UA71597C2 - Benzoheterocycles and use thereof as mek inhibitors - Google Patents

Abstract

The invention provides compounds having formula (I), wherein W is OH, or derivatives of the carboxylic acid, and Q is a heterocyclo-condensed ortho-phenylene residue. These compounds are useful as MEK inhibitors, particularly in the treatment of proliferative diseases such as cancer. (I)

Description

Description of the invention

The present invention relates to benzoheterocycles, such as benzoheteroaryls, with pharmacological activity. 2 Scope of the invention

MEK enzymes are dual-specificity kinases involved, for example, in immunomodulation, inflammation, and diseases associated with proliferation, such as cancer and restenosis.

Diseases associated with proliferation are caused by a defect in the intracellular signaling system or in the signal transduction mechanism of some proteins. Defects include changes in either the intrinsic activity, 70 or cellular concentration of one or more signaling proteins in the signaling cascade. A cell can produce a growth factor that binds its own receptors, resulting in an autocrine loop that continues to stimulate proliferation. Mutations or overproduction of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations result in the gene encoding a protein known as Kav, a protein that is activated when bound to STR and 72 Inactivated when bound to CRP. The above-mentioned growth factor receptors and many other mitogenic receptors, when they are activated, cause Kaz to change from the COP-bound position to the cTTP-bound position. This signal is an absolute prerequisite for proliferation in most cell types.

Defects in such a signaling system, especially in the deactivated Cavz-STR complex, are typical for cancer and lead to a signaling cascade below the constantly activated Kazv.

Activated Kaz, in turn, leads to the activation of the cascade of serine/hthreonine kinases. One group of kinases known to require active Kaz-STR for its own activation is the Kai family. They in turn activate MEK (for example, MEK; and MEK''), which then activate MAP kinase, EKK (EKK); and ECC"). Activation of MAP kinase by mitogens appears to be essential for proliferation; significant activation of this kinase is sufficient to induce cellular transformation. Blockade of the downstream Kaz signal, for example, when using a dominant c-negative Kai-1 protein, can completely inhibit mitogenesis generated either from cell surface receptors or from (3) tumorigenic Kaz mutants. Although Kaz does not contain a protein kinase, it participates in activation of Kai and other kinases, most likely through a phosphorylation mechanism. Once activated, Kai and other kinases phosphorylate MEK on two closely spaced serine residues 5218 and 5222 in the case of MEK-1, which is a necessary condition for MEK activation as kinases. MEK in turn phosphorylates MAP kinase on tyrosine U and threonine residue T83, separated by one amino acid. This dual phosphorylation activates MAP kinase, at least in Me) 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including a number of transcription factors and other kinases. The sum of these MAP kinase phosphorylations is mitogenically active for signaling proteins such as a kinase, transcription factor, or other cellular protein. In addition to Kai-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK exhibits high specificity for MAP kinase phosphorylation. In fact, more than one substrate for MEK does not differ from MAP kinase, so far it has been shown on EKK, and MEK does not phosphorylate proteins based on sequentially phosphorylated MAP kinase or phosphorylate denatured MAP kinase. MEK is also found to be tightly bound to MAP kinase before phosphorylating it. It is believed that "phosphorylation of MAP kinase by MEK may require prior strong interaction between the two proteins. Perhaps, both these requirements and the unusual specificity of MEK suggest that there may be sufficient differences in their mechanisms of action with respect to other protein kinases that selectively inhibit MEK, probably acting through allosteric mechanisms rather than through the usual blockade of the ATP binding site. .

The essence of the invention

The invention relates to the compound of the formula (1) below:

MU-OKI, MKoOK)u, MKAEv, MKoMEAE v, O(SN")».AMeAK v or MAKo(SN")". And MEAKv

K.-H, Su d-alkyl, C3-6-alkenyl, C3-6-alkynyl, C3-6-cycloalkyl, phenyl, (phenyl)C. /-alkyl, (phenyl)C3-6-alkenyl, (phenyl)C3 /-alkynyl, (C3-cycloalkyl)C4-alkyl, (C3-cycloalkyl) C3-alkenyl, (C3-cycloalkyl) Cz /-alkynyl, Cz.8 heterocyclic radical, (Cz.8 heterocyclic radical)C. -alkyl, (C3.8 heterocyclic radical)C3 -alkenyl, or (C3.8 heterocyclic radical)C3-/-alkynyl or (CH»)». And MasCo. ko E" - H, C1-6-alkyl, phenyl, C3-6-cycloalkyl, C3-6 heterocyclic radical, or (C3-65 cycloalkyl)methyl.

KA - H, Su c-alkyl, Czv-alkenyl, Czv-alkynyl, Czv-cycloalkyl, phenyl, (Czv8-cycloalkyl)C. /-alkyl, because (C3-C-cycloalkyl)C3-alkenyl, (C3-C-cycloalkyl)C3-/-alkynyl, C3-I heterocyclic radical, (C3-C heterocyclic radical). /-alkyl, (aminosulfonyl)phenyl, Camino-sulfonyl)phenyl| C. .4-alkyl, (aminosulfonyl)C. β-alkyl, (aminosulfonyl)C with. 6d-cycloalkyl, Caminosulfonyl)C3 6-cycloalkyl)|C 4,4-alkyl or (СНо)». ISS

Ev - N, Su. C-alkyl, C-alkenyl, C-alkynyl, C-alkenyl i-cycloalkyl or phenyl. о - one of the following formulas (I1)-(iii): b5 оо 2 и и Кк им Се

F (i) (her) where Kz - H or E;

Kk - halogen, MO», ZO2MKO(СН»)». And MKEK in, ZOomKEKe or (SOT.

T-C4 c-alkyl, C3 c-cycloalkyl, (MKeEKe)Cu.4-alkyl, OKe, -MKO(CH»)»AMKeKe or MKeEKe. 70 2 - one of the following formulas (im)-(miii):

КК ойпаожох I same PI But in Kv B in (their) (U) (m) I schi "Kk vo - (mi) (my) where one of Kb and Ke - H or methyl and the other of Kb and Ke - H, C. v-alkyl, C.v-alkenyl, C.v-alkynyl, phenyl, benzyl or -M-E-O.

M -O, CO, 505, MK), (CO)MKn, MAN(CO), MRN(ZO"), (502)MKn or CH".

E - (СН2)4.4 or (СНо)(СНо)р, where 1 " (for each т and р)x3 12 "(t Ж Р) x 4; or E - absent. sh s re o - KK OK. or MEuAk, in the event that p -1,tO 5 - N.

