UA73490C2 - Hydroxy diphenylurea sulfonamides as antagonists of receptor il-8 - Google Patents

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

Description of the invention

This invention relates to new sulfonamide-substituted compounds of diphenylurea, to pharmaceutical compositions, to methods of their preparation and to their use for the treatment of diseases mediated by II -8, eye, COD, OKO, MAR-2 and EMA-78.

Interleukin-8 (I/-8) has many different names, such as neutrophil attractant/activating protein (MAP-1), monocyte-derived neutrophil chemotaxis factor (NFCF), neutrophil-activating factor (MAREK), and chemotaxis factor T -cell lymphocytes. Interleukin-8 is an attractant for neutrophils, basophils and subseries 70 t-cells. It is produced by most nucleated cells, including macrophages, fibroblasts, endothelial or epithelial cells, exposed to TME, I--1o;, I--1D or IR P, and by neutrophils themselves upon their exposure

IRB or chemotaxis factors such as EMIR. |IM. Vaodioiyipi ek ai., 9. SiIip. Ipmevzi, 84, 1045 (1989);

U. Zspgodeg ei aiYi., 9. Ittipoi., 139, 3474 (1987) and 9. Ittipoi., 144, 2223 (1990); Zgiieeg ei aiYi., Zsiepse 243, 1467 (1989) and U.VioI.Spet., 264, 10621 (1989); Sazzageia ei ai., 9. Ittipoi., 148, 3216 (19923). t OKO, COD, OKO and MAP-2 also belong to the chemokine family. Like 1I-8, these chemokines also have different names. So, for example, ZKOo,r,y are denoted by MO5ZA o,r,y, respectively (activity that stimulates the growth of melanoma), see Kisptopa ei ai., 9. Seii. РНузиоиюду 129, 375 (1986) 5 Spapd ei ai., 9. Ittipoi. 148, 451 (1992)). All chemokines of the o-family, which have an EC motif located immediately before the SCHS motif, bind to the В II -8 receptor (SCHSK2).

I--8, ZKOd, COD, SKOU, MAR-2 and EMA-78 stimulate a number of functions of the ip and migo. It was shown that they have chemoattractant properties relative to neutrophils, and I-8 and ZKOou exhibit chemotactic activity relative to

T-lymphocytes and basophils. In addition, II/-8 can induce the release of histamine from basophils both in normal individuals and in allergic individuals. ZKO-o and II/-8 can, in addition, induce the release of the enzyme from lysosomes and stimulate the "respiratory burst" of neutrophils. II-8 has also been shown to enhance surface expression. at

Mas-1 (СО116/С2018) on neutrophils without de pomo protein synthesis. This can lead to an increase in the adhesion of neutrophils to the endothelial cells of blood vessels. Many known diseases are characterized by massive neutrophilic infiltration. Since IL-8 and zKOo, COD, KO», MAR-2 stimulate the accumulation and activation of neutrophils, these chemokines are involved in inducing a wide range of acute and chronic inflammatory disorders, (ав) including psoriasis and rheumatoid arthritis, IM. Vaoddioipi ef ai ., REVZ Iei, 307, 97 (1992); MSheg ei ai., b

Stop. Kem. Ittipoi. 12, 17 (1992); Orreppeiyt ei aYi., Appy. Chem. And so on. 9, 617 (1991); Bay" ei ai., 9. Siip.

Ipmevi, 87, 463 (1991); MiSheg ei ai.,, At.Kevgzrig.Oiv. 146, 427 (1992); Euopeiu ei aiYi., Iapsei 341, 643 "I (1993)). In addition, chemokines EI K (chemokines containing the amino acid motif EI K, located immediately before the motif of SCHS) are also involved in angiostasis, |ZygisFeg ei a!., Zsiepse 258, 1798 (1992).

Ip myo, 1-8, KO, SKOr, KOUu and MAP-2 induce a change in the shape of neutrophils, chemotaxis, the release of granules and "respiratory burst" by binding and activating receptors belonging to the family of conjugated with

C-protein of receptors with seven transmembrane domains and, in particular, by binding to receptors

I--8, and especially with the IIII-88 (SHSK2) receptor. |Ppotazvz ei ai., 9U.Vioi.SNet., 266, 14839 (1991); and Noitv ei ai., "

Zsiepse 253, 1278 (1991)). Previously, non-peptide low molecular weight antagonists for members of this family of receptors were obtained. See review of K. ERgeidipdeg "Rgodgezz ip Ogyd Kezeagv", MoiI.40, pp. 33-98; Vigknazeg Mepad, Z s Vaze! 1993. Therefore, the receptor for I/-8 represents a promising target for the development of new anti-inflammatory "» agents. Two high-affinity receptors for 1-8 (with homology 77905) have been characterized: I/-8K o, which binds only to I--8 with a high degree of affinity, and P/-8Kr, which has a high degree of affinity to II-8, as well as to ZKOo, COD, ZKOu and MAR-2. | See Noite ei aYi., see above; Mygriu ei aiYi., Zsiepse 253, 1280 - (1991); ee ei ai., 9. Vioi. Spet., 267, 16283 (1992); ЯКоза ей яй., 9U.VioЙ.Spet., 267, 25402 (1992); and Saue 9) ei ai., U.Vioi.Spet., 268, 7283 (1993)).

In this regard, obtaining compounds capable of binding to II/-8 receptors and necessary for the treatment of the above-mentioned diseases remains relevant. Therefore, conditions associated with increased (Ce) 50 production of 1I-8 (which is responsible for the chemotaxis of neutrophils and subsets of T cells in the area of inflammation) may be ameliorated by compounds that are inhibitors of binding to the EI-8 receptor. .

The present invention relates to a method of treating a disease mediated by chemokines, where the specified chemokine is a chemokine that binds to the II-8 o receptor; or p, and where the specified method provides for the introduction of an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt. In particular, the indicated chemokine is II-8.

GF) This invention also relates to a method of inhibiting the binding of II-8 to its receptors in mammals, which

GFs require this, where said method involves administering to said mammal an effective amount of a compound of formula (1). This compound also relates to novel compounds of formula (I) and to pharmaceutical compositions containing a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I) used in this invention have the structure: b5 and on (VB), me(o), М M

What I with (n what o "o (pit F where: 70 K independently represents hydrogen, MK 6K;, OH, OKA, Si 5-alkyl, aryl, aryl-C. -alkyl, aryl-C. alkenyl; cycloalkyl, cycloalkyl -C-5-alkyl, heteroaryl, heteroaryl-C6 alkyl, heteroaryl-C6 alkenyl, heterocyclic, heterocyclyl-C6 alkyl or heterocyclyl-C6 alkenyl groups, where all the specified groups can be optionally and independently substituted by one - three groups, such as halogen; nitro; halogen-substituted C. dalalkyl; C.4.alkyl; amino, mono- or di-C.4.-alkyl-substituted amine; OKa; 75. F(O)Ka; MKaC (OyuKa; OS(O)MKK;; hydroxy; MKeS(Ok.; Z(O)n Ka; C(O)MKeKk;; (OON, SOYU. (OHMAK;

MZ(O) Ka. Alternatively, two Ku substituents, taken together, can form a 3-10-membered ring, optionally substituted and independently containing, in addition to the optionally substituted C 4.lalkyl, 1-3 groups MKa, 0, 5, 5O or 505, which may be optionally unsaturated;

Ka represents alkyl, aryl, aryl-C 4.alkyl, heteroaryl, heteroaryl-C. lalkyl, 2o Heterocyclic, SOOC, or heterocyclyl-C..4alkyl group, each of which may be optionally substituted;

Ka represents alkyl, aryl, aryl-C 4.dylalkyl, heteroaryl, heteroaryl-C. /alkyl, heterocyclic or heterocyclyl-C..alkyl groups, each of which may be optionally substituted; t is equal to a whole number having a value of 1-3; t" is equal to 0 or a whole number with a value of 1 or 2; сч н is equal to a whole number with a value of 1-3; a is equal to 0 or a whole number with a value of 1-10; i)

Y is equal to 0 or a whole number having a value of 1 or 2; z is equal to a whole number with a value from 1 to Z;

Ki is independently selected from hydrogen, halogen, nitro, cyano, C-ralkyl, halogen-substituted C-oralalkyl, o-Co-oalkenyl, C-o-alkoxy, halogen-substituted C-o-alkoxy, azide, Z(ODK;, (Skek8)a5(OK ., hydroxy, hydroxy-substituted C. alkyl, aryl, aryl-C.-.alkyl, aryl-C.-alkenyl, aryloxy, aryl-C.alkyloxy, Me heteroaryl, heteroarylalkyl, heteroaryl-C.alkenyl, heteroaryl-C.alyloxy, heterocyclyl , "g heterocyclyl-C 4 allyl, heterocyclyl-C. allyloxy, heterocyclyl-Co 4 alkenyl, (SKaKa)aMKAK", (SKaKa)dE(O)MK AK, Co 1oalkenyl-SHO)MKA Ko", (SKaKa)zC( O)MKa Ko, Z(O)5Ka, (SKaKa)dsS(oMAe 11» and)

Co 1oalkenyl-C(O)K.4, Co 1oalkenyl-C5O)OK. 1. СТКаКа)дчНЗ(ОнаК.з, (СКаКв)д5(ОНМКАК», or two K. groups, taken together, can form O-(CH 2)5O or a 5-6--len saturated or unsaturated ring, and where alkyl, aryl, arylalkyl, heteroaryl and heterocyclyl groups may be optionally substituted;

K. and K5 are independently hydrogen, optionally substituted C 4-C alkyl, optionally substituted aryl, optionally substituted aryl-C..alkyl, optionally substituted heteroaryl, optionally substituted with heteroaryl-C. alkyl, heterocyclyl, heterocyclyl-C. /alkyl, or, K, and Co, taken together with the nitrogen atom, . with which they are connected, form a 5-7-membered ring, which may, but not necessarily, contain an additional heteroatom, and? selected isO, M and 5;

Kv and Kk; independently represent hydrogen or C.4-Sulalkyl, heteroaryl, aryl, alkylaryl,

C-di-heteroalkyl, each of which may be optionally substituted, or K in and K7, taken together with the nitrogen atom to which they are attached, form a 5-7-membered ring, which may, but not necessarily necessarily, contain an additional heteroatom selected from oxygen, nitrogen or sulfur, and which may be, optionally, substituted; and M represents hydrogen, halogen, nitro, cyano, halogen-substituted C 4-oalkyl, C-oalkyl, i.s. alkyl, aryl, aryl-Sialkyl, oaryloxy, aryl-C. dalalkyloxy, aryl-C» iralkenyl, ik heteroaryl, heteroarylalkyl, heteroaryl-C. lalalkyloxy, heteroaryl-C. zoalkenyl, heterocyclyl, o heterocyclyl-C 4 lalkyl, heterocyclyl-C » «ralkenyl, (SKaKa)aMKaAK», Co 1oalkenyl-SHO)MKA Co», (SKaKa)dS(O)MAK», (SKeaKa)dS(OMKK cho, Z(O)zKe, (SKaKa)dS(ОШК 1 , So-loalkenyl-C(O)K.1, (SKaKa)dS(OOK 4,

C2-Siralkenyl-"C(O)OK.ch, (SKaKav)z5(О)K 4, (SkaKv)d (ОМА СО, (СКК) НВ(ОХА) with, in "STKaKv)dOS(ODMKAK", (SKaKa )dС(МКАМе В», (СТаКа)дчКАС(МА ИК, or two groups of В, taken together, can form О-(СНо)5О or 5-6--len saturated or unsaturated ring, and where alkyl, aryl, arylalkyl , (F, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl groups may be optionally substituted;

Ka represents hydrogen or S. lalkil; in Co represents hydrogen or S. lalkil;

Co represents С..1ralkyl-С(О)2 in;

K.i1 represents hydrogen, optionally substituted C..4alkyl, optionally substituted aryl, optionally substituted aryl-C..alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C..alkyl, optional optionally substituted heterocyclyl or optionally substituted 65 Heterocyclyl-C .alkyl;

Kiz, In the corresponding case, is C alkyl, aryl, aryl-C.ialkyl, heteroaryl,

heteroaryl-C ..4alkyl, heterocyclyl or heterocyclyl-C. lalkil; or pharmaceutically acceptable salts thereof.

Compounds of formula (I) can also be used in veterinary medicine for the treatment of non-human mammals that require inhibition of ІІ-8 or other chemokines that bind to receptors ІІ-8 о, or р.

Chemokine-mediated diseases of animals that require therapeutic treatment or prevention are the pathological conditions specified in this description under the "Methods of Treatment" section.

In the corresponding case, Ku independently represents hydrogen, MK 6K/OH, OKA, Si v5alkyl, aryl, aryl-C. alkyl, aryl-Co dalkenyl, heteroaryl, heteroaryl-C. an alkyl, heteroaryl-C0-alkenyl, 7/0 heterocyclyl, heterocyclyl-C-.alkyl or heterocyclyl-C0-alkenyl group, where all the specified groups can be optionally and independently substituted by one to three groups, such as halogen, nitro, halogen-substituted C.. alkyl; C. alkyl; amino, mono- or di-Sialkyl-substituted amine; cycloalkyl, cycloalkyl-C.4 alkyl, OKa; C(O) kKa; MKaS(OOkK.; OS(O)MKoK;; aryloxy; aryl C. doxy, hydroxy, Si daloxy,

MKesS(O)kKa; Z(O)pKa; S(O)MKeK;; C(O)OH, C(O)OkKa, Z(OHMKoK;, MNZ(O) Ka. Alternatively, two substituents Kk. 7/5 taken together can form a 3-10-membered ring, optionally substituted and, which independently contains, in addition to carbon, 1-3 groups MKae, O, 5, ZO or 50", which may be optionally substituted;

In the corresponding case, Ka represents an alkyl, aryl, aryl-C 4-alkyl, heteroaryl, heteroaryl-C 4-alkyl, heterocyclyl, or heterocyclyl-C 4-alkyl group, each of which may optionally be substituted

In the corresponding case, K. is independently selected from hydrogen, halogen, nitro, cyano, halogen-substituted

C..zoalkyl, such as CE"; C 1-4 alkyl such as methyl, ethyl, isopropyl or n-propyl; S.i.4ralkenil; C.-1 ralkoxy, such as methoxy or ethoxy; halogen-substituted C 4 ralcoxy, such as trifluoromethoxy; azide, (СКаКа)д5(ОХК», where i is 0, 1 or 2, hydroxy, hydroxy-C. alkyl, such as methanol or ethanol; aryl, such as or phenyl naphthyl; aryl-C -alkyl, such as benzyl ; aryloxy, such as phenoxy; c aryl-Sialkyloxy, such as benzyloxy; heteroaryl, heteroarylalkyl, heteroaryl-C 4.oralalkyloxy, aryl-C" zralkenyl, heteroaryl-Co"oalkenyl, heterocyclyl-Co"oralkenyl, (СКаКа)аМКАК" , o

So loalkenyl-С(О)МКАК», (СКаКв)дС(OMКаАК), (СКаКа)дС(ОМАКАКио, З(О)3Н, З(О)зКв, (СКаКв)дС(О)МК 4,

So 1oalkenyl-C(O)K.4 , So 1oalkenyl-SHO)OK. 4. СКаКв)ачКАС(МК At, (СТаКв)дМН(ОзАК з, (СКаКа)дЗ(ОНМКАК»). осз зо All aryl-, heteroaryl- and heterocyclyl-containing groups can be, but not necessarily, substituted as described below.

As used herein, the terms "aryl-, heteroaryl-, and heterocyclyl-containing groups" mean both a ring and an alkyl, or, if present, alkenyl rings, such as aryl, arylalkyl, or arylalkenyl rings. In this description, the terms "groups" and "rings" may be used interchangeably.

In the corresponding case, K; and K5 independently represent hydrogen, optionally substituted C 4-C alkyl, and,

335 is optionally substituted aryl, optionally substituted aryl-C 4 -alkyl, optionally substituted heteroaryl, and - optionally substituted heteroaryl-C 4 -alkyl, heterocyclyl, heterocyclyl-C. alkyl, or, K, and K5, taken together with the nitrogen atom to which they are attached, form a 5-7-membered ring which may, but need not, contain another heteroatom selected from O, M, and 5 .

In the corresponding case, Ka independently represents hydrogen or C. lalkil. "

In the corresponding case, Co represents hydrogen or S. dalkil. шщ с In the corresponding case, 4 is equal to 0 or an integer from 1 to 10. and In the corresponding case, Co represents C..4dralalkyl-C(O)2Ra, such as СНС(О)-Н or СНС(О)СН» . and? In the relevant case, CC. represents hydrogen, C 4 alkyl, aryl, aryl-C 4 alkyl, heteroaryl, heteroaryl-C 4 alkyl, heterocyclyl or heterocyclyl-C. lalkil

In the corresponding case, Ki" represents hydrogen, C 4-40-alkyl, optionally substituted aryl or - and optionally substituted arylalkyl.

In the appropriate case, K/-z represents C. .bralkyl, aryl, arylalkyl, heteroaryl, heteroaryl-C. alkyl, heterocyclyl or heterocyclyl-C-alkyl, where all aryl-, heteroaryl- and heterocyclyl-containing groups can be optionally substituted.

In the corresponding case, MU is independently selected from hydrogen, halogen, nitro, cyano, halogen-substituted oC..loalkyl, C.i.loalkyl, C.o.alkenyl, C.i.loalkoxy, halogen-substituted C..ioalkoxy, azide, (SKaKv)385(OxKa, o hydroxy, hydroxy-C, alkyl, aryl, aryl-C, alkyl, aryloxy, aryl-C, alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl-C, alkyloxy, heterocyclyl, heterocyclyl-C, alkyl, aryl-C, zoalkenyl, heteroaryl-C»zoalkenyl, heterocyclyl-Co4arkenyl, (SKaKa)aMKAK», Co1oalkenyl-SHO)MKAK», 55. (СВаВв)аС(ОМАВ», (СРаВадаС(ОМА. Vo, В(О)зН, 8( O)zVv, (SteVv)k(O)V y,

Co lralkenyl-C(O)K.4, Co-Sioralkenyl-C(O)OK. 4, (SKaKa)(O)yuK. 2. (OHMAaK"; or two U groups taken together may form O-(CHO)5O or a 5-6-membered saturated or unsaturated ring. All of the above-mentioned aryl-, heteroaryl-, and heterocyclyl-containing groups may be necessarily substituted as defined in this description.

In the corresponding case, z is equal to a whole number from 1 to 3.

If U forms a dioxy bridge, then 5 is preferably equal to 1. If U forms an additional unsaturated ring, then it is preferably b--lene and forms a naphthalene ring system. These ring systems can be substituted by 1-3 other groups В defined above. 65 In the corresponding case, Ka represents alkyl, aryl-C 4 -alkyl, heteroaryl, heteroaryl-C. dalalkyl, heterocyclyl or heterocyclyl-C. alkyl, where all the specified groups can be, but not necessarily, substituted.

Y, preferably, represents halogen, C ..4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or aryl alkoxy, methylenedioxy, MKK", thio-C-.alkyl, thioaryl, halogen-substituted alkoxy, optionally substituted C .. d4alkyl hydroxyalkyl. More preferably, Y represents monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, and more preferred are groups mono- or disubstituted in the 2'-position or 2", 3'-position.

Although U can be substituted in any position on the ring, it is preferred that n equals 1.

Although Ki and M can both be hydrogen, it is preferred that at least one of said rings be substituted, and more preferably that both of said rings be substituted. 70 Unless otherwise indicated, the term "optionally substituted" as used herein refers to groups such as halogen, for example, fluorine, chlorine, bromine or iodine; hydroxy; hydroxy-substituted C 4 oalkyl,

C1-10alkyl, such as methoxy or ethoxy, 5(O) pC1-10alkyl, where t is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; amino, mono and disubstituted amino group, such as the group MK Kv, MHC(OK,,

С(О)МКАК», СООК;, 5(ОХМКАК», МНО(ОХК»ob, C 10 alkyl, such as methyl, ethyl, propyl, isopropyl or /5 tert-butyl, halogen-substituted C alkyl, such as CE z, optionally substituted aryl, such as phenyl, or optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, wherein aryl, heteroaryl or heterocyclyl groups may be substituted by one or two groups, such as halogen, hydroxy, hydroxy-substituted alkyl, C 1-6 alkyl, (OO) C 1-4 zoalkyl, amino, mono or disubstituted alkylamino, such as in the MKK group; or halogen-substituted C..ralalkyl, such as SR.

Kob, In the corresponding case, represents C alkyl, aryl, aryl-C.ialkyl, heteroaryl, heteroaryl-C 4.4alkyl, heterocyclyl or heterocyclyl C.alkyl.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and such salts include the basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, i) benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) can also be formed by a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known in the art and such cations include alkali metal cations, alkaline earth metal cations, ammonium cations and quaternary ammonium cations.

The terms used here mean: Me - "halogen" - all halogens, that is, chlorine, fluorine, bromine and iodine. "E - "C..loalkyl" or "alkyl" - straight or branched groups consisting of 1-10 carbon atoms, if the chain length is not specifically indicated, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, tert-butyl, n-pentyl, etc. cha - "Cycloalkyl" - a cyclic group consisting mainly of 3-8 carbon atoms, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, etc. - "Alkenyl" - in all cases, unless the chain length is specifically indicated, means a straight or branched group consisting of 2 to 10 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, « 2-propenyl, 2 -methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. with c - "aryl" - phenyl and naphthyl. - "heteroaryl" (as such or in any combination such as "heteroaryloxy" or "heteroarylalkyl") is a 5-10-membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from a group consisting of M, O, or 5, including, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, -I triazole, imidazole, or benzimidazole - "heterocyclyl" (as such or in any combination, such as "heterocyclylalkyl") - a 4- to 10-membered saturated or partially unsaturated ring system in which one or more rings contain one or more of their heteroatoms selected from the group consisting of M, OO or 5, including, but not limited to, pyrrolidine, 5or Piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine or imidazolidine. In addition, sulfur can be, but does not have to be, oxidized to a sulfone or sulfoxide. o - "arylalkyl" or "heteroarylalkyl" or "heterocyclylalkyl" - C..ralalkyl, defined above, and connected with aryl, heteroaryl or heterocyclyl groups, defined above, unless it is specifically indicated. - "sulfinyl" is the oxide 5(O) of the corresponding sulfide, the term "thio" means sulfide, and the term "sulfonyl" means the group О(О) oxidized by a cell." - the expression used here "where two K 4 groups (or two U groups) taken together can form 5-

F) or b-membered saturated or unsaturated ring" means the formation of an aromatic ring system, such as ka naphthalene, or represents a phenyl group having an attached b--membered partially saturated or unsaturated ring, such as C0-cycloalkenyl, i.e., hexene, or an N-cycloalkenyl group, such as cyclopentene.Illustrative compounds of formula (I) are:

M-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea;

M-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-M'-(2,3-dichlorophenyl)urea;

M-(2-hydroxy-3-M"-benzylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea;

M-(2-hydroxy-3-M"-benzylaminosulfonyl-4-chlorophenyl)-M'-(2,3-dichlorophenyl)urea; 65 IM-(2-hydroxy-3-(M",M"-dimethyl) aminosulfonyl-4-chlorophenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-hydroxy-3-M",M"-dimethylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea;

M-(2-hydroxy-3-M"-methylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea;

M-(2-hydroxy-3-M"-methylaminosulfonyl-4-chlorophenyl)-M'-(2,3-dichlorophenyl)urea;

I-(2-hydroxy-3-IM-(methoxycarbonylmethyl)aminosulfonyl|-4-chlorophenyl/|-M'-(2,3-dichlorophenyl)urea;

I-(2-hydroxy-3-(M"-(2-methoxycarbonyl)methyl)aminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea;

I-(2-hydroxy-3-((M"-(2-carboxymethyl)aminosulfonyl|-4-chlorophenyl)-M'-(2,3-dichlorophenyl)urea;

I-(2-hydroxy-3-(M"-2-carboxymethyl)aminosulfonyl|-4-chlorophenyl|-M'(2-bromophenyl)urea;

IM-(2-hydroxy-3-aminosulfonyl|-4-chlorophenyl|-M'-(2-chlorophenyl)urea;

IM-(2-hydroxy-3-aminosulfonyl|-4-chlorophenyl|-M'-phenylurea; 70 IM-(2-hydroxy-3-aminosulfonyl|-4-chlorophenyl|-M'-(2-phenoxyphenyl)urea;

M-(2-hydroxy-3-(M"-(33-carboxyethyl)aminosulfonyl|-4-chlorophenyl/|-ME(2-bromophenyl)urea;

I-(2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl|-M'(2-bromophenyl)urea;

IM-(2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl|-M''(2-chlorophenyl)urea;

IM-(2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl|-ME2,3-dichlorophenyl)urea;

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2-methoxyphenyl)urea;

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-methylenedioxyphenyl)urea;

M-(2-benzyloxyphenyl)-M'-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)urea;

IM-3-(M"-allylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-ME2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(M"-2-trifluoroethyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2,3-dichlorophenyl)-M'-(2-hydroxy-4-methoxy-3-M"-phenylaminosulfonyl)phenyl|urea;

M-(2-bromophenyl)-M'-(2-hydroxy-4-methoxy-3-M"-phenylaminosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy-3-(M"-2-methoxyethyl)aminosulfonyl|-phenyl|-ME2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-(2-methoxyethyl)aminosulfonyl|phenyl|urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-morpholinyl-sulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

IM-III-IM"-III-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl))urea;

M-(2-bromophenyl)-M'-I3-IM"-IZ-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urine; o zo M'-(3-(M"-( 33-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-N'(2-bromophenyl)urea trifluoroacetate;

M'-(3-(M"-(33-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'2-bromophenyl)urea hydrochloride; Me

M'-III-(M"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'E(2,3-dichlorophenyl)urea"g trifluoroacetate;

M-(2-bromophenyl)-M'-I3-I(M"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl)-4-chloro-2-hydroxyphenyl|urea)

Zv MNa; uh-

IM-3-(IM"-(2-aminoethyl)aminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'(2-bromophenyl)urea;

M-(2-bromophenyl)-M'-I3-((4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl/|-4-chloro-2-hydroxyphenyl|urea;

IR-IR-((4-(tert-butoxycarbonyl)piperazin-1-yl|Hisulfonyl)-4-chloro-2-hydroxyphenyl|-N'(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(1-piperazinylsulfonyl)phenyl|-ME2,3-dichlorophenyl)urea trifluoroacetate; with c M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(piperazin-1-ylsulfonyl)phenyl|urea trifluoroacetate; . IM-(d-chloro-2-hydroxy-3 -(M"-(3-methylthiopropyl)amino-sulfonyl|phenyl)|-M'-(2,3-dichlorophenyl)urea; and" M-(2-bromophenyl)-M'-I(4-chloro- 2-hydroxy-3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl|urea;

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea potassium salt;

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea sodium salt; -I M-(2-bromophenyl)-M'-I(4-chloro-z-(M",M"-di-(2-methoxyethyl)-aminosulfonyl|/|-2-hydroxyphenyl|urea;

IM-(4-chloro-3-(M",M"-di-(2-methoxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; o M-(2-bromophenyl) )-M'-I(4-chloro-3-(M"-(2-(dimethylamino)ethylaminosulfonyl)-2-hydroxyphenyl|urea hydrochloride;

IM-(4-chloro-3-(M"-(2-(dimethylamino)ethyl|aminosulfonyl|-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea se) hydrochloride; o IM-(d -chloro-2-hydroxy-3-(M"-3-(methylsulfonyl)propyl|-aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-(methylsulfonyl)propylaminosulfonyl|phenyl|urea);

IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethyl|-aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea hydrochloride;

IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinylethylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea hydrochloride;

F) M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-(4-morpholinyl)ethylIaminosulfonyl|phenyl|urea; ka IM-(d-chloro -2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl|urea; in M-(2-bromophenyl)-M'-I(4-chloro- 3-(M",M"-di-(2-hydroxyethyl)aminosulfonyl|-2-hydroxyphenyl|urea;

IM-(4-chloro-3-(M",M"-di-(2-hydroxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy|-3-(M"-III--"methylsulfinyl)propylaminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylsulfinyl)propyl|Iaminosulfonyl|phenyl|urea;

M-(2-bromophenyl)-M'-I3-IM"-K1-tert-butoxycarbonylpiperidin-4-yl)umethylaminosulfonyl)-4-chloro-2-hydroxy 65 enyl|urea;

IM-III-IM"-((1-tert-butoxycarbonylpiperidin-4-yl)umethyl|-aminosulfonyl|-4-chloro-2-hydroxyphenyl|)-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy)-3-(1-oxidothiomorpholinosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy)-3-(IM"-K(piperidin-4-yl)umethyl|amino-sulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea trifluoroacetate;

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-K(piperidin-4-yl)methylaminosulfonyl|phenyl|)urea hydrochloride;

IM-13-(1-azetidinesulfonyl)-4-chloro-2-hydroxyphenyl/|-ME(2-bromophenyl)urea; 70 IM-13-"1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

IM-IZ-"1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl)-2-hydroxyphenyl|urea potassium salt;

M-(2-bromophenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl)-2-hydroxyphenyl|urea sodium salt;

M-(2-bromophenyl)-M'-4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|urea;

M-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

IM-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxyl-3-(M"-propylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxyl-3-(M"-propylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea;

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-ethylaminosulfonyl))-2-hydroxyphenyl|urea;

IM-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

IM-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I3-(M"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl|Iaminosulfonyl|-4-chloro-2-hydroxyphenyl|urea;

I-III-(M"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl|aminosulfonyl|-4-chloro-2-hydroxyphenyl|)-M'-(2,3-dichlorophenyl)urea; i)

I-III3-(M"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl|aminosulfonyl|-4-chloro-2-hydroxyphenyl|)|-M'-(2-chloro-orphenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-hydroxyethyl)aminosulfonyl|urea; o zo IM-(2,3-dichlorophenyl)-M' -(4-chloro-2-hydroxy-3-(M'-(2-hydroxyethyl)aminosulfonyl|urea);

M-(2-bromophenyl)-M'-I-3-(M"-((2-bromophenylamino)carboxy|-ethylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urine Me wine; "E

IM-3-(IM"-(2-benzyloxyethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2-bromophenyl)urea;

IM-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4-chlorophenyl|-M'-(2,3-dichlorophenyl)urea; me)

IM-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4-chlorophenyl|-M'-(2-chlorophenyl)urea;

I-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4-chlorophenyl/|-ME(2-bromophenyl)urea;

I-(2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-4-chlorophenyl/|-ME(2-bromophenyl)urea;

IM-(2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-4-chlorophenyl|-M'(2-chlorophenyl)urea;

IM-(2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-4-chlorophenyl|-M'(2,3-dichlorophenyl)urea;

IM-(2-hydroxy-3-(M"-pyrrolidinylsulfonyl)-4-chlorophenyl|-M'-(2,3-dichlorophenyl)urea; with c I-(2-hydroxy-3-(M"-pyrrolidinylsulfonyl) -4-chlorophenyl|-M'-(2-bromophenyl)urea; » M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl|phenyl|urea;

IM-(d-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl|phenyl|-ME2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-(tetrahydro-2-furanyl)methylaminosulfonyl|phenyl|urea; -I IM-(d-chloro-2 -hydroxy-3-|((2-(tetrahydro-2-furanyl)methyl|-aminosulfonyl|phenyl-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methyl|aminosulfonyl|phenyl|urea; and o IM-(d -chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methyl|aminosulfonyl|phenyl|-N'-(2,3-dichlorophenyl)urea and quinone);

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methylIaminosulfonyl|phenyl|urea; ik M-(4-chloro- 2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methyl|aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)-urea o wine;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and two M-(2-chlorophenyl)-M'-Id-chloro- 2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl|urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea;

F) IM-(d-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea; ka M-(2-chlorophenyl)-M'-(4 -chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M'"-tetrahydroisoxazolylaminosulfonyl)phenyl|urea; in IM-(d-chloro-2-hydroxy-3-(M '"-tetrahydroisoxazolylamino-sulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-tetrahydroisoxazolylaminosulfonyl)phenyl|urea;

I-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-((2-isopropoxyethyl)aminosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy-3-(2-isopropoxyethyl)aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-((2-isopropoxyethyl)aminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea; 65 IM-(2-bromophenyl)-M'-I(I4- chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl)phenyl|urea;

IM-(d-chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(2-ethoxyethyl)aminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea;

I-(2-bromophenyl)-N'-(4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|!sulfonylphenyl|urea;

M-(4-chloro-2-hydroxy)-3-(2-methoxycarbonyl)azetidin-1-ylsulfonylphenyl)-M'-(2,3-dichlorophenyl)urea;

M-(4-chloro-2-hydroxy)-3-(2-carboxy)azetidin-1-ylsulfonylphenyl)-M'-(2,3-dichlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-«"4-morpholinyl)propylaminosulfonyl|phenyl|urea hydrochloride;

M-(4-chloro-2-hydroxy)-3-IM"-(3--4-morpholinyl)propylaminosulfonyl|phenyl|-M'-2,3-dichlorophenyl)urea hydrochloride and 70. M-Id-chloro- 2-hydroxy)-3-[M"-I3-(4-morpholinyl)propyl|aminosulfonyl|phenyl]-Im"(2-chlorophenyl)urea hydrochloride;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl|urea;

I-(2-bromophenyl)-N'-(4-chloro-2-hydroxy-3-I|5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|!sulfonylphenyl|urea;

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-ylsulfonyl|phenyl)|-M'-(2,3-dichlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl|-N'-(2-chlorophenyl)urea;

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(2-methoxycarbonyl)pyrrolidin-1-yl|sulfonylphenyl|urea;

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(2-carboxy)pyrrolidin-1-yl)|isulfonylphenyl|urea;

M-(2-bromophenyl)-M'-I3-IM"-(tert-butyl)aminosulfonyl)|-4-chloro-2-hydroxyphenyl|urea;

I-III-IM"-"tert-butyl)aminosulfonyl|-4-chloro-2-hydroxy-phenyl|-M'-(2,3-dichlorophenyl)urea

IM-III-IM"-"tert-butyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

I-III-IM"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl|aminosulfonyl|-4-chloro-2-hydroxyphenyl|)|-M'-(2-chloro-orphenyl)urea;

I-III-IM"-(b-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea hydrochloride; (8)

I-III-IM"-(b-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea hydrochloride;

I-III-IM"-I(b-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2-bromophenyl)urea ozo hydrochloride;

IM-(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; Me

IM-(2-bromophenyl)-M'-(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|urea; "g

IM-(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

IM-III-IM"-(2-(tert-butoxycarbonylamino)ethyl)iaminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)c me)

Z echovina; Cha

IM-3-(M"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxy-phenyl|-M'(2,3-dichlorophenyl)urea trifluoroacetate

IM-IZ-IM"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea;

IM-IZ3-(M"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-ME(2-chlorophenyl)urea trifluoroacetate;

M-(4-chloro-2-hydroxy)-3-(M",M"-dimethylaminosulfonyl)-phenyl|-M'-(2-chlorophenyl)urea; with c IM-(4-chloro-2-hydroxy-3-(aminosulfonyl)phenyl/|-M'(2-bromo-3-fluorophenyl)urea; . IM-(d-chloro-2-hydroxy-3-" (aminosulfonyl)phenyl|-M'-(2-chloro-3-fluorophenyl)urea; |-methylaminosulfonyl/)-2-hydroxyphenyl|urea hydrochloride;

M-(4-chloro-3-(1-ethylpyrrolidin-2-yl|methylaminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea-I hydrochloride;

IM-(4-chloro-3-K(1-ethylpyrrolidin-2-yl)methylaminosulfonyl|-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea and hydrochloride; 15" or their pharmaceutically acceptable salts.

