-10 alkenyl - C (O) ORn, (CR8R8) qC (O) ORn, (CR8R8) qOC (O) Rn, (CR8R8) qNR4C (0) Rn, (CR8R8) qC (NR4) NR4R5, (CR8R8) qNR4C (NR5) R ??, (CR8R8) qNHS (O) tR? 3,

(CR8R8) qS (O) tNR4R5, or two R-i portions together can form O- (CH2) sO or a saturated or unsaturated ring of 5 to 6 elements, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic portions can be substituted

optionally; R4 and R5 independently are hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclic, heterocyclic CM alkyl, or R4 and R5 together with the nitrogen to which they are joined together form a ring of 5 to 7 elements, which may comprise as an option an additional heteroatom selected from O, N and S; Re and R7 independently are hydrogen, or an alkyl of heteroaryl, aryl, alkylaryl, alkyl-heteroalkyl of CM, which can be optionally substituted or R6 and R7 together with the nitrogen to which they are attached form a ring of 5 to 7 elements, which can be understand as an option an additional heteroatom selected from oxygen, nitrogen or sulfur, and which can be optionally substituted; Y is hydrogen, halogen, nitro, cyano, CMO alkyl substituted with halogen, CMO alkyl, C2-10 alkenyl. C 0 -alkoxy, C-MO alkoxy substituted with halogen, azide, (CR8R8) qS (O) tRa, (CR8Rd) ORa, hydroxy, C-M alkyl substituted with hydroxy, aryl; arylalkyl of CM, aryloxy, arylalkyloxy of CM, arylalkenyl of C2-10, heteroaryl, heteroarylalkyl, heteroarylalkyloxy of CM, heteroarylkenyl of C2-10, heterocyclic, alkyl of heterocyclic CM, alkenyl of C2-10 heterocyclic, (CR8R8) qNR4R5, alkenyl of C2-10 - C (O) NR4R5, (CR8R8) qC (O) NR4R5, (CR8R8) qC (O) NR4R10, S (O) 3R8, (CR8R8) qC (0) Rn, C2-10 alkenyl - C (O) Rn , (CR8R8) qC (O) ORn, C2-10 alkenyl - C (O) ORn, (CR8R8) qOC (O) Rn, (CR8R8) qNR4C (0) R ??, (CR8R8) qNHS (O) tRi3 , (CR8R8) qS (O) tNR4R5, (CR8R8) qC (NR4) NR4R5,

(CR8R8) qNR4C (NR5) R ??, or two portions Y together can form O- (CH2) sO or a saturated or unsaturated ring of 5 to 6 elements, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl groups , heterocyclic, heterocyclic alkyl may be optionally substituted; R8 is hydrogen or C-alkyl; RT is hydrogen or C-M alkyl; RIO is C (0) 2R8 of C 0 alkyl; Rn is hydrogen, optionally substituted CM alkyl, optionally substituted aryl, optionally substituted C arylalkyl, optionally substituted heteroaryl, optionally substituted C? -4 heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic CH alkyl; R-? 3 is suitably alkyl of CM, aryl, arylalkyl of CM, heteroaryl, heteroarylalkyl of CM, heterocyclic, or alkyl of heterocyclic CM; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, further characterized in that R-i is replaced at position 4 by a portion that removes electrons.
3. The compound according to claim 2, further characterized in that R-i is halogen, cyano or nitro.
4. The compound according to claim 3, further characterized in that R-i is halogen.
5. The compound according to claim 4, further characterized in that R-i is independently fluorine, chlorine or bromine.
6. The compound according to claim 1, further characterized in that Y is mono-substituted at the 2 'position or the 3' position or is di-substituted at the 2 'or 3' position of a monocyclic ring.
7. The compound according to claim 6, further characterized in that Y is halogen.
8. The compound according to claim 4, further characterized in that Y is independently fluorine, chlorine or bromine.
9. The compound according to claim 1, further characterized in that Rb is hydrogen, alkyl of CM, O alkyl of C-i-4 substituted with C (0) OH or C (0) ORa.
10. The compound according to claim 1, further characterized in that Y is halogen, n is 1 or 2, Ri is halogen, m is 1 or 2, and Rb ß is independently hydrogen, CM alkyl, CM alkyl substituted with C (O) OH or C (O) ORa.
11. The compound according to claim 1, further characterized in that it is selected from the group consisting of: N- (2-hydroxy-3-aminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-aminosulfonyl-4-chlorophenyl) -N '- (2,3-dichlorophenol) urea; N- (2-Hydroxy-3-N "-benzyl aminosuifonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N" -benzyl aminosulfonyl-4-chlorophenyl) ) -N '- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- (N ", N" -dimethyl) -aminosulfonyl-4-cyranophenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-Hydroxy-3-N ", N" -dimethylaminosulfonyl-4-cyranophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N "-methylaminosulfonyl-4-chlorophenyl) -N '- (2-bromophenyl) urea; N- (2-Hydroxy-3-N" -