K; - H, C, C-alkyl, C-alkenyl, C-alkynyl, C-C-cycloalkyl, phenyl, 2-pyridyl, C-pyridyl, 4-pyridyl, (o) (CH2)i2Ag, where Ago - phenyl, 2-pyridyl, Z-pyridyl or 4-pyridyl, ZOzMKN(CH»2)» A MAK/Kk, (SOHCHN»2)» MK Ak OO or (CO) H(CH2)2» AMEKk.

Hi - O, 5, MK or SNK»o; M 20 X" - O, 5 or SNK"U; and

Xz-O or 5. (22)

In one of the variants, if-X/; or Xo - CHCo, the claimed compound can also be a tautomerized indole.

Kv - H, C..4-alkyl, phenyl, 2-pyridyl, Z-pyridyl, 4-pyridyl, (CH»)..2Ag, where Ag is phenyl, 2-pyridyl, Z-pyridyl or - from 4- pyridyl, C» d-alkenyl, Co l-alkynyl, , C3 d-cycloalkyl, or (Co /-alkyl)/mK., Ku provided that K; and Ka together have not M more than 14 carbon atoms, without K,, Km, Kik

Co - Su.d-alkyl, phenyl, 2-pyridyl, C-pyridyl, 4-pyridyl, C3.l-alkenyl, C3-l-alkynyl, C3-b-cycloalkyl, (SOOK, (Co l-alkyl/MK., Km, (SOMAMSN»)» A MK, KM (SOM, Km, (SOHCHN»)»A-MA., Km or (CH»)4 2Ag, where Ag is phenyl, 2-pyridyl, Z-pyridyl or pyridyl . " 20 Co - C./-alkyl, phenyl, 2-pyridyl, C-pyridyl, 4-pyridyl, C" y-alkenyl, C" d-alkynyl, C 3 y-cycloalkyl, (CO)OKr, -v c (So d-alkylchK. Km, (CO)MKM(CH")". AME. Km, (CO)MEK, Km, (CO)(CH")". A-MK., Km, or (CH") 42Ag, where Ag is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. cycloalkyl or (СН2»)» MK, Km

Co - H, methyl, halogen or MO". 15 Ku 4 - H, methyl, halogen or MO". -1 Each of Co, Co, Ke, Ke, Ku, Ku, Kk, K, and Km are independently selected from the group consisting of H, C, /-alkyl, C3,1-alkenyl,

C3-6-alkynyl, C3-6-cycloalkyl and phenyl; each of MACoCo, MKEKe, MEUKK and MK, Km can also independently be - morpholinil, piperazinil, pyrrolidinil, or piperadinil. Each of Kn, Kk, Ko is independently H, methyl or ethyl. Finally, each of the above hydrocarbon radicals or heterocyclic radicals is optionally substituted with 1-3 substituents independently selected from the group halogen, C1-4-alkyl, C3-6-cycloalkyl, C1-6-alkenyl, (se) Co -alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl and MO", where each substituent alkyl, cycloalkyl, alkenyl, "m alkynyl or phenyl is in turn optionally substituted with 1-3 substituents independently selected from the group that includes halogen, C.4.5-alkyl, hydroxyl, amino and MO". In addition to the compounds listed above, the invention also relates to their pharmaceutically acceptable salts or C..7 esters. 5 The invention also relates to a pharmaceutical composition comprising (a) a benzoheterocycle (for example, formulas (I) and (c) a pharmaceutically acceptable carrier. (F) Further, the invention relates to a method of treating proliferative diseases such as cancer, restenosis, psoriasis,

Ge autoimmune disease and atherosclerosis. Other aspects of the invention include methods of treating MEK-induced (including gas-induced) cancers, either solid or hematopoietic. Examples of cancers include rectal cancer (colorectal cancer), cervical cancer (cervical cancer), breast cancer, ovarian cancer, brain cancer, acute leukemia, stomach cancer, non-small cell lung cancer, pancreatic cancer, and kidney cancer.

Further aspects of the invention include methods of treating or reducing symptoms of xenograft rejection (cell(flow), organ, limb, skin or bone marrow transplant), osteoarthritis, rheumatoid arthritis, cystic fibrosis, complicated diabetes (including retinopathic v5 diabetes and nephropathic diabetes), hepatomegaly ( enlargement of the liver), cardiomegaly, stroke (such as acute focal ischemic stroke and extensive cerebral ischemia), heart failure, septic shock,

asthma, Alzheimer's disease. The compounds of the invention are also suitable as antiviral agents for the treatment of viral infections, such as NIM, hepatitis (B), virus (HVM), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus. These methods include the step of administering to a patient in need of such treatment or suffering from such a disease or condition a pharmaceutically effective amount of the claimed compound or a pharmaceutical composition based thereon. Preferably, in the above-described methods of treatment, the compound according to the invention is a selective MEK inhibitor.

The invention also relates to methods of combined therapy, such as a method of treating cancer that includes X-ray therapy or chemotherapy, for example, using mitotic inhibitors such as /o taxane or vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine and vinflunine. Other therapeutic combinations include a MEK inhibitor of the present invention and an anticancer agent such as cisplatin, 5-fluorouracil (5 GU), flutamide, and gemcitabine.

Chemotherapy or X-ray therapy may be administered prior to, concurrently with, or subsequent to the administration of the claimed compound, according to the patient's needs.

The invention also features the synthetic methods and synthetic intermediates disclosed herein.

Other aspects of the invention are set forth below in the description, examples, and claims.

Detailed description of the invention

The invention relates to benzoheterocyclic compounds, pharmaceutical compositions based on them and methods of using such compounds and compositions.

According to the first aspect of the invention, the compounds are MEK inhibitors. The MEK inhibition assay includes the cascade assay for MAP kinase inhibitors by the pathway described in column 6, line 3b, to column 7, line 4 in US Pat. No. 5,525,625 and the MEK assay of ip mygo in column 7, lines 4-27 of the same patent , the full disclosure of which is incorporated by reference (see also Examples 22-25 below).

A. Terms of school

Certain terms are defined below as they are used in this description.

Alkyl groups include aliphatic groups (that is, hydrocarbon structures of radicals containing hydrogen and carbon atoms) with free valency. Alkyl groups include straight chains and branched structures.

Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, heptyl and octyl. Cycloalkyl groups M zo include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl groups may be substituted with 1,2,3 or more substituents independently selected from the group consisting of Me halogen (fluorine, chlorine, bromine or iodine), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, and aryloxy , arylalkyloxy, heterocyclic radical and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, n"7 benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, ( 2-thienyl)ethyl, hydroxypropyl, n-aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, M-pyridinylethyl, diethylamino-ethyl and cyclobutylmethyl.