Compounds of formulas (I)-(MII) can be obtained by synthesis methods, some of which are illustrated in and, the schemes below. The synthesis shown in these schemes can be carried out to give compounds of the formulas o ()-(MII) having various groups K, K and 7 which are reactive, using optional suitably protected substituents to ensure compatibility with reactions described below. In these cases, after the removal of protection, compounds having basically the described structure are obtained. After obtaining urea from the rings, other compounds of the specified formulas can be obtained in accordance with standard methods used for the mutual transformation of functional groups.

F) name) 60 b5

Scheme 1 VN BOM zo,mAV"

EE and a and where | Y nn m inn: and more - -o and M and I. 1 2 z o 5O,MNAV BO,MEV ZOM

SI de si e si Odessa in s on

I -- ry I he -0 . -at

Mm? shcha g I 5 Cheeks

From o 4 o o

Bon vOMAV vov'ya" a he e sa on nFe lsh a op izh dE | o: He mo o A V ! Mn. M M 5 about them! n 5 7 a) ) MO5, AsON, N-O, Her) MA'KN, alkali B) N»ZO,, NMO», c) MabAs, 18-crown-b, a) NhZO,, Meon, f) Ra/S, No i)

KSMO, DMF.

The required 4-chloro-M-(33-sulfonamido-2-hydroxyphenyl)-M"-phenylurea can be synthesized from commercially available 2,6-dichlorothiophenol by the method shown in Scheme 1. The thiol can be oxidized to the corresponding sulfonyl halide with by using a halogenating agent such as MC5, MV5, SI » or Vg» in the presence (U) of a protic solvent such as water, acetic or acid or alcohol or combinations thereof. The yield can be increased if a buffering agent such as such as sodium or potassium acetate, and the reaction is carried out at or below room temperature. The corresponding sulfonyl halide can then be ozo-condensed with an amine in the presence of a base such as pyridine, triethylamine, potassium carbonate, or sodium hydride to give the analogous sulfonamide 2 represented by in Scheme 1. Dichlorosulfonamide 2, Scheme 1, can (o) be nitrated using a strong acid, such as nitric acid in sulfuric acid, to form the aromatic nitro compound 3, Scheme 1. Chlorine, which from placed ortho to the nitro group can be selectively hydrolyzed using an acetic acid salt such as sodium acetate in the presence of a crown ether such as 18-crown-b6 to give acetate 4, Scheme 1. The acetate group can be hydrolyzed under acidic conditions in an alcoholic solvent such as methanol or ethanol in the presence of a catalytic amount of acid to give phenol 5, Scheme 1. The nitro group can be reduced under conditions well known to those skilled in the art, such as using hydrogen and palladium-on-carbon, stannous chloride in methanol, zinc in acetic acid or thiol, to form the corresponding aniline 5, Scheme 1. Then, the indicated aniline can be reacted with a commercially available isocyanate or thioisocyanate to form the desired urea or from the thiourea. Alternatively, the desired isocyanates can be prepared by condensation of the amine with triphosgene in the presence of a base (such as potassium carbonate) or by the reaction of the carboxylic acid with diphenylphosphorazide in the presence of a base (such as triethylamine).

Scheme 2 -I (95) "where 5O,MchN, vo,mAn 50.mvk t si Odes si Odes s ode so y | -а ж Ж i -В s -0 ho -0 mo o m M 1 0s- 2 Z o a) Ma, EH, B) Man A"H. o If sulfonamide 1, scheme 2 (3, scheme 1) is unfunctionalized K-K"-H, then, if necessary, it can be functionalized by alkylation. Said 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 give compound 2, Scheme 2. Said sulfonamide can then be alkylated a second time using sodium hydride and another alkyl halide with formation of compound 3, scheme 2. Then the obtained compound can be converted into the required urea by the method shown in scheme 1. b5

Scheme Z

BA zazhma yin

SI s 1 s a a sn d- SI zh -60--tosh |ro-- go. y -o that 1 2 Z Y o zo»n 8O;Ma zov" si si a s Go si y g zny no r.o what -:O

M m M

Cheek! More

From o 4 o | 5 o a) i) MS5, AsONn, N.O, her) maon meon b) NoZO,, NMO", c) Mason meon, 49) RSiI5, ROSI", e) MNE", EBM.

An alternative route to compound 5, Scheme C (3, Scheme 1) is shown above in Scheme 3, where commercially available 6,6-dichlorothiol can be oxidized to the sulfonyl halide using a halogenating agent such as MC5, MB5, chlorine or bromine in the presence a protic solvent such as alcohol, acetic acid or water. Said sulfonyl halide can be hydrolyzed using a metal hydroxide such as sodium or potassium hydroxide to form the corresponding sulfonic acid salt. This sulfonic acid salt can then be nitrated under nitrating conditions, such as in the presence of nitric acid in a solution of a strong acid such as sulfuric acid, to form nitrophenylsulfonic acid 3, Scheme 3. Said d) sulfonic acid 3, Scheme 3, can be converted to sulfonamide 5, Scheme 3, by a three-step method involving the formation of a metal salt using a base such as sodium hydroxide, sodium hydride, or sodium carbonate to give compound 4, Scheme 3. The sulfonic acid is then converted to the sulfonyl chloride using PCI »5 with ROSIz as a solvent. Then the specified sulfonyl chloride can be transformed into the corresponding sulfonamide using the desired amine MNE" in triethylamine at a temperature ranging from -7892C to 600C with the formation of the corresponding sulfonamide 5, scheme C (3, scheme 1).

Said sulfonamide 5, Scheme 3, can then be processed by the method shown in Scheme 1. This method is not limited to the preparation of 2,6-dichlorophenylthiol, and it can also be used to prepare co 2,6-difluorophenylthiol, 2,6-dibromophenylthiol and 2,6-diiodophenylthiol. Halogens in these compounds can be converted into the corresponding cyano-, amino-, thiol-, or alkoxy compounds by nucleophilic substitution reactions using nucleophiles such as alkylthiolates, alkoxides, amines, and cyanides. The mentioned halogens can also be functionalized by the coupling reaction with palladium and the carbonylation reaction, well known to the experts, with the formation of the corresponding amide-, carbonyl-, alkenyl-, alkyl-, phenyl- and heterocyclyl-substituted "products, if necessary according to the formulas (1)- (MINE). WITH

New intermediate compounds of this invention include compounds of formulas (I), (11), (IM), (M), (MI) and (MI): (jaB), M(O), ro

Her and ro . in and - I B, B; and '

WHAT THE HELL! (m (95) i» SI ay so novo. hg, nn o

Ge) | ro | t- av viya

I) I) o where Ku is not hydrogen.

The stages of the synthesis of new compounds described in this application involve the conversion of chlorine-containing compounds of the formula (MII) into phenol of the formula (II) using sodium acetate and 18-crown-b6 followed by hydrolysis with sulfuric acid and methanol, and a similar transformation is achieved in one step using sodium hydride 60 and water in THF. b5

SI on (VB), M5O, | MO, (vbu,Me(0), I mo,

I and - r

ANdt (pr slu (V)t (o

The second stage of the synthesis of new compounds involves nitration of sulfonic acid or sodium salt of the formula (MIII) into a nitro compound of the formula (IX) using nitric acid in sulfuric acid. K-N or Ma.

The present invention is described in the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the present invention. All temperatures are given in degrees Celsius, all solvents are of the highest purity, and all reactions are conducted under anhydrous conditions under 72 argon unless otherwise noted.

In these examples, all temperatures are given in degrees Celsius (C). Mass spectra were obtained on a MO 7ar mass spectrometer by fast atom bombardment, unless otherwise indicated. "H-NMR spectra (hereinafter referred to as "NMR") were recorded at 250 MHz on a Vgykeg AM 250 or At 400 spectrometer. The spectral lines have the following designations: c-singlet, d-doublet, t-triplet, quad-quartet, and width 720 means broad signal. "Sat" means saturated solution, "eq" means the number of molar equivalents of the reactant relative to the main reactant. Purification, yield and spectral characteristics for each individual compound are listed below.

Example 1

Preparation of the sodium salt of M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea.: and c

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)urea Ge) 2,6-Dichlorobenzenesulfonyl chloride

2,6-dichlorobenzenethiol (10.0 grams (hereinafter "g"), 55.8 millimol (hereafter "mmol"), M-chlorosuccinimide (37.28g, 27U9mmol) and potassium acetate (2.29g, 27.9mmol). The resulting mixture was stirred at 09C and then warmed to room temperature overnight. After that, the given the mixture is diluted with 200 ml of dichloromethane and washed with (He) water (100 mlx3). The organic layer is dried (Ma»5O)) and concentrated to obtain the desired product (11 g, « 8096). "H-NMR (SOCI"): 5 7.57 (d , 2H), 7.47 (t, 1H). 2,6-dichlorobenzenesulfonamide o

A solution of 2,6-dichlorobenzenesulfonyl chloride (10.50 g, 42.77 mmol) in 100 ml of pyridine was added dropwise to a beaker containing 100 ml of pyridine, bubbling anhydrous ammonia gas through the solution. After 4 hours at 09C, this mixture is acidified to рН»1 bn aqueous NOSI, then extracted with ethyl acetate. Then, the combined organic layer is dried (Ma»z O,) and concentrated to obtain the desired product (8.69g, 9090). EI-MS (t/z) 225.0, 2271 (M-). « 2,6-dichloro-3-nitrobenzenesulfonylamide

Nitric acid (1.74 ml, 41.4 mmol) was added dropwise to a solution of 2,6-dichlorobenzenesulfonamide (7.8 g, 34.5 mmol) with 630 ml of concentrated sulfuric acid at 02С. The resulting mixture was stirred at 09 for 2 hours, and then 200 ml of water was added, resulting in the formation of a precipitate. The resulting mixture is filtered. The white solid was collected, washed with water and dried in vacuo to give the desired product (7.17 g, 7695). "H-NMR (DMSO-d6): δ 8.25 (s, 2H), 8.20 (d, 2H), 7.92 (d, 1H). 2-acetyl-b-chloro-3-nitrobenzenesulfonamide - A solution of 2,6-dichloro-3-nitrobenzenesulfonamide (2.04g, 7.5mmol), potassium acetate (2.21g, 22.5mmol) and OO 18-crown-b (5.95g, 22.5mmol) in 30ml of dimethylsulfoxide heated to 452 for 7 days. The resulting mixture was acidified to 10 with aqueous HCl, then extracted with ethyl acetate. Then, the organic layer was concentrated to give the crude product. After column chromatography on silica gel, eluting with a mixture

Ge) 20 ethyl acetate/hexane/acetic acid (50/49/1 v/v/v) gave the desired product (1.67 g, 76965). EI-MS (t/g) 293.1, 295.1 (M-). m b-Chloro-2-hydroxy-3-nitrobenzenesulfonylamide

A solution of 2-acetyl-b-chloro-33-nitrobenzenesulfonamide (1.72g, 5.83mmol), chlorotrimethylsilane (2ml) and fuming sulfuric acid (0.bml) in methanol was refluxed for 20 hours. 22 The solvent is evaporated. The residue is diluted with ethyl acetate and washed with water. Then the organic layer is dried

F! (Ma»5O)) and concentrated, resulting in the desired product (1.0 g, 6890). EI-MS (t/2) 251.1, 253.2 (M-). o 3-amino-b6-chloro-2-hydroxybenzenesulfonylamide

1090 60 Ra/s (500 mg) is added to a solution of β-chloro-2-hydroxy-3-nitrobenzenesulfonylamide (1.1 g, 4.3 mmol) in ethyl acetate. The resulting mixture is purged with argon, and then stirred in an atmosphere of hydrogen supplied from a cylinder for 4 hours at room temperature. This mixture is filtered through celite and the celite is washed with ethanol. The solvent is evaporated to obtain the desired product (0.9 g, 9395). EI-MS (t/z2) 221.1, 223.4 (M-).

M-(4-chloro-2-hydroxy-3-aminosulfonyl)-M'-(2,3-dichlorophenyl)urea

A solution of 3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.88 g, 3.0 mmol) and 2,3-dichlorophenyl isocyanate (0.62 ml, 1 mmol) in 5 ml. M,M-dimethylformamide is stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70-50/50 v/v) and subsequent recrystallization from dichloromethane and hexane, the required product is obtained (1.18 g, 7495). T.pl. 241-242.

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)urea

A solution of 3-amino-b-chloro-2-hydroxybenzenesulfonamide (b5mg, 0.29mmol) and 2,3-dichlorophenylisocyanate (45μl, 00.5mmol) in 2ml of M,M-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70-40/60 v/v)/p0, the desired product (5Omg, 4195) is obtained. EI-MS (t/z2) 418.2, 420.2, 422.2 (M-).

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea sodium salt

To a solution of M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea (1.47 g, 59 mmol) in 1500 ml of acetone is added 2.4 bml of an aqueous Mahon solution (1.45 M ). The mixture is stirred for 16 hours at room temperature and the solvent is evaporated. The residue was recrystallized from acetone and dichloromethane to obtain the desired product (1.41 g, 91 95). 7"H-NMR (DMSO-siv): δ 9.27 (s, 2H), 8.01 (m, ЗН), 7.77 (d, 1H), 7.26 (m, 2H), 6, 05 (d, 1H).

Examples 2 and 3

Preparation of IM-3-(M"-benzylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea and

IM-3-(M'"-benzylamino-sulfonyl)-4-chloro-2-hydroxyphenyl)-M'-(2-bromophenyl)urea 20 M-Benzyl-2-acetyl-6b-chloro-3-nitrobenzenesulfonamide

A mixture of 2-acetyl-b-chloro-3-nitrobenzenesulfonamide (500mg, 1.69mmol), potassium carbonate (46O9mg, 3.39mmol) and benzyl bromide (0.24ml, 2.0mmol) in 20ml of M,M-dimethylformamide is heated to 752С within 24 hours. The mixture is acidified with aqueous HCl, and then extracted with ethyl acetate. The solvent is concentrated to give the crude product. After column chromatography on silica gel eluting with a mixture of He 25 ethyl acetate/hexane/acetic acid (50/49/1, v/v/06), the desired product (274 mg, 4295) was obtained. EI-MS (t/z) (5) 383.3, 385.3 (M-).

M-benzyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

A solution of M-benzyl-2-acetyl-b-chloro-3-nitrobenzenesulfonamide (225mg, 0.5Ommol), OTml of chlorotrimethylsilane and 2 drops of fuming sulfuric acid in ethanol is heated to the distillation temperature "(2 30 for 20 hours. Solvent evaporate. The residue is diluted with ethyl acetate and washed with water. The organic layer is dried (Ma»5O,) and concentrated to obtain the desired product (189 mg, 9496). "H-NMR (DMSO-d»v): 5 7.92 (d, 1H), 7.18 (m, 5H), 6.93 (d, 1H), 4.15 (s, 2H).

M-benzyl-3-amino-b6-chloro-2-hydroxybenzenesulfonamide co

To a solution of M-benzyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (18mg, 0.52mmol) in ethyl acetate

1095 Ra/C (7Omg) are added to Zo. The mixture is purged with argon, and then stirred in an atmosphere of hydrogen supplied from a cylinder for 71 hours at room temperature. The resulting mixture is filtered through celite and the celite is washed with methanol. The solvent is evaporated to obtain the desired product (140 mg, 8596). "H-NMR (DMSO-iv): δ 8.73 (t, 1H), 7.24 (m, 5H), 6.78 (d, 1H), 4.09 (d, 2H). "

IM-IZ-"M'"-Benzylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea Z7Z

A solution of M-benzyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (54 mg, 0.17 mmol) and 2,3-dichlorophenyl isocyanate (3.4 μl, 0.2 mmol) in 2 ml of M,M-dimethylformamide is stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (60/40, v/v), the desired product (1mg, 1295) was obtained. EI-MS (t /2) 498.2, 500.1, 502.1 (M-).

IM-IZ-(M"-Benzylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-ME"2-bromophenyl)urea - Solution of M-benzyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (8Omg, 0 ,2bmmol) and 2-bromophenylisocyanate (4) (47μl, 0.33vmmol) in 2ml of M,M-dimethylformamide are stirred at room temperature for 20 hours.

The mixture was diluted with ethyl acetate and washed with water to give the crude product. After cleaning it! . ! ! column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70-70/30, v/v) (Ce) 50 gives the desired product (8Omg, 61905). EI-MS (t/2) 508.1, 510.2, 512.2 (M-).

Examples 4 and 5 c Preparation of /-M-I(4-chloro-3-(M",M'-dimethylaminosulfonyl)-2-hydroxy-phenyl|-M'-(2,3-dichlorophenyl)urea and

M-(2-bromophenyl)-M'-(4-xpor-3-(M".M"-dimethylaminosulfonyl)-2-hydroxyphenyl|urea

M,M-Dimethyl-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide 99 To a mixture of 2-acetyl-b-chloro-3-nitrobenzenesulfonamide (30mg, 1.02mmol) and sodium hydride (122mg,

HF) C, vol.mmol) in t00ml of M,M-dimethylformamide add iodomethane (0.6b4ml, 10.2mmol). The mixture is stirred at room temperature for 20 hours. The resulting mixture is acidified with aqueous HCl, and then extracted with ethyl acetate. The solvent is concentrated to give the crude product. After column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), the desired product (14 Ω, 49965) was obtained. "H-NMR (DMSO-α): δ 8.05 (d, 1H), 7.03 (d, 1H), 2.87 (s, 6H).

M,M-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide

To a solution of M,M-dimethyl-b-chloro-2-hydroxy-3-nitrobenzene-sulfonamide (14Omg, 0.5O0mmol) in ethyl acetate is added 1095 Pa/cС (5Omg). The mixture is purged with argon, and then stirred in an atmosphere of hydrogen supplied from a 65 cylinder under pressure for 1.5 hours at room temperature. The resulting mixture is filtered through celite and the celite is washed with methanol. The solvent was evaporated to give the desired product (100 mg, 8095). "N-NMR

(DMSO-a in): δ 6.87 (t, 1H), 6.80 (m, 5H), 2.82 (s, 6H).

M-(4-chloro-3-(M",M"-dimethylaminosulfonyl)-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

A solution of M,M-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (in mg, 00.32 mmol) and 2,3-dichlorophenyl isocyanate (500 μl, 0.3 mmol) in 2 ml of M,M-dimethylformamide is stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (20/80, v/v) and subsequent recrystallization from ethyl acetate and hexane, the desired product is obtained (bZmg, 4596). "H-NMR (DMSO-iv): δ 10.51 (s, 1H), 9.34 (s, 1H), 9.27 (s, 1H), 8.29 (d, 1H), 7.32 (m, 70. 2H), 7.16 (d, 1H), 2.87 (c, 6H).

M-(2-bromophenyl)-M'-(I4-chloro-3-(M",M"-dimethylaminosulfonyl|-2-hydroxyphenyl|urea

A solution of M,M-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (in mg, 0.32 mmol) and 2-bromophenyl isocyanate (47 μl, 0.3 mmol) in 2 ml of M,M-dimethylformamide is stirred at room temperature for 20 hours . The mixture was diluted with ethyl acetate and washed with water to give the crude product. 75 After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (20/80, v/v) and subsequent recrystallization from ethyl acetate and hexane, the desired product is obtained (88 mg, 6290). EI-MS (t/2) 446.2, 448.3, 450.3 (M-).

Examples b and 7

Preparation of IM-(d-chloro-2-hydroxy-3-(M'-methylamino-sulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M'-methylaminosulfonyl)phenyl|urea

M-Methyl-2-acetyl-6b-chloro-6-nitrobenzenesulfonamide

To a mixture of 2-acetyl-b-chloro-3-nitrobenzenesulfonamide (300mg, 1.02mmol) and sodium hydride (5mg, 1.32mmol) in 10ml of M,M-dimethylformamide is added iodomethane (70mg, 1.12mmol). The mixture is stirred at room temperature for 66 hours. The resulting mixture is acidified with 1N aqueous CARRIER, and then extracted with ethyl acetate. Ge

The solvent is concentrated to give the crude product. After column chromatography on silica gel with (5) eluting with a mixture of ethyl acetate/hexane/acetic acid (50/49/1, v/v/v/v), the desired product (185 mg, 59905) was obtained. EBI-MS (t/:) 307.3, 309.3 (M-).

M-methyl-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

A solution of M-methyl-2-acetyl-6b6-chloro-3-nitrobenzenesulfonamide (17Omg, 0.55mmol), 0.bml of chlorotrimethylsilane (3 and 3 drops of fuming sulfuric acid in ethanol is boiled with an inverted refrigerator for 20 hours b

The solvent is evaporated. The residue is diluted with ethyl acetate and washed with water. The organic layer is dried (Ma»z OO.) and concentrated to obtain the desired product (16Omg, 210090). EI-MS (t/z) 265.2, 267.2 (M-). "AND

M-methyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide p

1095 Ra/C (bOmg) was added to a solution of M-methyl-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (14Omg, 0.5Zmmol) in ethyl acetate. The mixture is purged with argon, and then stirred in a hydrogen atmosphere supplied from a cylinder for 1.5 hours at room temperature. The mixture is filtered through celite and this celite is washed with methanol. The solvent is evaporated to obtain the desired product (1b0mg, 210095). "H-NMR (DMSO-aiv): 5 7.95 (shr.s, 1n), 6.85 (dn), 6.79 (d, 1n), 2.48 (d, ZN). "5

IM-(d-chloro-2-hydroxy-3-(M'"-methylaminosulfonyl)phenyl|-M'(2,3-dichlorophenyl)urea

A solution of M-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (7mg, 0.29mmol) and c) 2,3-dichlorophenylisocyanate (57μl, 044mmol) in 2ml of M,M-dimethylformamide is stirred at room temperature for 66 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70, v/v), the desired product is obtained (bOmg, 4995, three stages). EI-MS (t/2) 422.3, 424.2, 426.3 (M-). - M-(2-bromophenyl)-M-|4-chloro-2-hydroxy-3-(M'-methylaminosulfonyl|phenyl|urea oo Solution of M-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (7Omg , 0.29 mmol) and 2-bromophenyl isocyanate (55 µL, 0.44 mmol) in 2 mL of M,M-dimethylformamide was stirred at room temperature for 66 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification

Gee! 20 column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70, v/v) gave the desired product (85 mg, 6795, three stages). EI-MS (t/2) 432.3, 434 2, 436.3 (M-). with Examples 8, 9, 10 and 11

Obtaining

IM-(4-chloro-2-hydroxy-3-(M"-(2-(methoxycarbonyl)methyl|iaminosulfonyl|phenyl-M'-(2,3-dichlorophenyl)urea, 25 M-III-I(M" -(2-carboxymethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea,

F! M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-IM"-(2-(methoxycarbonyl)methylaminosulfonyl|phenyl|urea and

IM-(2-bromophenyl)-M'-I3-(M"-(2-carboxymethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|urea o I-(2-(methoxycarbonyl)methyl|)|-2- acetyl-b-chloro-3-nitrobenzene-sulfonamide

To a mixture of 2-acetyl-b-chloro-3-nitrobenzenesulfonamide (300mg, 1.02mmol) and sodium hydride (81mg, 2.02mmol) 60 in 1b0ml of M,M-dimethylformamide is added methyl bromoacetate (106bml, 1.12mmol). The resulting mixture was heated to 802C for 20 hours, and then an additional amount of sodium hydride (81 mg, 2.02 mmol) was added and stirred at room temperature for 66 hours. The resulting mixture is acidified with 1N aqueous CARRIER, and then extracted with ethyl acetate. The solvent is concentrated to give the crude product. After column chromatography on silica gel, eluting with a mixture of ethyl acetate/hexane/acetic acid (60/39/1, v/v/v), the desired product (350 mg, 9596) was obtained. "H-NMR (DMSO-α): δ 7.76 (d, 1H), 6.12 (d, 1H), 4.57 (s, 2H), 3.66 (s, ЗН), 2.22 (c, ZN).

I-(2-(methoxycarbonyl)methyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

A solution of /M-I(2-(methoxycarbonyl)methyl|)|-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (35Omg, 0.95 mmol),

O.bml of chlorotrimethylsilane and C drops of fuming sulfuric acid in methanol are boiled with inverted

Refrigerate for 20 hours. The solvent is evaporated. The residue is diluted with ethyl acetate and washed with water. The organic layer was dried (Ma»z5O)) and concentrated to give the desired product (182mg, 5995). EI-MS (t/2) 323.0, 325.0 (M-).

M-(2-(methoxycarbonyl)methyl|-3-amino-b-chloro-2-hydroxybenzenesulfonamide

1095 Pa/C (8Omg) was added to a solution of M-(2-(methoxycarbonyl)methyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (17Omg, 0.52mmol) in 7/0 ethyl acetate. The mixture is purged with hydrogen, and then stirred in an atmosphere of hydrogen supplied from a cylinder for 3 hours at room temperature. The mixture is filtered through celite and this celite is washed with methanol. The solvent is evaporated to obtain a mixture of the desired product and impurities. This mixture is used in the next stage without additional purification. "H-NMR (DMSO-sv): δ 8.68 (m, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 3.83 (s, 2H), 3.53 (c, ZN).

IM-(4-chloro-2-hydroxy-3-(M"-(2-methoxycarbonyl)methyl|amino-sulfonyl|phenyl/|-M'-(2,3-dichlorophenyl)urea

A solution of I-(2-(methoxycarbonyl)methyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.2 mmol) and 2,3-dichlorophenyl isocyanate (41 μl, 0.3 mmol) in 2 ml of M,M-dimethylformamide stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (40/60, v/v) the desired product was obtained (35mg, 2895, two stages ).EI-MS (t/g2) 479.9, 428.0, 483.9 (M-).

IM-III-IM"-(2-carboxymethyl)aminosulfonyl|-4-chloro-2-hydroxy-phenyl/|-M'-(2,3-dichlorophenyl)urea

Mixture

IM-(4-chloro-2-hydroxy-3-(M"-(2-(methoxycarbonyl)-methyl|Iaminosulfonyl|phenyl|-M-(2,3-dichlorophenyl)urea He (20 mg, 0.041 mmol) and monohydrate) lithium hydroxide (40mg, 0.95mmol) in 5ml of methanol (9595) was stirred at room temperature for 20 hours. The resulting mixture was acidified with aqueous NH, resulting in the formation of a precipitate. The resulting mixture was then filtered, the white solid was collected and dried in vacuo, As a result, the desired product is obtained (15 mg, 7895).EI-MS (t/2) 465.9, 467.9, 469.9 (M-).

M'Y(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-(2-(ethoxycarbonyl)-methylIamylaminosulfonyl|phenyl|urea av)

A solution of I-(2-(methoxycarbonyl)methyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.2 mmol) and 2-bromophenyl isocyanate (Zvmkl, 0.31 mmol) in 2 ml of M,M-dimethylformamide is stirred at room temperature F for 20 hours. The mixture is diluted with ethyl acetate and washed with water to give the crude product.

After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70, v/v), the desired product is obtained (4Omg, 3190, two stages). EI-MS (t/z) 489.9, 491.9, 493.9 (M-). at

M -(2-bromophenyl)-M'-(3-(M"-(2-carboxymethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|urea ich-

Mixture

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-(methoxycarbonyl)methylaminosulfonyl|phenyl|urea) (15mg,

0.OZ mmol) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) in 5 ml of methanol (9595) are stirred at room temperature for 20 hours. The resulting mixture is acidified with 1N aqueous NOSI, resulting in the formation of a precipitate.

The resulting mixture is then filtered, the white solid is collected and dried under vacuum, resulting in the desired product (1Omg, 70905). EI-MS (t/2) 476.1, 478.1, 490.1 (M-). By methods similar to those described above, the following compound was additionally obtained: Example 12: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2-chlorophenyl)urea

A solution of 3-amino-6b-chloro-2-hydroxy-3-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-chlorophenyl isocyanate (33 mg, 0.22 mmol) in 1 ml of M,M-dimethylformamide was stirred at room temperature for 18 hours. -I The mixture is diluted with ethyl acetate and washed with water to obtain the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70, v/v) and subsequent recrystallization from acetone and hexane, the desired product is obtained (ZOmg, 4495). EI-MS (t/2) 374.3, 376.1 (M-). d» Example 13: Preparation of M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-phenylurea

According to the general method of obtaining urea, described in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and phenyl isocyanate (32 mg, 0.27 mmol) are subjected to 2 coupling reactions to obtain the desired urea (25mg, 41,905). EI-MS (t/2) 340.3, 342.3 (M-).

Example 14: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2-phenoxyphenyl)urea

According to the general method of obtaining urea, described in example 12,

C-amino-b-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-phenoxyphenyl isocyanate (4 mg, 0.22 mmol) were subjected to a coupling reaction to obtain the desired urea (41 mg, 52 95). "H-NMR (DMSO-div): δ 10.69 (s, 1H), 9.25 (2, 1H), 9.11 (s, 1H), 8.18 (m, 4H), 7.41 (m, 2H), 7.04 (m, 8H), 6.84 (d, 1H), where Examples 15 and 16: Preparation

IM-(d-chloro-2-hydroxy-3-(M'-(2-(methoxyethyl)aminosulfonyl|phenyl|M'-(2,3-dichlorophenyl)urea sodium salt 60 1 m-A(2-bromophenyl) -M'-(4-chloro-2-hydroxy-3-IM"-(2-(methoxyethyl)aminosulfonyl|phenyl|urea)

The general method of obtaining sulfonamide is described below.

M-2-(methoxyethyl)-2,6-dichloro-3-nitrobenzosulfonamide

To a solution of 2,6-dichloro-3-nitrobenzosulfonyl chloride (b0Omg, 2.0bmmol) in 15ml of dichloromethane at -782C, add a solution of 2-methoxyethylamine (153mg, 2.0bmmol) and triethylamine (77Omcl, 5.15mmol) in TOml bo dichloromethane. The mixture is heated to room temperature and stirred for 16 hours. The resulting mixture is acidified with aqueous NH! to rno»1, and then extracted with ethyl acetate. The combined organic layer is concentrated to give the crude product. After purification by column chromatography on silica gel, eluting with a mixture of ethyl acetate/hexane (30/70, v/v), the desired product (64Omg, 94905) is obtained. EI-MS (t/z2) 327.1, 329.1 (M-).

A general method for the hydrolysis of dichlorosulfonamide with the formation of phenol is described below.