methylaminosulfonyl-4-chlorophenyl) -N- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- [N- (methoxycarbonylmethyl) aminosulfonyl] -4-chlorophenyl] -N '- (2,3-dicyorophenyl) urea; N- [2-Hydroxy-3- (N "- (2-methoxycarbonyl) -methyl) -aminosulfoniyl-4-chlorophenyl] -N '- (2-bromo phenyl) urea; N- [2-Hydroxy-3] - [(N "-2-carboxymethyl) -aminosulfonyl-4-chlorophenyl] -N '- (2,3-dichloro-phenyl) -urea; N- [2-Hydroxy-3- (N "-2-carboxymethyl) -aminosulfonyl-4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3-aminosulfonyl-4-chlorophenyl] -N '- (2-chlorophenyl) urea; N- [2-Hydroxy-3-aminosulfonyl-4-chlorophenyl] -N'-phenylurea; N- (2-Hydroxy-S-aminosulfoniM-chloropheniO-N' - ^ - Phenoxyphenyl Jurea; N- (2-Hydroxy-3- [N "- (3-carboxyethyl) -aminosulfonyl] -4-chlorophenyl) -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (isopropylaminosulfonyl ) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (isopropylaminosulfonyl) -4-chlorophenyl] -N' - (2-chlorophenyl) urea; N- [2 Hydroxy-3- (isopropylaminosulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- (4-chloro-2-hydroxy-3-aminosulfonyl) -N' - (2-methoxyphenyl) urea; N- (4-chloro-2-hydroxy-3-amino sulfonylphenyl) -N '- (2,3-methylenedioxyphenyl) urea; N- (2-benzyloxyphenyl) -N '- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) urea; N- [3- (N "-alilaminosu! Fonyl) -4-chloro-2-hydroxy phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [ N "- (2-trifluoroethyl) amino sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2,3-dichlorophenyl) -N '- [2-hydroxy-4-methoxy-3-N "- (phenylaminosulfonyl) phenyl] urea; N- (2-bromophenyl) -N' - [2-hydroxy] 4-methoxy-3-N "- (phenylaminosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) aminosulfoniI] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-2-hydroxy-3- [N "- (2-methoxyethyl) aminosulfonyl] phenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (4-morpholinosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- (4-morpholinylsulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- [3-ter-

butoxycarbonylamino) propyI] aminosulfonyl-3-4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [3- [N "- [3- (tert-butoxycarbonylamino) propyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N-trifluoroacetate] "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxy phenyl] -N '- (2-bromophenyl) urea; N- [3- [N "- (3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea hydrochloride; N- [3- [N" - (N-trifluoroacetate]] 3-aminopropyl) aminosulfonyl] -4-chloro-2-hydroxy phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N "- (2-aminonoyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- (2-bromophenyl) -N '- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl] -4-chloro-2-hydroxy phenyljurea; N- [3 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl] -4-cyclo-2-hydroxy-phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (1-piperazinyl-sulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (piperazin-1-ylsulfonyl) phenyl] urea trifluoroacetate; N- [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyl] -N '- (2,3-dichloro-phenyl) -urea; N- (2-bromophenyl) -N' - [4-chloro-2-hydroxy-3- [N "- (3-methylthiopropyl) aminosulfonyl] phenyl] urea; Potassium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea; Sodium salt of N- (4-chloro-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenii) urea; N- (2-bromophenyl) -N '- [4-chloro-3- [N ", N" -di- (2-methoxyethyl) aminosulfonyl] -2-hydroxy phenyljurea; N- [4-chloro-3- [N ", N" -di- (2-methoxyethyl) aminosulfonyl] -2-hydroxy-phenyl] -N '- (2,3-dichloro-phenyl) -urea; N- (2-bromophenyl) -N '- [4-chloro-3- [N "- [2- (dimethylamino) ethyl] aminosulfonyl] -2-hydroxyphenyljurea hydrochloride; N- [4-chloro-3-] hydrochloride [N "- [2- (dimethylamino) ethyl] amino