Alkenyl groups are similar to alkyl groups, but have at least one double bond (two bonded carbon atoms). Depending on the location of the double bond and the substituents, if they are present, the geometry of the double bond can be such that the substituents are on the opposite side (E) or on the same side (7) of the double bond -cis or trans isomers Similarly, alkynyl groups have at least one o /- s triple bond (two bonded carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a combination thereof; like alkyl groups, "" unsaturated groups may be straight or branched chain and may be substituted as described above for alkyl groups and as will be disclosed in the examples. Examples of alkenyl, alkynyl, and substituted forms include cis-2-butenyl, trans -2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, / 33-(2'-fluorophenyl)-2-propynyl, -I 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy- 2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, with 3-(3-fluorophenyl)-2-propynyl and 2-methyl-2-propenyl. In formula (I) alkenyl and alkynyl groups can be, for example, С» 4 or Со в, preferably Сз 4 or Сз с. , i.s. fluoro-, chloro- or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl-, etc., or combinations of substituents. Therefore, "And according to formula (I), substituted alkyls include hydroxyalkyl, aminoalkyl , nitroalkyl, haloalkyl, alkylalkyl (branched alkyls such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl and (heterocyclic radical)oxyalkyl. Yes Kk! includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl,

F, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (halogenoaryl)alkyl, (hydroxyaryl)alkynyl, and so on. Similarly, Kd includes hydroxyalkyl and aminoaryl, Kv includes hydroxyalkyl and aminoaryl and hydroxyalkyl(heterocyclic radical)alkyl. Heterocyclic radicals that include, but are not limited to, heteroaryl include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl and their non-aromatic analogues . Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl. 65 Selective MEK inhibitors! or MEK2 are compounds that inhibit, respectively, MEK! or MEK2 enzymes, without significant inhibition of other enzymes, such as MKKZ, RKS, SakhA, phosphorylase kinase, ESE and ROSE receptor kinases and C-vgs. In general, selective MEKI or MEKZ inhibitors have ISso for MEKI! and MEK2, which is at least one-fiftieth (1/50) of the IC for one of the other enzymes listed above.

A selective inhibitor having an IC of at least 1/100, preferably 1/500, and more preferably 1/1000, 1/5000, or less than an IC of one or more of the above is preferred enzymes

B. Compounds

One type of compounds disclosed in accordance with the features of the invention is shown in formula (I) in the section on the essence of the invention. Variants of the invention include compounds of formula (I), where: t (8) 2 - formula (i); (B) Kz - H or fluorine; (c) Ku - fluorine, chlorine or bromine; (9) K./o- H, methyl, fluorine or chlorine; (e) K44 - methyl, chlorine, fluorine, nitro or hydrogen; ki-n; (9) Kch4-fluorine; (p) each of Co and K44 - fluorine; () Ku - H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, Cz. 5-alkenyl, C3-6-cycloalkyl, (C3-56-cycloalkyl)C3-alkyl, (C3;-heterocyclic radical) C3-5-alkyl or (CH0)»l MKsCo (Y) C3-5 or (C3) ./-cycloalkyl)C 4 5-alkyl; (Ю РЕ» - H or methyl; (I) BA has at least one hydroxyl substituent; (t) KA - H, methyl, ethyl, isobutyl, hydroxyethyl, phenyl, 2-piperidin-1-yl-ethyl, 2, 3-dihydroxy-propyl, 3-N4-(2-hydroxyethyl)-piperazin-1-yl|-propyl, 2-pyrrolidin-1-yl-ethyl or 2-diethylamino-ethyl; and

Ev-N; or where

Ev - methyl and KA - phenyl; i) (p) M - MEeAKvV or MAK»MKAK in; (o) MU - MKH(CH2)2-AMEAKv or O(CH2)2-3 MAK B; (r) UU-MkoOK.; cha (94) MU-OK.; (d) 2 - formula (M); or Me (8) Hi - ME, K»7 - H; Chi yu (In their combination.

In formula (I), the values for 7 are shown from left to right or the numbering is oriented clockwise --

Around the phenyl ring c). h-

According to one aspect of the invention, the compound of formula (I) has a structure where:

O - formula (i) or (ii);

Kz - H or fluorine;

Ku - fluorine, chlorine or bromine; "

K.o- H, methyl or chlorine; with Ku. - chlorine, fluorine or hydrogen; . Ku - H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, apyl, Czv-alkenyl, Cz.v-cycloalkyl, and (Cz.5-cycloalkyl)C 4.»-alkyl, (Cz.5 heterocyclic radical ). .»-alkyl or (CH2a)» AMasCo;

Ku - H or (C3-cycloalkyl)C 4. »-alkyl;

P" - H or methyl; -I For one of the implementation options of this type, Kh. - MKa. An example is cyclopropylmethoxyamide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-((2'-morpholinyl)-ethyl)|-2-(phenyl)-benzoimidazole-5-carboxylic acid. - Variants of implementation of this invention also include compounds where Co - H; Kio is methyl or chlorine and where Co is chlorine. In some implementations, K7 and Ku together have no more than 14 carbon atoms, without K,, Km, K) and Kk. 50p Examples of this include compounds where K;7 and Kv together have not more than 13 carbon atoms, not more than 7, 8 se) or 10 carbon atoms, from 4 to 8 carbon atoms, from 1 to 10 carbon atoms, from 1 up to 8 carbon atoms and no more than 6 carbon atoms.

Preferably, when one of KIKo, KA, Kv, Ks Ko KE KE KOKKeK Km Ko, KnKK Ko and Kr is an alkenyl or alkynyl group, its double or triple bond, respectively, is not adjacent to the attachment site. For example, when MU is MK OK), Co is preferably prop-2-ynyl or but-2 or 3-enyl and less preferably prop-1-ynyl or but-1-enyl. (F, Listed below are some of the better structures that can be synthesized using Schemes 1, 2, 10, and 11. The free acids, free hydroxamic acids, and cyclopropylmethyl hydroxamates are grouped together. For example, compounds 1, 11, and 21 differ only in the "M/" element (as specified in the claims); for compounds 2, 12 and 22 are similarly related. Preferred compounds also include 2-chloro (replacing 2-methyl) analogs of the listed compounds.