M-2-(methoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzosulfonamide

A mixture of M-2-(methoxyethyl)-2,6-dichloro-3-nitrobenzosulfonamide (490mg, 1.4ummol), 6095 sodium hydride (179mg, 4.47mmol) and water (27μl, 1.49mmol) is heated to 352C while standing in an argon atmosphere during

From days The progress of the reaction is monitored using TN-NMR. If the reaction is not complete, then add 70 U/L to the mixture. water If the reaction is almost complete, as indicated by H-NMR, then the solvent is evaporated. The residue is diluted with ethyl acetate and washed with 1N aqueous HCl. The solvents are concentrated to give the crude product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (40 /58/2, ob/ob/06) yield the desired product (27Omg, 9895).EI-MS (t/z2) 309.1, 311.1 (M-).

A general method of hydrogenation of nitro compounds to form aniline is described below.

M-2-(methoxyethyl)-3-amino-b-chloro-2-hydroxy-benzosulfonamide

1095 Ra/s (100 mg) was added to a solution of /M-(2-methoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (26 mg, 0.4 mmol) in ethyl acetate. The mixture is purged with argon, and then stirred in an atmosphere of hydrogen supplied from a cylinder for 3 hours at room temperature. The mixture is filtered through celite and this celite is washed with methanol. The solvent is evaporated to obtain the desired product (210 mg, 8995). EI-MS (t/z2) 281.1, 283.1 (M-).

A general method of obtaining urea is described below.

IM-(d-chloro-2-hydroxy-3-(M'-(2-methoxyethyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea

A solution of N-(2-(methoxyethyl)-3-amino-b-chloro-2-hydroxy-3-hydroxybenzenesulfonamide (772 mg, 2.75 mmol) and C 2,3-dichlorophenyl isocyanate (56 mg, 3.0 mmol) in 2 mL of M ,M-dimethylformamide was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by silica gel column chromatography eluting with a mixture of ethyl acetate/hexane (30/70, v/v) and recrystallization from acetone and of hexane gave the desired product (72Omg, 5695).Elemental analysis: calcd C, 41.0095; H, 4.44905; M, 8.9695; found: C, 40.77905; H, 3.28905; M, 8, 8390. (av)

The general method of obtaining sodium salt is described below. Phew

IM-(d-chloro-2-hydroxy-3-(M'-(2-methoxyethyl)aminosulfonyl|-phenyl)|-M'(2,3-dichlorophenyl)urea sodium salt "

To a solution of M-I (4-chloro-2-hydroxy-3-(M'-(2-methoxyethyl)-aminosulfonyl|phenyl-M'-(2,3-dichlorophenyl)urea c (307 mg, 0.6 mmol) in 3 mL of acetone is added to 1.20 mL of Mahon's aqueous solution (0.54 M). The mixture is stirred for 16 hours at room temperature and the solvent is evaporated. The residue is recrystallized from acetonitrile to give the desired product (288 mg, 8995). "H-NMR (DMSO-iv ): 5 9.31 (s, 1H), 9.27 (s, 1H), 8.00 (d, 1H), 7.78 (d, 1H), 7.26 (m, 2H), 6, 05 (d, 1H), 3.36 (t, 2H), 3.20 (s, ЗН), 2.80 (m, 2H).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-methoxyethyl)-aminosulfonyl|phenyl|urea "

According to the general method of obtaining urea, described in example 15, 49. M-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (140mg, 0.5Omol) and 2-bromophenylisocyanate C with (119mg, 0 , bOmmol) are subjected to a coupling reaction to obtain the required urea (174 mg, 72 90). EI-MS (ti/l) "» 476.0, 478.0, 479.9 (M-). " Example 17: Preparation

M-(4-chloro-2-hydroxy-3-(3-carboxyethylaminosulfonyl)phenyl/|-M'-(2-chlorophenyl)urea a). M-(3-ethoxycarbonylethyl)-2,6-dichloro-3-nitrobenzenesulfonamide

Ш- According to the general method of obtaining sulfonamide, described in example 15,

Ha 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5g, 5.17mmol), p-alanine ethyl ether (0.95ml, b.2mmol) and triethylamine (1.vml, 12.9mmol) are reacted to form the desired of the product (1.8 g, 94 90). EI-MS (ti/l) shk 370 (M-N)-. (Te) 20 c). M-(3-carboxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, with M-(3-ethoxycarbonylethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.82g, 4.9mmol), Ma (6095, 588mg, 14.7mmol) and water (10 mg, 5.88 mmol) was reacted to give the desired product (1.0 g, 63 90). EI-MS (t/lg) 323.5 (M-H)-. with). M-(3-Carboxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide 52 According to the general hydrogenation method described in Example 15,

HF) M-(3-carboxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1000 mg, 0.3 mmol) was reduced with hydrogen in the presence of Ra/C (100 mg) to give the desired product (62 mg, 68 905). EI-MS (t/2) 293.5 (М-Н)-. about a). M-(4-chloro-2-hydroxy-3-(3-carboxyethylaminosulfonyl)phenyl/|-M'-(2-bromophenyl)urea

According to the general method for the preparation of urea described in Example 15, 60 M-(3-carboxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (62 mg, 0.21 mmol) and 2-bromophenyl isocyanate (42 mg, 0.21 mmol) undergo a coupling reaction to obtain the desired urea (Z5mg, 34 90). EI-MS (t/z) 491.7 (M-H)-.

Examples 18, 19 and 20: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(isopropylaminosulfonyl|phenyl|urea,

IM-(d-chloro-2-hydroxy-3-(isopropylaminosulfonyl|phenyl|-M'-(2-chlorophenyl)-urea and bo IM-(d-chloro-2-hydroxy-3-(isopropylaminosulfonyl)-phenyl/ |-M'-(2,3-dichlorophenyl)urea a) M-isopropyl-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for preparing the sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.17 mmol), isopropylamine (0.44 mL, 5.17 mmol), and triethylamine (1.08 mL, 7, 7bmmol) are reacted with the formation of the desired product (1.3g, 8190). EI-MS (t/2) 312 (М-Н)-.

B). M-isopropyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-isopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.3g, 4.15mmol), Ma (6095, 50mg, 12.45mmol) and water (89mg, 4.98mmol) were reacted to give the desired product (0 ,7g, 5790). EI-MS (t/2) 293.5 (М-Н)-. 70 s). M-isopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-isopropyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.7 g, 2.3 mmol) is reduced with hydrogen in the presence

Ra/s (0.7g) with obtaining the desired product (0.62/south, 9895). EI-MS (t/2) 263.5 (М-Н)-. and). Mm-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(isopropylaminosulfonyl)phenyl|urea

According to the general method for the preparation of urea described in example 15,

M-isopropyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.88 mmol) and 2-bromophenyl isocyanate (174 mg,

O.88mmol) are subjected to a coupling reaction to obtain the required urea (11Omg, 29 90). EI-MS (t/zg) 461.7 (M-H)-. is). M-I4-chloro-2-hydroxy-3-(isopropylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method of obtaining urea, described in example 15,

M-isopropyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (188 mg, 0.75 mmol) and 2,3-dichlorophenyl isocyanate (141 mg, 0.75 mmol) are subjected to a coupling reaction to obtain the desired urea (104 mg, 3290). EI-MS (t/g2) 451.7 (M-H)-.

In M-I (4-chloro-2-hydroxy-3-(isopropylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea

According to the general method of obtaining urea, described in example 15,

M-isopropyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.88 mmol) and 2-chlorophenyl isocyanate (135 mg, i)

O.88mmol) are subjected to a coupling reaction to obtain the desired urea (11Omg, 32905). EI-MS (t/2) 417.1 (М-Н)-.

Example 21: M-(4-chloro-2-hydroxy-3-aminosulfonyl)-M'-(2-methoxyphenyl)urea o z o According to the general method for the preparation of urea described in example 12,

3-Amino-b6-chloro-2-hydroxybenzenesulfonamide (40mg, 0.18mmol) and 2-methoxyphenylisocyanate (3Zmg, 0.22mmol) were subjected to a coupling reaction to obtain the desired urea (2Zmg, 3490). EI-MS (t/2) 370.3, 372.1 (M-). "

Example 22: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-methylenedioxyphenyl)urea 2,3-(methylenedioxy)benzoic acid i)

A solution of 2,3-(methylenedioxy)benzaldehyde (1b0mg, 1.0bmmol), potassium carbonate (9bOmg, b, 9mmol) and 2.4ml of hydrogen peroxide (30-32w/9% solution in water) in 10ml of methanol is stirred for 16 hours at room temperature. The mixture is washed with diethyl ether. The aqueous layer is acidified with Tn water. NCI to pH 21, and then extracted with ethyl acetate. The organic layer was dried over Mo50O, and then concentrated to give the desired product (17Omg, 96 90). BI-MS (t/7) 164.8 (M-). "

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-methylenedioxyphenyl)urea with a mixture of 2,3-(methylenedioxy)benzoic acid (17Omg, 1.02mmol), diphenylphosphoryl azide (338mg , 1.23 mmol). and triethylamine (0.17ml, 1.23mmol) were stirred at room temperature for 3 days. Do you mix?" concentrate C3-amino-b-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) is added to the residue in 1 ml of M,M-dimethylformamide. The resulting mixture is stirred at room temperature for 16 hours. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (50/50, v/v), the desired product (40 mg, 10905) is obtained. EI-MS (t/2) 386.2, 388.2 (M-).

Example 23: M-(2-benzyloxyphenyl)-M'-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)urea and According to the general method for the preparation of urea described in example 12, their 3-amino-b6-chloro- 2-Hydroxybenzenesulfonamide (52mg, 0.233mmol) and 2-benzyloxyphenyl isocyanate (4Omg, 0.17mmol) are subjected to a coupling reaction to obtain the desired urea (2Omg, 26905). EI-MS (t/z) 446.2, 448.3 450.2 (M-). Example 24: M-III-(M'"-allylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; o M-allyl-2-acetyl-b-chloro- 3-nitrobenzenesulfonamide

A mixture of 2-acetyl-b-chloro-3-nitrobenzenesulfonamide (1500 mg, 0.51 mmol), potassium carbonate (84 mg, 0.51 mmol), and allyl bromide (0.18 mL, 2.0 mmol) in 3 L of M, M-dimethylformamide is heated to 602C for 4 days. The mixture is acidified with aqueous HCl and then extracted with ethyl acetate. The solvent is concentrated to give the crude product. After purification by column chromatography on silica gel, eluting with a mixture of ethyl acetate/hexane/acetic acid (50/49/1, v/v/o06), the desired product (40 mg, 1290) was obtained. EI-MS (t/z) ko 333.3, 335.2 (M-).

M-allyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide in a solution of M-allyl-2-acetyl-b6-chloro-3-nitrobenzenesulfonamide (3 mg, 0.09 mmol), 0.0 ml of chlorotrimethylsilane and 2 drops of sulfuric acid, that smokes, boil under reflux for 20 hours. The solvent is evaporated. The residue is diluted with ethyl acetate and washed with water. The organic layer is dried (Ma 2550,) and concentrated to obtain the desired product (2bmg, 10095). "H-NMR (MeOyu-al): δ 8.01 (d, 1H), 7.20 (d, 1H), 5.70 (m, 1H), 5.16 (m, 1H), 5.05 (m, 1H), 3.62 (m, 2H). bB M-allyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide

A solution of M-allyl-b6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (25 mg, 0.09 mmol) and stannous chloride dihydrate

(I) (101 mg, 0.044 mmol) in 5 ml of ethanol is stirred at room temperature. The mixture is concentrated, the residue is diluted with ethyl acetate and 10956 aqueous Manso with. The organic layer was dried over NaCl5SO4 and concentrated to give the crude product (20 mg), which was used in the next step without purification. EI-MS (t/zg) 253.1, 265.2 (M).

IM-3-(M'"-allylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;

A solution of crude M-allyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (2mg) and 2,3-dichlorophenylisocyanate (12μl, 0.09mmol) in 1ml of MM-dimethylformamide was stirred at room temperature for 20 hours.

The mixture was diluted with ethyl acetate and washed with water to give the crude product. After purification by 7/0 K column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (30/70, v/v) and recrystallization from acetone and hexane, the desired product is obtained (1Omg, 2995, for two stages). EI-MS (t/z2) 450.2, 452.2, 4541 (M-).

Example 25: Obtaining

M-4I-chloro-2-hydroxy-3-(M"-2-trifluoroethyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea 2,6-dichloro-3-nitrobenzenesulfonic acid

Lithium hydroxide hydrate (12.64g, 0.301mmol) was added to a solution of 2,6-dichlorobenzenesulfonyl chloride (35.53g, 0.14bmol) in Meon (bOOml), and the reaction was allowed to stir for 3 hours at room temperature. The reaction mixture is filtered to remove suspended solids and then concentrated. The resulting solid was dried under vacuum overnight to remove any residual Meon. Then the solid is dissolved in NaOH (300 ml) and cooled in an ice bath. To the above reaction mixture, over 90 minutes, slowly add a solution of H»zoO, (35 ml) and HMO» (13.2 ml). The reaction mixture was heated to room temperature overnight, and then slowly poured into ice water (1200 ml) and extracted with EtOAc. The combined organic layers were dried (Mo950,) and concentrated to give 2,6-dichloro-3-nitrobenzosulfonic acid (44.35 g, 9990) as a dihydrate. EI-MS (t/z2) 270 (М-Н)-. c 2,6-dichloro-3-nitrobenzenesulfonyl chloride

Potassium hydroxide (12.07g, 0.215mol) was added to a solution of 2,6-dichloro-3-nitrobenzenesulfonic (8) acid dihydrate (44.35g, О0.144mol) in MeOHN (850ml), and the reaction mixture was left for 14 hours at room temperature for mixing. The reaction mixture was concentrated, and the resulting solid was dried under vacuum overnight.

RSIB (30.00 g, 0.144 mol) is added to this substance, and then ROSIz (475 ml) and the mixture is boiled with inverted o

With the refrigerator during the night. Then the reaction mixture is cooled to room temperature and concentrated.

The resulting mixture is dissolved in E(OAc) and cooled in an ice bath. Me pieces of ice are slowly added to the reaction mixture to quench any residual PCI 5. After the formation of bubbles stops, water is added and the reaction mixture is extracted with EtOAc. The organic layer is dried (M950) ) and concentrated to obtain 2,6-dichloro-3-nitrobenzosulfonyl chloride (40.42 g, 97965). "H-NMR (DMSO-α): δ 7.88 (d, 1H), 7.75 (d, 1H). o

M-(2-trifluoroethyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method for preparing the sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (5mg, 1.933mmol), 2-trifluoroethylamine hydrochloride (261mg, 1.93mmol) and triethylamine (0.89mg, 5.79mmol ) react with the formation of the desired product (490 mg, 72 90). "

EI-MeS (ti/l) 351.1, 353.1 (M-).

M-(2-trifluoroethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide - to a solution of M-(2-trifluoroethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (13O0 mg, 0.5 mmol) in 5 bBml and 6095 Ma (4 µg, 1.08 mmol) and methanol (15 μl, 0.5 mmol) are added to tetrahydrofuran. The mixture is stirred for 16 hours at room temperature. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (49/50/1, v/v/v), the desired product (44 mg, ZZFo) was obtained. BI-MS (t/) 333.1, 335.1 (M-). - I M-(2-trifluoroethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation procedure described in example 15, o M-(2-trifluoroethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (40 mg, 0.12 mmol) is reduced with hydrogen and 1095

ChK" Ra/s (20mg) with obtaining the desired product (Zbmg, 10095). EI-MS (t/2) 303.1 305.1 (M-).

IM-(d-chloro-2-hydroxy-3-(M'-(2-trifluoroethyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea) according to the general method of obtaining urea described in example 15 , 2 M-(2-trifluoroethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (Zbmg, 0.12 mmol) and 2,3-dichlorophenyl isocyanate (27 mg, 0.14 mmol) are subjected to a coupling reaction to form the desired urea (2Zmg , 38905). ), 3.79 (m, 2H).

Example 26 and 21. Obtaining

GF! M-(2,3-dichlorophenyl)-M'-(2-hydroxy-4-methoxy-3-(M'"-phenylaminosulfonyl)phenyl|urea and

M-(2-bromophenyl)-M'-(2-hydroxy-4-methoxy-3-(M'"-phenylaminosulfonyl)phenyl|urea o M-phenyl-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 60 2,6-dichloro-3Z-nitrobenzenesulfonyl chloride (54 Ωg, 1.85 mmol), aniline (17 Ωg, 1.85 mmol) and triethylamine (0.6 mL, 5.55 mmol) are subjected to reactions with obtaining the desired product (13Omg, 2096). "H-NMR (MeO-a4): δ 7.65 (d, 1H), 7.58 (d, 1H), 7.40 (d, 2H), 7.15 (m, ЗН).

M-phenyl-2-hydroxy-b-methoxy-6-nitrobenzenesulfonamide

According to the general method of hydrolysis described in Example 15, M-phenyl-2,6-dichloro-3-nitrobenzenesulfonamide (13Omg, 0.37mmol), 6095 Ma (44mg, 1.11mmol) and methanol (15μl,

0.37 mmol) are subjected to the reaction. The crude mixture (7Omg) is used in the next stage without purification.

M-phenyl-3-amino-2-hydroxy-b6-methoxybenzenesulfonamide

According to the general method of hydrogenation described in example 15, crude

M-phenyl-2-hydroxy-b-methoxy-3-nitrobenzenesulfonamide (7Omg) is reduced with hydrogen in the presence of Ra/s (35mg).

The crude mixture is used in the next stage without purification.

M-(2,3-dichlorophenyl)-M'-(2-hydroxy-4-methoxy-3-(M'-phenylaminosulfonyl)phenyl|urea

According to the general method of obtaining urea, described in example 15, crude

M-phenyl-3-amino-2-hydroxy-6-methoxybenzenesulfonamide and 2,3-dichlorophenyl isocyanate (4 mg, 0.2 mmol) are subjected to 7/o coupling reaction to obtain the desired urea (3.5 mg, 4 95 for three stages). EI-MS (t/z) 480.2, 482.1 (M)-.

M-(2-bromophenyl)-M'-(2-hydroxy-4-methoxy-3-(M"-phenylaminosulfonyl)phenyl|urea

According to the general method of obtaining urea, described in example 15, crude

M-phenyl-3-amino-2-hydroxy-b6-methoxybenzenesulfonamide and 2-bromophenylisocyanate (46 mg, 0.2 mmol) are subjected to a coupling reaction to obtain the desired urea (5.0 mg, 5.6 90). EI-MS (p/z) 490.1, 492.1 (M)-.

Examples 3 and 31: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl|urea and

IM-(d-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea 2,6-dichloro-1-(4-morpholinylsulfonyl)-3-nitrobenzene

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), morpholine (15 mg, 1.72 mmol) and triethylamine (479 μL, 3.44 mmol) are reacted to give of the desired product (43Omg, 7390). LC-MS (t/2) 341.0 (M-). b-chloro-2-hydroxy-1-(4-morpholinylsulfonyl)-3-nitrobenzene

According to the general hydrolysis method described in Example 15, 2,6-dichloro-1-(4-morpholinylsulfonyl)-3-nitrobenzene (410 mg, 1.20 mmol), 6095 Ma (144 mg, 3 mmol) and water with dv (2 mmol , 1.44 mmol) are reacted to obtain the desired product (220 mg, 57965). EI-MS (t/2) 321.1, 323.1 o (M-). 4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)aniline

According to the general hydrogenation method described in example 15, crude b-dichloro-2-hydroxy-1-(4-morpholinylsulfonyl)-3-nitrobenzene (210 mg, 0.ppmmol) is reduced with hydrogen in (3 in the presence of Ra/C ( 100 mg) to obtain the desired product (180 mg, 9595). "H-NMR (MeO0O-a,): 5 6.28 (m, 2H), 3.68 (t, 4H), 3, 30 (t, 4H) F

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)-phenyl|urea ch;E

According to the general method for the preparation of urea, described in example 15, 4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)aniline (9Omg, 0.Zimmol) and 2-bromophenyl isocyanate (4bMl, 0.37mmol) are subjected to a coupling reaction with obtaining the required urea (81 mg, 53 90). EI-MS (t/2) 487.76, 489/75, 491.74 i- (MU-.

IM-(d-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15, "4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)aniline (9Omg, 0.31mmol) and 2,3-dichlorophenylisocyanate (7Omcl, 0.37mmol) are subjected to coupling reactions to obtain the desired urea (77mg, 52,905). EI-MS (t/l) 477.68, - with 479.72, 481.63 (M)-. Examples 32 and 36: Preparation of "I-IZ-IM"-I(3-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea and M'-I-(3-M"-(3-aminopropyl)uaminosulfonyl|-4-chloro-2-hydroxyphenyl|-ME(2,3-dichlorophenyl)urea of trifluoroacetate - I IM-IZ-"tert-butoxycarbonylamino )propyl|-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method of obtaining sulfonamide, described in example 15, about 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmol), tert-butyl-M-(3-aminopropyl)ucarbamate (0.bOmg, g 3.44 mmol) and triethylamine (9 μmol, 6.88 mmol) are reacted to give the desired product (1.44 g, 98905).

BI-MS (t/z2) 426.1, 428.1, 430.1 (M-H)-. i-o IM-IZ-"tert-butoxycarbonylamino)propyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide 2 According to the general hydrolysis method described in Example 15,

M-(33-"tert-Butoxycarbonylamino)propyl|-2,6-dichloro-3-nitrobenzenesulfonamide (45mg, 1.05mmol), bObO Ma (168mg, 4.2mmol) and water (21µl, 1.15mmol) were reacted with obtaining the desired product (250 mg, 58965).

BI-MS (t/2) 408.1, 410.1 (M-H)-.

I-III-"tert-butoxycarbonylamino)propyl|-3-amino-b6-chloro-2-hydroxybenzenesulfonamide o According to the general hydrogenation method described in Example 15, ko I-III-"tert-butoxycarbonylamino)propyl|-b- chloro-2-hydroxy-3-nitrobenzenesulfonamide (25 Ω, 0.1 bimole) is reduced with hydrogen in the presence of Ra/C (100 mg) to obtain the desired product (220 mg, 9596). "H-NMR 6bo (meO0O-a"): 5 6.82 (m, 2H), 3.06 (t, 2H), 2.92 (t, 2H), 1.60 (m, 2H), 1 ,41 (from, 9H).

IM-IZ-IM"-IZ-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

IM-IZ-(tert-butoxycarbonylamino)propyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (110mg, 0.29mmol) (65) 2,3-dichlorophenylisocyanate (b5µl, 0.35mmol) is subjected to a coupling reaction to give of the required urea (9Omg, 55905). BI-MS (t/l) 565.64, 567.74, 569.60 (M)-.

The general procedure for removing the Vos protective group is described below

M'-(3-(M"-(33-aminopropyl)amino-sulfonyl|-4-chloro-2-hydroxyphenyl)|-M'E(2-bromophenyl)urea trifluoroacetate

Solution

M'-(3-(M"-(3-(tert-butoxycarbonylamino)propyl|-aminosulfonyl|-4-chloro-2-hydroxyphenyl)-M'-(2,3-dichlorophenyl)s urea (33Zmg, 0.058 mmol) in iml of trifluoroacetic acid is stirred at room temperature for a while

REFERENCE Then the solvent is concentrated. The residue is diluted with methanol, then concentrated. This procedure is repeated twice and the crude product is obtained. After recrystallization from methanol and water, the desired product is obtained (23 mg, 6895). EI-MS (t/) 466.7, 468.8, 470.8 (M)-. 70 Examples 33, 34 and 35: Obtaining

M-(2-bromophenyl)-M'-I3-IM"-III-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urea and; M-I3-(M"-(3Z-aminopropyl) aminosulfonyl|-4-chloro-2-hydroxyphenyl(I|-M'2-bromophenyl)urea tryptoacetate and

I-III-IM"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-ME2-bromophenyl)urea hydrochloride

M-(2-bromophenyl)-M'-(3-(M"-3-(tert-butoxycarbonylamino)propyl|-aminosulfonyl|-4-chloro-2-hydroxyphenyl|se /5 Copper

According to the general method for the preparation of urea described in example 15,

IM-IZ-(tert-butoxycarbonylamino)propyl|-3-amino-6-chloro-3-hydroxybenzenesulfonamide (110mg, 0.29mmol) (2-bromophenylisocyanate (bOmCl, 00.35mmol) is subjected to a coupling reaction to obtain the desired urea ( 14Omg, 84 90).EI-MS (t/2) 575.53, 577.61, 579.62 (M)-.

M'-(3-(M"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxy-phenyl)|-M'E(2-bromophenyl)urea trifluoroacetate

According to the general procedure for removing the Bos protecting group described in Example 15,

M-(2-bromophenyl)-M'-I3-IM"-IZ-(tert-butoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urea in (21mg, 0.03bmmol) is stirred in 1ml of trifluoroacetic acid and obtained desired product (16bmg, 7596). "H-NMR (MeOO-y/): δ 8.28 (d, 1H), 7.80 (d, 1), 7.59 (d, 1H), 7.33 (t, 1H), 7.07 (d, 1H), 7.02 (d, s

L1H), 3.05 (m, 4H), 1.87 (m, 2H). at

M-(3-(M"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-ME(2-bromophenyl)urea hydrochloride

Solution

M-(2-bromophenyl)-M'-(3-(M"-3-(tert-butoxycarbonylamino)propyl))aminosulfonyl|-4-chloro-2-hydroxyphenyl|urea (ZZmg, O0.058mmol) in Tml 4.0 M NOI in 1,4-dioxane is stirred at room temperature for 1 hour)

Then the solvent is concentrated. After recrystallization from acetone and hexane, the desired product (45 mg, F 85965) is obtained. LC-MS (t/z2) 477.0 (M).

Examples 37 and 38: Obtaining "I

M-(2-bromophenyl)-M'-I3-IM"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl) -4-chloro-2-hydroxyphenyl|-ME(2-bromophenyl)urea tert-butyl-M-(2-aminoethyl)carbamate -

A solution of ethylenediamine (3.0g, 49.9mmol), di-tert-butyl dicarbamate (3.63g, 16.mmol) and triethylamine (6.95ml, 49.9mmol) in 100ml of dichloromethane was stirred at room temperature for 16 hours. The mixture is filtered to remove the solid substance formed during the reaction. The filtrate was washed with water, dried over Na95O, concentrated and dried in vacuo, resulting in the desired product (1.79 g, b'Zv). LC-MS (t/z) 160.97 (M-). - c 1-(2-(tert-butoxycarbonylamino)ethyl)-2,6-dichloro-3-nitrobenzene-sulfonamide and According to the general method of obtaining sulfonamide described in example 15, -» 2,6-dichloro-3- Nitrobenzenesulfonyl chloride (1.0g, 3.44mmol), tert-butyl-N-(2-aminoethyl)carbamate (0.6g, 3.44mmol) and triethylamine (0.72μl, 5.1bmmol) are reacted to give the desired product ( 1.29Gg, 9090). "H-NMR (MeO-4)): δ 7.93 (d, 1H), 7.78 (d, 1H), 3.12 (m, 4H), 1.41 (s, 9H).

Che I-(2-(tert-butoxycarbonylamino)ethyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

Ge) According to the general hydrolysis method described in Example 15,

M-(2-(tert-butoxycarbonylamino)ethyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.63g, C, 94mmol), 6095 Ma (60mg, te 15.8mmol) and water (71µL, 3.94mmol) react with the desired product (200 mg, 1396). "H-NMR (se) 50 (MeO0O-a,): 5 8.10 (d, 1H), 7.21 (d, 1H), 3.15 ( t, 2H), 3.08 (t, 2H), 1.41 (s, 9H). o I-(2-(tert-butoxycarbonylamino)ethyl I|-3-amino-b-chloro-2-hydroxy-benzenesulfonamide

According to the general hydrogenation method described in Example 15,

MM-(2-(tert-butoxycarbonylamino)ethyl|/|-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (200mg, 0.51mmol) was reduced with hydrogen in the presence of Ra/C (100mg) to give the desired product (170mg, 92965). "H-NMR (meO0O-a"): 5 6.84 (m, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 1.42 (s, 9H ). (F) M-(2-bromophenyl)-M'-I3-IM"-(2-(tert-butoxycarbonylamino)ethylamino-sulfonyl|-4-chloro-2-hydroxyphenyl|urea wine

According to the general method for the preparation of urea described in Example 15, 60 I-(2-(tert-butoxycarbonylamino)propyl|-3-amino-6-chloro-3-hydroxybenzenesulfonamide (170mg, 0.47mmol) (|and 2-bromophenylisocyanate (92mg, 0.47mmol) is subjected to a coupling reaction to obtain the desired urea (12Omg, 4990).LC-MS (t/2) 560.0 (M)7.

IM-3-(IM"-(2-aminoethyl)aminosulfonyl/|-4-chloro-2-hydroxyphenyl]|-M'(2-bromophenyl)urea trifluoroacetate

According to the general procedure for removing the Bos protecting group described in example 15, bvB 0 M-(2-bromophenyl)-M'-(3-(M"-(2-(tert-butoxycarbonylamino)ethyl)aminosulfonyl|-4-chloro -2-hydroxyphenylurea (in mg, O0.14 mmol) is mixed in one ml of trifluoroacetic acid and the desired product is obtained (22 mg, 34905).

LC-MS (t/z2) 465.0 (M).

Examples 39 and 42: Obtaining

M-(2-bromophenyl)-M'-I3-((4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl/|-4-chloro-2-hydroxy-phenyl|urea and

MA(2-bromophenyl)-M'-(d4-chloro-2-hydroxy-3-(piperazin-1-ylsulfonyl)phenyl|urea trifluoroacetate 1-(4-tert-butoxycarbonyl)piperazin-1-yl|isulfonyl- 2,6-dichloro-3-nitrobenzene

According to the general procedure for the preparation of the sulfonamide described in Example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500mg, 1.72mmol), tert-butyl-1-piperazinecarboxylate (32Omg, 1.72mmol) and triethylamine (479μl, 3, 44mmol) are subjected to a reaction to obtain the desired product (6b5Omg, 84905). 70... ХХ-MO (ti/z) 440.2 (M). 1-(4-tert-butoxycarbonyl)piperazin-1-yl|Isulfonyl-b-chloro-2-hydroxy-3-nitrobenzene

According to the general hydrolysis method described in Example 15, 1-(4-tert-butoxycarbonyl)piperazin-1-yl|isulfonyl-2,6-dichloro-3-nitrobenzenesulfonamide (200 mg, 0.45 mmol), 6090 Ma (54 mg , 1.35 mmol) and water (µl, O0.45 mmol) are reacted to obtain the desired product (bOmg, 75 3295). BI-MS (t/z2) 420.1, 4221 (MU. 3-(I4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl-4-chloro-2-hydroxyaniline

According to the general hydrogenation method described in Example 15, 1-(4-(tert-butoxycarbonyl)piperazin-1-yl|sulfonyl-b-chloro-2-hydroxy-3-nitrobenzene (256 mg, 0.1 bimmol) is reduced with hydrogen in in the presence of Ra/C (120mg) to give the desired product (220mg, 9395). 27 (M, AN), 1.43 (c, 9H).

M-(2-bromophenyl)-M'-I3-((4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl-4-chloro-2-hydroxyphenyl|urea

According to the general method for the preparation of urea described in Example 15, 3-I4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl-4-chloro-2-hydroxyaniline (11Omg, 0.28mmol) and 2-bromophenyl isocyanate (6b7mg, O.34 mmol) are subjected to a coupling reaction to obtain the desired urea (bomg, p. 29 3695). Elemental analysis: calculated C, 44.80905; H, 4.44905; M, 9.5095; found: C, 44.6595; H, 4.1595; M, 9.2095. Go)

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(piperazin-1-yl)usulfonylphenyl|urea trifluoroacetate

According to the general procedure for removing the Bos protecting group described in Example 36,

M-(2-bromophenyl)-M'-I3-((4-(tert-butoxycarbonylamino)piperazin-1-yl|Isulfonyl|-4-chloro-2-hydroxyphenyl)|urea (100 mg, 0.019 mmol) is stirred in 1 ml of trifluoroacetic acid and obtain the desired product (5 mgH, 0 30 4995). "H-NMR (MeO0-ad): δ 8.28 (d, 1H), 7.91 (d, 71H), 7/60 (d, 71H) , 7.33 (t, 1H), 7.14 (tn), 7.02 (DN), FI 3.64 (t, 4H), 3.33 (m, 4H).

Examples 40 and 1: Obtaining

IM-IZ-((4-(tert-butoxycarbon)-piperazin-1-yl|isulfonyl)|-4-chloro-2-hydroxyphenyl|urea |i (ze)

IM-(4-ospor-2-hydroxy-3-piperazin-1-yl)usulfonylphenyl|-M'-(2,3-dichlorophenyl|urea trifluoroacetate m 35 I-III-((4-(tert-butoxycarbonyl)piperazine -1-yl|isulfonyl/|-4-chloro-2-hydroxyphenyl-N'-(2,3-dichlorophenyl)urea

According to the general procedure for the preparation of urea, described in example 15, 3-N4-(tert-butoxycarbonyl)piperazin-1-yl|isulfonyl/|-4-chloro-2-hydroxyaniline (11Omg, 0O.28mmol) and "du 2, 3-dichlorophenyl isocyanate (b4 and 4 μl, O0.34 mmol) is subjected to a coupling reaction to obtain the desired urea - (Zamg, 25905). BI-MS (t/l) 576.65, 578.65, 580.67 (M)-. c IM-(d-chloro-2-hydroxy-3-(piperazin-1-yl)usulfonylphenyl|-M'-(2,3-dichlorophenyl)urea trifluoroacetate :c» According to the general procedure for removal of the Bos protecting group described in example 36,

IR-IR-((4-(tert-butoxycarbonylamino)piperazin-1-yl))sulfonyl/|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urine (20 mg, O0, 034 mmol) is mixed in tTml of trifluoroacetic acid and the desired product is obtained (13.5 mg, -I 6690). EI-MS (t/) 481.7, 483.7, 485.7 (M).