sulfonyl] -2-hydroxy phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfonyl) propyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) ) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfonyl) propyl] amino sulfonyl] phenyl] urea; N- [4-Cioro-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea Hydrochloride; N-Hydrochloride; [4-chloro-2-hydroxy-3- [N "- [2- (morpholinyl) ethyl] aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N, - [4-chloro-2-hydroxy-3- [N "- [2- (4-morpholinyl) ethyl] aminosulfonyl] phenyljurea; N- [4-chloro- 2-hydroxy-3- (4-thiomorpholinylsulfonyl) phenyl] -N '(2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-2-hydroxy-3- (4- thiomorpholinyl sulfonyl) phenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-3- [N ", N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxy phenyljurea; N- [4-chloro-3- [N ", N" -di- (2-hydroxyethyl) aminosulfonyl] -2-hydroxyphenyl] -N '- (2,3-dichloro-phenyl) -urea; N- [4-chloro] -2-hydroxy-3- [N "- [3- (methylsulfinyl) propyl-3-aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (methylsulfinyl) propyl] amine-sulfonyl] phenyljurea; N- (2-bromophenyl) ) -N '- [3- [N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyI] amino sulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N "- [(1-tert-butoxycarbonylpiperidin-4-yl) methyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (1-oxidothiomorpholinesulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro -2-hydroxy-3- (1-oxidothiomorpholysulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] amino] trifiuoroacetate sulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea;

N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [(piperidin-4-yl) methyl] aminosulfonyl] phenyl] urea hydrochloride; N- [3- ( 1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -

N '- (2-bromophenyl) urea; N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea; N- [3- (1-azetidinylsulfonyl) -4-chloro-2-hydroxy-phenyl] -N '- (2,3-dichlorophenyl) urea; Potassium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxy-phenyl] urea; Sodium salt of N- (2-bromophenyl) -N '- [4-chloro-3- (N ", N" -dimethylaminosulfonyl) -2-hydroxyphenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl) urea; N- [4-chloro-3- (N "-cyclopropylaminosulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- [4-chloro-3- (N" -cyclopropylaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- (N "-propylaminosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxyl-3- (N" -propylamine sulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxyl-3- (N "-propylaminosulfonyl) phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-3-] (N "-ethylaminosulfonyl) -2-hydroxyphenyl] urea; N- [4-chloro-3- (N "-ethalaminosulfonyl) -2-hydroxy-phenyl] -N '- (2-chlorophenyl) urea; N- [4-chloro-3- (N" - ethylaminosulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromopheni!) - N '- [3- [N "- [5-tert-butoxycarbonylamino) -5-carboxylpentyl] amino sulfonyl] -4-chloro-2-hydroxy-phenyljurea; N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxylpentyl] amino sulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxylpentyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) ) -N '- [4-chloro-2-hydroxy-3- [N "- (2-hydroxyethyl) aminosulfonyl] urea; N- (2,3-dichlorophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- (2-hydroxyethyl) aminosulfonyl] urea; N- (2-bromophenyl) -N'- [3- [N "- [[(2-bromophenylamino) carboxyl] ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N "- (2-benzyloxyethyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea;

N- [2-Hydroxy-3- (N "-cyclopropylmethylaminosulfonyl) -4-chlorophenyl] -N '- (2,3-dichloro phenyl) urea; N- [2-Hydroxy-3- (N" -cyclopropylmethylaminosulfonyl) -4-chlorophenyl] -N '- (2-chlorophenyl) urea; N- [2-Hydroxy-3- (N "-cyclopropylmethylaminosulfonyl) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N" -methoxy-N "-methylaminosulfonyl) - 4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N "-methoxy-N" -methylaminosulfonyl) -4-chlorophenyl] -N' - (2-chlorophenyl) urea; N - [2-Hydroxy-3- (N "-methoxy-N" -methylammonosulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- (N "-pyridinyl-sulfonyl) -4-chlorophenyl] -N '- (2,3-dichlorophenyl) urea; N- [2-Hydroxy-3- (N "-pyrrolidinylsulfonyl) -4-chlorophenyl] -N '- (2-bromophenyl) urea; N- [2-Hydroxy-3- (N" -pyrrolidinylsulfonyl) -4-chlorophenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(4-pyridinylaminosulfonyl] phenyl] urea; N- [4-chloro-2-hydroxy-3 - [(4)] -pyridinylaminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-2-hydroxy-3 - [[[2- (tetrahydro -2-furanyl) methyl] aminosulfonyl] phenyljurea; N- [4-chloro-2-hydroxy-3 - [[[2- (tetrahydro-2-furanyl) methyl] amino sulfonyl] phenyl] -N '- (2, 3-dichlorophenol) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) methyl] amino sulfonyljphenyljurea; N- [4-chloro-2-hydroxy-3 - [[[(2R) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichloro phenyl) urea; N - (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanyl) methyl] amino sulfonyl] phenyl] urea; N- [4-chloro -2-hydroxy-3 - [[[(2S) - (tetrahydro-2-furanyl) methyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) - N '- [4-chloro-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- (N" -cyclopentylaminosulfonyl) phenyl] -N' - (2,3-dichlorophenyl) urea, and N- (2-chlorophenyl) -N '- [4-chlor o-2-hydroxy-3- (N "-cyclopentylaminosulfonyl) phenyljurea; N- (2-bromophenyl) -