Examples of compounds include: 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (ARC ISvo-475-17pM); 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazole-5-carboxylic acid; 65 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5) thiadiazole-5-carboxylic acid, 7-fluoro-6-(4-iodo-2-methyl-phenylamino) )-benzo|1,2,5) oxadiazole-5-carboxylic acid,

7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-hydroxyethyl)-1H-benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-dimethylamino-ethyl)-1H-benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-acetyl-benzoimidazole-5-carboxylic acid; 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid hydroxyamide, 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzooxazole-5-hydroxyamide - carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazole-5-carboxylic acid hydroxyamide; hydroxyamide 70 of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylic acid hydroxyamide; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-hydroxyethyl)-1H-benzoimidazole-5-carboxylic acid hydroxyamide; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-dimethylamino-ethyl)-1H-benzoimidazole-5-carboxylic acid hydroxyamide; /7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-acetyl-benzoimidazole-5-carboxylic acid hydroxyamide; hydroxyamide of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid hydroxyamide; cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid; cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazole-5-carboxylic acid; cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazole-5-carboxylic acid; cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid; cyclopropylmethoxy-amide 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)| oxadiazole-5 carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-hydroxyethyl)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethoxyamide; cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-dimethylamino-ethyl)-1H-benzo-imidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-acetyl-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; cyclopropylmethoxy-amide of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid; i) cyclopropylmethoxy-amide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid.

The following list of examples is presented in Schemes 3-9. As before, free acids, free hydroxamic acids and cyclopropylmethyl hydroxomates are grouped together. For example, compounds Z1, 45 and 59 M zo Differ only in "MU" (as defined in the claims); compounds 32, 46 and 60 are similarly related. Preferred compounds also include 2-chloro (replacing 2-methyl) analogs of the listed compounds. Me

Examples of compounds from schemes 3-9 include: 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-β6-carboxylic acid; 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzoxazole-b6-carboxylic acid, 5-(2-chloro-4-iodo-phenylamino)-6,7-difluoro-ZH-benzoimidazole-4 - carboxylic acid; -- 6,7-difluoro-2-(2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4-carboxylic acid; y-6,7-difluoro-5-(4-iodo-2-methyl-phenylamino)-benzo-oxazole-4-carboxylic acid; 6,7-difluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-4-carboxylic acid; 7,8-difluoro-6-(4-iodo-2-methyl-phenylamino)-quinoxaline-5-carboxylic acid; 6-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline-5-carboxylic acid; « 5-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline-b-carboxylic acid; with c 8-chloro-5-(4-iodo-2-methyl-phenylamino)-quinoxaline-6-carboxylic acid; 4-dimethylamide

C-cyclopropyl-7-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4,6-dicarboxylic acid; ;" 7-bromo-4-(4-iodo-2-methyl-phenylamino)-benzoxazole-5-carboxylic acid; 7-(2-chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-b6-carboxylic acid; 7-(4-iodo-2-methyl-phenylamino)-4-nitro-benzooxazole-b6-carboxylic acid; hydroxyamide -I of 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-b-carboxylic acid; hydroxyamide of 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzoxazole-b6-carboxylic acid; hydroxyamide - 5-(2-chloro-4-iodo-phenylamino)-6,7-difluoro-ZN-bezoimidazole-4-carboxylic acid; 6,7-difluoro-2-(2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4-carboxylic acid hydroxyamide; 6,7-difluoro-5-(4-iodo-2-methyl-phenylamino)-benzoxazole-4-carboxylic acid hydroxyamide; 6,7-difluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-4-carboxylic acid hydroxyamide; hydroxyamide "M 7,8-difluoro-6-(4-iodo-2-methyl-phenylamino)-quinoxaline-5-carboxylic acid; hydroxyamide 6-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline -5-carboxylic acid; 5-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline-b6-carboxylic acid hydroxyamide; 8-chloro-5-(4-iodo-2-methyl-phenylamino) hydroxyamide -quinoxaline-b-carboxylic acid; b-hydroxyamide 4-dimethylamide

C-cyclopropyl-7-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4,6-dicarboxylic acid; hydroxyamide

F) 7-bromo-4-(4-iodo-2-methyl-phenylamino)-benzoxazole-5-carboxylic acid; 7-(2-chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-b-carboxylic acid hydroxyamide; 7-(4-iodo-2-methyl-phenylamino)-4-nitro-benzoxazole-b-carboxylic acid hydroxyamide; cyclopropylmethoxyamide of 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-b-carboxylic acid; cyclopropylmethoxy-amide of 4-fluoro-5-(4-iodo-2-methyl-phenylamino)-benzoxazole-b6-carboxylic acid; 5-(2-chloro-4-iodo-phenylamino)-6,7-difluoro-ZN-bezoimidazole-4-carboxylic acid cyclopropylmethoxy-amide; cyclopropylmethoxy-amide of 6,7-difluoro-2-(2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4-carboxylic acid; 6,7-difluoro-5-(4-iodo-2-methyl-phenylamino)-benzoxazole-4-carboxylic acid cyclopropylmethoxy-amide; 65 cyclopropylmethoxy-amide of 6,7-Difluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-4-carboxylic acid; cyclopropylmethoxy-amide of 7,8-difluoro-6-(4-iodo-2-methyl-phenylamino)-quinoxaline-5-carboxylic acid;

6-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline-5-carboxylic acid cyclopropylmethoxy-amide; cyclopropylmethoxy-amide of 5-(4-iodo-2-methyl-phenylamino)-8-nitro-quinoxaline-b6-carboxylic acid; cyclopropylmethoxy-amide of 8-chloro-5-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid; b-cyclopropylmethoxy-amide 4-dimethylamide

C-cyclopropyl-7-(4-iodo-2-methyl-phenylamino)-ZH-benzoimidazole-4,6-dicarboxylic acid; cyclopropylmethoxy-amide of 7-bromo-4-(4-iodo-2-methyl-phenylamino)-benzoxazole-5-carboxylic acid; 7-(2-chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-b-carboxylic acid cyclopropylmethoxy-amide; 7-(4-iodo-2-methyl-phenylamino)-4-nitro-benzooxazole-b-carboxylic acid cyclopropylmethoxy-amide. 70 V. Syntheses

The claimed compounds can be synthesized according to the following 11 schemes or variants thereof. These synthesis strategies are further explained in Examples 1-22 below.

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I waved my hand. The basis of no

GO ", - ож Х ва вий ож вк

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Kk o t

The restorative agent is the same as the restorative agent. ---- n-th century m vk c

N vav" I; Ve oh yauo still Wo

Iodizing reagent Ha no deuterification -- shK' ro -- 8Sh -60th

Mk 'xx with Ka

Ka -r 5th-

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Restorative agent yo o F What "in us v. still t VV p kn? Ky (ky ke

Y vyt "v Vo -I Iodizing reagent De-esterification , o De-esterification t g Vi Ky ! - v gy . v 1 no. o y to V Kichum o vo "o Vo- Kok, "xx i-o A, Vk! i, Mr. I

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Scheme With no. 00 no 0o what n-ysv ch n-o-a --yu i om du Basis ozh khz Catalyst

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IN

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Catalyst ож к І они Кі рве вк ' 0. 20 to і В В,

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Scheme 5

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In -0 80 n-o-vo Vo-m and Vo ke novo - » ii

Katapizator v i ve Bason GU y o - 53252525 oz v v om yak

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Kk BI Gi kyu S Wo

Replenishment agent 1) Dezotization of the part of M. » and ----- Y nm i 2unhr nx XX voke ozh vi -0.-50 i no byu o ve v

Removal of protection nm x. shi k no --- nya (I -"I" from 7 nkh pishna I ! vi Vu ke hi Vu v

Ve "p podo

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Kai-M-O-V, Mezim i - 5 - yaya t, and writes p

Kk Where!