Examples 43, 51 and 6: Preparation of 1M-(d-chloro-2-hydroxy-3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl/|-M'-(2,3-dichlorophenyl)urea, IM-(d-chloro-2-hydroxy-3-(M"-3--(methylsulfonyl)propylamiosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-(M"-III--"methylsulfonyl)propyl|aminosulfonyl|phenyl|-ME(2,3-dichlorophenyl)urea is) M-(3-methylthiopropyl) -2,6-dichloro-3-nitrobenzenesulfonamide oz According to the general method of obtaining sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2 g, 6.88 mmol), 3-(methylthio)propylamine (0.72 mg , 6.88mmol) and triethylamine (1.92ml, 13.7bmmol) were reacted to give the desired product (2.07g, 8296). ), 7.79 (d, 1H), 3.16 (t, 1H), 2.47 (t, 1H), 2.00 (s, ЗН), 1.76 (m, 2H).

M-(3-methylthiopropyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

F) According to the general hydrolysis method described in example 15, co M-(3-methylthiopropyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 mg, 2.78 mmol), 6095 Ma (330 mg, 8.1 mmol) and water (5Oml, 3.25mmol) are reacted to obtain the desired product (b5Omg, 69905). EI-MS (t/l) 339.86, 6o 341.84 (M).

M-(3-methylthiopropyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-(3-methylthiopropyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg, 0.88 mmol) was reduced with hydrogen in the presence of Ra/C (120 mg) to give the desired product (250 mg, 9195). "H-NMR (MeO0O-a,): 5 6.84 (m, 2H), bo 6.77 (d, 1H), 2.93 (t, 2H), 2.40 (t, 1H), 1 .89 (c, ЗН), 1.63 (m, 2Н).

IM-(d-chloro-2-hydroxy-3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

M-(3-methylthiopropyl)-3-amino-b-chloro-2-hydroxybenzosulfonamide (250 mg, 0.800 mmol) and 2,3-dichlorophenyl isocyanate (182 mg, 0.97 mmol) are subjected to a coupling reaction to obtain the desired urea (278 mg, 7095 ). "H-NMR (MeO0O-a,): δ 8.29 (d, 1H), 8.06 (d, 1H), 7.24 (t, 2H), 7.05 (d, 1H), 3, 07 (t, 2H), 2.48 (t, 2H), 1.98 (s, ЗН), 1.74 (m, 2H).

IM-(d-chloro-2-hydroxy-3-(M"-3-(methylsulfonyl)propyl|amino-sulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea

A solution of IM-(d-chloro-2-hydroxy-3-(M"-(3-methylsulfonyl)-phenyl|-M'(2,3-dichlorophenyl)urea) (5 mg,

0.1 mmol) and oxone (9 mg, 0.15 mmol) in acetonitrile (1 ml) and water (1 ml) were stirred for 3 hours at room temperature. The mixture was diluted with ethyl acetate and washed with water to give crude product 70. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (49/50/1, v/v/0b) and subsequent recrystallization from acetone and hexane, the desired product (4 mg, 8790) is obtained. EI-MS (t/2) 527.53, 529.57, 531.55 (M).

IM-(d-chloro-2-hydroxy-3-(M"-3--(methylsulfonyl)propylaminosulfonyl|-phenyl|-M'(2,3-dichlorophenyl)urea

A solution of IM-(d-chloro-2-hydroxy-3-(M"-(3-methylsulfonyl)-phenyl|-M'(2,3-dichlorophenyl)urea (5Omg, 75 0 1Omol) and sodium periodate (2bmg, 0.12 mmol) in acetonitrile (bml) and water (2ml) was stirred for 3 days at room temperature. The resulting mixture was diluted with ethyl acetate and washed with water to give the crude product. After recrystallization from acetone and hexane, the desired product (42mgH, 8196) was obtained. NMR (DMSO-Ov) 5: 9.32 (s, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.29 (d, 1H), 8.07 (m, 1H), 7.33 (m, 2H), 7.13 (d, 1H), 3.00 (m, 2H), 2.75 (m, 1H), 2.65 (m, 1H) , 2.47 (c, ЗН), 1.79 (m, 2Н).

Examples 44, 52 and 61: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl|urea,

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-I(3-"methylsulfonyl)propylaminosulfonyl|phenyl|urea and

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylsulfinyl)propyl|Iaminosulfonyl|Iphenyl)urea

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl)urea c

According to the general method of obtaining urea, described in example 15, Ge)

M-(3-methylthiopropyl)-3-amino-b-chloro-2-hydroxybenzosulfonamide (250 mg, 0.8 mmol) and 2-bromophenyl isocyanate (191 mg, 0.97 mmol) are subjected to a coupling reaction to obtain the desired urea (30 mg, 7495). "H-NMR (meOO-a/) 6: 828 (d, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.05 ( d, 71Н), 7.00 (t, 1Н), 3.08 (t, 2Н), 2.48 (t, 2Н), 1.98 (s, ЗН), 1.74 (m, 2Н). at

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3--"methylsulfonyl)-propylaminosulfonyl|phenyl|urea (o)

According to the oxidation procedure described in Example 51,

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylsulfonyl)phenylurea (5mg, 10mmol) and oxon C (9mg, 0.15mmol ) were reacted to give the desired product (41 mg, 77905). Elemental analysis: co found: C, 33.5890; H, 3.3790; M, 7.5995; calculated: C, 37.75905; H, 3.5495 M, 7,779.

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-I(3-"methylsulfinyl)propylaminosulfonyl|phenyl|urea -

According to the oxidation procedure described in Example 51,

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-methylsulfonyl)phenyl)urea (5mg, 00.1mmol) and sodium periodate (25mg, 0, 12 mmol) are reacted to obtain the desired product (8 mg, 1695). LC-MS (t/2) 526.0 (M). " 20 Examples 47, 58, 48 and 59: Preparation of

M-(2-bromomethyl)-M'-(4-chloro-3-IM",M"-di-(2-methoxyethyl)aminosulfonyl|ureas, with M-(2-bromomethyl)-M'-(4- chloro-3-IM",M"-di-(2-hydroxyethyl)aminosulfonyl|/|-2-hydroxyphenyl|urea, :z» IM-(4-chloro-3-(M",M"-di-( 2-methoxyethyl)aminosulfonyl-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)-urea and

M-(4-chloro-3-(M",M"-di-(2-hydroxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea 415 M,M-di-( 3-Methoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide -1 According to the general method of obtaining sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.82 g, 6.2 mmol), bis (2 -methoxyethyl)amine (83Omg, 6.2bmmol) and i95)triethylamine (1.7ml, 12.52mmol) were reacted to give the desired product (2.16mg, 89965). LC-MS (t/z2) i5" 387, 2 (MU). M,M-di-(2-methoxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, ise) M,M-di-(2-methoxyethyl)-2,6-dichloro-1-(3-nitrobenzene)usulfonamide (800 mg, 2.07 mmol), bObo Ma ( 248 mg, about 6.21 mmol) and water (45 μl, 2.48 mmol) are reacted to give the desired product (420 mg, 5590). EI-MS (t/7) 366.89, 368.81 (M). M,M-di-(2-methoxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15, 5B M,M-di-(3-methoxyethyl)-6-dichloro-2-hydroxy-3-nitrobenzenesulfonamide (100 mg, 0.27 mmol) is reduced with hydrogen in the presence of Ra/C ( 5Omg) to obtain the desired product (8Omg, 87965). "H-NMR (MeO0-au) 5: 6.85 (m, 2H),

IF) 3.58 (t, 4H), 3.47 (t, 4H), 3.21 (c, 6H). co M-(2-bromophenyl)-M'-I(4-chloro-3-|M",M"-di-(3-methoxyethyl)-aminosulfonyl-2-hydroxyphenyl|urea

According to the general method for the preparation of urea described in example 15, 60 /M,M-di-(3-methoxyethyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.12 mmol) and 2-bromophenyl isocyanate (2Zmkl, 0.12mmol) are subjected to a coupling reaction to obtain the desired urea (ZOmg, 61,905). EI-MS (t/z) 534.6, 536.6 (M)-.

M-(2-bromophenyl)-M'-I(4-chloro-z-(M",M"-di-(3-hydroxyethyl)amino-sulfonyl/|-2-hydroxyphenyl|urea

A solution of M-(2-bromophenyl)-M'-(4-chloro-3-|M",M"-di-(2-hydroxyethyl)-aminosulfonyl|-2-hydroxyphenylurea 65 (9.9 mg, 0.018 mmol) and of aluminum bromide (4.2 mg, 0.018 mmol) in 2 mL of ethanethiol was stirred for 16 hours at room temperature. The mixture was diluted with ethyl acetate, then washed with Mn aq. HCl, the organic layer was dried over Mo2O, and concentrated. After recrystallization from acetone and methanol, the desired product was obtained (4mg, 4495). "H-NMR (MeOY-a/): δ 8.30 (d, 1H), 7.92 (d, 71H), 7.59 (d, 1H), 7.33 (t , 1H), 7.07 (d, 1H), 7.01 (t, 1H), 3.68 (t, 4H), 3.51 (m, 4H).

IM-(D-chloro-3-(M",M"-di-(2-methoxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

M,M-di-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (4mg, 0.12mmol) and 2,3-dichlorophenylisocyanate (22μl, 0.12mmol) are subjected to a coupling reaction to obtain the desired urea (BBmg, 8795). "H-NMR (MeOYU-ad): δ 8.27 (m, 1H), 8.03 (m, 1H), 7.23 (m, 2H), 7.03 (m, 1H), 3.61 (m, 4H), 3.45 70 (m, 4H), 3.23 (c, 6H).

IM-(D-chloro-3-(M",M"-di-(2-hydroxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

According to the deprotection procedure described in Example 58,

IM-(4-chloro-3-(M",M"-di-(2-methoxyethyl)-aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea (15 mg, 0.028 mmol) and ammonium bromide (18.7mg, O0.07mmol) is reacted to give the desired product (2mg, 14905).

LC-MS (t/z) 500.0 (M U.

Examples 49 and 50: Obtaining

M-(2-bromophenyl-chloro-3-(M"-(2-(dimethylamino)ethylaminosulfonyl)|-2-hydroxyphenyl|urea hydrochloride and

IM-(4-chloro-3-(M"-(2--(dimethylamino)ethylaminosulfonyl|-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea hydrochloride -(2-(dimethylamino)ethyl) -2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (400 mg, 1.3 v8 mmol), M,M-dimethylethylenediamine (121 mg, 1.3 v8 mmol) and triethylamine (0.3 Oml, 2, 7bmmol) are subjected to a reaction to obtain a crude product (480 mg), which is then subjected to hydrolysis without purification. LC-MS (pt/7) 341.88 (M-). with

I-(2--(dimethylamino)ethyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide Ge)

According to the general hydrolysis method described in Example 15,

M-(2-(dimethylamino)ethyl|-2,6-dichloro-1-(3-nitrobenzene)sulfonamide (48O0mg), 60956 Ma (168mg, 4.2mmol) and water (25µl, 1.4mmol) were reacted. The crude product (8Omg) is used in the next stage without purification.

EI-Me (t/z) 321.98, 323.96 (M). at

I-(2--(Dimethylamino)ethyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide Ge»)

According to the general method of hydrogenation described in example 15, crude -(2-(dimethylamino)ethyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (8Omg) is reduced with hydrogen in the presence of C 1096 Ra/C (40mg) with by obtaining a crude product (7Omg), which is used without purification to obtain urea.

M-(2-bromophenyl)-M'-I(4-chloro-3-(M"-(2--dimethylamino)ethylamino-sulfonyl-2-hydroxyphenyl|urea - hydrochloride)

According to the general method of obtaining urea, described in example 15, -(2--(dimethylamino)ethyl|-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (335 mg) and 2-bromophenyl isocyanate (28 μl, "

O.14 mmol) are subjected to a coupling reaction to obtain the desired urea (12 mg, 20 90 for 4 stages). EI-MS (t/l) Z7Z 70 490.7, 492.7, 494.7 (M)-. c IM-(4-chloro-3-(M"-(2--(dimethylamino)ethylaminosulfonyl|-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea" with hydrochloride

According to the general method for the preparation of urea described in example 15, -(2--(dimethylamino)ethyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (35mg) and 2,3-dichlorophenylisocyanate (2bml, 0O.14mmol) undergo a coupling reaction to obtain the desired urea (5.8 mg, 10 95, for four stages).

V. EI-MS (t/z) 428.80, 484.78 (M). (95) Examples 53, 54 and 55: Preparation of i» IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl) )urea hydrochloride, M-I(4-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea (Ce) 20 hydrochloride and M- (2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-|(M"-I(2-(4-morpholinyl)ethylaminosulfonyl|phenyl|urea o I-(2-(morpholinyl)ethyl) -2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (bOOmg, 2.07mmol), 4-(2-aminoethyl)morpholine (269mg, 2.07mmol) and triethylamine (0.58ml , 4.133mmol) are reacted to obtain the crude product (5933mg, 7595). LC-MS (t/2) 384.0 (M). (F) M-(2-(morpholinyl)ethyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

GI According to the general hydrolysis method described in Example 15,

M-(2-(morpholinyl)ethyl-2,6-dichloro-1-(--3-nitrobenzene-sulfonamide (400 mg, 1.04 mmol), bObO Ma / (125 mg, in 3.12 mmol) and water (233 μl, 1.25 mmol) react with the crude product (b0Omg), which is used in the hydrogenation stage without purification.EI-MS (t/7) 363.95, 365.94 (M-).

M-(2-(morpholinyl)ethyl/|-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general method of hydrogenation described in example 15, crude

I-(2-(morpholinyl)ethyl/|-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (30Omg) is reduced with hydrogen in the presence of v5 1096 Ra/C (8Omg) to obtain the crude product (30Omg), which is used without purification for obtaining urea.EI-MS (t/2) 338.93, 340.98 (M).

IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethylaminosulfonyl|phenyl|-M'(2,3-dichlorophenyl)urea hydrochloride

According to the general method for the preparation of urea described in Example 15, crude -(2-(morpholinyl)ethyl/)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (15mg) and 2,3-dichlorophenyl isocyanate (49μl, 0, 2bmmol) are subjected to a coupling reaction to obtain the desired urea (2Zmg, 1595, for 3 stages). EI-MS (t/z2) 522.72, 524.65, 526.70 (M).

IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinylethylIaminosulfonyl|-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea hydrochloride 70) According to the general method of obtaining urea, described in the example 15, crude -(2-(morpholinyl)ethyl)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (183mg) and 2-chlorophenylisocyanate (4Omg, 0.2bmmol) are subjected to a coupling reaction to obtain the desired urea (5Omg, 39 95, for 3 stages.) LC-MS (t/2) 489.2 (M).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-(4-("morpholinyl)-ethylaminosulfonyl|phenyl|urea

According to the general method for the preparation of urea, described in example 15, -(2-(morpholinyl)ethyl)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (15mg) and 2-bromophenyl isocyanate (51mg, 0.2bmmol) are reacted combination with obtaining the required urea (1Omg, 790, for C stages). EI-MS (t/z2) 535.64, 537.56, 539.61 (M).

Examples 56 and 57: Preparation of 20. M-I-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)-phenyl|)urea 2,6-dichloro-3-nitro-1-(4-thiomorpholinylsulfonyl) benzene

According to the general method of preparation of sulfonamide described in example 15, 2,6-dichloro-Z-nitrobenzenesulfonyl chloride (2.0 g, 6.8 mmol), thiomorpholine (71 Ω, 6.88 mmol) and triethylamine SM (1.92 ml, 13.7 mmol ) are subjected to the reaction to obtain the desired product (2.3Omg, 94965). "H-NMR (MeO0-yu): 5 He) 7.95 (d, 1H), 7.85 (d, 1H), 3.68 (t, 4H), 2.69 (t, 4H). b -chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinylsulfonyl)benzene

According to the general hydrolysis method described in Example 15, 2,6-dichloro-3-nitro-1-(4-thiomorpholinylsulfonyl)benzene (1.04 g, 2.9 mmol), 6095 Ma (349 mg, 8.7 mmol) and water o (bZmcl, 3.5 mol) are reacted with the desired product (3ZOmg, 3396). EI-MS (t/2) 336.89, 338.93 du (M-). 4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)aniline in

According to the general method of hydrogenation described in example 15, so b-chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinylsulfonyl)benzene (333Omg, 0.97 mmol) is reduced with hydrogen and 1090 33 rus (1500 mg) to give crude product (240mg, 8095). "H-NMR (MeO0-au): δ 7.08 (d, 1H), 6.98 (d, - 1H), 3.59 (t, 4H), 2.68 (t, 4H).

IM-(d-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea, described in example 15, "di 4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)aniline (120 mg, 0.5 mmol) and 2,3-dichlorophenyl isocyanate (bv8μl, - s O, Zbmmol) undergo a coupling reaction to obtain the required urea (5Omg, 2895). "H-NMR (MeO0-ad): δ 8.31 (m, 1H), 8.05 (m, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 3.61 (m, 4H), 2.69 (m, 4H). ; t M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl)urea

According to the general method for the preparation of urea described in example 15,

3-Chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl) aniline (120mg, 0.2bmmol) and 2-bromophenylisodianate (72mg, -10.5mmol) are subjected to a coupling reaction to obtain the desired urea (11Omg, 60,965). "H-NMR (DMSO-dv): δ 9.25 (s, 1H), 8.98 (s, 1H), 8.34 (d, 1H), 7.92 (d, 71H), 7.65 (d, 1H), 7.35 (t, 1H), 7.19 (d, 1H), 7.01 (t, o 1H), 3.54 (t, 4H), 2.67 (t, 4H ). t» Example 45: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea potassium salt. SO 50 According to the general method described in example 15, obtain

Mm-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea potassium salt. "H-NMR (DMSO-aiv): 5 m) 9.27 (s, 2H), 8.01 (m, ЗН), 7.81 (d, 1H), 7.26 (m, 2H), 6 ,15 (m, 1H).

Example 46: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea sodium salt.

According to the general method described in example 15, 59 M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M"-(2,3-dichlorophenyl)urea sodium salt is obtained. "H-NMR (DMSO-aiv ): 5

F! 9.27 (c, 2H), 8.01 (m, ЗН), 7.77 (d, 1H), 7.26 (m, 2H), 6.05 (d, 1H).

Examples 62, 67, 63 and 66: Preparation of M-(2-bromophenyl)-M'-(3-IM"-K1-tert-butoxycarbonylpiperidin-4-yl)umethylaminosulfonyl|/|-4-chloro-2-hydroxyphenyl

Isechins, because M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy)-3-IM"-Kpiperidin-4-yl)umethylIaminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl) urea hydrochloride,

M'-(3-(M"-K1-tert-butoxycarbonylpiperidin-4-yl)umethylaminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-(M"-Kpiperidin-4-yl)umethyl|iaminosulfonyl|phenyl|-M'(2,3-dichlorophenyl)urea or trifluoroacetate

IM-((1-tert-butoxycarbonylpiperidin-4-yl)methyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method of obtaining the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.2 g, 4.1 mmol), M-(tert-butoxycarbonyl)-4-aminomethylpiperidine (0.88 g, 4.13 mmol) ) and triethylamine (0.8 bml, 6.20 mmol) were reacted to give the desired product (1.52 g, 79965). LC-MS (t/z2) 468.2 (M).

I-I 1-tert-butoxycarbonylpiperidin-4-yl)methyl I-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-((1-tert-butoxycarbonylpiperidin-4-yl)methyl/|-2,6-dichloro-3-nitrobenzenesulfonamide (800mg, 1.89mmol), 6090 70. Ma (227mg, 5.67mmol) and water (41μl , 2.27 mmol) were reacted to give the desired product (495 mg, 58905). EI-MS (t/2) 447.92, 449.84 (M).

IM-((1-tert-butoxycarbonylpiperidin-4-yl)methyl I|-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

I-I 1-tert-butoxycarbonylpiperidin-4-yl)methyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (480mg, 75.1.07mmol) is reduced with hydrogen and Ra/sC (240mg). The crude product (460 mg) is used in the next stage without purification. "H-NMR (MeOO-a/): 5 6.86 (m, 2H), 4.00 (d, 2H), 2.83 (m, ЗН), 2.78 (m, 2H), 1, 60 (m, ZN), 1.44 (s, 9H), 1.00 (m, 2H).

M-(2-bromophenyl)-M'-I3-IM"-K1-tert-butoxycarbonylpiperidin-4-yl)methyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|urea

According to the general method of obtaining urea, described in example 15, crude

IM-((1-tert-butoxycarbonyl-piperidin-4-yl)methyl/|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (23mg) and 2-bromophenylisocyanate (129mg, 0.55mmol) are subjected to a coupling reaction to obtain of the required urea (110Omg, 3095 for two stages).LC-MS (t/z2) 619.0 (M).

M-(2-bromophenyl)-M'-I(4-chloro-3-(M"-Kpiperidin-4-yl)umethylaminosulfonyl|phenyl|urea hydrochloride with

Ho solution)

M-(2-bromophenyl)-M'-(3-IM"-K1-tert-butoxycarbonyl-piperidin-4-yl)umethylaminosulfonyl|-4-chloro-2-hydroxypheniol (27mg, 0.044mmol) in 1.0ml 4.One NCI in 1,4-dioxane was stirred for 10 minutes at room temperature. The mixture was concentrated. After recrystallization from acetone and hexane, the desired product was obtained (1bmg, 6595). LC-MS (t/z) 519.2 (M7) o

IM-IZ-IM"-((1-tert-butoxycarbonylpiperidin-4-ylmethylaminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'-(2,3-diHe)lorphenyl)urea

According to the general method of obtaining urea, described in example 15, crude Z

IM-((1-tert-butoxycarbonyl-piperidin-4-yl)methyl/|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (23mg) and 2,3-dichlorophenylisocyanate (122μl, 0.5mmol ) are subjected to a coupling reaction to obtain the desired urea (100 mg, 2995 for two stages). "H-NMR (MeOO-ad): δ 8.29 (d, 1H), 8.05 (m, 1), 7.25 ( m, 2H), 7.06 (d, 1H), and 4.35 (d, 2H), 2.83 (m, 2H), 2.49 (m, 2H), 1.69 (m, ЗН) , 1.43 (s, 9H), 1.00 (m, 2H).

IM-(d-chloro-2-hydroxy-3-(M"-Kpiperidin-4-yl)umethyl|amino-sulfonyl|phenyl/|-M'-(2,3-dichlorophenyl)urea trifluoroacetate « 20 According to the general methods of removing the Bos protecting group, described in example Zb, with M-(3-(M"-M-K1-tert-butoxycarbonylpiperidin-4-yl)umethyl|aminosulfonyl)|-4-chloro-2-hydroxyphenyl/ |-M'-(2,3-dichloroorphenyl)urea (20 mg, 0.03 mmol) was stirred in trifluoroacetic acid to give the desired product ;" (Omg, 44965). LC-MS (ti/) 509.0 (M) .

Examples 64, 140, 65 and 141: Obtaining

M-Id-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl/|-M'-(2,3-dichlorophenyl)urea, -and IM-(d-chloro-2-hydroxy-3-(1 -oxidothiomorpholinosulfonyl)phenyl|)|-M'-(2,3-dichlorophenyl)urea sodium salt,

M-(2-bromophenyl)-I(4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl|urea |i o IM-(d-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl) |-M'-(2-chlorophenyl)urea from b-chloro-2-hydroxy-3-nitro-1-(1-oxidothiomorpholinosulfonyl)benzene

A solution of b-chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinosulfonylbenzene) (100 mg, 0.3 mmol) and sodium periodate (95 mg, 0.44 mmol) in acetonitrile (1 mL) and water (2 mL) is stirred within 3 days at room temperature. o The mixture is diluted with ethyl acetate and washed with water, dried (Mo95O), and concentrated to obtain the desired product (106.4 mg, 10095). EI-MS (t/:) 352.89, 354.87 (M-). 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline

According to the general hydrogenation method described in example 15, b-chloro-2-hydroxy-3-nitro-1-(1-oxidothiomorpholinosulfonyl)benzene (10 mg, 0.29 mmol) is reduced with hydrogen and i) 1095 Pa/C (5 mg) with obtaining the desired product (89mg, 9595). LC-MS (t/z2) 325.0 (M). ko IM-(d4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea, described in Example 15, 60 /4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.5 mmol) and 2,3-dichloro-phenyl isocyanate (72 mg, 0, 38 mmol) are subjected to a coupling reaction to obtain the desired urea (79 mg, 4495). "H-NMR (DMSO-a,): δ 9.34 (s, 1H), 9.27 (s, 1H), 8.28 (d, 1H), 8.05 (m, 1H), 7, 32 (m, 2H), 7.21 (d, 1H), 3.75 (m, 2H), 3.65 (m, 2H), 2.89 (m, 4H).

IM-(4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl)-M'-(2,3-dichlorophenyl)urea sodium salt According to the general method for preparing the salt described in example 15,

IM-(d-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl-M'-(2,3-dichlorophenyl)urea (275 mg, 0.53 mmol)

and O.5On water. Mahon (1.0bmg, 0.5Zmmol) is reacted to obtain the desired sodium salt (25O0mg, 8795). "H-NMR (DMSO-iv): δ 9.30 (s, 2H), 8.00 (d, 1H), 7.67 (d, 1H), 7.25 (m, 2H), 5.89 (d, 1H), 3.68 (m,

AN), 2.90 (t, 2H), 2.75 (t, ZN).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl|urea

According to the general method for the preparation of urea, described (in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (88mg, 0.27mmol) and 2-bromophenylisocyanate (b5mg, 00.33mmol) are subjected to a coupling reaction with obtaining the required urea (b5 mg, 46 95). LC-MS (t/z2) 524.2 (M.

IM-(d-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)-(M'-(2-chlorophenyl)urea

According to the general method for the preparation of urea described in Example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.5 mmol) and 2-chlorophenyl isocyanate (58 mg, 0.28 mmol) are subjected to a coupling reaction with obtaining the required urea (58 mg, 35 95). LC-MS (t/zg) 478.0 (M).

Examples 68, 69 and 790: Obtaining

IM-IZ-«1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-M'(2-bromophenyl)urea, 79. M-IZ-(1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-M '-(2-chlorophenyl)urea and

IM-IZ-"1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl-1-M'-(2,3-dichlorophenyl)urea 1-(azetidin-1-yl)usulfonyl-2,6-dichloro-3-nitrobenzene

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmol), azetidine hydrochloride (320 µg, 3.44 mmol) and triethylamine (1.44 ml, 10.32 mmol ) react with the desired product (510 mg, 4895). , 2.29 (m, 2H). 1-(azetidin-1-yl)usulfonyl-b-chloro-2-hydroxy-3-nitrobenzene

According to the general hydrolysis method described in Example 15, 1-(azetidin-1-yl)usulfonyl-2,6-dichloro-3-nitrobenzene (510 mg, 1.64 mmol), 6096 Ma (197 mg, 4.92 mmol) and water c (ZBmkl, 1.97mmol) is reacted to obtain the desired product (240Omg, 5096). heh)

TNA-NMR (MeOr-a)): δ 8.09 (d, 193), 7.25 (dn), 415 (t, 48), 229 (m, 2H).

C-(azetidin-1-yl)usulfonyl-4-chloro-2-hydroxyaniline

According to the general hydrogenation method described in Example 15, 1-(azetidin-1-yl)usulfonyl-b-chloro-2-hydroxy-3-nitrobenzene (2400 mg, 0.82 mmol) is reduced with hydrogen and Ras o

Zo (100mg) with obtaining the desired product (210mg, 10095). "H-NMR (MeO0-a/): 5 6.91 (m, 2H), 4.01 (t, 48), .F 2.23 (m, 2H). "t

IM-IZ-"1-(azetidinesulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2-bromophenyl)urea

According to the general method for the preparation of urea described in example 15, 33-(azetidin-1-yl)usulfonyl-4-chloro-2-hydroxyaniline (215 mg, 0.82 mmol) and 2-bromophenyl isocyanate (195 μl, 0.98 mmol) were combined undergo a coupling reaction to obtain the desired urea (bOmg, 18 90). LC-MS (t/z) 462.0 (M).

IM-IZ-"1-(azetidinesulfonyl)-4-chloro-2-hydroxyphenyl|-M'"(2-chlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

3-(Azetidin-1-yl)usulfonyl-4-chloro-2-hydroxyaniline (215 mg, 0.82 mmol) and 2-chlorophenyl isocyanate /(134 mg, « b,Ummol) are subjected to a coupling reaction to obtain the desired urea (200 mg, 54 95 ). LC-MS (t/z) 416.0 (M tu, shsh s IM-IS-(1-(azetidinesulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea and Accordingly to the general method for the preparation of urea described in example 15, "" 3-(azetidin-1-yl)usulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.0 mmol) and 2,3-dichlorophenyl isocyanate (16 U9 μl,

O.9mmol) are subjected to a coupling reaction to obtain the required urea (1bOmg, 4095). LC-MS (t/2) 450.0 (M 7).

Example 71: M-(2-bromophenyl)-M'-I(4-chloro-3-(M",M"-dimethylaminosulfonyl|-2-hydroxyphenyl|urea potassium-I salt) According to the general method described in the example 15, receive

M-(2-Bromophenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl|-2-hydroxyphenyl|urea potassium salt; "H-NMR t. (DMSO-α): 5 9 .20 (s, 1H), 8.99 (s, 1H), 7.82 (d, 1), 7.66 (d, 1H), 7.57 (d, 1H), 7.29 (t, 1H), 6.95 (t, s 50 1H), 5.93 (d, 1H), 2.83 (s, 6H).

Example 72: M-(2-Bromophenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl|-2-hydroxyphenyl|urea (ze) sodium salt).

According to the general method described in example 15, it is obtained

IM-(2-Brocphenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl|-2-hydroxyphenyl|-urea sodium salt

M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea sodium salt. Elemental analysis: o calculated (1.252 square meters of water): C, 36.5395; H, 3.3795; M, 8,520; Ma 4.6695; found: C, 36.3290; H, 3.3495; M, 8.3895,

Ma 4.69905. ko Examples 73, 74 and 75: Obtaining

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|urea, 60 0 M-Id4-chloro-3-(M"-cyclopropylaminosulfonyl)-2- hydroxyphenyl|-M'-(2-chlorophenyl)urea and

M-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

M-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.39g, 4.78mmol), cyclopropylamine (27µg, 4.78mmol) and triethylamine bo (1.0ml, 7.17mmol ) are subjected to a reaction to obtain the desired product (1.15 g, 77965). "H-NMR (MeO0b-au): 5 7.72

(m, 2H), 7.65 (d, 1H), 2.34 (m, 1H), 0.75 (m, 4H).

M-cyclopropyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.15 g, 3.7 mmol), 6095 Ma (444 mg, 11.1 mmol) and water (b7 µl, 3.70 mmol) were reacted to give the desired product (74 mg, 6896). "H-NMR (MeO0-ad): δ 8.06 (d, 1H), 7.24 (d, 1H), 2.29 (m, 1H), 0.60 (m, 4H).

M-cyclopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15, 70.M-cyclopropyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (740mg, 2.53mmol) is reduced with hydrogen and 1095 Pa/C (VOmg) to give the desired product ( 6bOmg, 99965). "H-NMR (MeO-a,): δ 6.83 (m, 2H), 2.20 (m, 1H), 0.56 (m, 4H).

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl)urea

According to the general method for the preparation of urea described in example 15,

M-cyclopropyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-bromophenyl isocyanate (199 mg, 1.01 mmol) are subjected to a coupling reaction to obtain the desired urea (135 mg, 35 90). LC-MS (t/) 462.0 (M7.

IM-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

M-cyclopropyl-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-chlorophenyl isocyanate (155 mg, 1.01 mmol) are subjected to a coupling reaction to obtain the desired urea (15 mg, 43 95). LC-MS (t/g) 416.2 (M7.

M-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea, described in example 15, with 29 M-cyclopropyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (22Omg, 0.4mmol) and 2,3-bromophenylisocyanate (190mg, (U1.01mmol) ) are subjected to a coupling reaction to obtain the desired urea (17bmg, 4695). LC-MS (t/z) 452.0 (M).

Examples 76, 7 and 78: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|urea, o zo IM-(4-chloro-2-hydroxy-3-(M "-propylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|-ME(2-chlorophenyl)urea (o)

M-propyl-2,6-dichloro-3-nitrobenzenesulfonamide "

According to the general method of preparation of sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.3g, 4.48mmol), propylamine (2b4mg, 4.48mmol) and triethylamine c (0.94ml, 6.72mmol ) are subjected to the reaction to obtain the desired product (1.0 g, 7195) "H-NMR (MeOHO-ad): 5 7.92 im (d, 1H), 7.78 (d, 1H), 3.00 (T, 2H), 1.50 (m, 2H), 0.88 (t, ЗН).