N '[4-chloro-2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) phenyl] urea; N- [4-chloro-2-hydroxy-3- (N" -isoxazolidinylaminosulfonyl) phenyl] -N'- (2,3-dichlorophenyl) urea; N- (2-chlorophen-I) -N '- [4-chloro-2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) phenyl] urea; N- (2-bromophenyl) -N' - [4-chloro] -2-hydroxy-3- (N "-tetrahydroxyaoxaminoaminesulfonyl) phenyljurea; N- [4-chloro-2-hydroxy-3- (N "-tetrahydroisoxazilaminosulfonyl) phenyl] -N'- (2,3-dichloro phenyl) urea; N- (2-chlorophenyl) -N '- [4-chloro] -2-hydroxy-3-N "- (tetrahydroisoxazilaminosulfonyl) phenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] urea; N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl] aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3 - [(2-isopropoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] urea; N- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3 - [(2-ethoxyethyl) aminosulfonyl] phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonyl phenyljurea; N- [4-chloro-2-hydroxy-3 - [(2-methoxycarbonyl) azetidin-1-yl] sulfonylphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3 - [(2-carboxy) -azetidin-1-yl] sulfonylphenyl] -N '- (2,3-dichlorophenol) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propyl] aminosulfonyl] phenyl] urea hydrochloride; N- [4] -hydrochloride -chloro-2-hydroxy-3- [N "- [3- (4-morpholinyl) propyl] -aminosulfoniI] phenyI] -N '- (2,3-dichlorophenyl) urea and N- [4-chlorohydrate] 2-hydroxy-3- [N "- [3- (4-morpholinyl) propyl] aminosulfonyl]

, phenyl] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonylphenyl] urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) pyrrolidin-1-yl] sulfonylphenyljurea; N- [4-chloro-2-

hydroxy-3- [S - (-) - (2-methoxymethyl) pyrrolidin-1-yl] sulfonylphenyl] -N '- (2,3-diorophenyl) urea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) -pyrrolidin-1-ylsulfonyl] phenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- [S - (-) - (2-methoxymethyl) -pyrrolidin-1-yl] sulfonyl-phenyl] -N '- (2-chlorophenyl) urea; N- [4-Chloro-2-hydroxy-3- [S - (-) - (2-hydroxymethyl) -pyrrolidin-1-yl] sulfonyl-lien] -N '- (2-chlorophenyl) urea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S - (- methoxycarbonyl) pyrrolidin-1-yl] sulfonylphenyljurea; N- (2-bromophenyl) -N '- [4-chloro-2-hydroxy-3- [S- (2-carboxy) pyrrolidin-1-yl] sulfonyl] urea; N- (2-bromo-phenyl) -N '- [3- [N "- (tert-butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] urea; N- [3- [N" - (ter -butyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea and N- [3- [N "- (tert-butyl) aminosulfonyl] -4-chloro- 2-Hydroxyphenyl] -N '- (2-chlorophenol) urea; N- [3- [N "- [5- (tert-butoxycarbonylamino) -5-carboxypentyl] aminosulfonyl] -4-chloro-2- hydroxyphenyl] -N '- (2-dorophenyl) urea; N- [3- [N "- (5-amino-5-carboxypentyl) amino suphonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea hydrochloride; N- [3- Hydrochloride] [N "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- (5-amino-5-carboxypentyl) aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-bromophenyl) urea hydrochloride; N- [4- chloro-3- (1,1-dioxidothiomorpholino sulfonyl) -2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- (2-bromophenyl) -N' - [4-chloro-3- (1 , 1-dioxidothiomorpholinosulfoniI) -2-hydroxypheniI urea, N- [4-chloro-3- (1,1-dioxidothio morphoinsulfonyl) -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea; N- [3- [N "- [2- (tert-butoxycarbonylamino) ethyl] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea; N- [3- [N "- (2-aminoethyl) aminosulfoniyl] -4-doro-2-hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea trifluoroacetate; N- [3- [N" - [ 2- (tert-butoxycarbonylamino) etiI] aminosulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-