Scheme 6 Ge) no. ro no. oh no 20 sky Nitration "y y MH, nom g y-

TSI " - o t- tk iz om o o In Ge"! t Kk. vk -0 ro OO

Kiyi kyu ko no Yayu IF) nok: nm. and ON the basis of N.M. M for

Catalyst and Y! om wu yang om v 4 che: de vi Z Ky 0. 20 th o. lo -

Vi no Kyu vyr schi no Ko

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Iodizing reagent VenoM M. De-esterification Kv. KA, z

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Scheme 7

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Catalyst in x z o, V. In chn, You are Mn o 0.20 oo vi in

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Scheme 8 25 o what. oh no. oh no what

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Catalyst B --k r; them in Ge) vu i, oh; you "Well, Languages

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Restorative agent Bo V. Mov Vyh z « --6-6566IVYUCHTSSNYA TUOT' 98's | 2! - in pl. ki Ma

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Scheme 9 no. what but - oh no shao

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V. 12

Removal of protection in, t And that Sa Vikha KA - about - what

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M |! 1st language YOU

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Scheme 11

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D. Use

The claimed compounds are suitable for both prevention and therapeutic treatment of diseases or conditions as indicated in the section on the essence of the invention, as well as diseases or conditions modulated by the MEK cascade.

Examples include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and various tumors such as ovarian, lung, pancreatic, brain, prostatitis, and rectal cancer. 1. Doses -

Specialists in this field are able to determine, according to known methods, the appropriate dose for patients, taking into account such factors as age, weight, general health, symptoms requiring treatment, and the use of other drugs. Generally, the effective amount is 0.1 to 100mg/kg/day, preferably 1-100mg/kg of body weight, and daily doses are 10 to 5000mg for an adult of normal weight. Capsules, tablets, or other forms (such as liquid or film-coated tablets) may have a weight of 5 to 200 mg, such as 10, 15, 25, 35, 5Omg, bOmg, and 10Omg and may be administered according to the disclosed methods. - c 2. Formulations and Forms of unit doses include tablets, capsules, dragees, powders, granules, aqueous and non-aqueous oral "» solutions and suspensions and parenteral solutions packaged in containers adapted for distribution into individual doses.

Unit dosage forms can also be adapted for various routes of administration, including controlled release forms such as subcutaneous implants. Routes of administration include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracavitary, intravaginal, intraperitoneal, intravesical, topical (drops, powders, ointments, gels, or cream) administration, and inhalation (spraying in the mouth or in nose). 1 Parenteral forms include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, SO 50 emulsions and sterile powders for their preparation. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and acceptable organic ethers such as ethyl oleate. Fluidity can be supported by the use of a coating such as lecithin, a surfactant or by maintaining suitable particle sizes. Carriers for solid dosage forms include a) fillers or fillers, b) binders, c) wetting agents, and d) disintegrating agents, e) dissolution retarders, g) absorption accelerators, g) adsorbents, c) lubricants, and) buffering agents and k) propellants.

Compositions may also contain auxiliary substances, such as preservatives, wetting, emulsifying and disintegrating agents; antimicrobial agents such as parabens, chlorobutanol, phenol and sorbic acid; ime) isotonic agents, such as sugar or sodium chloride; agents that prolong absorption, such as aluminum monostearate and gelatin; and absorption enhancing agents. 60 Z. Family compounds

The invention covers compounds, and related pharmaceutically acceptable forms of these compounds, such as salts, ethers, amides, hydrates or their solvated forms; hidden or protective forms; and racemic mixtures of enantiomers, or optically pure forms.

Pharmaceutically acceptable salts, esters, and amides include salts of carboxylic acids (e.g., C 4-6 alkyl, 65 cycloalkyl, aryl, heteroaryl, or nonaromatic heterocycles), amino acid addition salts, esters, and amides that, with an acceptable benefit/risk ratio, are pharmacologically effective and suitable for contact with patient tissues without excessive toxicity, irritation or allergic reaction. Salts represented include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate , glucoheptonate, lacthiobionate and lauryl sulfonate. This may include alkali metals and alkaline earth cations such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations (organic amines) such as tetramethylammonium, methylamine, trimethylamine and ethylamine. See, for example, 5.M.Vegde, ei ai.,, "Rpaptasecshiisa! Zav", 9). RIagt. Zsi., 1977, 66:1-19, which are incorporated herein by reference. The pharmaceutically acceptable amides presented in the invention include their derivatives with /o ammonia, primary C..in-alkylamines and secondary di(C.in.-c-alkyl)amines. Secondary amines include 5- or b-membered heterocyclic or heteroaromatic rings containing at least one nitrogen atom and optionally 1 or 2 additional heteroatoms. The best amides are ammonia derivatives, primary C3.3-alkylamines, and di(C1.0-alkyl)yaamines. The pharmaceutically acceptable esters presented in the invention include C 14.7-alkyl,

C/-cycloalkyl, phenyl and phenyl (C. c) alkyl ethers. Preferred esters include methyl esters.

The invention also includes compounds having one or more functional groups (eg, hydroxyl, amino, or carboxyl) masked by a protective group. Some of these masked or protected compounds are pharmaceutically acceptable, others will be useful as intermediates. The synthesized intermediates and processes disclosed herein, and major modifications thereof, are also included within the scope of this invention. Examples of synthesized intermediates according to the invention include РХО202885, РО2О3337, РО218001, РО254551 and

RO201601

Protective hydroxyl groups

Protective hydroxyl groups include: simple and complex esters and protection for 1,2- and 1,3-diols. Ester protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and silyl ethers converted to other functional groups. high school

Substituted methyl ethers

Substituted methyl esters include: methoxymethyl, methylthiomethyl, tert-butylthiomethyl, i) (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-ethoxy-benzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl . . ,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.