M-propyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-propyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.0g, 3.19mmol), 6095 Ma (39Zmg, 3.19mmol) and water (58μl, «

C/19mmol) are subjected to a reaction to obtain the desired product (650mg, 6995). LC-MS (ti/zg) 295.0 (M). - with M-propyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide and According to the general method of hydrogenation described in example 15, "» M-propyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (65Omg, 2 ,2mmol) is reduced with hydrogen and 1095 Pa/C (32Omg) to obtain the desired product (56b0mg, 9696). "H-NMR (MeO0-a/): 5 6.83 (m, 1H), 2.86 (t, 2H), 1.50 (m, 2H), 0.87 (t, ЗН). -i M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|urea syu According to the general method of obtaining urea, described in example 15,

M-propyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (18 mg, 0.7 mmol) and 2-bromophenyl isocyanate (14 mg, 0.71 mmol) are subjected to a coupling reaction to obtain the desired urea (149 mg, 46 95). LC-MS (t/) 464.0 s 50 (MU.

IM-(d-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea (ze) According to the general method for the preparation of urea described in example 15,

M-propyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2,3-dichlorophenyl isocyanate (13 mg, 0.71 mmol) are subjected to a coupling reaction to obtain the desired urea (259 mg, 81 95) . LC-MS (t/) 452.0 (MU.

F! IM-(d-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl|-ME(2-chlorophenyl)urea

According to the general method of obtaining urea, described in example 15, o M-propyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (180 mg, 0.7 mmol) and 2-chlorophenyl isocyanate (108 mg, 0.71 mmol) are subjected to a coupling reaction with obtaining the required urea (148mg, 5095). LC-MS (u/z) 418.2 (M 7). 60 Examples 79, 80 and 81: Obtaining

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-ethylaminosulfonyl)|-2-hydroxyphenyl|urea,

IM-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M-(2-chlorophenyl)-urea and

M-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

M-ethyl-2,6-dichloro-3-nitrobenzenesulfonamide bo According to the general method of obtaining sulfonamide described in example 15,

2,6-dichloro-3-nitrobenzenesulfonyl chloride (800mg, 2.75mmol), ethylamine (4.13ml, 8.2bmmol) and triethylamine (1.15ml, 8.3bmmol) were reacted to give the desired product (b10mg, 7495). "H-NMR (MeO0-ad): δ 7.92 (d, 1H), 7.78 (d, 1H), 3.08 (q., 2H), 1.11 (t, ЗН).

M-ethyl-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-ethyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.16g, 3.88mmol), 6095 Ma (46bmg, 11.64mmol) and water (7µl, 3.88mmol) are reacted. The crude product (1.34 g) is used in the next stage without purification. "H-NMR (MeO0O-a4): δ 8.07 (d, 1H), 7.25 (d, 1H), 3.05 (q., 2H), 1.12 (t, ЗН).

M-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-ethyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.34g) was reduced with hydrogen and 1095 Ra/C (400mg) to give the desired product (800mg, 8295, for two stages). TN-NMR (meOoO-a/): δ 6.85 (d, 1H), 6.78 (d, 1H), 2.85 (q., 2H), 0.95 (t, ЗН). 12 M-(2-bromophenyl). M'-(4-chloro-3-M"-ethylaminosulfonyl)-2-hydroxyphenyl)urea

According to the general method for the preparation of urea described in example 15,

M-ethyl-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (26bmg, 1.0bmmol) and 2-bromophenylisocyanate (211mg, 1.0bmmol) are subjected to a coupling reaction to obtain the desired urea (211mg, 44 95). LC-MS (t/) 450.0 (M7.

IM-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea

According to the general method for the preparation of urea described in example 15,

M-ethyl-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (26 mg, 1.0 mmol) and 2-chlorophenyl isocyanate (16 mg, 1.0 mmol) were subjected to a coupling reaction to obtain the desired urea (142 mg, 33 95). LC-MS (t/2) 04.0 (M 7.

M-(4-chloro-3-M"-ethylaminosulfonyl)-2-hydroxyphenyl)|. ME(2,3-dichlorophenyl)urea

According to the general method of obtaining urea, described in example 15, o

M-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (26bmg, 1.0bmmol) and 2,3-dichlorophenylisocyanate (20Omg, 1.0bmmol) are subjected to a coupling reaction to obtain the desired urea (19Zmg, 4195). LC-MS (t/z2) 440.0 (M).

Examples 82 and 136: Preparation of ozo M-(2-bromophenyl)-M'-I3-IM"-I5-(tert-butoxycarbonylamino)-5-carboxypentyl|aminosulfonyl|-4-chloro-2-hydroxyphenyl|Urea and Me)

IM-III-IM"-(2-amino-5-carboxypentyl)-aminosulfonyl|-4-chloro-2-hydroxyphenyl/)|-ME(2-bromophenyl)-urea"E of trifluoroacetate

I-(b-(tert-butoxycarbonylamino)-5-methoxycarboxypentyl)-2,6-dichloro-3-nitrobenzenesulfonamide and

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), Bos-Iuz-OMe-acetate (2.206 g, 6.88 mmol) and triethylamine (2.4 μl, 17.2 mmol) were reacted to give the desired product (1.25 g, 3595). "H-NMR (meO0O-a,) 5: 7.93 (d, 1H), 7.78 (d, 1H), 4.02 (m, 1H), 3.70 (s, ЗН), 3, 04 (t, 2H), 1.69 (m, 2H), 1.50 (m, 4H), 1.43 (s, 9H).

I-Ib-(tert-butoxycarbonylamino)-5-carboxypentyl|/|-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in example 15, Sh-c I-Ib-(tert-butoxycarbonylamino)-5-methoxycarbonylpentyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.2 g, c 2.333 mmol) , 6095 Mann (37O9mg, 9.32mmol) and water (84µl, 4.6bmmol) are reacted to obtain the desired product (85Omg, 7695). "H-NMR (MeOO-a)) 5: 8.05 (d, 1H), 7.22 (d, 1H), 4.00 (m, 1), 3.01 (t, 2H), 1, 72 (m, 2H), 1.50-165 (m, 4H), 1.44 (s, 9H).

I-(b-(tert-butoxycarbonylamino)5-carboxypentyl|-3-amino-b6-chloro-2-hydroxybenzenesulfonamide -i According to the general hydrogenation method described in example 15, about I-(b-(tert-butoxycarbonylamino) )-5-carboxypentyl β-chloro-2-hydroxy-3-nitrobenzenesulfonamide (204 mg,

O.42mmol) is reduced with hydrogen and 1095 Ra/C (100mg) to give the desired product (189mg, 10095). "H-NMR o (meO0O-a,) 5: 6.84 (m, 1H), 4.08 (m, 1H), 2.92 (t, 2H), 1.75 (m, 2H), 1 .55 (m, 4H), 1.44 (s, 9H).

Te) 20 M-(2-bromophenyl)-M'-I3-IM"-I5-(tert-butoxycarbonylamino)-5-carboxypentylaminosulfonyl|)|-4-chloro-2-hydroxyphenyl|urea m According to the general method of preparation of urea, which is described in example 15,

I-(b-(tert-butoxycarbonylamino)-5-carboxy-pentyl/|-3-amino-6-chloro-3-hydroxybenzenesulfonamide (189 mg, 0.42 mmol) and 2-bromophenyl isocyanate (84 mg, 0.42 mmol) are reacted combination to obtain the required 59 urea (20 mg, 795). LC-MS (t/") 651.2 (M)".

HF) IM-IZ3-M"-(2-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2-bromophenyl)urea and trifluoroacetate

According to the general procedure for removing the Bos protecting group described in Example 36,

M-(2-bromophenyl)-M'-I3-I(M"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl)|aminosulfonyl|-4-chloro-2-hydroxyf 60 enyl|urea (108mg, O0 .17 mmol) is mixed in 1 ml of trifluoroacetic acid, and the desired product is obtained (7Bmg, 66 95). LC-MS (t/z) 551.2 (M).

Examples 83 and 137: Obtaining

and

I-III-IM"-(b-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea trifluoroacetate

I-III-IM"-(5-(tert-butoxycarbonylamino)-5-carboxypentylaminosulfonyl|)|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method of obtaining urea described in example 15,

I-(b-(tert-butoxycarbonylamino)-5-carboxypentyl/|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (23 mg, 0.518 mmol) and 2,3-dichlorophenyl isocyanate (98 mg, 0.518 mmol) are subjected to a coupling reaction with obtaining the required urea (100 mg, 3095). LC-MS (t/z) 641.2 (M).

I-III-IM"-(5-amino-5-carboxypentyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea 70 trifluoroacetate

According to the general procedure for removing the Bos protecting group described in Example 36,

M-(3-I(IM"-(5-(tert-butoxycarbonylamino)-5-carboxypentyl)|aminosulfonyl/|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorphenyl)urea ( 108mg, 0.17mmol) was mixed in one ml of trifluoroacetic acid and the desired product (78mg, 74 90) was obtained.LC-MS (ti/zg) 541.0 (M).

Examples 84 and 85: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-hydroxyethyl)aminosulfonyl|urea and

M-(2-bromophenyl)-M'-I3-I(M"-((2-(bromophenylamino)carboxy|ethylaminosulfonyl|-4-chloro-2-hydroxyphenyl| urea 2-Benzyloxyethylamine

6095 Ma (3.27g, 81.8mmol) is added to a solution of ethanolamine (5g, 81.8mmol) in 100ml of dry THF at room temperature. The mixture is refluxed for 30 minutes, and then benzyl chloride (9.32 g, 75.6 mmol) is added. The resulting mixture is refluxed for 3 hours. The mixture is concentrated and the residue is diluted with other water. NSI and extracted with dichloromethane. The aqueous layer is brought to pH 14 by adding 1095 water. Mahon, and then extracted with dichloromethane. The organic extract was dried over Na95O and concentrated to give the desired product (10.11 g, 8295). "H-NMR (SOCI3): δ 7.34 (m, 5H), 4.54 (s, 23), CSE 3.54 (t, 2H), 2.93 (t, 2H). o

M-(2-benzyloxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of sulfonamides described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-benzyloxyethylamine (1.04 g, 6b, 88 mmol) and triethylamine (1.92 μl , 13.7 mmol) are reacted to obtain the desired product (2.31 g, 8395). "H-NMR o (meOO-a,) 5: 7.69 (d, 1H), 7.53 (d, 1H), 7.25 (m, ЗН), 7.14 (d. 2H), 4 .26 (s, 2H), 3.45 (t, 2H), 3.36 (t, 2H). He»!

M-(2-benzyloxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in example 15, Z

M-(2-benzyloxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (2.31g, 5.71mmol), 6095 Ma (6833mg, 17.mmol) and water (10µl, 5.72mmol) are reacted with obtaining the desired product (1.70g, 7795). LC-MS (t/l) 387.5 m (MU,

M-(2-benzyloxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-(2-benzyloxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (3 bbmg, 0.95 mmol) is reduced with hydrogen and « 20 Pa/s (170 mg). The crude product (265 mg) is used in the next stage without purification. -in

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-hydroxyethyl)-aminosulfonyl|urea and with M-(2-bromophenyl)-M'-I3 -IM"-((2-bromophenylamino)carboxy|ethylaminosulfonyl|-4-chloro-2-hydroxyphenyl|-urea :z" According to the general method of obtaining urea described in example 15, crude

M-(2-Hydroxyethyl)-3-amino-b-chloro-3-hydroxybenzenesulfonamide (265 mg) and 2-bromophenyl cyanate (187 mg, 15 0.95 mmol) are subjected to a coupling reaction to give the desired urea 84 (54 mg, 1295 for two steps) . -I LC-MS (t/z) 466.0 (M); and urea 85 (1Omg, 1.695 for two stages). LC-MS (t/z2) 663.0 (M).

Examples 86 and 149: Preparation and IM-3-(IM"-(2-benzyloxyethyl)aminosulfonyl|)|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichloro-phenyl)urea and their IM -3-(M'-(2-hydroxyethyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea

M-(2-benzyloxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide se) A mixture of M-(2-benzyloxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (157 mg, 0.41 mmol) in THF (15 ml) and about 596 water. MansSoO»z (100 ml) is stirred at room temperature and sodium dithionite (1.5 g) is added in 0.2 g portions. The mixture is acidified with water. NSI and extracted with ethyl acetate. The organic layer was dried over Mo5O and concentrated to give the desired product (120mg, 82905). LC-MS (ti/g) 357.0 (M.

IM-IZ-(IM"-(2-benzyloxyethyl)aminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

According to the general method of obtaining urea described in example 15, iF) M-(2-benzyloxyethyl)-3-amino-b-chloro-3-hydroxybenzenesulfonamide (119mg, 0.33mmol) and co 2,3-dichlorophenylisocyanate (44mg , 0.23 mmol) are subjected to a coupling reaction to obtain the desired urea (94 mg, 7590). LC-MS (t/2) 546.0 (M); 60 IM-IZ-(M"-(2-hydroxyethyl)aminosulfonyl)-4-chloro-2-hydroxy-phenyl|-M'-(2,3-dichlorophenyl)urea

To the solution

IM-III-IM"-(2-benzyloxyethyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl)-M'-(2,3-dichlorophenyl)urea (46bmg,

0.Ommol) in 3ml of dichloromethane add iodotrimethylsilane (38mg, 0.19mmol). The mixture is stirred for 16 hours at room temperature. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane (60/40, pro/pro), the desired product (14 mg, 3790) was obtained. LC-MS (t/g): 455.8 (M7.

Examples 87, 88 and 89: Obtaining

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxyphenyl|urea,

M-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)-urea and

M-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxy|phenyl|-M'-(2-chlorophenyl)urea

M-cyclopropylmethyl-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), aminomethylcyclopropane hydrochloride (0.5 bml, 5.2 mmol) and triethylamine (1.8 ml, 12.9 mmol) are reacted to give the desired product (1.28 mg, 8496). 70... ХХ-МО (t/z2) 325 (M). b-chloro-M-cycloproptmethyl-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-cyclopropylmethyl-2,6-dichloro-3-nitrobenzenesulfonamide (0.85g, 2.b6mmol), 8095 Man (0.23g, 9.vmmol) and water (Bbmcl, 3, Tmmol) are reacted to obtain the desired product ( 0.58g, 7295). LC-MS (t/zg) 307 (M.

3-Amino-6-chloro-M-cyclopropylmethyl-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, b-chloro-M-cyclopropylmethyl-2-hydroxy-3-nitrobenzenesulfonamide (0.1 g, 3.2 mmol) is reduced with hydrogen and 1095

Ra/C (0.1g) to obtain the desired product (0.08g, 8990). LC-MS (t/z2) 277 (M).

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxyphenyl)urea

According to the general method of obtaining urea described in example 15,

3-amino-6-chloro-M-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23g, 0.77mmol) and 2-bromophenylisocyanate (100μl, 0.8mmol) are subjected to a coupling reaction to obtain the desired urea (0.19g, 52 95) . ХХ-МС (t/z) 474 (MU.

M-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea c

According to the general method of obtaining urea, which is described in example 15, d)

3-Amino-6-chloro-M-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23g, 0.77mmol) and 2,3-dichlorophenylisocyanate (100µM, 0.7bmmol) are subjected to a coupling reaction to obtain the desired urea (0.19g, 53 95). LC-MS (t/z2) 464 (M).

IM-(4-chloro-3-(M"-cyclopropylmethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea o

According to the general method of obtaining urea described in example 15, Ge»!

3-Amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23g, 0.77mmol) and 2-chlorophenylisocyanate (95μl, 0.7U9mmol) are subjected to a coupling reaction to obtain the desired urea (0.07g, 21965). LC-MS (t/z) 430 Z (MU. Gze)

Examples 90, 91 and 92: Obtaining

M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-methoxy-M'"-methylaminosulfonyl)phenyl|urea, -

IM-(d-chloro-2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-phenyl-M'-(2,3-dichlorophenyl)urea and

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)phenyl|-urea (M-methoxy-M-methyl)-2,6 -dichloro-3-nitrobenzenesulfonamide "

According to the general method of obtaining sulfonamide described in example 15, from 70 2,6-dichloro-Z-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), M,O-dimethylhydroxylamine hydrochloride (0.52 ml, s 5.3 mmol) and triethylamine (2.00 ml, 14.3 mmol) are reacted to give the desired product (1.04 g, 63905). with LC-MS (t/g) 315 (M). (M-methoxy-M-methyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in example 15, - (M-methoxy-M-methyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 g, 3.2 mmol), 8095 Mam (0.30 g, 9 ,bmmol) and water (5vml, 3.2mmol) are reacted to obtain the desired product (0.66bg, 6995). LC-MS (t/zg) 297 (MU. o (M-methoxy-M-methyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide their According to the general hydrogenation method described in example 15, (M" -methoxy-M"-methyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.66 g, 2.2 mmol) is reduced with hydrogen and 1095 ish Ra/C (0.66 g) to obtain the desired product (0.50 g , 8590). LC-MS (ti/) 266.8 (M). o M-(2-bromophenyl)-M'-I(4-chloro-3-2-hydroxy-((M"-methoxy-M "-methylaminosulfonyl)phenyl)urea

According to the general method for the preparation of urea described in example 15, (M'-methoxy-M'-methyl)-3-amino-6-chloro-M-2-hydroxybenzenesulfonamide (0.15 g, 0.5 mmol) and 2- bromophenyl isocyanate (bOmcl, 0.5 mmol) is subjected to a coupling reaction to obtain the desired urea (0.12 g, 4595). LC-MS (ti/z) 464 (M). o IM-(d-chloro-2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)phenyl|-M'(2,3-dichlorophenyl)urea ime) According to the general method of obtaining urea described in Example 15, (M"-methoxy-M"-methyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.5 mmol) and 60 2,3-dichlorophenyl isocyanate (74 μl, 0.5 mmol) are subjected to coupling reactions with obtaining the desired urea (0.086 g, 34 95). LC-MS (ti/) 454 (M).

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)phenyl|urea

According to the general method of obtaining urea described in example 15, (M"-methoxy-M"-methyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.5 mmol) and 2-chlorophenyl isocyanate b5 (b8Vmkl, 0.5bmmol) are subjected to a coupling reaction to obtain the desired urea (0.077g, 33905). LC-MS (t/z) 420 (MU).

Examples 93, 94 and 95: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-pyrrolidinylaminosulfonyl)phenyl|urea,

IM-(d-chloro-2-hydroxy-3-(M'"-pyrrolidinylaminosulfonyl)phenyl-M'-(2,3-dichlorophenyl)urea and

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M'"-pyrrolidinylaminosulfonyl)phenyl|-urea (M-pyrrolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method of preparation of sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.51g, 5.2mmol), pyrrolidine (435μl, 5.2mmol) and triethylamine (1.1ml, 7.vmmol) ) are subjected to a reaction to obtain the desired product (1.16 g, 68965). LC-MS (t/2) 325 (M"). 70 (M-pyrrolidinyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, (M-pyrrolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.12 g, 34 mmol), 8095 Ma (0.31 g, 10.3 mmol) and water (74 μl , 4, Immol) are subjected to a reaction to obtain the desired product (0.94g, 6995). LC-MS (t/l) 307 (M. (M-pyrrolidinyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide

According to the general method of hydrogenation described in example 15, (M-pyrrolidinyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.7 g, 2.4 mmol) is reduced with hydrogen and 1095 Ra/s (0.73 g) with obtaining the desired product (0.69 g, crude). MS (t/2) (MAN) 276.9, 278.89, 279.88.

M-(2-bromophenyl)-M'-(4-chloro-3-(M"-pyrrolidinylaminosulfonyl)phenyl)-urea

According to the general method for the preparation of urea described in example 15, (M-pyrrolidinyl)-3-amino-b6-chloro-M-2-hydroxybenzenesulfonamide (0.23 g, 08 mmol) and 2-bromophenyl isocyanate (102 μl, 0.8 mmol) subject to a coupling reaction to obtain the desired urea (0.1 g, 2690). LC-MS (t/z) 476 (M).

IM-(d-chloro-2-hydroxy-3-(M"-pyrrolidinylaminosulfonyl)phenyl|-M'(2,3-dichlorophenyl)urea

According to the general method of obtaining urea, which is described in example 15, Ge! (M-pyrrolidinyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.23 g, 0.8 mmol) and 2,3-dichlorophenyl isocyanate o (110 μl, 0.83 mol) are subjected to a coupling reaction to obtain the desired urea (0 , 10g, 2695). LC-MS (ti/l) 464 (M).

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-pyrrolidinylaminosulfonyl)phenyl|urea

According to the general method of obtaining urea described in example 15, | "c) (M-pyrrolidinyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.23g, 0.8mmol) and 2-chlorophenylisocyanate (1O0Omkl, Fo

0.8Zmmol) are subjected to a coupling reaction to obtain the required urea (0.1g, 2895). LC-MS (t/z) 420 (M).

Examples 96 and 97: Obtaining "

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl)phenyl|urea and

IM-(d-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl)phenyl-M'-(2,3-dichlorophenyl)urea

Zo M-(4-pyridinyl)-2,6-dichloro-3-nitrobenzenesulfonamide and

According to the general procedure for the preparation of sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (50 mg, 1.72 mmol), 4-aminopyridine (165 mg, 1.75 mmol) and triethylamine (0.0 mL, 2.58 mmol ) react to obtain the desired product (446bmg, 7695). LC-MS (t/2) 346 (M). "

M-(4-pyridinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide -

According to the general hydrolysis method described in Example 15, with M-(4-pyridinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (540 mg, 1.55 mmol), 8095 Man (217 mg, 7.25 mmol) and water: with" (0.045ml, 2.4bmmol) are reacted with the desired product (17Omg, 3390). LC-MS (t/lz) 328 (M).

M-(4-pyridinyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, - 15 M-(4-pyridinyl)-6-chloro-2-hydroxy-3-nitrobenzene-sulfonamide (22.0 mg, 0.0 b6bmmol) is reduced with hydrogen and Ra/s (10,Zmg) to obtain the desired product (18,Omg, 9090). EI-MS (t/2) 298 (М-Н)-. (95) M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl)phenyl|urea 1» According to the general method of obtaining urea described in example 15,

M-(4-pyridinyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (52.bmg, 0.17mmol) and 2-bromophenylisocyanate (se) 50 (0.0216bmcl, 0.17mmol) are subjected to a coupling reaction to give of the required urea (66.5 mg, 76905). EI-MS (t/z2) at 496 (М-Н)-.

IM-(d-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl|phenyl|-ME2,3-dichlorophenyl) urea

According to the general method of obtaining urea described in example 15,

M-(4-pyridinyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (52.bmg, 0.017 mmol) and 2,3-dichlorophenyl isocyanate (0.02 mL, 0.17 mmol) are subjected to a coupling reaction to obtain the desired urea (62 ,8mg, 7390). EI-MS (t/z)

GF) 485 (М-Н)-. 7 Examples 98 and 99: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-(tetrahydro-2-furanyl)methyliaminosulfonyl|phenyl|urea |i

IM-(d-chloro-2-hydroxy-3-((2-(tetrahydro-2-furanyl)methyl|aminosulfonyl|-phenyl|-M'-(2,3-dichlorophenyl)urea 60 M-(2-tetrahydrofurfuryl) )-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (997 mg, 3.4 mmol), 2-tetrahydrofurfurylamine (0.37 ml, 3.58 mmol) and triethylamine (0.72 ml, 5 ,1bmmol) are reacted to obtain the desired product (1.04g, 8690). EI-MS (ti/l) 353 (M-H)-. bo M-(2-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-(2-tetrahydrofurfuryl)-2,6-dichloro-3-nitrobenzenesulfonamide (bbOmg, 1.8bmmol), 8095 Man (169mg, 5.6Zmmol) and water (0.035ml, 1.95mmol) are reacted to give the desired product (Z8Omg, 6195). EI-MS 50 (t/2) 335 (М-Н)-.

M-(2-tetrahydrofurfuryl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-(2-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (340mg, 1.01mmol) was reduced with hydrogen and Ra/C (158mg) to give the desired product (304mg, 9895). EI-MS (t/2) 305 (М-Н)-. 70 M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-(tetrahydro-2-uranyl)umethyl|Iaminosulfonyl|Iphenyl)urea

According to the general method of obtaining urea described in example 15,

M-(2-tetrahydrofurfuryl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (152 mg, 0.49 mmol) and 2-bromophenyl isocyanate (0.061 μl, 0.49 mmol) are subjected to a coupling reaction to obtain the desired urea (98 mg, 40905) . EI-MS (t/l) 504 (М-Н)-.

IM-(d-chloro-2-hydroxy-3-|((2-(tetrahydro-2-furanyl)methyl|-aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method of obtaining urea described in example 15,

M-(2-tetrahydrofurfuryl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (152 mg, 0.49 mmol) and 2,3-dichlorophenyl isocyanate (0.065 mL, 0.49 mmol) are subjected to a coupling reaction to obtain the desired urea (184 mg, 76905). EI-MS (t/z7) 492 (М-Н).-.

Examples 100 and 101: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((2K)-tetrahydro-2-furanyl)methylIaminosulfonyl|-phenylurea and

IM-(d-chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methyl|Iaminosulfonyl|phenyl|-M'(2,3-dichlorophenyl)-urea

M-(2K)-tetrahydrofurfuryl)-2,6-dichloro-3-nitrobenzenesulfonamide in accordance with the general method for obtaining sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (993 mg, 1 mmol), (2K )-tetrahydrofurfurylamine (0.3bml, 3.49mmol) and triethylamine (0.72ml, 5.17mmol) were reacted to give the desired product (1.17g, 9790). EI-MS (t/2) 353 (М-Н)-. and)

M-(2K)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-(2kK)-tetrahydrofurfuryl)-2,6-dichloro-Z-nitrobenzenesulfonamide (1.17g, 3Z3.2Omol), 8095 Man (zO0Zmg, o

0.mmol) and water (0.06ml, 3.49mmol) are reacted to give the desired product (690mg, 6390). EI-MS (t/2) 335 (М-Н)-. Me

M-(2K)-tetrahydrofurfuryl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide "g

According to the general hydrogenation method described in Example 15,

M-(2K)-Tetrahydrofurfuryl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (bbOmg, 1.9bmmol) was reduced with OHNeM and Pa/3 (ZOoOZmg) to give the desired product (563Zmg, 9490). EI-MS (t/) 305 (М-Н)-. M

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)-methylaminosulfonyl)phenyl|-M'-(2,3 - dichlorophenyl)urea

According to the general method of obtaining urea described in example 15,

M-(2K)-tetrahydrofurfuryl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (26mg, 0.85mmol) and "2-bromophenylisocyanate (0.11μl, 0.85mmol) are subjected to a coupling reaction to obtain the desired urea with (127 mg, ZO9v) . EI-MS (t/z2) 504 (М-Н).-. . IM-(d-chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methyl|-aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea wine

According to the general method of obtaining urea described in example 15,

M-(2K)-tetrahydrofurfuryl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (26mg, 0.85mmol) and -I 2,3-dichlorophenylisocyanate (0.11ml, 0.85mmol) are subjected to a coupling reaction to obtain the desired urea (Zobmg, 7590). BI-MS (t/2) 492 (М-Н)-. and Examples 102 and 103: Preparation of their M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methylIaminosulfonyl|-phenylurea and bo 0 M-I4-chloro-2-hydroxy-3-|((25)tetrahydro-2-furanyl)methyl)aminosulfonylIphenyl/|-M'-(2,3-dichlorophenyl)urea and M-(25)-tetrahydrofurfuryl) -2,6-dichloro-3-nitrobenzenesulfonamide o According to the general method of obtaining sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.00 mg, 3.44 mmol), (25)-tetrahydrofurfurylamine /( 0.3 ml, 3.20 mmol) and triethylamine (0.72 ml, 5.17 mmol) were reacted to give the desired product (1.12 g, 9990).

M-(25)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (F) According to the general hydrolysis method described in example 15, M-(25)-tetrahydrofurfuryl)-2,6-dichloro -Z-nitrobenzenesulfonamide (1.12g, 3, Bmmol), 8095 Ma (284mg, 9.47mmol) and water (0.057ml, 3.1bmmol) were reacted to give the desired product (280mg, 2695). EI-MS bo (t/2) 335 (М-Н)-.

M-(25)-tetrahydrofurfuryl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15,

M-(25)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (27mg, 0.800mmol) was reduced with hydrogen and Ra/C (14mg) to give the desired product (226bmg, 9495). EI-MS (t/2) 305 (М-Н)-. 65 M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methylIaminosulfonyl)phenyl|urea

According to the general method of obtaining urea described in example 15,

M-(25)-tetrahydrofurfuryl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (113 mg, 0.37 mmol) and 2-bromophenyl isocyanate (0.045 μl, 0.37 mmol) are subjected to a coupling reaction to obtain the desired urea (14 mg, 7790 ). BI-MS (t/z2) 504 (М-Н).-.

IM-(d-chloro-2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methyl|-aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea wine

According to the general method of obtaining urea described in example 15,

M-(25)-tetrahydrofurfuryl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (113 mg, 0.37 mmol) and 2,3-dichlorophenyl isocyanate (0.049 ml, 0.37 mmol) are subjected to a coupling reaction to obtain the desired urea 7/ 0. (52, omg, 2990) . BI-MS (t/g2) 492 (М-Н)-.

Examples 104, 105 and 106: Obtaining

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-"M-cyclopentylaminosulfonyl)phenyl|urea,

IM-(4-chloro-2-hydroxy-3-(M-cyclopentylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

M-(2-chlorophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-cyclopentylsulfonyl)phenyl|urea (M-cyclopentyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.6 mg, 5.5 mmol), cyclopentylamine (0.54 ml, 5.5 mmol) and triethylamine (1.0 ml, 7 , vmmol) are subjected to a reaction to obtain the desired product (1.1 g, 5990). LC-MS (t/l:) 339 (M). (M-cyclopentyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, (M-cyclopentyl)-2,6-dichloro-3-nitrobenzenesulfonamide (0.7bg, 2.2mmol), 8095 Ma (0.22g, 7.3mmol) and water (DBmcl, 2.5 mmol) were reacted to give the desired product (0.49 g, 6895). LC-MS (t/zg) 321 (MU. (M-cyclopentyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, Ge! (M-cyclopentyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.54g, 1.7mmol) was reduced with hydrogen and 1095 Ra/C (5) (0.54g) to obtain the desired product (0.45g, unrefined). ХХ-МС (t/2) 291 (M.

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl)urea

According to the general method for the preparation of urea described in example 15, (M-cyclopentyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (0.15 g, O0.52 mmol) and 2-bromophenyl isocyanate (b4 μl, (2 0, Bammol) are subjected to a coupling reaction to obtain the desired urea (0.1 g, 3995). LC-MS (t/z) 488 (M). b

IM-(d-chloro-2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15, (M-cyclopentyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2,3-dichlorophenyl isocyanate (b8 μl, 0.52 mmol) are subjected to a coupling reaction to obtain the desired urea (0.10 g, 40965). LC-MS (t/z:) 478

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-cyclopentylamino-sulfonyl)phenyl|urea

According to the general method for the preparation of urea described in example 15, (M-cyclopentyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2-chlorophenyl isocyanate (6b2μl, "

0.52 mmol) are subjected to a coupling reaction to obtain the required urea (0.1 g, 4390). LC-MS (t/z) 444 (M). - 70 Examples 107, 108 and 109: Preparation of M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea, :z» IM-( d-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)-phenyl|-M'-(2,3-dichlorophenyl)urea |i

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl| urea

M-(Ethoxycarbonyl)isoxazolidine - 15 1,3-dibromopropane (5.8 ml, 0.057 mol) was added to a solution of KOH (b6.4 g, 0.1 mol) and hydroxyurethane (12 g, 0.1 mol) in ethanol (5 mL). The resulting suspension is refluxed for 1 (95) hours. After cooling the mixture to room temperature, add another portion of KOH (3.2 g, 0.055 mol) and 1" of dibromopropane (2.9 ml, 0.028 mol). Then, the mixture is refluxed for 1 hour, cooled to room temperature and the solvent is evaporated. The residue is suspended three times in boiling (Ce) 50 ether and filtered. The combined filtrates are dried over sodium sulfate, filtered and evaporated. 3 - a portion of the crude product is purified by flash column chromatography (E(Ac/hexane, gradient elution) to obtain 1.18 g of M-(ethoxycarbonyl)isoxazolidine. 2.15 (sq., 2H), 3.55 (t, 2H), 3.8 (t, 2H), 4.1 (sq., 2H).