dorophenyl) urea; N- [3- [N "- (2-aminoethyl) anesulfonyl] -4-chloro-2-hydroxyphenyl] -N '- (2-chlorophenyl) urea trifluoroacetate; N- [4-chloro-2-hydroxy] -3- (N ", N" -dimethylamino sulfonyl) fenll] -N '- (2-chlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N '- (2-bromo-3-fluorophenyl) urea; N- [4-chloro-2-hydroxy-3- (aminosulfonyl) phenyl] -N' - (2-chloro-3-fluorophenyl) urea; N-Hydrochloride; (2-Bromophenyl) -N '- [4-chloro-3 - [(1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxyphenyl] urea; N- [4-Chlorohydrate] 3 - [(1-ethyl-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxyphenyl] N '- (2,3-dichloro phenyl) urea; N- [4-chloro-3 - [(1)] hydrochloride -eti-pyrrolidin-2-yl) methylaminosulfonyl] -2-hydroxyphenyl] -N '- (2-chlorophenyl) urea, or a pharmaceutically acceptable salt thereof
12. A compound according to claim 1, further characterized in that it is selected from the group consisting of: N- (4-cyclo-2-hydroxy-3-aminosulfonylphenyl) -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy] 3- [S - (-) - (2-methoxymethyl) prrolidin -1-yl] su -phonylphenyl] -N '- (2,3-dichlorophenyl) urea; N- [4-chloro-2-hydroxy-3- (N "-isoxazolidinylaminosulfonyl) phenyl] -N, - (2,3-dichlorophenol) urea; N- [4-chloro-2-hydroxy-3] - (1-oxidothiomorpholinesulfonyl) phenyl] -N '- (2,3-dichlorophenyl) urea; and N- [4-chloro-3- [N ", N" -di- (2-methoxyethyl) aminosulfonyl] -2- hydroxyphenyl] -N '- (2,3-dichlorophenyl) urea
13. The compound according to claim 12, further characterized in that the compound is in its sodium salt form
14. The compound according to claim 12, further characterized in that the compound is in its potassium salt form.
15. - A pharmaceutical composition comprising a compound according to any of claims 1 to 14 and a pharmaceutically acceptable carrier or diluent.
16. The use of a compound of the formula as set forth in any of claims 1 to 14, for the preparation of a medicament for treating a chemokine-mediated disease, wherein the chemokine binds to a a or b receptor. IL-8 in a mammal.
17. The use as claimed in claim 16, wherein the chemokine-mediated disease is selected from atopic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, suffocation syndrome in adults, inflammatory bowel disease, Crohn, ulcerative colitis, cerebrovascular accident, septic shock, multiple sclerosis, endotoxic shock, psoriasis, gram-negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, rejections of aiografts, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and release of unwanted hematopoietic stem cells and diseases caused by respiratory viruses, herpes viruses and hepatitis viruses, meningitis, herpes encephalitis, CNS vasculitis, traumatic brain injury , CNS tumors, subarachnoid hemorrhage, post-surgical trauma, interstitial pneumonitis, hypersensitivity, crystal-induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis,
poiimiositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, obstruction of air flow, air hlper-response, organized pneumonia bronchiolitis obliterans, bronchiolitis, bronchitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnia , hyperinflation, hypoxemia, hypoxia, reduction of surgical lung volume, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, sarcoidosis, small airway disease, ventilation-perfusion uncoupling, wheezing and lupus. 1d.- A compound selected from the group consisting of formulas (II), (III), (IV), (V) and (VI) below: (V), (VI) and (VII) where Ri does not It is hydrogen.
19. A method for converting a chlorine compound of formula (VII) to a phenol of formula (III) by reaction with sodium acetate and 1d-C-6 followed by hydrolysis with sulfuric acid and methanol.

(VIII) (IX) wherein R represents H or Na; and R-i is in accordance with claim 1, above.
20. - A method for converting a chlorine compound of formula (VII) to a phenol of formula (III) by reacting the chlorine compound as sodium hydride and water in THF, R = H or Na

(VIII) (IX) wherein R represents H or Na; and R-i is in accordance with claim 1, above.
21. A method for converting a compound of formula (VIII) to a nitro compound of formula (IX) by reacting the sulfonic acid compound with nitric acid in sulfuric acid R = H or Na.