Substituted ethyl ethers --

Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxymethyl, 1-1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

Substituted benzyl ethers

Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6b-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, C -methyl-2-picolyl M-oxy, pt») with diphenylmethyl, p,p'-dinitrobenzidryl, 5-dibenzosubiryl, triphenylmethyl, A-naphthyl-diphenylmethyl, . p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, and? 4-(4-bromophenacyloxy)phenyldiphenylmethyl, 4,4 4"-tris(4,5-dichlorophthalimidophenyl) methyl, 4,4 4"-tris(levulinoyloxyphenyl)methyl, 4,4,4"-tris(benzoyloxyphenyl)methyl,

3-(imidazol-1-yl-methyl)bis(4,4"-dimethoxyphenyl)-methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, -I 9-(9- phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl 8,8-dioxy.

Silyl Ethers - Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, c diethylisopropylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, boron/tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxy-phenylsilyl. ik Ethers "M Protective ether groups include: complex ethers, carbonates, auxiliary products for cleavage, mixed ethers and sulfonates.

Complex ethers

Examples of protective esters include: formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,

F) p-P-phenylacetate, Z-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, ka adamanthoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate and 2,4,6 -trimethylbenzoate (mesitoate).

Carbonates in Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p- nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, 5-benzylthiocarbonate, 4-ethoxy-1-naphthyl and methyldithiocarbonate.

Cleavage Auxiliary Products 65 Examples of auxiliary cleavage products for protecting groups include: 2-iodobenzoate, 4-acidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4-(methylthiomethoxymethyl)benzoate and 2-(methylthiomethoxymethyl)benzoate.

Mixed ethers

In addition to the above classes, mixed esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenate (tiglinate), o-(methoxycarbonyl)benzoate, p-P-benzoate, A-naphtholate, nitrate, alkyl M,M, M';,M'-tetramethyl phosphorodiamidate, M-phenylcarbamate, borate, dimethyl-phosphinothioyl and 2,4-dinitrophenyl sulfenate.

Sulfonates 70 Protective sulfates include: sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-diols

Protection for 1,2- and 1,3-diols includes: cyclic acetals and ketals, cyclic ortho ethers and silyl derivatives.

Cyclic acetals and ketals.

Cyclic acetals and ketals include: methylene, ethylidene, 1-tert-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p- methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene and 2-nitrobenzylidene.

Cyclic ortho ethers

Cyclic ortho ethers include: methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxymethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1-(M,M-dimethylamino)ethylidene derivative, o-(M,M-dimethylamino) derivative )benzylidene and 2-oxacyclopentylidene.

Protection for the carboxyl group

Airs

Protective ether groups include: esters, substituted methyl ethers, 2-substituted ethyl ethers, sub-substituted benzyl ethers, silyl ethers, activated esters, mixed derivatives and esters of stannous acid.

Substituted methyl ethers o

Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, A-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and M-phthalimidomethyl. 2-substituted ethyl ethers 2-substituted ethyl ethers include: 2,2,2-trichloroethyl, 2-haloethyl, 2-chloroalkyl, 2-trimethylsilyl)ethyl, and 2-methylthioethyl, 1,3-dithianyl-2-methyl , 2(p-nitrophenyl-sulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, ku 2-(2'i-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, tert- butyl, cyclopentyl, cyclohexyl, allyl,

3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, A-methylcinnamyl, phenyl, p-(methylmercapto)-phenylbenzyl. 7

Substituted benzyl ethers. uh-

Substituted benzyl ethers include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)danthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-b6-chromylmethyl, /2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl and 4-P-benzyl. "

Silyl ethers shsh c Silyl ethers include: trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, and phenyldimethylsilyl and di-tert-butylmethylsilyl. and? Mixed derivatives

Mixed derivatives include: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxalanes, ortho ethers, phenyl group and complex pentaamino Soc). - and Stannyl esters (stannic acid esters)

Examples of stannyl ethers include: triethylstannin and tri-n-butylstannyl. - Amides and hydrazides c Amides include: M,M-dimethyl, pyrrolidinyl, piperidinyl, 5,6b-dihydrophenanthridinyl, o-nitroanilides,

M-7-nitroindolyl, M-8-nitro-1,2,3,4-tetrahydroquinolyl and p-P-benzenesulfonamides. Hydrazides include: M-phenyl, is, M,M'-diisopropyl and other dialkyl hydrazides. "And protection for the amino group

Carbamates

Carbamates include: carbamates, substituted ethyl, cleavage auxiliaries, photolytic cleavage products, urea-type derivatives, and mixed carbamates.

Carbamates and F) Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, ko 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-tert-butyl-(9-(10 ,10-dioxo-10,10,10,10-tetrahydro-thioxanthyl))methyl and 4-methoxyphenacyl. in Substituted ethyl

Substituted ethyl protecting groups include: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-"1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl- 2,2-dibromethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-tert-butylphenyl)-1-methylethyl . , M-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,

9-anthrylmethyl and diphenylmethyl.

Auxiliary products for cleavage

Protection by cleavage aids includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, (2-(1,3-dithianyl))methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl , 2-phosphoniethyl, 2-triphenyl-phosphoniisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic cleavage products 70 Methods of photolytic cleavage use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6b-nitrobenzyl and phenyl(o-nitrophenyl)methyl.

Derivatives of the urea type

Examples of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative,

M'-p-toluenesulfonylaminocarbonyl and M'-phenylaminothiocarbonyl.

Mixed carbamates

In addition to those described above, mixed carbamates include: tert-amyl, 5-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyclooxybenzyl, diisopropylmethyl, 2,2-dimethoxy-carbonylvinyl, o-( M,M-dimethyl-carboxamido)-benzyl, 1,1-dimethyl-3-(M,M-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, di(2-pyridyl) methyl, 2-furanylmethyl, 2- iodethyl, isobornyl, isobutyl, isonicotinyl, p(p'-methoxyphenyl-azo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1- methyl-1(p-henylazo-phenyl)-ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri -tert-butylphenyl, 4-(trimethylammonium)-benzyl and 2,4,6-trimethylbenzyl.

Amides sch

Amides

Amides include: M-formyl, M-acetyl, M-chloroacetyl, M-trichloroacetyl, M-trifluoroacetyl, M-phenylacetyl, and)

M-Z-phenylpropionyl, M-picolinoyl, M-Z-pyridylcarboxamide, derivative M-benzoylphenylalanyl, M-benzoyl («

M-p-phenylbenzoyl.