Isoxazolidine hydrochloride

M-(ethoxycarbonyl)isoxazolidine (1.18g, 9U,mmol) was dissolved in aqueous HCl (bln, 7ml) and boiled with (F) under reflux for 2 hours. After cooling to room temperature, this solution is washed with ether (3) and then evaporated to give crude isoxazolidine hydrochloride, which is recrystallized from an ethanol/ether mixture to give 0.79 g (8095) of isoxazolidine hydrochloride. TN-NMR; (SOSI"; CH3Ob): 5: 2.5 (q, 2H), 3.55 (t, 2H), 4.2 (t, 2H). (M-isoxazolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general procedure for the preparation of the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), isoxazolidine hydrochloride (0.5 bml, 5.2 mmol) and triethylamine (2.2 ml, 15.5 mmol) are reacted to obtain the desired product (1.2 g, 7190). LC-MS (t/2) 327 b5 (M). (M-isoxazolidinyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, (M-isoxazolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.08g, 3,3mmol), 8095 Man (0.3g, 10.00mmol) and water (72 μl, 4 mmol) were reacted to give the desired product (0.79 g, 7795). LC-MS (t/2) 309 (M). (M-isoxazolidinyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in Example 15, (M-isoxazolidinyl)-b-chloro-2-hydroxy-3-nitro-benzenesulfonamide (0.84 g, 2.7 mmol) is reduced with hydrogen and 1095

Ra/C (0.84g) to obtain the desired product (0.75g, crude). LC-MS (t/2) 279 (M 7).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl)urea 70 According to the general method of obtaining urea described in example 15, (M-isoxazolidinyl )-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (0.25 g, 0.9 mmol) and 2-bromophenyl isocyanate (110 μl, 0.9 mmol) are subjected to a coupling reaction to obtain the desired urea (0.1 g, 2395). LC- MS (t/z) 476 (M).

IM-(d-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)-phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15, (M-isoxazolidinyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (0.25 g, 0.900 mmol) and 2,3-dichlorophenyl isocyanate (120 μl, 0, 91 mmol) are subjected to a coupling reaction to obtain the desired urea (0.10 g, 2495). LC-MS (t/z) 466 (M).

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea

According to the general method for the preparation of urea described in example 15, (M-isoxazolidinyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (0.25 g, 0.9 mmol) and 2-chlorophenyl isocyanate (110 μl, 0.91 mmol) ) are subjected to a coupling reaction to obtain the desired urea (0.1 g, 23965). LC-MS (t/z) 432 (M7.

Examples 110, 111 and 112: Obtaining p

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M'"-tetrahydroisoxylaminosulfonyl)phenyl|urea, Ge)

IM-(d-chloro-2-hydroxy-3-(M"-tetrahydroisoxacylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-tetrahydroisoxacylaminosulfonyl)phenylurea

M-(ethoxycarbonyl)tetrahydroisoxazine

To a solution of KOH (3.34g, 59.bmmol) and hydroxyurethane (b.1g, 58.5mmol) in ethanol (25ml) was added 1,4-dibromobutane (33.5ml, 29.3mmol). The resulting suspension is boiled under reflux for 1 He»! hours After cooling the mixture to room temperature, add another portion of KOH (1.65g, 29.4mmol) and dibromopropane (1.8ml, 15mmol). Then, the mixture is refluxed for 1 hour, M is cooled to room temperature and the solvent is evaporated. The residue is suspended three times in boiling ether and filtered. The combined filtrates are dried over sodium sulfate, filtered and evaporated. 4 g - a portion

The crude product is purified by flash column chromatography (E(SO/hexane, gradient elution) to obtain 1.85 g of M-(ethoxycarbonyl)tetrahydroisoxazine. "H-NMR (SOSIZ) 5: 1.05 (q., ZN), 1.45 (dd, 2H), 1.55 (dd, 2H), 3.4 (t, 2H), 3.7 (t, 2H), 3.95 (q., 2H).

Tetrahydroisoxazine hydrochloride « 20 M-(ethoxycarbonyl)tetrahydroisoxazine (1.85g, 11.bmol) is dissolved in aqueous NaCl (bln, 7.bml) and refluxed for 7 hours. After cooling to room temperature, this solution c is washed with ether (3x), and then evaporated to obtain crude isoxazolidine hydrochloride, which is recrystallized from an ethanol/ether mixture, resulting in 0.74 g (5290) of tetrahydroisoxazine hydrochloride. TN-NMR (SNZOB) 5:1.85 (dd, 2H), 1.95 (dd, 2H), 3.4 (t, 2H), 4.25 (t, 2H). (M-Tetragidoisoxazyl)-2,6-dichloro-3-nitrobenzenesulfonamide - and According to the general method of obtaining the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.75 g, 6.00 mmol), hydrochloride tetrahydroisoxazine (0.63 g, 5.1 mmol) and triethylamine (2.2 mL, 15.5 mmol) were reacted to give the desired product (1.32 g, 7590). LC-MS (ti/z) g" 341 (MU. (M-tetrahydroisoxazyl)-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide o According to the general method of hydrolysis described in example 15, c (M-tetrahydroisoxazyl) -2,6-dichloro-3-nitrobenzenesulfonamide (0.1g, 0.29mmol), 8095 Man (26bmg, 0.88mmol) and water (6.3ml, 0.3bmmol) are reacted to give the desired product (50mg, 5395 ). LC-MS (t/z2) 323 (M). (M-tetrahydroisoxazyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, o (M-tetrahydroisoxazyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.76 g, 2.35 mmol) is reduced with hydrogen and 1096 Pa/C (0.76 g ) to obtain the desired product (0.89 g crude). LC-MS (t/zg) 293 (M. yu Preparation of M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-tetrahydroisoxazylaminosulfonyl)phenyl)urea

According to the general method for the preparation of urea described in example 15, 60 (M-tetrahydroisoxazyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.3 g, 1.0 mmol) and 2-bromophenyl isocyanate (126 bml, 1.0 mmol ) are subjected to a coupling reaction to obtain the required urea (0.1 g, 20 95). LC-MS (t/2) 490 (MU.

IM-(d4-chloro-2-hydroxy-3-(M'"-tetrahydroisoxacylaminosulfonyl)-phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15, (M-tetrahydroisoxazyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.3 g, 1.0 mmol) and

2,3-dichlorophenyl isocyanate (135 μl, 1.0 mmol) is subjected to a coupling reaction to obtain the desired urea (0.10 g, 2090). LC-MS (t/zg) 480 (M7).

M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-tetrahydroisoxacylaminosulfonyl)phenyl)urea

According to the general method of obtaining urea described in example 15, (M-tetrahydroisoxazyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (0.3 g, 1.0 mmol) and 2-chlorophenyl isocyanate (124 μl, 1.0 mmol) ) are subjected to a coupling reaction to obtain the required urea (0.1 g, 2290). LC-MS (t/2) 446 (M7.

Examples 113, 114 and 115: 70. Preparation of Mm-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(2-isopropoxyethyl)aminosulfonyl)phenyl|urea,

IM-(d-chloro-2-hydroxy-3-((2-isopropoxyethyl)aminosulfonyl)-phenyl|-M'-(2,3-dichlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-((2-isopropoxyethyl)aminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea

M-(2-isopropoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method of preparation of sulfonamide described in example 15, 75. 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.1 mmol), 2-aminoethylisopropyl ether (0.533 g, 5.1 mmol) and triethylamine (1 .42ml, 10.32mmol) are reacted to obtain the desired product (1.63g, 89965).

LC-MO (ti/z) 357.0 (M).

M-(2-isopropoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-(2-isopropoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.635g, 4.58mmol), 6090 Man (0.41g, 13.74mmol) and water (0.099ml, 5.50mmol) were reacted. The crude product (1.676 g) is used in the next stage without purification. LC-MS (t/z) 340 (M-H)".

M-(2-isopropoxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, crude p

M-(2-isopropoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.17g) is reduced with hydrogen and Ra/C (350mg). d)

The crude product (1.086 g) is used in the next stage without purification. "H-NMR (MeOO-a,) 5: 6.92 (d, 1H), 6.85 (d, 1H), 3.45 (m, 1H), 3.39 (t, 2H), 3, 10 (t, 2H), 1.05 (d, 6H).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-isopropoxyethyl).aminosulfonyl)phenyl)urea

According to the general method of obtaining urea, which is described in example 15, crude o

M-(2-isopropoxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (362 mg) and 2-bromophenyl isocyanate (0.132 ml, "F) 1.07 mmol) are subjected to a coupling reaction to obtain the desired urea (155 mg, 29905 for Z stages). LC-MS and « (t/2) 508 (М-Н) 7.

IM-(d-chloro-2-hydroxy-3-((2-isopropoxyethyl)aminosulfonyl)-phenyl|-M'-(2,3-dichlorophenyl)urea (ze) with According to the general method for the preparation of urea described in example 15, unrefined M

M-(2-isopropoxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (362 mg) and 2,3-dichlorophenyl isocyanate (0.141 mL, 1.07 mmol) are subjected to a coupling reaction to obtain the desired urea (264 mg, 3095 for C stages ). LC-MS (t/2) 498 (М-Н)7.

IM-(d-chloro-2-hydroxy-3-(2-isopropoxyethyl)aminosulfonyl)-phenyl|-M'-(2-chlorophenyl)urea

According to the general method for the preparation of urea described in example 15, crude 2s M-(2-isopropoxyethyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (362mg) and 2-chlorophenyl isocyanate (0.129ml, 1, 07mmol) are subjected to a coupling reaction to obtain the required urea (17Omg, 3495 for C stages). LC-MS;" (t/2) 462 (М-Н)".

Examples 116, 117 and 118: Preparation of 45. M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl)phenyl|urea, -and IM-(d -chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea o M-(2-ethoxyethyl)-2,6-dichloro-3- nitrobenzenesulfonamide and" According to the general method of obtaining sulfonamide described in example 15, so 50 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50g, 5.1bmmol), 2-aminoethyl ether (0.46g, 5.1bmmol) and triethylamine (1.42ml, 10.32mmol) were reacted to give the desired product (1.78g, 10090).LC-MS (42) (t/2) 345.0 (M).

M-(2-ethoxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-(2-ethoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.78g, 5.1bmmol), 8095 Man (0.46g, 15.48mmol) and water (111μl, 6.20mmol) are reacted . The crude product (1.63 g) is used in the next stage without purification. LC-MS (t/z) 325.0 (M-H)"7. ko IM-(2-ethoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general hydrogenation method described in example 15, crude 60 O/M-(2-ethoxyethyl)-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.98g) is reduced with hydrogen and Ra/C (25OmgHg).

The crude product (1.01 g) is used in the next stage without purification. "H-EMR (MeOO-sdl) 5: 6.88 (m, 2H), 3.40 (t, 2H), 3.36 (m, 2H), 3.13 (t, 2H), 1.08 (t, ZN).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-ethoxyethyl)amino-sulfonyl)phenyl)urea

According to the general method of obtaining urea, described in example 15, crude M-(2-ethoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (33 mg) and 2-bromophenyl isocyanate (204 mg,

1.03 mmol) are subjected to a coupling reaction to obtain the desired urea (13 Ω, 26 95 for 3 stages). LC-MS (t/2) 494.0 (M-H) "7.

IM-(d4-chloro-2-hydroxy-3-(2-ethoxyethyl)aminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method of obtaining urea, which is described in example 15, crude

M-(2-ethoxyethyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (33mg) and 2,3-dichlorophenylisocyanate (194mg, 1.03mmol) are subjected to a coupling reaction to obtain the desired urea (185mg, 3795 for 3 stages) . LC-MS (t/2) 484.0 (M-H) "7.

IM-(d-chloro-2-hydroxy-3-(2-isoproxyethyl).aminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea 70 According to the general method of obtaining urea, in example 15, crude

M-(2-ethoxyethyl)-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (3333mg) and 2-chlorophenyl isocyanate (158mg, 1.03mmol) are subjected to a coupling reaction to obtain the desired urea (138mg, 3095 for C stages). LC-MS (t/2) 448.2 (M-H)7.

Examples 119, 120 and 121: Preparation of 15... MA(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(2-methoxycarbonyl)azetidin-1-yl|isulfonylphenyl|-urea,

IM-(4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|!sulfonylphenyl|-M'-(2,3-dichlorophenyl)urea and

IM-(4-chloro-2-hydroxy-3-((2-carboxy)-azetidin-1-yl|isulfonylphenyl|-M'(2,3-dichlorophenyl)urea 2-Acetoxy-1-azetidine

A solution of I-azetidinecarboxylic acid (700 mg, 6b, 92 mmol) and 1 ml of chlorotrimethylsilane in 1 ml of methanol was refluxed overnight. The mixture is concentrated to obtain the desired product with a quantitative yield (76b9mg), while purification is not carried out. "H-NMR (SOSIvs) 5: 9.49 (s, 1H), 5.20 (m, 2H), 4.27 (m, 1H), 4.14 (m, 1H), 3.82 (s .

According to the general method of preparation of sulfonamide described in example 15, with 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.01 g, 6.92 mmol), 2-acetoxy-1-azetidine (79 mg, b, b2 mmol) and (39 triethylamine (1.75 ml, 17.3 mmol) was reacted with the desired product (1.84 g, 7295). "H-NMR (SOCI") 6: 7.68 (d, 1H), 7.61 (d, 1H ), 5.09 (t, 1H), 4.46 (m, 1H), 4.06 (m, 1H), 3.59 (s, ЗН), 2.55 (m, 1H), 2.49 (m, 1Hn). b-chloro-2-hydroxy-1-(2-methoxycarbonyl)azetidin-1-yl|isulfonyl-3-nitrobenzene z. To a solution of 2,b-dichloro-1-(2-methoxycarbonyl)azetidine -1-yl|sulfonyl-3-nitrobenzene (1.9 at, mmol) at room temperature, potassium superoxide (946 mg, 13.3 mmol) is added in 5 µg portions. The resulting mixture is stirred with F3 for 20 hours. The mixture is acidified with sodium hydroxide, and then extracted with ethyl acetate. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (40/58/2, v/v/v), the desired product (767 mg, 4295) was obtained. LC-MS (t/z) 351.0 (M). o b-khlo p-2-hydroxy-1-(2-methoxycarbonyl)azetidin-1-yl|Isulfonyl-aniline chn

According to the general hydrogenation method described in Example 15, b-chloro-2-hydroxy-1-(2-methoxycarbonyl)azetidin-1-yl|isulfonyl-3-nitrobenzene (742 mg, 2.12 mmol) is reduced with hydrogen and 1095 Ra /C (250mg) to obtain the desired product (649mg, 96965). "H-NMR (MeOr-ad) 5: 6.86 (m, 2H), 4.95 (t, 1H), 4.17 (m, 1H), 3.94 (m, 1H), 3, 56 (s, ZN), 2.45 (m, 2H).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|!sulfonylphenyl|urea 8 s) According to the general method for obtaining urea, which is described in example 15, b-chloro-2-hydroxy-1-(2-methoxycarbonyl)azetidin-1-yl|Isulfonylaniline (325 mg, 1.0 mmol) and "» 2-bromophenyl isocyanate (201 mg, 1.0 mmol) are subjected to a coupling reaction with obtaining the required urea (39Omg, 7490).LC-MOS (ti/zg) 520.0 (M).

IM-(4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|isulfonylphenyl-M'-(2,3-dichlorophenyl)urea -| According to the general method of obtaining urea, described in Example 15, b-chloro-2-hydroxy-1-(2-methoxycarbonyl)azetidin-1-yl|Isulfonylaniline (325 mg, 1.0 mmol) and 2,3-dichlorophenyl isocyanate (190 mg, 1.0 mmol) are subjected to a coupling reaction with obtaining the required urea, vol. (479 mg, 9395). LC-MS (vol/l) 510.0 (M). s 50 M-(4-chloro-2-hydroxy-3-((2-carboxy)azetidine-1 -yl,isulfonylphenyl|-M'(2,3-dichlorophenyl)urea

Solution with IM-I (4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|isulfonylphenyl|-M'-(2,3-dichlorophenyl)urea) (359 mg, 0.71 mmol ) and lithium hydroxide monohydrate (29bmg) in methanol (1Oml) and water (1Iml) were stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was acidified with aq. HCl. The resulting mixture was filtered, after which the white solid was collected and dried in a vacuum with the desired result

GF) of the product (332mg, 9595). LC-MS (t/z2) 496.0 (M).

Examples 122, 123 and 124: Preparation of M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-(4-morpholinyl)/propylaminosulfonyl)phenyl|urea hydrochloride, 60 M-Id-chloro-2-hydroxy-3-IM"-(3-(4-morpholinyl)-propylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea hydrochloride and

IM-(d-chloro-2-hydroxy-3-(M"-(3-(4-morpholinyl)/propyl)aminosulfonyl|phenyl-M'-(2-chlorophenyl)urea hydrochloride

IM-IZ-4-morpholinyl)propyl|-2,6-dichloro-3-nitrobenzenesulfonamide

According to the general method of preparation of sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.8 mmol), 4-(33-aminopropyl)umorpholine (99 mg, 6.88 mmol) and triethylamine (1.92ml, 13.7bmmol) were reacted to give the desired product (2.04g, 7490). LCD-MS (th/s)

398 (MU).

IM-IZ-"4-morpholinyl)propyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15, 85 M-13-(4-morpholinyl)propyl|-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 g, 2.51 mmol), 6090 Ma (301 mg , 7.53 mmol) and water (54 μl, 3.0 mmol) are reacted. The resulting mixture is acidified with 4.On HCI in 1.4-dioxane and concentrated to obtain the crude product (1.01g), which is used in the next stage without purification. LC-MS 380.0 (M7.

IM-3-(4-morpholinyl)propyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide 70 According to the general hydrogenation method described in example 15, crude

M-(3-(4-morpholinyl)propyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.01g) is reduced with hydrogen and 1095 Ra/s (250mg). The crude product (890mg) is used in the next step without purification. (MeOyu-a,) 5: 6.86 (m, 2H), 3.87 (m, 4H), 3.15 (m, 6H), 2.98 (t, 2H), 1.92 ( m, 2H).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(3-(4-morpholinyl)-propylaminosulfonyl)phenyl)urea hydrochloride

According to the general method of obtaining urea, o| described in example 15, crude

IM-IZ-(4-morpholinyl)propyl|-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (297 mg) and 2-bromophenyl isocyanate (16 bml, 00.8 mmol) are subjected to a coupling reaction to obtain the desired urea (191 mg, 3995 for From stages). LC-MS (t/27) 549.2 (M).

IM-(d-chloro-2-hydroxy-3-(M"-(3-(4-morpholinyl)/propyl)iaminosulfonyl)phenyl|-M'(2,3-dichlorophenyl)urea hydrochloride

According to the general method of obtaining urea, which is described in example 15, crude

IM-IZ-«4-morpholinyl)propyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (297 mg) and 2,3-dichlorophenyl isocyanate (157 mg, 0.8 mmol) are subjected to a coupling reaction to obtain the desired urea (134 mg, 2895 for C stages). c 29 LC-MS (t/g) 539.2 (M). at

1M-(d-chloro-2-hydroxy-3-(M"-13-4-morpholinyl)propylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea hydrochloride

According to the general method of obtaining urea, which is described in example 15, crude

IM-IZ-(4-morpholinyl)propyl|-3-amino-6-chloro-2-hydroxybenzenesulfonamide (297 mg) and 2-chloro-phenyl isocyanate - (127 μl, 0.8 μmol) are subjected to a coupling reaction to obtain the desired urea (13 μg, 2995 for Z stages). Ge")

LC-MS (t/z) 503.2 (M).

Examples 125 and 126: Obtaining Z

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|sulfonyl-phenyl|urea and co

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|!sulfonylphenyl|-urea

Zo 2,6-dichloro-1-|5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonyl-3-nitrobenzene -

According to the general method of obtaining the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.8 mmol), 5-(-)-(2-methoxymethyl)pyrrolidine (79 mg, 6.88 mmol) ) and triethylamine (1.9 ml, 13.7 mmol) are reacted to give the desired product (2.2 g, 8790). LC-MS (t/z) « 20 369.0 (MU. with b-chloro-2-hydroxy-1-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|-c-sulfonyl- 3-nitrobenzene c According to the general hydrolysis method described in example 15, 2,6-dichloro-|5-(-)-(-2-methoxymethyl)pyrrolidin-1-yl|-3-nitrobenzene (1 .0g, 2.71mmol), 6095 Mann (325mg, 8.133mmol) and water (59µL, 33.3mmol) are reacted. The crude product (1.0g) is used in the next step without

Cleaning. LC-MS 351.0 (M tu, -I 4-chloro-2-hydroxy-3-|5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|-sulfonylaniline

According to the general hydrogenation method described in example 15, and β-chloro-2-hydroxy-1-(5-(-)-(-2-methoxymethyl)pyrrolidin-1-ylIsulfonyl-3-nitrobenzene (1.0 g) reduced with hydrogen, and "iz" 1096 Ra/C (320mg). The crude product (0.92g) is used in the next stage without purification. "H-NMR 5o (mMeOO-a,) 6: 6.91 (d, 1H), 6.89 (d, 1H), 4.41 (m, 1H), 3.39 (m, 2H), 3.21 (s, ЗН), 1.83-1.97 (m, 6H). -o M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-ylcisulfonylphenyl|urea) o According to the general method of preparation urea described in example 15, crude 4-chloro-2-hydroxy-3-|5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|sulfonylaniline (ZObmg) and 2-bromophenyl isocyanate (188mg, 0, 95 mmol) are subjected to a coupling reaction to obtain the required urea (170.4 mg, 3595 for 3 stages).

LCD-MO (ti/zg) 520.0 (M). o M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-hydroxy-methyl)pyrrolidin-1-yl|sulfonylphenyl|urea

The solution contains) M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(58-(-)-(2-hydroxymethyl)pyrrolidin-1-yl)|sulfonylphenyl|urea ( 92 mg, 0.18 mmol) in dichloromethane in an ice bath add 1.0 M boron tribromide (0.533 ml, 0.5 mmol) in 60 dichloromethane. The resulting mixture is stirred for 16 hours. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane ( 50/50, vol/vol) yield the desired product (b5mg, 73905).

LC-MS (t/z) 506.0 (M).

Examples 127 and 128:

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxy-methyl)pyrrolidin-1-yl-isulfonylphenyl|-M'-(2,3-dichlorophenyl)-urea and b5 0 M -ID-chloro-2-hydroxy-3-I5-(-)-(2-hydroxymethyl)-pyrrolidin-1-ylsulfonyl|phenyl|-M'(2,3-dichlorophenyl)urea

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl|-M'-(2,3-dichlorophenyl)urea

According to the general method for the preparation of urea described in example 15, crude 4-chloro-2-hydroxy-3-15-(-)-(2-methoxymethyl)pyrrolidin-1-yl|IIsulfonylaniline (ZObmg) and 2,3-dichlorophenylisocyanate (179 mg, 0.95 mmol) are subjected to a coupling reaction to obtain the desired urea (218 mg, 4595 for C stages).

LC-MS (t/g) 510.0 (M).

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)-pyrrolidin-1-yl|Isulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea

According to the deprotection procedure described in example 126, 4-chloro-2-hydroxy-3- )urea (8Omg, 0O.1bmmol) and 1.0M boron tribromide (0.78ml, 0.78mmol) are subjected to a coupling reaction to obtain the desired 70. product (5Omg, 64965). LC-MS (ti/) 494.0 (M7).

Examples 129 and 130:

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea and

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|isulfonylphenyl/|-M'-(2-chlorophenyl)urea

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxy-methyl)pyrrolidin-1-yl]isulfonylphenyl|-M'-(2-chlorophenyl)urea

According to the general method of obtaining urea described in example 15, crude 4-chloro-2-hydroxy-3-(5-(-)-(2-methoxycarbonyl)-pyrrolidin-1-yl|sulfonylaniline (ZObmg) and 2- chlorophenyl isocyanate (146 mg, 0.9 mmol) is subjected to a coupling reaction to obtain the desired urea (129 mg, 29905 for three stages).

ХХ-МО (ti/z) 474.2 (M).

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea

According to the deprotection procedure described in example 126,

IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxy-methyl)pyrrolidin-1-yl|isulfonylphenyl|-M'-(2-chlorophenyl)urea (bZmg, O0, 1Zmmol) and 1.0M boron tribromide (0.65ml, 0.65mmol) are subjected to a coupling reaction to obtain the desired product (ZBmg, 58905). LC-MS (t/l) 460.0 (M).

Examples 131 and 132; IS

MA(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(5-(2-methoxycarbonyl)pyrrolidin-1-ylsulfonylphenyl|urea and g)

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(2-carboxy)pyrrolidin-1-yl)ylsulfonylphenyl|urea 2,6-dichloro-1-I8- (2-Methoxycarbonyl)pyrrolidine-1-ylcisulfonyl-3-nitrobenzene

According to the general method for obtaining the sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (4.79 g, 16.5 mmol), I-proline methyl ether hydrochloride (2.7 mg, about 16.5 mmol) and triethylamine (4.60ml, ZbBmmol) are reacted to give the desired product (5.02g, 7996). b

LCD-MO (ti/) 383.0 (M). b-chloro-2-hydroxy-1-(5-(2-methoxycarbonyl)pyrrolidin-1-yl|isulfonyl-3-nitrobenzene M

To a solution of /2,6-dichloro-1-I5-(2-methoxycarbonyl)pyrrolidin-1-yl|-3-nitrobenzene (1.0 g, 2.bmmol) at 95 room temperature, 5 mg - portions of potassium superoxide (37 mg , 5.2 mmol). The resulting mixture is stirred

From within 16 hours. The mixture is acidified with water. NSI, and then extracted with ethyl acetate. After purification - by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (50/48/2, v/v/v), the desired product (384 mg, 4095) was obtained. LC-MS (t/2) 365.2 (M). 4-chloro-2-hydroxy-1-3-(2-methoxycarbonyl)pyrrolidin-1-yl|-sulfonylaniline « du According to the general method of hydrogenation described in example 15, with b-chloro-2-hydroxy-1- (5-(2-Methoxycarbonyl)pyrrolidin-1-yl|isulfonyl-3-nitrobenzene (38Omg, 1.04mmol) was reduced with hydrogen and Ra/C (110mg) to give the desired product (34Omg, 9896). "H-NMR (MeO0-au) 5: 6.84 with (m, 2H), 4.58 (m, 1H), 3.67 (s, ЗН), 2.25 (m, 2H), 2.10 (m, 2H), 1.95 (m, 2H).

M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(2-methoxycarbonyl)pyrrolidin-1-yl)|sulfonylphenyl|urea

According to the general method for the preparation of urea described in example 15, -I 4-chloro-2-hydroxy-3-I5-(2-methoxycarbonyl)pyrrolidin-1-yl|isulfonylaniline (339 mg, 1.0 mmol) and 2-bromophenyl isocyanate (201mg, 1.0immol) are subjected to a coupling reaction to obtain the desired urea (223ZmgH, about 4190). LC-MS (t/z) 534.0 (M). i» 1-(2-bromophenyl)-N'-(4-chloro-2-hydroxy-3-18-(2-carboxy)pyrrolidin-1-yl|isulfonylphenyl|urea

A solution of 1-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-18-(2-methoxycarbonyl)pyrrolidin-1-yl|isosulfonylphenyl|urea (4 mg, 0.075 mmol) and hydroxide monohydrate lithium (40mg) in methanol (1Oml) and water (Iml) are stirred at room temperature for 16 hours. The mixture is concentrated, the residue is acidified with sodium hydroxide solution. The resulting mixture is filtered, the white solid is collected and dried in vacuo to give the desired product (ZOmg , 10090). LC-MS (t/zg) 520.0 (MU).

Examples 133, 134 and 135; Obtaining

IF) M-(2-bromophenyl)-M'-I3-IM"-(tert-butyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl|urea, ko IM-3-IM"-(tert-butyl)aminosulfonyl |-4-chloro-2-hydroxyphenyl/|-M'(2,3-dichlorophenyl)urea and

IM-III-IM"-(tert-butyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2-chlorophenyl)urea 60 M-(tert-butyl)-2,6-dichloro-3 -nitrobenzenesulfonamide

According to the general method of preparation of sulfonamide described in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.8 v8 mmol), tert-butylamine (50 µg, 6.88 mmol) and triethylamine (14 µg, 10.32 mmol ) are subjected to a reaction to obtain the desired product (1.67 g, 75965). "H-NMR (MeO-a,) 5: 7.91 (d, 1H), 7.78 (d 1), 1.25 (s, 9H). b5 M-(tert-butyl)-6-chloro -2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in Example 15,

M-(tert-butyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.67g, 5.1mmol), bO95 Man (612mg, 15.3mmol) and water (92μl, 5.1mmol) were reacted to give the crude of the product (1.54 g), used in the next stage without purification. TN-NMR (meO0-a,) 5: 8.00 (d, 1H), 7.08 (d, 1H), 1.24 (s, 9H).

M-(tert-butyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide

According to the general method of hydrogenation described in example 15, crude

M-(tert-butyl)-6b-chloro-2-hydroxy-3-nitrobenzene-sulfonamide (1.54 g) is reduced with hydrogen and 1095 Pa/sC (67Omg).

The crude product (1.23 g) is used in the next stage without purification. "H-NMR (MeOO-a) 5:6.82 (m, 2H), 1.22 (s, 9H).

M-(2-bromophenyl)-M'-3-(M"-(tert-butyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl|urea

According to the general method of obtaining urea, which is described in example 15, crude

M-(tert-butyl)-3-amino-b-chloro-2-hydroxybenzenesulfonamide (410 mg) and 2-bromophenyl isocyanate (322 mg, 1.62 mmol) are subjected to a coupling reaction to give the desired urea (228 mg, 3295 for C stages). LC-MS (t/2) 478.0 (M7.

IM-III-IM"-(tert-butyl)aminosulfonyl|)4-chloro-2-hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea

According to the general method of obtaining urea, described in example 15, crude

M-(tert-butyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (410mg) and 2,3Z-dichlorophenyl isocyanate (304mg, 1.62mmol) are subjected to a coupling reaction to obtain the desired urea (336.1mg, 4995 for Z stages). LC-MS (t/2) 468.0 (M).

M-3-IM"-(tert-butyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2-chlorophenyl)urea

According to the general method of obtaining urea, described in example 15, crude

M-(tert-butyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (410 mg) and 2-chlorophenyl isocyanate (249 mg, 1.62 mmol) are subjected to a coupling reaction to give the desired urea (24 mg, 3895 for 3 stages). LC-MS (t/2) 432.0 ch (M7. 29 Example 138 and 139: Preparation of Ho)

I-III-IM"-(5-(tert-butoxycarbonylamino)-5-carboxypentylaminosulfonyl|)|-4-chloro-2-hydroxy-phenyl/|-M'-(2-chlorophenyl) urea and hydrochloride

IM-IZ-IM"-(5-amino-5-carboxypentyl)aminosulfonyl|)|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea o zo I-IZ-IM"-(5 -(tert-butoxycarbonylamino)-5-carboxypentyl|-aminosulfonyl|-4-chloro-2-hydroxyphenyl|/|-M'-(2-x lorphenyl)urea (o)

According to the general method of obtaining urea described in example 15, "

M-(5-(tert-butoxycarbonylamino)-5-carboxypentyl|-3-amino-b6-chloro-2-hydroxybenzenesulfonamide (233 µg, 0.52 mmol) and 2-chlorophenyl isocyanate (8 µg, 0.52 mmol) are subjected to a coupling reaction to give required Ge)

From cane (97mg, 3195). LC-MS (t/z2) 605.2 (MU). them

IM-III-IM"-(5-amino-5-carboxypentyl)aminosulfonyl|)|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea hydrochloride

According to the general method of removing the protection of Vos, which is described in example 36,

1-3-IM"-(5-(tert-butoxycarbonylamino)-5-carboxypentylaminosulfonyl|/|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophen 20 nyl)urea (104 mg, 0.17 mmol) ) are mixed in 17 ml of trifluoroacetic acid to obtain the desired product from c (b4 mg, 6190). LC-MS (pt/l) 505.0 (M). Examples 142, 143 and 144: Preparation of a IM-(4-chloro- 3-(1,1-dioxydo-thiomorpholinosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea,

IM-(2-bromophenyl)-M'-(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|urea and

M-Id-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)2-hydroxyphenyl/|-M'«(2-chlorophenyl)urea - and b-chloro-1-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxy- Z-nitrobenzene

A solution of b-chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinosulfonyl)benzene (563 mg, 1.67 mmol) and o m-chloroperbenzoic acid (1.73 g, 5.01 mmol) in dichloromethane (bOml) is stirred at for 3 days at their room temperature. The mixture was diluted with ethyl acetate and washed with water to obtain the crude 5r product. After purification by column chromatography on silica gel eluting with a mixture of ethyl acetate/hexane/acetic acid (49/50/1, vol/vol/o0b6), the desired product (230 mg, 3790) was obtained. EI-MS (t/z) with 368.92, 371.03 (M). 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline

According to the general hydrogenation method described in Example 15, β-chloro-(1,1-dioxydothiomorpholinosulfonyl)-2-hydroxy-3-nitrobenzene (220 mg, 0.000 mmol) is reduced with hydrogen and at 1096 Pa/C (100 mg) with obtaining the desired product (186mg, 9695). "H-NMR (MeO-4au) 5: 6.88 (m, 2H), 3.85 (t, 1H), 3.22 (t, 4H). where IM-(d4-chloro-3-(1 ,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

According to the general method of obtaining urea described in example 15, 60 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (b2 mg, 0.18 mmol) and 2,3-dichlorophenyl isocyanate (d4 mg, 0, 22 mmol) are subjected to a coupling reaction to obtain the desired urea (32 mg, 34 90). LC-MS (t/z) 528.0 (MU.

M-(2-bromophenyl)-M'-I(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|urea

According to the general method for the preparation of urea described in example 15, b / d-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (b2 mg, 0.18 mmol) and 2-bromophenyl isocyanate (44 mg,

0.22 mmol) are subjected to a coupling reaction to obtain the desired urea (28 mg, 2995). LC-MS (t/z2) 539.8 (M.

IM-(D-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea

According to the general method of obtaining urea described in example 15, a-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (b2mg, 0.18mmol) and 2-chlorophenyl isocyanate (Za4Amg, 0.22mmol) are subjected to the reaction combination with obtaining the required urea (29mg, 3295) . LC-MS (t/z2) 496.0 (M.

Example 145 and 146: Obtaining

IM-IZ-IM"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea and trifluoroacetate 70... M-IZ-(M "-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea

IM-III-IM"-(2-(tert-butoxycarbonylamino)ethyl)iaminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)sequine

According to the general method of obtaining urea described in example 15,

I-(2-(tert-butoxycarbonylamino)ethyl)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (22Omg, 0.bmmol) and 75 2,3-dichlorophenylisocyanate (125mg, 0.6bmmol) are subjected to a coupling reaction with obtaining the required urea (220mg, 6695). LC-MS (t/z2) 553.2 (M).

IM-IZ3-(M"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea trifluoroacetate

According to the general method of removing the Vos-protection, which is described in example 36,

M-(3-(M"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl/|-4-chloro-2-hydroxyphenyl|-M'E(2,3-dichlorophenyl)-urea)) mixed in trifluoroacetic acid to obtain the desired product (57 mg, 10090).

LC-MS (t/z2) 453.0 (M).

Example 147 and 148: Obtaining

I-III-IM"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl|)|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea and trifluoroacetate M-I3-(M"-(2 -aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)-urea c

IM-IZ-IM"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl)|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea g) ina

According to the general method of obtaining urea described in example 15,

I-(2-(tert-butoxycarbonylamino)ethyl I|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (220mg, PRO, bOmmol) and 2-bromophenyl isocyanate (101mg, 0.bbmmol) are subjected to a coupling reaction to obtain the desired urea ( 169 mg, o

Beru, LC-MS (t/z) 519.2 (M). Fo

IM-3-(M"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2-chlorophenyl)urea trifluoroacetate

According to the general method of removing Vos-protection, which is described in example 36, c

M-(3-(M"-(2-(tert-butoxycarbonylamino)ethylaminosulfonyl|-4-chloro-2-hydroxyphenyl|-ME(2-chlorophenyl)urea salt) (57 mg, 0.1 mmol) is stirred in trifluoroacetic acid with obtaining the desired product (51 mg, 87905).

LC-MS (t/y) 4192 (MU). -

Example 150: Obtaining

IM-(d-chloro-2-hydroxy)-3-(M",M"-dimethylaminosulfonyl)phenyl|-ME(2-chlorophenyl)urea a) M-dimethyl-2,6-dichloro-3-nitrobenzenesulfonamide According to the general procedure for the preparation of the sulfonamide described in Example 15, from 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, b.9 mmol), dimethylamine (2.0 M in Meon, 3.5 ml, 6.9 mmol ) and triethylamine (1.44 ml, 10.35 mmol) are reacted to give the desired product (1.45 g, 70.490). EI-MS:z" (t/2) 298 (М-Н)-.

B) M",M"-dimethyl-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in example 15, - 75 M",M"-dimethyl-2,6-dichloro-3-nitrobenzenesulfonamide (2.64 g, 8.83 mmol), Mann (6095, 1.06 bg, 26 .5mmol) and water (191mg, 10.bmmol) were reacted to give the desired product (2.3g, 9390). EI-MS (t/2) 279.5 (M-H)-. (95) p). M",M"-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide 1" According to the general hydrogenation method described in example 15,

M",M"-dimethyl-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide (2.3g, 8.2mmol) is reduced with hydrogen and Ra/cS (2.3g) (Ce) 20 to give the desired product (2, 0g, 9790). EI-MS (t/2) 249.5 (М-Н)-. o a) M-(4-chloro-2-hydroxy-3-((M",M"-dimethylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea

According to the general method of obtaining urea, in example 15,

M",M"-dimethyl-3-amino-b-chloro-2-hydroxybenzenesulfonamide (200 mg, 0.mmol) and 2-chlorophenyl isocyanate (12 mg,

O, vmmol) are subjected to a coupling reaction to obtain the required urea (27Omg, 8390). EI-MS (t/z2) 403.2 (M-H)-.

Example 151: Preparation of M-|4-chloro-2-hydroxy)-3-aminosulfonyl)phenyl|-M'-(2-chloro-3-fluorophenyl)urea

HF) a) 2-chloro-3-fluoronitrobenzene 7 M-chlorosuccinimide (5.69 g, 42.mmol) in THF (20 ml) is added to a solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 ml) at -78C , and then add MaHnNMO5 (1M in THF, 28.4 ml, 28.4 mmol) dropwise so that the internal temperature is maintained below -75 2. The resulting mixture is stirred for 30 minutes at -189260. Then it is distributed between 595 NCI and ethyl acetate. The combined organic layer is dried over MOZO and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (2090 ethyl acetate/hexane mixture) to give the desired product (231 mg, 9.295). EI-MS (t/2) 176.5 (MU).

B) 2-chloro-3-fluoroaniline 65 To a solution of 2-chloro-33-fluoronitrobenzene (231mg, 1.32mmol) in ethanol (LOml) add tin (I) chloride (1.48g, 6b,bmmol). The reaction mixture was stirred at room temperature for 16 hours. Then they add

Manso" (aqueous) to pH-7. Then the mixture is extracted with ethyl acetate (III). The combined organic layer is dried over

Ma5o,, is filtered and concentrated under reduced pressure to obtain the desired product (13bmg, 71905). EI-MS (t/2) 146.5 (M). with). M-(d4-chloro-2-hydroxy-3-(aminosulfonyl)phenyl|-M'-(2-chloro-3-fluorophenyl)urea

Triphosgene (111mg, 0.37mmol) and triethylamine (0.13ml, 1.12mmol) were added to a solution of 2-chloro-3-fluoroaniline (13g, 0.94mmol) in toluene (10ml). The reaction mixture is stirred at 802C for 4 hours. The reaction mixture was then concentrated under reduced pressure and added to 3-amino-b-chloro-2-hydroxybenzenesulfonamide (104 mg, 0.47 mmol) in DMF (ml). The reaction mixture was stirred at room temperature for 16 hours. After 70 chromatography of the obtained liquid on silica gel (a mixture of 3095 ethyl acetate/hexane), the desired product is obtained (vOmg, 4390). EI-MS (t/2) 395.2 (M).

Example 152: Preparation of M-I4-chloro-2-hydroxy-3-(aminosulfonyl)phenyl)-M'-(2-bromo-3-fluorophenyl)urea a) 2-chloro-3-fluoronitrobenzene

M-bromosuccinimide (7.58 g, 42.mmol) in THF (20 ml) was added to a solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 ml) at -7892C, and then MaANMO5 (1 M in THF, 28.4 ml, 28.4 mmol), so that the internal temperature is maintained below -75 "Sb. The resulting mixture is stirred for 30 minutes at -189260. Then it is distributed between 595 NCI and ethyl acetate. The combined organic layer is dried over MOZO and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (2090 ethyl acetate/hexane mixture) to give the desired product (ZOOmg, 9.695). EI-MS (t/z2) 221 (M).

B) 2-chloro-3-fluoroaniline

To a solution of 2-bromo-3-fluoronitrobenzene (10Omg, 0.4 mmol) in ethanol (ml) add tin (II) chloride (520Omg, 2.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then add Manso with (water) to pH-7. Then the mixture is extracted with ethyl acetate (3x). The combined organic layer was dried over NaSO, filtered and concentrated under reduced pressure to give the desired product (8Omg, 9390). EI-MS (t/2) 191 p. (MU. o p.). M-I(d-chloro-2-hydroxy-3-(aminosulfonyl)phenyl|-ME2-bromo-3-fluorophenyl)urea

To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.022 mmol) in toluene (5 mL) was added triphosgene (2 mg, 0.09 mmol) and triethylamine (0.04 mL, 0.2 mmol). The reaction mixture is stirred at 802C for 4 hours. The reaction mixture was then concentrated under reduced pressure and added to 3-amino-b-chloro-2-hydroxybenzenesulfonamide (44 mg, 0.22 mmol) in DMF (ml). The reaction mixture was stirred at room temperature for 16 hours. After b" chromatography of the obtained liquid on silica gel (a mixture of 3095 ethyl acetate/hexane), the required product is obtained (7 mg, "t 790). EI-MS (t/z2) 439.6 (M).

Examples 153, 154 and 155: Obtaining i)

M-(2-bromophenyl)-M'-I(4-chloro-3-(1-ethylpyrrolidin-2-yl)umethylaminosulfonyl/|-2-hydroxyphenyl|-urea n-hydrochloride,

M-(4-chloro-3-K1-ethylpyrrolidin-2-yl)-methylaminosulfonyl|)|-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)-urea hydrochloride and

M-(4-chloro-3-(1-ethylpyrrolidin-2-yl)-methylaminosulfonyl|-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea " Hydrochloride with c I-I 1-ethylpyrrolidin-2- yl)umethyl|-2,6-dichloro-3-nitrobenzenesulfonamide. According to the general method of obtaining sulfonamide, which is described in example 15, and? 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0g, 6.8vmmol), 2-aminomethyl-1-ethyl-pyrrolidine (882mg, 6.88mmol) and triethylamine (1.92ml, 13.7bmmol) were reacted. The crude product (2.64 g) is used in the next stage without purification. LC-MS (t/z) 382.0 (M). -I IM-((1-ethyl-pyrrolidin-2-yl)methyl/|-6b-chloro-2-hydroxy-3-nitrobenzenesulfonamide

According to the general hydrolysis method described in example 15, crude

Mami M-((1-ethylpyrrolidin-2-ylmethyl1-2,6-dichloro-Z-nitrobenzene sulfonamide (1.50g), 6095 Ma (471mg, 11.7vmmol) and "g" water (85μl, 4.72mmol) subjected to the reaction to obtain the crude product (1.98 g), which is used in the next step without purification.LC-MS (t/z2) 364.2 (M).

I-((1-ethyl-pyrrolidin-2-yl)methyl/)|-3-amino-b-chloro-2-hydroxy-benzenesulfonamide "2 According to the general hydrogenation method described in example 15, crude

M-((1-ethyl-pyrrolidin-2-ylylmethyl|-b-chloro-2-hydroxy-3-nitrobenzenesulfonamide) (2.18g) is reduced with hydrogen and 1095

Ра/сС (З0Омг). The crude product (1.85 g) is used in the next stage without purification.

M-(2-bromophenyl)-M'-I(4-chloro-3-(1-ethyl-pyrrolidin-2-yl)umethyl-aminosulfonyl|-2-hydroxyphenyl|urea hydrochloride

IF) According to the general method for the preparation of urea described in example 15, crude imi) IM-((1-ethyl-pyrrolidin-2-yl)methyl/)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (616 bmg ) and 2-bromophenyl isocyanate (17 mg, 0.89 mmol) undergo a coupling reaction to obtain the desired urea (14 mg, 390 for 4 stages). 60 LC-MS (t/g2) 533.0 (M).

M-(4-chloro-3-K1-ethyl-pyrrolidin-2-yl)umethylaminosulfonyl|)|-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea hydrochloride

According to the general method of obtaining urea, which is described in example 15, crude

I-I 1-ethyl-pyrrolidin-2-yl)umethyl/|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (616 mg) and 65 2,3-dichlorophenyl isocyanate (167 mg, 89 μmol) are subjected to a coupling reaction to obtain the desired urea (1Zmg, 2.395 for 4 stages). LC-MS (t/zg) 523.2 (M).

IM-(4-chloro-3-(1-ethyl-pyrrolidin-2-yl)umethylaminosulfonyl|-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea hydrochloride

According to the general method of obtaining urea, which is described in example 15, crude

IM-((1-ethyl-pyrrolidin-2-yl)methyl)|-3-amino-b-chloro-2-hydroxybenzenesulfonamide (410 mg) and 2-chlorophenyl isocyanate (249 mg, 1.62 mmol) are subjected to a coupling reaction to obtain the desired urea (5Omg, 9.695 for stage 4).

LC-MS (t/z2) 487.2 (M).

Compounds of formula (I) or their pharmaceutically acceptable salts can be used for the purpose of manufacturing a medicinal product for or preventing the therapeutic treatment of any pathological condition in or in a human 70 other mammal, aggravated or caused by excessive or unregulated production of cytokine 1I-8 cells of the specified mammal, including, but not limited to, monocytes and/or macrophages, or other chemokines that bind to II receptors; or p, which are also called type I or type I receptors.

Accordingly, the present invention relates to a method of treating a chemokine-mediated disease, wherein said chemokine is a chemokine that binds to I/-8 5 or p receptors, and wherein said method involves administering an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.

In particular, these chemokines are 1-8, zKOo, COD, OKO, MAR-2 or EMA-78.

Compounds of formula (I) are administered in amounts sufficient to inhibit cytokine function, and in particular, II-8, OKO, OKCOod, OKOu, MAR-2, or EMA-78, so that their physiological function is biologically regulated to normal levels. or, in some cases, to subnormal levels, which would result in the attenuation of the pathological condition. So, for example, in the context of this description, abnormal levels of II-8, zZKOso, KOD, OKO"

MAR-2 or EMA-78 are considered to be: (i) levels of free P/-8 that exceed 1 picogram per ml; (iii) any cellular levels of I-8, ZKOo, COD, OKOUu, MAP-2 or EMA-78 that exceed normal physiological levels; or (iii) the levels of I--8, ZKOo, COD, ZKOUu, MAR-2 or EMA-78, which exceed the basal levels in tissues or cells in which 1-8, zZKOo, COD, SKOUu, MAR-2 are present or EMA-78, respectively. c 25 It has been shown that the compounds of formula (I) have a longer (5) and have improved bioavailability (o) when administered orally compared to the compounds described in applications M/O 96/25157 and MO 97/29743, which are administered in this description by reference.

There are many pathological conditions in which the production of excess and unregulated levels of III-8 will lead to the enhancement and/or induction of the disease. Chemokine-mediated diseases are psoriasis, atonic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, (o) adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, sepsis caused by gram-negative bacteria, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, (ze) 35 thrombosis, graft-versus-host reaction, Alzheimer's disease, allograft rejection, malaria, m restinosis, angiogenesis , atherosclerosis, osteoporosis, gingivitis, unwanted release of hematopoietic stem cells, and diseases caused by respiratory viruses, herpesviruses and hepatitis viruses, meningitis, encephalitis caused by herpes virus, CNS vasulitis, brain injuries, CNS tumors, subarachnoid hemorrhage, injuries caused by surgical intervention, interstitial pneumonitis, hypersensitivity, and rheumatism, crystal-induced diarrhea, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airway obstruction, hypersensitivity respiratory tract, :z" obliterating bronchiolitis causing pneumonia, bronchiectasis, bronchiolitis, obliterating bronchiolitis, chronic bronchitis, pulmonary heart, shortness of breath, emphysema, hylercapnia, excessive lung expansion, hypoxemia, hypoxia, reduction of lung volume after surgery, pulmonary fibrosis, pulmonary hypertension, -1 hypertrophy of the right ventricle, sarcoidosis, diseases of the small airways, violation of the ventilation-perfusion process, stridor and lupus. (95) These diseases are characterized mainly by massive neutrophilic infiltration, T-cell infiltration or revascularization, and are associated with increased production of cytokines 1-8, ZKO y, ZKOD, oKOUu, MAP-2 or EMA-78, which are responsible for chemotaxis of neutrophils to areas of inflammation or directed growth of re) endothelial cells. Unlike other inflammatory cytokines (I-I, TM and 1-6), 1-8, oKOo, COD, OKO", o MAR-2 or EMA-78 have a unique ability to stimulate chemotaxis of neutrophils, to release enzymes, including , but not limited to it, the release of elastases, as well as to the production and activation of superoxide, o-chemokines, and in particular, II/-8, ZKOso, COD, KO, MAP-2 or EMA-78, which act with the help of II receptor -8 type | or III, can stimulate neovascularization of tumors by inducing directed growth of endothelial cells. Therefore, inhibition of II -v8-induced chemotaxis or activation can lead to i) a direct decrease in neutrophil infiltration. Recent data also indicate a definite role of chemokines in the treatment of HIV infections,

Shshetanp ei ai., Mayte 381, pp. 661 (1996) and Kosher ei ai., Mayige 381, pp. 667 (1996)). 60 Currently available data also indicate the use of I/-8 inhibitors for the treatment of atherosclerosis. In the first work |Voizmegi ei ai., 9U.Siip.OIpmevi 1998, 101:353-363), it was shown, with the help of bone marrow transplantation, that the absence of I/-8 receptors on stem cells (and therefore on monocytes/macrophages) leads to a decrease in the formation of atherosclerotic plaques in mice with a deficiency of the I OI receptor. Other works that confirm these facts are given below: IArozioioriotsioz ei ai., Apegiozsieg. Tigot Magzs.Vio|. 65 1996, 16:1007-1012; ши ей аиЙ., Agpegiozsieg. Tpgotbr.mavzs.Vioi. 1997, 17:317-323; Nod eishiaai.,

AiSHPegozsiegovii, 1996, 127:263-271; MUapd sei ai., 9. Vioi. Spet. 1996, 271:8837-8842; Mie, ei ai., Eishg. 3.

RIPPaptasoi. 1993, 240:81-84; Kosp eyi aiYi., At.).RaiyoYi. 1993, 142:1423-1431; | ее ее a). And so on. Gay, 1996, 53, 109-113; and TetgkenNats ei ai., Apegiozsieg. Tygotb. 1994, 14:47-53).

The present invention also relates to methods of treatment of individuals with an existing acute lesion of the CNS, as well as its prevention in individuals approximately susceptible to lesions of the CNS, using compounds of formula (I), which are antagonists of chemokine receptors.

As used herein, the term "CNS lesions" refers to an open or penetrating head injury, such as a surgical injury, or a closed head injury, such as a head injury. This definition also includes ischemic stroke, and in particular, in the area of the brain.

Ischemic stroke can be defined as a focal neurological disorder caused by insufficient blood supply to a specific area of the brain, usually resulting from embolism, thrombosis, or focal blockage of blood vessels by atherosclerotic plaques. The role of inflammatory cytokines in this area was discovered, and the present invention relates to a method of possible treatment of these lesions. There is already 7/5 Relatively little experience in treating acute lesions such as those listed above.

TME is a cytokine that has a pro-inflammatory effect, including the expression of a molecule that has adhesive properties in relation to an endothelial leukocyte. Leukocytes infiltrate ischemic areas of the brain, and therefore compounds that inhibit or reduce TME levels may be used to treat ischemic brain damage. | See work (ish ei ai.,, ZigoKe, Moi. 25, Mo 7, yr. 1481-88 (1994)), description

Which is entered using a link.

Models of closed brain injuries and their treatment with mixed agents 5-I 0/CO are discussed in the work

IZpoipati ei ai., 9U.oi Maivs 5 Siipisa! Rpuzioyudu apa RIagtasoiodu, Moi.3, Mo.2, pp. 99-107 (1992) |), the description of which is introduced by reference. Treatment that reduces edema formation has been found to improve functional prognosis in treated animals. with

Compounds of formula (I) are administered in an amount sufficient to inhibit the binding of II/-8 to receptors 1-8 alpha or beta, which occurs as a result of the binding of these compounds to the specified receptors, which is evidenced by a decrease in chemotaxis and activation of neutrophils . The finding that the compounds of formula (I) are inhibitors of I/-8 binding is based on the effects of the compounds of formula (I) in the Ip myo receptor binding assays described in this application. It was shown that the compounds of the formula (I) are inhibitors of the II--8 type II II-8 receptors.

As used herein, the term "II-I-mediated disease or pathological condition" means any or all pathological conditions in which II-8, ZKO 5, COD, OKO, MAR-2 or EMA-78 play a defined role or "I by producing I/-8, ZKO o, COD, ZKOUu, MAP-2, or EMA-78 themselves, or by their production of another monokine that is released, including, but not limited to, 1-1, I/-6, or TME. And therefore, a pathological condition, Shk in which 1-1 is the main component, the production or action of which enhances or induces a reaction in response to h-

I/-8 should be considered as a pathological condition, mediated by II! -8.

As used herein, the term "chemokine-mediated disease or pathological condition" refers to any or all pathological conditions in which chemokines that bind to the II-8 receptor, or D receptor, play a defined role, including, but not limited to them, II/-8, KO o, SKOD, OKOUu, MAR-2 or EMA-78. Such conditions include a pathological condition in which II-8 plays a defined role either by producing II-8 itself or by causing it to produce another monokine that is released, including, but not limited to, I! -1I, I -6 or h» TME. Therefore, a pathological condition in which 1-1 is the main component, the production or action of which enhances or "induces" the reaction in response to II-8, should be considered as a pathological condition mediated by II-8.

As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells, and is a molecule that modulates the interaction between cells in the production of an immune, inflammatory, or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of the cells producing them. So, for example, a monokine is a molecule that is mainly produced and secreted by a mononuclear cell, such as a macrophage and/or a monocyte. However, monokines are produced by many other cells, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, brain stromal cells, epidermal keratinocytes, and B lymphocytes. Lymphokines are molecules that are mainly produced by lymphocytes. Examples of cytokines include, but are not limited to, interleukin-1 (I!-Y), (ze) interleukin-6 (II-6), interleukin-8 (II-8), tumor necrosis factor-alpha (TME-o) and tumor necrosis factor-beta (TME-D).

As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of 59 cells and is a molecule that modulates the interaction between cells in the production of immune, inflammatory or

GF) of the hematopoietic response, and this term is analogous to the term "cytokine" defined above. Chemokine is secreted mainly through cell cytoplasmic membranes 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, KO o, OKOD, OKOUu, MAR-2, 60 EMA-78, IR-1O, MIR-19, MIR-1D, PE4, and MCP 1,2 and 3 .

When using a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy, this compound is, of course, included in a pharmaceutical composition in accordance with standard pharmaceutical practice. Therefore, the present invention also relates to a pharmaceutical composition containing an effective non-toxic amount of a compound of formula (I) and its pharmaceutically acceptable carrier or diluent. for Compounds of formula (I), its pharmaceutically acceptable salts and pharmaceutical compositions that include them,

can be basically administered by any of the standard methods commonly used for drug administration, such as orally, topically, parenterally, or by inhalation. The compounds of formula (I) can be administered in the form of standard dosage forms prepared by combining the compound of formula (I) with standard pharmaceutical carriers according to conventional methods. Compounds of formula (I) can also be administered in the form of standard dosage forms in combination with a known second therapeutically active compound. Said methods may involve mixing, granulating and pressing or dissolving said ingredients required for administration. At the same time, it should be noted that the form and nature of a pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient, in combination with the 7/0 it is used, the method of administration and other well-known factors. This carrier must be "acceptable" in the sense that it must be compatible with the other ingredients of this composition and not have a negative effect on the recipient.

The pharmaceutical carrier used can be, for example, either solid or liquid. Examples of solid carriers are lactose, high-grade gypsum, sucrose, talc, gelatin, agar, pectin, gum arabic, /5 magnesium stearate, stearic acid, etc. Examples of liquid carriers are syrup, peanut oil, olive oil, water, etc. Similarly, this carrier or diluent may include a sustained release material well known in the art, such as glycerol monostearate or glycerol distearate, alone or in combination with a wax.

A wide range of pharmaceutical forms can be used. So, for example, if a solid carrier is used, then this drug can be tableted, placed in a hard gelatin capsule in powder or granular form, or made in the form of a lozenge or pill. The amount of solid carrier can vary widely, but preferably, it is from about 25 mg to about 1 g. If a liquid carrier is used, this preparation can be made in the form of a syrup, emulsion, soft gelatin capsule, a sterile liquid for injection, such as a liquid filled into an ampoule, or as an anhydrous liquid suspension.

Compounds of formula (I) can be applied locally, that is, by non-systemic administration. Such i) application involves application of the compound of formula (I) externally to the epidermis or introduction into the buccal cavity, instillation of the specified compound into the eye, ear or nose, so that this compound does not, in principle, enter the bloodstream. In contrast, systemic administration involves oral, intravenous, intraperitoneal, or intramuscular administration.

Compositions suitable for topical application are preparations suitable for the penetration of the medicinal product through the skin at the site of inflammation, such as liquid ointments, lotions, creams, thick ointments or pastes, and drops suitable for administration to the eyes , or ears and nose. The active ingredient can be from 0.00195 to 109% by weight, for example, from 195 to 290% by weight of the composition. However, it can be up to 109 wt.m., but preferably, it is less than 595 wt.m., and more preferably, from 0.195 to 195 wt.m., by weight of the composition. M

According to the present invention, lotions are preparations suitable for application to the skin or instillation into the eyes. The eye lotion may include a sterile aqueous solution, optionally containing a bactericide, and may be prepared by methods similar to those for making drops. Lotions or liquid ointments for application to the skin may also include a rapid drying and cooling agent such as acetone, and/or a humectant such as glycerin or an oil such as castor oil or peanut oil. According to this invention, creams, thick ointments or pastes are semi-solid compositions of the active ingredient for external use. They can be made by mixing the active ingredient in ;" in finely ground or powdered form, taken alone or in suspension solution in an aqueous or anhydrous liquid, by means of a suitable device and using a fatty or non-fatty base. This base may contain hydrocarbons such as hard, soft or liquid paraffin, glycerin, beeswax, metallic soap, slime, -And natural oil such as almond, corn, peanut, castor or olive oil; lanolin (wool fat) or its derivative or a fatty acid such as stearic or oleic acid in combination with an alcohol such as propylene glycol or macrogel. This composition may include any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural resins, cellulose derivatives or inorganic materials such as silica and other ingredients such as lanolin may also be included. o In accordance with the present invention, the drops may contain sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably include surface - active substance. Then, the resulting solution can also be clarified by filtration and transferred to a suitable container, which is then sealed and sterilized by autoclaving or

F) holding at 98-1002C for half an hour. Alternatively, the specified solution can be sterilized by filtration and transferred to a container under aseptic conditions. Examples of bactericidal and fungicidal agents suitable for inclusion in these drops are phenyl mercury nitrate or acetate (0.002905), benzalkonium chloride (0.0195) and chlorohistidine acetate (0.0195). Suitable solvents for preparing an oil solution are glycerin, diluted alcohol and propylene glycol.

The compounds of formula (I) can be administered parenterally, that is, by intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are especially preferable. Suitable dosage forms for such administration b5 Can be prepared by standard methods. The compounds of formula (I) can also be administered by inhalation, that is, by intranasal or oral inhalation. Suitable dosage forms for the indicated administration, such as an aerosol composition or a metered dose inhaler, can be prepared by standard methods.

For all methods of use of the compounds of formula (I) described herein, the daily oral dose is preferably from about 0.01 to about 8Omg/kg based on total body weight. The daily parenteral dose is preferably from about 0.001 to about 8Omg/kg based on the whole body weight. The daily dose for local administration is preferably from about 0.1 to about 15Omg/kg based on the entire body weight and is administered from one to four times, and preferably two times a day. The daily dose for inhalation is preferably from about 0.01 mg/kg to about mg/kg per day. It should also be noted that the optimal amount and 7/0 distribution of individual doses of the compound of formula (I) or its pharmaceutically acceptable salt depends on the nature and degree of the disease amenable to treatment, on the form, method and place of administration, as well as on the specific patient who is treatable, and this optimal amount can be determined by standard methods.

It should also be noted that the optimal course of treatment, i.e., the number of doses of the compound of the formula (Its) or its pharmaceutically acceptable salt, administered daily for a specified number; days, can be established 7/5 by a specialist using standard tests used to prescribe a course of treatment.

The present invention is described in the following biological examples, which are given for illustrative purposes only and should not be considered as limitations of the present invention.

Biological examples

The inhibitory effect of the compounds of this invention on chemokines I/-8 and KO was determined in the following tests

Mygo-analyses:

Receptor binding assay

H25SHCI/-85 (human recombinant) with a specific activity of 2000Ci/mmol was obtained from Ategepat

Sogr., Apipdiop Neiidniv, I. ZKO»d was received from MEM-Memzhm/ Epdiapa Mysieag. All chemical compounds were of analytical grade. High levels of recombinant human type II -8 receptors o and VD were separately expressed in "M cells of the Chinese hamster ovary, as previously described |Noitvs ei a!., Zsiepse 253, 1278)|. Membranes of Chinese hamster ovary cells were homogenized according to the previously described protocol.

U.VioI.Spet., 249, pp. 2195-2205 (1974)), except that the buffer for homogenization was replaced by 10MM

Tris-HCl, 1MM Mazo, 0.5MM EOTA (ethylenediaminetetraacetic acid), 1MM RMBE (o-toluenesulfonyl fluoride), 0.5mg/l leupeptin, pH 7.5. The concentration of the membrane protein was determined according to (2) using a kit for microanalysis of Riegze Co. using bovine serum albumin as a standard. All Ge! analyzes were performed in a 96-well microplate. Each reaction mixture contains 7291-III -8 (0.25nM) or 729I- ZVOd, and 0.5 µg/ml II -8Co; or 1.0 µg/ml I -8KD membrane in 20 mM bis-Tris-propane and 0.4 mM Tris-HCl buffer, pH 8.0, which contains 1, 2 mM Ma5oO5, 0.1 mM EOTA, 25 mM Ma and 0.0395 SNARb. In addition, the desired drug or compound that was previously dissolved in DMSO was added to a final concentration from 0.01 mM to 100 µM. m

The analysis was initiated by the addition of 722I-II-8. After standing for 1 hour at room temperature, the contents of the plate were collected, using a Toties 9b-well plate collector, on a glass fiber filter blocked with a mixture of 195 polyethyleneamine/0.595 B5A, and washed three times with 25 mM Masi, 10 mM Tris-HCII, 1 mM MazoO, , 0.5 EOTA, 00396 SNARB, pH 7.4. The filter was then dried and counted on a Weilaria liquid scintillation counter. Recombinant receptor I/-8K of type I, hereinafter also referred to as non-permeable receptor, and recombinant receptor I-8K or type I, hereinafter also referred to as . permeative receptor. "" In this assay, representative compounds of formula (I), Examples 1-106, have positive inhibitory activity at levels of ISvoxZOmMkm.

Analysis of chemotaxis -I The inhibitory properties of the indicated compounds were determined in the analysis of chemotaxis of neutrophils, which is described in manual I (Siggepi Rgoiosoiiv ip Ittipiodu, my.I, Zi"urri I, Opii 6.12.3), which in its entirety about is incorporated into this description by reference. Neutrophils were isolated from human blood as described in the manual (Siggepi Rgoiosoiiv ip Ittipiodu, my, Ziurri I, Opii 3.2.5.4i, which is incorporated in its entirety

In this description by reference. Chemoattractants for II/-8, KO o, ZKOr, KO and MAR-2 were placed in the lower compartment of a 48-well chamber (Meshgo Rgobe, Sabrip dopp, MO) at a concentration from 0.1 to ТООНМ. These two compartments were separated by a half-carbonate 5 μM filter. When testing the compounds of this invention, they were mixed with cells (0.001-1000NM) immediately before adding the cells to the upper chamber. Incubation was carried out for a period of time from about 45 to 90 minutes at approximately 372C in a 5956 CO" incubator with increased humidity. At the end of the incubation period, the polycarbonate membrane was removed and its upper side was washed, then the membrane was stained using the OY OciskK staining protocol (Vakhieg Rhodisiv,

IF) MSOSam/ Ragk, BOTH). Cells migrating in the direction of the chemokine were visually counted under a microscope. Basically, each sample was counted in four fields, these numbers were averaged and the average number of migrating cells was obtained. Each sample was tested in triplicate, and the test was repeated at least four times 60 times for each compound. No compound was added to some cells (positive control cells) and these cells presented the maximal chemotactic response for these cells. In the case when a negative control (unstimulated cells) was required, chemokines were not added to the lower compartment of the chamber. The difference between the positive control and the negative control is the chemotactic activity of the cells.

Elastase Release Assay 65 Compounds of this invention were tested for their ability to prevent elastase release from human neutrophils. Neutrophils were isolated from human blood as described in the manual

Mo, zi, Urri I, Opic 7.23.1). PMM cells, 0.88x105, suspended in Ringer's solution (Massi 118, KSI 4.56, MansSo», 25, KNoRO,, 1.03, glucose, 11.1, NERE5, 5MM, pH 7.4) were placed in each well of a 96-well plate in volume

BOmkl. The tested compound (0.001-1000 OHM) in a volume of 5 Ωcl, cytochalasin B in a volume of 5 Ωcl (2 Ωkg/ml) and Ringer's buffer in a volume of 5 Ωcl were added to this tablet. These cells were left to heat (372C, 5956 CO, 9595 KN) for 5 minutes, and then 1-8, zZKOo, COD, SKOUu or MAP-2 were added to a final concentration of 0.01-1000 nM. The reaction was carried out for 45 minutes, and then the 9b-well plate was centrifuged (800 xg, BbBmin.) and 100 µl of the supernatant was removed. This supernatant was added to a second 96-well plate, and then an artificial elastase substrate (MeOzZys-Aa-AIa-Rho-MaI-AMS, Moma Viospet, Ia Khdoia, CA) was added to a final concentration of 70 bmcg/ml, dissolved in phosphate-buffered saline. physiological solution. The plate was then immediately placed in a fluorescent 9b-well plate reader (Suioitsog 2350, MiProge, Waitoga, MA) and data was collected from

With minute intervals by the McCait method, 9U.Vioi.Spet. 254, 4027 (1979). The amount of elastase released from PMM was calculated by measuring the rate of decomposition of MeOsis-AlIa-AlIa-Rgo-MaI-AMO.