Auxiliary products for cleavage. M zo Groups of auxiliary products for cleavage include: M-o-nitrophenylacetyl, M-o-nitrophenoxyacetyl,

M-acetoacetyl, (M'-dithiobenzyloxycarbonylamino)acetyl, M-3-(p-hydrophenyl)propionyl, Me

M-9Z-(o-nitrophenyl)propionyl, M-2-methyl-2-(o-nitrophenoxy)propionyl, M-2-methyl-2-(o-phenylazophenoxy)propionyl, mu

M-4-chlorobutyryl, M-3-methyl-3-nitrobutyryl, M-o-nitro-cinnamoyl, M-acetylmethionine derivative, M-o-nitrobenzoyl,

M-O-(benzoyloxymethyl)benzoyl and 4,5-diphenyl-3-oxazolin-2-one. --

Derivatives of cyclic imides

Derivatives of cyclic imides include: M-phthalimide, M-dithiasuccinoyl, M-2,3-diphenyl-maleoyl,

M-2,5-dimethylpyrrolyl, M-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl -1,3,5-triazacyclohexan-2-one and 1-substituted 3,5-dinitro-4-pyridonyl. "

Special -MH protecting groups with c Protecting groups for -MH include: M-alkyl and M-aryl amines, imine derivatives, enamine derivatives and derivatives with

M-heteroatom (such as M-metal, M-M, M-P, M-5i and M-5), M-sulfenyl and M-sulfonyl. ;" M-alkyl and M-aryl amines.

M-alkyl and M-aryl amines include: M-methyl, M-allyl, M-(2-"trimethylsilyl)ethoxyl|-methyl,

M-3-acetoxypropyl, / M-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3-yl), quaternary ammonium salts, M-benzyl, -I M-di(4-methoxyphent)methyl , M-5-dibenzosuberyl, M-triphenylmethyl, M-(4-methoxyphenyl)diphenylmethyl,

M-9-phenylfluorenyl, M-2,7-dichloro-9-fluorenylmethylene, M-ferrocenylmethyl and M-2-picolylamine M'-oxide. - Imine derivatives with Imine derivatives include: M-1,1-dimethylthiomethylene, M-benzylidene, M-p-methoxybenzylidene,

M-diphenylmethylene, M-K2-pyridyl)mesityl|methylene, M(M',M'-dimethylaminomethylene), M,M -isopropylidene, and M-p-nitrobenzylidene, M-salicylidene, M-5-chlorosalicylidene, M- (5-chloro-2-hydroxyphenyl)-phenylmethylene and "MM-cyclohexylidene.

Derivatives of enamines

An example of an enamine derivative is M-(5,5-dimethyl-3-oxo-1-cyclohexenyl).

Derivatives containing an M-hetero atom

M-metal derivatives include: M-borane derivatives, M-diphenylboric acid derivative,

F) M-Ifenyl (pentacarbonylchromium or tungsten)| carbenyl and M-copper or M-zinc chelate. Examples of M,M derivatives include: M-nitro, M-nitroso, and M-oxide. Examples of M-P derivatives include: M-diphenylphosphinyl,

M-dimethylthiophosphinyl, M-diphenylthiophosphinyl, M-dialkyl phosphoryl, M-dibenzyl phosphoryl and M-diphenyl 6o phosphoryl. Examples of M-sulfenyl derivatives include: M-benzenesulfenyl, M-o-nitrobenzenesulfenyl,

H-2,4-dinitrobenzenesulfenyl, M-pentachlorobenzenesulfenyl, M-2-nitro-4-methoxy-benzenesulfenyl,

M-triphenylmethylsulfenyl and M-3-nitropyridinesulfenyl. M-sulfonyl derivatives include: M-p-toluenesulfonyl,

M-benzenesulfonyl, M2,3,6-trimethyl-4-methoxybenzenesulfonyl, M-2,4,6-trimethoxybenzenesulfonyl,

M-2,6-dimethyl-4-methoxy-benzenesulfonyl, M-pentamethylbenzenesulfonyl, 65 M-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl, M-4-methoxybenzenesulfonyl,

H-2,4,6-trimethyl-benzenesulfonyl, M-2,6-dimethoxy-4-methylbenzenesulfoyl,

M-2,2,5,7,8-pentamethylchroman-b-sulfonyl, M-methanesulfonyl, M-B-trimethylsilylethane-sulfonyl,

M-9-anthracenesulfonyl, M-4--42,8'-dimethoxynaphthylmethyl)-benzenesulfonyl, M-benzylsulfonyl,

M-trifluoromethylsulfonyl and M-phenacylsulfonyl.

Disclosed compounds that are masked or protected may be prodrugs, compounds that are absorbed or otherwise transformed ip mimo into the claimed final compound, for example, rapidly in the course of metabolism. The transformation may be effected by hydrolysis or oxidation, by contact with a body fluid such as blood, or by the action of acids or enzymes of the liver, stomach, intestines, or other enzymes. 70 Features of the invention are further described in the examples below.

D. examples

Example 1

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (RO 205293) (ARK

ISvo-14pM; 26 intestinal cells, ISvso-21OμM)

Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid

Vaporizing nitric acid (3.4 ml, 0.07 bmol) is added to carefully stirred concentrated sulfuric acid (bOml). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) is directly added there. After 45 minutes of stirring, the reaction mixture is a yellow-hot, homogeneous solution, which is poured into cold water (400 ml). The obtained aqueous suspension is extracted with diethyl ether (3x20Oml).

The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give 12.30 g of an opaque light yellow solid. Recrystallization from chloroform (5 Oml) allows obtaining 9.54 g of a pale yellow microcrystalline product; output 7890; t.pl.; 7H-NMR (400 MHz; DMSO) δ 14.29 (width, s, 1H), 8.43-8.38 (m, 1H); 1Z3C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, ds-v-270.1, 10.7 Hz), 148.35 (dd, dUsv-267.0, 9.2 Hz), 14123 C (dt, Us-in-253.4Hz), 133.95, 123.30 (d, Us-in-2.2Hz), 116.92 (dd, Us-is-18.2.3.8Hz); o 19g-NMR (376 MHz; DMSO) 5 from -120.50 to -120.63 (m), from -131.133 to -131.27 (m), from -153.63 to -153.74 (m).

Step p: Preparation of 4-amino-2,3-difluoro-5-nitrobenzoic acid

Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) is dissolved in concentrated ammonium hydroxide (25 ml) to instantly obtain a yellow solution. A precipitate begins to form within 5 minutes, after which the mixture is acidified to pH with concentrated aqueous hydrochloric acid. Very quickly Ge") a yellow precipitate falls out. The mixture is heated to boiling and filtered hot. The yellow solid precipitate is washed with 1095% aqueous hydrochloric acid and dried by suction to obtain 0.47 g of a yellow powder; output 6490; "- 7H-NMR (400MHz; DMSO) δ 13.32 (s, 1H). 8.36 (d, 1H, 9-7.6 Hz), 7.98 (s, 2H); "and what 19g-NMR (376MHz; DMSO) 5 from -128.69 to -128.76 (m), -153.60 (d).