Analysis for TME-o, in case of traumatic brain injury

This analysis was performed to assess the expression of tumor necrosis factor mRNA in specific brain regions after experimentally induced traumatic brain injury (TBI) in rats by unilateral fluid percussion. Adult Zrgadoe-Oauleu rats (p-42) were anesthetized with pentobarbital sodium (bOmg/kg, i.r.) and their brains were subjected to moderate damage by unilateral percussion with a liquid (2.4 atm.) directed above the left temporal lobe of the cortex of the brain (p-18), or rats were subjected to "false" treatment (anesthesia and surgical intervention that does not cause damage to the brain, p-18). At 1.6 and 24 hours after brain injury, the animals were killed by decapitation, the brains were removed, and tissue samples were obtained from the left (injured) parietal lobe of the cerebral cortex (IS), which corresponds to the region opposite the right lobe of the cerebral cortex (CO ), the area adjacent to the damaged area of the parietal lobe of the cerebral cortex (GA), which corresponds to the adjacent area in the right lobe of the cerebral cortex (CA), the left hippocampus (IN) and the right hippocampus (CN). All RNA was isolated, Northern blot hybridization was carried out and quantified in comparison with TME RNA of a positive control (macrophage-10095). A significant increase in the expression of TME-y mRNA was observed in IN (104 -1795 from the positive control, p«0.05 in comparison with the false injury), C (105 21905, p«0.05) and GA (698596, p«0.01) and in the traumatized cerebral hemisphere 1 hour after injury. Increased expression of TME-o mRNA was also observed in I H (464-895, p«0.05), I C (303905, p«0.01) and GA (32--396, p«0.01) after b hours, F) and normalized 24 hours after the injury. In the opposite hemisphere, TME-9 mRNA expression increased in CN (464-295, p«0.01), CS (4-3905) and CA (22--8965) after 1 hour, and in CN (28-- 1195), CS (7-590) and KA (26-695, p«0.05) after b hours, but not after 24 hours after injury. In case of false injury to the brain (surgical intervention without injury) or in healthy animals, in not a single case was there a corresponding change in the expression of TME-ou mRNA in all b regions of the brain in any hemisphere. The obtained results showed that after damage to the parasagittal region of the brain caused by liquid percussion, the temporary expression of TME-o mRNA changed in specific regions of the brain, including regions of the non-traumatized hemisphere. Since TME-u is capable of inducing nerve tissue growth factor (NGF) and stimulating the release of other cytokines from activated astrocytes, this post-traumatic change in the expression of TME-u genes plays an important role in both the acute and regenerative response to injury. central nervous system a ANS injury model for mRNA 1I--1r -» This analysis is characterized by the regional expression of interleukin 1r (1-13) mRNA in specific brain regions after experimentally induced traumatic brain injury (TBI) in rats by unilateral fluid percussion. Adult Zrgadoe-OaulLeu rats (p-42) were anesthetized with sodium pentobarbital (bOmg/kg, i.r.) and their brains were subjected to moderate damage by unilateral percussion with liquid (2.4 atm.) directed above the left temporal lobe lobes of the cerebral cortex (p-18), or rats were subjected to "false" treatment (anesthesia and surgical intervention that does not cause brain damage, p-18). At 1, 6 and 24 hours after brain injury, animals were killed on day 20 by decapitation, the brains were removed, and tissue samples were obtained from the left (injured) parietal lobe (CI), corresponding to the region opposite the right lobe of the cerebral cortex. (CS), area m) adjacent to the damaged area of the parietal lobe of the cerebral cortex (GA), which corresponds to the adjacent area in the right lobe of the cerebral cortex (CA), the left hippocampus (IN) and the right hippocampus (CN). All RNA was isolated, Northern blot hybridization was performed, and the amount of mRNA 11-13 of brain tissue was expressed as a percentage of 22 radioactivity in relation to the radioactivity of RNA 1I-1d-positive macrophage, which was loaded on the same

F! the gel itself. 1 hour after the brain injury, a noticeable and significant increase in the expression of mRNA 1I(-1r) was observed in SS (20.0-0.795, from the positive control, p-b, p«0.05 in comparison with the false one after the injury of the animal), IN (24.5--0.9905, p«0.05) and HA (21.5--3.195, p«0.05) in the affected cerebral hemisphere, which remained at an elevated level for hours, including after the defeat in /C (4.0 0.495, p-b, p«005) and in IN 60 (5.0--1.395, p«0.05)3. In case of accidental injury or in non-traumatized animals, in none of the relevant areas in the brain, no expression of II-1p mRNA was observed. The obtained results showed that after TM, the temporary expression of 1-1 dD mRNA was regionally stimulated in specific regions of the brain. These regional changes in the expression of cytokines, such as I-1p, play a defined role in 65 All publications, including but not limited to patents and patent applications, cited in the actual specification are incorporated herein by reference as if they were were entered separately in their entirety.

The above description describes the present invention in detail, including its best options.

The scope of the following claims includes modifications and improvements of the specifically described variants of the invention.

It is obvious that, according to the above description, a specialist can independently implement this invention in its entirety without unnecessary experimentation.

Therefore, the examples described here are illustrative and do not limit the scope of the invention.

The embodiments of this invention in which exclusive or privileged rights are claimed are defined below.

Claims (17)

Formula of the invention 10 1. Hydroxydiphenylurea sulfonamides of the formula (1): -alkyl, aryl, aryl-C. -C./-alkyl or heterocyclyl-Co/--alkenyl group, where all the specified groups can be optionally and independently substituted by one to three groups, such as C. 29 halogen, nitro, halogen-substituted C..4-alkyl, C.i.4-alkyl, amino, mono- or di-C.- -alkyl substituted amine, OKa, Ho) c(Ota, MKaC(O)OkK., OS(O)MKK", hydroxy, MKUS(Ok. . ring, optionally substituted, which independently contains, in addition to optionally substituted C 4.4 alkyl, 1-3 groups MKa, 0, o 30 5, 5O or 505, which may be optionally unsaturated; Ka i includes alkyl, aryl, aryl-C, 4-alkyl, heteroaryl, heteroaryl-C. /-alkyl, He) heterocyclic, SOOC, or heterocyclyl-C. /-alkyl group, each of which may be optionally substituted; Ka represents alkyl, aryl, aryl-C 4.4-alkyl, heteroaryl, heteroaryl-C../-alkyl, heterocyclic or heterocyclyl-C. /-alkyl group, each of which may be optionally substituted; Ge) t is equal to a whole number having a value of 1-3; m 35 t" equals 0 or a whole number having a value of 1 or 2; n equals a whole number having a value of 1-3; a is equal to 0 or a whole number having a value of 1-10; Y is equal to 0 or a whole number, having a value of 1 or 2; "du c is equal to a whole number having a value from 1 to 3; - Ki is independently selected from hydrogen, halogen, nitro, cyano, C..4o-alkyl, halogen-substituted C..40o-alkyl, c So-lo-alkenyl, C..1o-alkoxy, halogen-substituted C.-1o-alkoxy, azide, З(ОхДК;, (СКаКа)д5(ОзКА, hydroxy, :з» hydroxy-substituted C. /-alkyl, aryl, aryl-C../-alkyl, aryl-C./-alkenyl, aryloxy, aryl-C./-alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl-C./-alkenyl, heteroaryl-C./-alkyloxy, heterocyclyl, heterocyclyl-C 4 /-alkyl, heterocyclyl-C. /-alkyloxy, heterocyclyl-Co 4o-alkenyl, (СКаКа)аМКАК», -1 (СКаКа)дЕ(О)МК AK, Со 1o-alkenyl-СХО)МКАК», (СКаКа )dS(O)MKa Ko, Z(O)5Ka, (SKaKa)aS(O)MA 414, Co. 1o-alkenyl-CSO)K 44, So l1o-alkenyl-C(O)OK 4, (SKaKa)dS(O)OK i, (SkKaKaddOS(OK i, (StKaKa)dachKAS(O)K i, (95) (SEaKv)ds(Me MAK, (SKaKv)dchKAS(MA IA, (STKaKa)dchNZ(OnAK.z, (SKaKv)d5(ONMKAK), or two groups K., і» taken together can form O-(CH 2) 5O or 5-6--len saturated or unsaturated ring, and where alkyl, aryl, arylalkyl, heteroaryl and heterocyclyl groups can be optionally substituted; (Ce) 20 Ku and K5 independently represent hydrogen, optionally substituted C 4.4-alkyl, optionally substituted by aryl, optionally substituted aryl-C../-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C..4-alkyl, heterocyclyl, heterocyclyl-C. ./-alkyl, or K,., and K5, taken together with the nitrogen atom to which they are bound, form a 5-7-membered ring which may, but does not necessarily, contain an additional heteroatom selected from isO, M and 5; Ke and KK independently represent hydrogen or C 4 -C 1 -alkyl, heteroaryl, aryl, alkylaryl, HF) alkyl-C 1 -heteroalkyl, each of which can be and optionally substituted, or Kb and K;7, taken together with the HF nitrogen atom to which they are bound, form a 5-7-membered ring, which may, but not necessarily, contain an additional heteroatom selected from oxygen, nitrogen or sulfur, and which may be optionally substituted; in M is hydrogen, halogen, nitro, cyano, halogen-substituted C 4-40-alkyl, C-4-4-alkyl, C 0-alkenyl, C 1-alkoxy, halogen-substituted Si. 1o-Alkoxy, azide, (SKaKa)de(OXKa, (SKaKa)aOKa, hydroxy, hydroxy-substituted C./-alkyl, aryl, aryl-C..-alkyl, aryloxy, aryl-C..-alkyloxy, aryl-C » 1o-alkenyl, heteroaryl, heteroarylalkyl, heteroaryl-C./-alkyloxy, heteroaryl-C 40-alkenyl, heterocyclyl, heterocyclyl-C 4.2-alkyl, heterocyclyl-C» 4o-alkenyl, (СКаКа)аМКаАКо, Со 10-alkenyl -"С(О)МКАК»5, vv AvKv)aS(O MK, (SKeRv)d(O)MK Ko, Z(O)zKv, (SKaKv)dS(O Ku, Solo-alkenyl-С(O) MK. 1, (SKaKa)die (OK 11» Co-Sio-alkenyl-SHO)OK. 4, (SkKakazDOoS(ОЖ 11» (SKaKa)dichkaA (OK. 1, (SKaKa)aMN(OX 3, (SKaKv)de(OHMA B", (SKaKa)dS(MKA)IMKAK", (SKaKv)dchKAS(MA 5), or two groups of U, taken together, can form O-(CH.)O or 5-6- is a saturated or unsaturated ring, and where alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl groups may be optionally substituted; Ka is hydrogen or C-4-alkyl; K»o is hydrogen or C ..4-alkyl; Co represents C..40-alkyl-C(O)2 Pv; K.i41 is hydrogen, optionally substituted C 4.4-alkyl, optionally substituted aryl, optionally /o substituted aryl-C.i-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C. .-alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl-C 4 /-alkyl; Kiz, In the appropriate case, represents C 1-4-alkyl, aryl, aryl-C..-alkyl, heteraryl, heteroaryl-C 4.4-alkyl, heterocyclyl or heterocyclyl-C. /-alkyl; or pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, where K.; substituted in the 4-position by an electron-withdrawing group. 3. The compound according to claim 1, where K/ represents halogen, cyano or nitro. 4. The compound according to claim 1, where K is a halogen. 5. The compound according to claim 1, where Ku independently represents fluorine, chlorine or bromine. b. The compound according to claim 1, where M is monosubstituted in the 2'-position or in the 3'-position, or disubstituted in the 2- or in the 3'-position of the monocyclic ring. 7. The compound according to claim 1, where M is a halogen. 8. The compound according to claim 1, where X independently represents fluorine, chlorine or bromine. 9. The compound according to claim 1, where Ku represents hydrogen, C..4-alkyl or C..-alkyl substituted by SIOOOH or C(IO)OK". high school 10. The compound according to claim 1, where Х is a halogen, n is 1 or 2, K/ is a halogen, t is 1 or 2, and КУ is independently hydrogen, C..4-alkyl or C..4- alkyl substituted by SIOOOH or C(IOOC". i) 11. The compound according to claim 1, selected from the group consisting of: M-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea; M-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-M'-(2,3-dichlorophenyl)urea; M-(2-hydroxy-3-M"-benzylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea; M-(2-hydroxy-3-M"-benzylaminosulfonyl-4-chlorophenyl)- M'-(2,3-dichlorophenyl)urea; Me IM-(2-hydroxy-3-(M",M"-dimethyl)aminosulfonyl-4-chlorophenyl)|-M'-(2,3-dichlorophenyl)urea; "g M-(2-hydroxy-3-M",M"-dimethylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea; M-(2-hydroxy-3-M"-methylaminosulfonyl-4-chlorophenyl)-M'-(2-bromophenyl)urea; me) M-(2-hydroxy-3-M"-methylaminosulfonyl-4-chlorophenyl)- M'-(2,3-dichlorophenyl)urea; i- I-(2-hydroxy-3-IM-(methoxycarbonylmethyl)aminosulfonyl|-4-chlorophenyl|-M'(2,3-dichlorophenyl)urea; I-(2-hydroxy-3-(M"-(2 -methoxycarbonyl)methyl)aminosulfonyl-4-chlorophenyl|-M'(2-bromophenyl)urea; I-(2-hydroxy-3-((M"-(2-carboxymethyl)aminosulfonyl|-4-chlorophenyl|-M' -(2,3-dichlorophenyl)urea; I-(2-hydroxy-3-(M"-2-carboxymethyl)aminosulfonyl-4-chlorophenyl|-M'(2-bromophenyl)urea; "IM-(2-hydroxy -3-aminosulfonyl-4-chlorophenyl|-M'-(2-chlorophenyl)urea; with 1M-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl|-M'-phenylurea; . IM-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl|-M'-(2-phenoxyphenyl)urea; and» IM-(2-hydroxy-3-(M"-(3-carboxyethyl)aminosulfonyl)| -4-chlorophenyl|-M'(2-bromophenyl)urea; I-(2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl|-M'E(2-bromophenyl)urea; IM-(2-hydroxy- 3-isopropylaminosulfonyl)-4-chlorophenyl|-M'-(2-chlorophenyl)urea; -I IM-(2-hydroxy-3-isopropylaminosulfonyl)-4-chlorophenyl|-M'E(2,3-dichlorophenyl)urea ; M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2-methoxyphenyl)urea; o M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2, 3-methylenedioxyphenyl)ureas; their M-(2-benzyloxyphenyl)-M'-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)ureas; IM-3-(M"-allylaminosulfonyl)-4-chloro-2- hydroxyphenyl|-M'(2,3-dichlorophenyl)urea; and IM-(d-chloro-2-hydroxy-3-((M"-(2-trifluoroethyl)aminosulfonyl|phenyl|)|-M'-(2 ,3-dichlorophenyl)urea; o IM-(2,3-dichlorophenyl)-M'-(2-hydroxy-4-methoxy-3-M"-(phenylaminosulfonyl)phenyl|urea; M-(2-bromophenyl)- M'-(2-hydroxy-4-methoxy-3-M"-(phenylaminosulfonyl)phe nil|urea; IM-(d-chloro-2-hydroxy-3-((M"-(2-methoxyethyl)iaminosulfonyl|-phenyl|-M'E2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'- I(4-chloro-2-hydroxy-3-((M"-(2-methoxyethyl)aminosulfonyl|phenyl|urea; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3 -(4-morpholinylsulfonyl)phenyl|urea; F) IM-(d-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea; ka I-IZ- IM"-(3-(tertbutoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)s urea; in M-(2-bromophenyl)-M'-I3-(М "-(3-(tertbutoxycarbonylamino)propylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urea; M'-(3-(M"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M '-(2-bromophenyl)urea trifluoroacetate; M'-(3-(M"-(3-aminopropyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/)|-M'-(2-bromophenyl)urea hydrochloride; M'-3-(M"-(3-aminopropyl)uaminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'(2,3-dichlorophenyl)urea 65 trifluoroacetate; M-(2-bromophenyl)-M'- I3-(M"-(2-(tertbutoxycarbonylamino)ethylaminosulfonyl)-4-chloro -2-hydroxyphenyl|urea and; IM-3-(IM"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/)-M'-(2-bromophenyl)urea; M-(2-bromophenyl)-M'-I3-( (4-(tertbutoxycarbonyl)piperazin-1-yl|!sulfonyl|-4-chloro-2-hydroxyphenyl|urea; IM-IZ-((4-("tertbutoxycarbonyl)piperazin-1-yl|sulfonyl|-4-chloro -2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; IM-(d-chloro-2-hydroxy-3-(1-piperazinylsulfonyl)phenyl|-M'-(2,3-dichlorophenyl) urea trifluoroacetate; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(piperazin-1-ylsulfonyl)phenyl|urea trifluoroacetate; IM-(d-chloro-2-hydroxy-3 -(M"-(3-methylthiopropyl)aminosulfonyl|-phenyl)|-M'(2,3-dichlorophenyl)urea; 70 M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy- 3-(M"-(3-methylthiopropyl)aminosulfonyl|phenyl|urea; potassium salt M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea; sodium salt M -(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-3-(M", M"-di-(2-methoxyethyl)-aminosulfonyl|-2-hydroxyphenyl|urea; IM-(D-chloro-3-(M",M"-d i-(2-methoxyethyl)aminosulfonyl|-2-hydroxyphenyl|-N'-(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-3-(M"-(2-(dimethylamino)ethyl|-aminosulfonyl|-2-hydroxyphenyl|urea hydrochloride; IM-(d-chloro-3 -(M"-(2--dimethylamino)ethylaminosulfonyl|-2-hydroxyphenyl|-ME(2,3-dichlorophenyl)urea hydrochloride; IM-(d-chloro-2-hydroxy-3-(M"-( 3Z--methylsulfonyl)propyl|-aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M "-I(Z--"methylsulfonyl)propylaminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethylaminosulfonyl|phenyl|-M'-(2, 3-dichlorophenyl)urea hydrochloride; IM-(d-chloro-2-hydroxy-3-(M"-(2-(morpholinyl)ethyl|iaminosulfonyl|phenyl|-M'-(2-chlorophenyl)urea hydrochloride; sch M -(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-(4-morpholinyl)ethylaminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy -3-(4-thiomorpholinylsulfonyl)phenyl|-M'(2,3-dichlorophenyl)urea; i) M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(4- thiomorpholinylsulfonyl)phenyl|urea; M-(2-bromophenyl)-M'-I(4-chloro-3-(M",M"-di-(2-hydroxyethyl)aminosul phenyl/|-2-hydroxyphenyl|urea; IM-(D-chloro-3-(M",M"-di-(2-hydroxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; o zo IM-(d- chloro-2-hydroxy|-3-(M"-(3Z--"methylsulfinyl)propyl)aminosulfonyl|phenyl|-ME(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'- I(4-chloro-2-hydroxy-3-(M"-3-(methylsulfinyl)propylaminosulfonyl|phenyl|urea; Me M-(2-bromophenyl)-M'-(3-I(M"-(1- tertbutoxycarbonylpiperidin-4-yl)umethylIaminosulfonyl/|-4-chloro-2-hydroxyphen "g yl|Urea; IM-IZ-IM"-(1-tertbutoxycarbonylpiperidin-4-yl)umethyl|-aminosulfonyl|-4-chloro-2 -hydroxyphenyl/|-M'-(2,3-dichlorophenyl)urea; 3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl|urea; IM-(d-chloro-2-hydroxy-3 -(M"-Kpiperidin-4-yl)umethylIaminosulfonyl|phenyl|)|-M'-(2,3-dichlorophenyl)urea trifluoroacetate; « M-(2-bromophenyl)-M'-I(4-chloro-2 -hydroxy-3-(M"-Kpiperidin-4-yl)umethylaminosulfonyl|phenyl|urea with c hydrochloride in; . I-III-(1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-N'(2-bromophenyl)urea; and?" IM-IZ-"1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea; IM-IZ-"1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl/|-M '-(2,3-dichlorophenyl)urea; potassium salt. M-(2-bromophenyl)-M'-(4-chloro-3-(M",M"-dimethylaminosulfonyl)-2-hydroxyphenyl|urea; -I sodium salt M-(2-bromophenyl)-M'-( 4-chloro-3-(M",M"-dimethylaminosulfonyl)-2-hydroxyphenyl|urea; M-(2-bromophenyl)-M'-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl |ureas; o IM-(4-chloro-3-(M"-cyclopropylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea; their IM-(4-chloro-3-(M"-cyclopropylaminosulfonyl) )-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea;M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-propylaminosulfonyl)phenyl| urea; ik IM-(d-chloro-2-hydroxyl-3-(M"-propylaminosulfonyl)phenyl|-ME2,3-dichlorophenyl)urea; o IM-(d-chloro-2-hydroxyl-3-( M"-propylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea; M-(2-bromophenyl)-M'-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|urea; IM -(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea; IM-(4-chloro-3-(M"-ethylaminosulfonyl)-2-hydroxyphenyl| -M'(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I3-(M"-(5-(tertbutoxycarb onylamino)-5-carboxypentylaminosulfonyl|-4-chloro-2-hydroxy F) phenyl|urea; ka IM-IZ-IM"-(5-(tertbutoxycarbonylamino)-5-carboxypentylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; in I-IZ-IM"- (5-(tertbutoxycarbonylamino)-5-carboxypentylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-N'-(2-chlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-(2-hydroxyethyl)aminosulfonyl|urea; M-(2,3-dichlorophenyl)-M'-( 4-chloro-2-hydroxy-3-(M"-(2-hydroxyethyl)aminosulfonyl|urea; M-(2-bromophenyl)-M'-I-3-(M"-((2-bromophenylamino)carboxy| )ethylaminosulfonyl|-4-chloro-2-hydroxyphenyl|urea; that IM-3-(IM"-(2-benzyloxyethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/)-M'-(2-bromophenyl) urea; -BO0- IM-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4-chlorophenyl|-ME(2,3-dichlorophenyl)urea; IM-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4 -chlorophenyl|-M'-(2-chlorophenyl)urea; I-(2-hydroxy-3-(M"-cyclopropylmethylaminosulfonyl)-4-chlorophenyl|-M'(2-bromophenyl)urea; IM-(2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-4-chlorophenyl/|-ME(2-bromophenyl)urea; IM-(2-hydroxy-3-(M"- methoxy-M"-methylaminosulfonyl)-4-chlorophenyl|-M'-(2-chlorophenyl)urea; IM-(2-hydroxy-3-(M"-methoxy-M"-methylaminosulfonyl)-4-chlorophenyl|-M '-(2,3-dichlorophenyl)urea; IM-(2-hydroxy-3-(M"-pyrrolidinylsulfonyl)-4-chlorophenyl|-M'-(2,3-dichlorophenyl)urea; I-(2-hydroxy -3-(M"-pyrrolidinylsulfonyl)-4-chlorophenyl/|-ME(2-bromophenyl)urea; 70 IM-(2-hydroxy-3-(M"-pyrrolidinylsulfonyl)-4-chlorophenyl|-M'-(2-chlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-2 -hydroxy-3-(4-pyridinylaminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy-3-(4-pyridinylaminosulfonyl|phenyl|-M'(2,3-dichlorophenyl)urea; M-(2) -bromophenyl)-M'-I(4-chloro-2-hydroxy-3-((2-(tetrahydro-2-furanyl)methylaminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy-3-( (2-(tetrahydro-2-furanyl)methyl|Iaminosulfonyl|phenyl-M'-(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methylIaminosulfonyl|phenyl|urea; IM-(d-chloro-2 -hydroxy-3-(((2K)-(tetrahydro-2-furanyl)methyl|aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-I (4-chloro-2-hydroxy-3-(((25)-(tetrahydro-2-furanyl)methylIaminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy-3-(((25)-( tetrahydro-2-furanyl)methyl|aminosulfonyl|phenyl)|-M'-(2,3-dichlorophenyl)urea WE; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-cyclopentylaminosulfonyl)phenyl|urea; IM-(d-chloro-2-hydroxy-3-(M"- Cdcyclopentylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea; M-(2-chlorophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-cdcyclopentylaminosulfonyl)phenyl|urea; M -(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea; IM-(d-chloro-2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl|urea; M-(2-chlorophenyl)-M'-(4-chloro- 2-hydroxy-3-(M"-isoxazolidinylaminosulfonyl)phenyl|urea; i) M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(M"-tetrahydroisoxazolylaminosulfonyl)phenyl|urea ; IM-(d-chloro-2-hydroxy-3-(M"-tetrahydroisoxazolylaminosulfonyl)phenyl|-M'-(2,3-dichlorophenyl)urea; M-(2-chlorophenyl)-M'-I(4- chloro-2-hydroxy-3-(M"-tetrahydroisoxazolylaminosulfonyl)phenyl|urea; |phenyl|urea; IM-(d-chloro-2-hydroxy-3-(2-isopropoxyethyl)aminosulfonyl|phenyl|-ME2,3-dichlorophenyl)urea; Me IM-(d-chloro-2-hydroxy- 3-((2-isopropoxyethyl)aminosulfonyl|phenyl|-M'-(2-chlorophenyl)urea; "g M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-((2 -ethoxyethyl)aminosulfonyl|phenyl|urea; IM-(d-chloro-2-hydroxy-3-(2-ethoxyethyl)aminosulfonyl|phenyl|-M'-(2,3-dichlorophenyl)urea; me) IM-(d-chloro-2-hydroxy-3-((2-ethoxyethyl)aminosulfonyl|phenyl|-M'-(2-chlorophenyl)urea; i-M-(2-bromophenyl)-M'-I(4 -chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl|isulfonylphenyl|urea; IM-(4-chloro-2-hydroxy-3-((2-methoxycarbonyl)azetidin-1-yl| !sulfonylphenyl|-M'-(2,3-dichlorophenyl)urea; IM-(4-chloro-2-hydroxy-3-((2-carboxy)azetidin-1-yl|sulfonylphenyl/)-M'-(2 ,3-dichlorophenyl)urea; M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(M"-I3-(4-morpholinyl)propyl|iaminosulfonyl|phenyl|)urea" Hydrochloride; sh2 s IM-(d-chloro-2-hydroxy-3-(M"-I3-"4-morpholinyl)propyl|Iaminosulfonyl|phenyl|-M'(2,3-dichlorophenyl)urea hydrochloride; ; » IM-(d-chloro-2-hydroxy-3-(M"-(3-"4-morpholinyl)/propylaminosulfonyl|phenyl|-M'-(2-chlorophenyl)urea hydrochloride; M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl|urea; -I M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl)|isosulfonylphenyl|urea; IM- (d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|isulfonylphenyl)|-M'-(2,3-dichlorophenyl)urea; o IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-ylsulfonyl|phenyl/|-M'-(2,3-dichlorophenyl)urea; their IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea; IM-(d-chloro-2-hydroxy-3-(5-(-)-(2-hydroxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea; ik M-(2-bromophenyl)-M'-(4-chloro-2-hydroxy-3-(5-(2-methoxycarbonyl)pyrrolidin-1-yl|sulfonylphenyl|urea; o M-(2-bromophenyl)-M'-I(4-chloro-2-hydroxy-3-(5-(2-carboxy)pyrrolidin-1-yl)ylsulfonylphenyl|urea; M-(2-bromophenyl)- M'-I3-IM"-(tertbutyl)aminosulfonyl)-4-chloro-2-hydroxyphenyl|urea; IM-I3-IM"-(tertbutyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'- (2,3-dichlorophenyl)urea; IM-III-IM"-(tertbutyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2-chlorophenyl)urea; I-III-IM"-(5-(tertbutoxycarbonylamino)-5-carboxypentylIaminosulfonyl /)-4-chloro-2-hydroxyphenyl|-M'-(2-chloro F) phenylurea; ka IM-III-IM"-(5-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'-(2-chlorophenyl)urea hydrochloride; in IM-III-IM"-(5-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'(2,3-dichlorophenyl)urea hydrochloride; IM-III-IM"-( 5-amino-5-carboxypentyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl/|-M'E«2-bromophenyl)urea hydrochloride; IM-(d-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; 65 M-(2-bromophenyl)-M'-I(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl|urea; IM-(4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl) -2-hydroxyphenyl|-M'-(2-chlorophenyl)urea; IM-III-IM"-(2-(tertbutoxycarbonylamino)ethylaminosulfonyl)-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea; IM-III-(M"-(2-aminoethyl) )aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl). urea trifluoroacetate; I-III-IM"-(2-(tertbutoxycarbonylamino)ethylaminosulfonyl)|-4-chloro-2- hydroxyphenyl|-M'(2-chlorophenyl)urea and; IM-3-(M"-(2-aminoethyl)aminosulfonyl|-4-chloro-2-hydroxyphenyl|-M'-(2-chlorophenyl)urea trifluoroacetate; IM -(d-chloro-2-hydroxy-3-(M",M"-dimethylaminosulfonyl)phenyl|-M'-(2-chlorophenyl)urea; 70 IM-(4-chloro-2-hydroxy-3-(aminosulfonyl) )phenyl/|-M'-(2-bromo-3-fluorophenyl)urea; IM-(d-chloro-2-hydroxy-3-aminosulfonyl)phenyl|-M'-(2-chloro-3-fluorophenyl) urea; M-(2-bromophenyl)-M'-I(4-chloro-3-(1-ethylpyrrolidin-2-yl)umethylaminosulfonyl|-2-hydroxyphenyl|urea hydrochloride; IM-(4-chloro-3-K1 -ethylpyrrolidin-2-yl)umethylaminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea 7/5 Hydrochloride; IM-(4-chloro-3-(1-ethylpyrrolidin-2-yl)umethylaminosulfonyl |-2-hydroxyphenyl|-M E(2-chlorophenyl)urea hydrochloride or their pharmaceutically acceptable salts. 12. The compound according to claim 11, selected from the group consisting of: M-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-M'-(2,3-dichlorophenyl)urea, IM-(d-chloro- 2-hydroxy-3-(5-(-)-(2-methoxymethyl)pyrrolidin-1-yl|sulfonylphenyl|-M'-(2-chlorophenyl)urea, IM-(d-chloro-2-hydroxy-3- (M"-isoxazolidonylaminosulfonyl)phenyl/|-M'-(2,3-dichlorophenyl)urea, IM-(d-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl|-M'-(2,3 -dichlorophenyl)urea and IM-(D-chloro-3-(M",M"-di-(2-methoxyethyl)aminosulfonyl|-2-hydroxyphenyl|-M'-(2,3-dichlorophenyl)urea). 13. The compound according to claim 12, which differs in that it is in the form of a sodium salt. high school 14. The compound according to claim 12, which differs in that it is in the form of a potassium salt. 15. A pharmaceutical composition containing a compound specified in any of claims 1-14 and a pharmaceutically acceptable carrier or diluent. 16. A method of treating a chemokine-mediated disease in mammals, where the specified chemokine binds to the I./-850 receptor; or d, which is characterized by administering to said mammal an effective amount of a compound of formula (I) as set forth in any one of claims 1-14. Fo 17. The method according to claim 16, characterized in that said mammal suffers from a chemokine-mediated disease selected from atonic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, psoriasis, sepsis caused by gram-negative bacteria, toxic shock syndrome, injury during and - cardiac and renal reperfusion, glomerulonephritis, thrombosis, graft-versus-host reaction ", Alzheimer's disease, allograft rejection, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, unwanted release of hematopoietic stem cells, diseases caused by respiratory "viruses, herpesviruses and hepatitis viruses, meningitis, encephalitis caused by herpes virus, vasculitis of Tsne , traumatic injury mainly brain tumors, CNS tumors, subarachnoid hemorrhage, surgical trauma, cystic fibrosis, premature birth, cough, pruritus, interstitial pneumonitis, hypersensitivity, crystal-induced arthritis, Lyme arthritis, progressive osteogenic » fibrodysplasia, acute and chronic pancreatitis , acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, stomach and duodenal ulcers, celiac disease, esophagitis, glossitis, airway obstruction, airway hypersensitivity, - bronchiolitis obliterans causing pneumonia, bronchiectasis, bronchiolitis , obliterating bronchiolitis, o chronic bronchitis, pulmonary heart, shortness of breath, emphysema, hypercapnia, excessive lung expansion, hypoxemia, hypoxia, lung volume reduction after surgery, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, sarcoidosis, diseases of children d airways, about 20 violations of the ventilation-perfusion process, stridor and lupus. (ze) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 8, 15.08.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5