Step c: Preparation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate

Hydrogen chloride is dissolved in anhydrous methanol (3 ml) until the solution becomes warm. Solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g, 0.00215 mol) is dissolved in this solution and the reaction mixture is refluxed with vigorous stirring for 23 hours in a nitrogen atmosphere. з с The reaction mixture itself cools slowly at the workplace. The yellow precipitate formed is collected. filtered in a vacuum and dried by suction to obtain 0.35 g of yellow microfilament, the yield is 7090; t. pl. 183.5-1842C; 7H-NMR (400 MHospoda.c; DMSO) δ 8.36 (dd, 1H, 9-7.3, 1.7Hz), 8.06 (s, 2H), 3.78 (s, ЗН); 19g-NMR (376 MHz; DMSO) 5 from -128.85 to -128.92 (m), -153.29 (d); and M(ARSI-)231(M-1,100); - IR (KVg) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm"; Calculated composition/found: CaNeB»M»O,C, 41.39/41.40; H, 2.61/2, 50; M, 12.07/11.98; E, 16.37/16.58. o Step a: Preparation of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate ( Ce) 20 Solid methyl 4-amino-2,3-difluoro-5-nitrobenzoate (0.087g, 3.7xX10"mol) is dissolved in ortho-toluidine (3ml, 0.02vmol). The reaction mixture is stirred at a temperature of 2007C for 35 minutes in a nitrogen atmosphere. Then the mixture is distributed between diethyl ether (150 ml) and 1096 aqueous hydrochloric acid (150 ml). The ether phase is dried with anhydrous magnesium sulfate and concentrated in vacuo to a crude solid. The crude product is dissolved in BbBml of dichloromethane and filtered through a thin layer of 25 pressed quartz glass sand. Elution with dichloromethane allows obtaining 0.095 g of a yellow solid

GF) substances; exit 8190; 164-1687C; 7 TN-NMR (400MHz; DMSO) 5 9.20 (s, 1H), 8.52 (d, 1H, 9-1.7Hz), 7.57 (s, 2H), 7.19 (d, MH , 9U-7.3Hz), 7.12-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.95-6.91 (m, 1H), 3.78 (c, ZN), 2.21 (c, ZN); in 19g-NMR (376MHz; DMSO) 6-141.13 (s);

Me(ARSI)Z20O(M1,100); (ARSI-)318(M-1,100);

IV (KVh) 3467, 3346, 1690, 1305 cm";

Calculated composition/found: Si5NaEM30500.21 NYO C, 55.77/55.97; H, 4.50/4.55; M, 13.01/12.61; B, b5 2.88/5.95.

Step e: Preparation of methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-5-benzoate

A mixture containing methyl 4-amino-33-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (2.52g, 0.00789mol), tetrahydrofuran (50ml), methanol (50ml) and washed Raney nickel ( 0.5g), at the initial stage under a pressure of 48.6 psi (pounds per square inch) is exposed to gaseous hydrogen at a temperature of 30.2"C in a shaker for 4 hours 48 minutes. The mixture is filtered, and the filtrate is concentrated in vacuo to obtain 2.20g orange-pink amorphous solid; yield 96905; "NA-NMR (400MHz; DMSO) 5 7.84 (s, 1H), 7.04 (d, 1H, 9U-7.1Hz), 6.98 (d, 1H, 9-1.2Hz), 6.95-6.91 (m, 1H), 6.68-6.64 (m, 1H), 6.40-6.36 (m, 1H), 5, 39 (c, 2H), 4.73 (c, 2H), 3.66 (c, Н), 2.21 (c, Н); 19g-NMR (376 MHz; DMSO) δ -139.66 (s).

Step 7: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylate

A stirred solution containing methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (1.78Hg, 0.00615mMol) in formic acid (Aiaghisi, 95-9795, 10Oml, 2.B5mol), refluxed for 3 hours, followed by concentration in vacuo to a crude brown solid. The crude product was triturated with chloroform (40 ml) and subsequently collected by vacuum filtration. The solid substance was dried by suction to obtain 1.09 g of pale purple powder.

The filtrate is concentrated in vacuo to give a crude solid, which is triturated with 10 ml of chloroform-dichloromethane. These solids are collected by vacuum filtration, washed with dichloromethane and dried by vacuum suction to obtain an additional 0.55 g of pale purple powder (total yield: 1.64 g); output 8790; t. pl. 259-262";

TNA-NMR (400MHz; DMSO) 5 8.42 (s, 1), 8.03 (s, 1H), 7.93 (width, s, 1H), 7.12 (d, MH, 9-7, 0Gu), 6.99-6.95 (m, 1H), 6.75-6.71 (m, 1H), 6.48-6.44 (m, 1H), 3.81 (s, ЗН) , 2.30 (c, ZN); 19g-NMR (376 MHz; DMSO) δ -132.84 (s);

MSek (ARSI ZOM 1, 100); (ARSI-)298 (M-1,100); with

IV (KVh) 3322, 1689, 1437, 1326, 1218 cm"; about

Calculated composition/found: C46Ni4EM3025010.32 NYO C, 62.99/63.01; H, 4.84/4.61; MA 13.77/13.70.

Step d: obtaining methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylate

A stirring mixture containing methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylate M (0.2492g, 8.326x10" mol), benzyltrimethylammonium dichloroiodinate (Aiaghisi, 95905, 0, 3934g, 0.0011Zmol) and zinc chloride (0.1899g, 0.00139mol) in glacial acetic acid (2Oml), refluxed for 15 minutes. The hot suspension was filtered to separate the precipitate, which was dried in a vacuum oven hot water (907, 10 mm Hg) overnight to obtain 0.2392 g of green powder, yield 6890, t.p. 219-22070

DISTRIBUTION; -

TNA-NMR (400 MHz; DMSO) δ 8.71 (s, 1H), 8.02 (s, 1H), 7.85 (width, s, 1H). 7.43 (d, 1H, 9-1.7Hz), 7.24. (dd, 1H, 9-85, 2.2Hz), 6.24 (dd, 1H, 9U-8.5, 5.4Hz), 3.76 (s, ЗН), 2.22 (s, ЗН) ; 19g-NMR (376 MHz; DMSO) δ -132.86 (s);

MS (ARSI k) 426 (M--1, 48) 169 (100); " (ARSI-3424 (M-1,100); 70 IU (KVh) 1704, 1508, 1227 cm". of N-benzoimidazole-5-carboxylic acid. ; c" To a stirring solution containing methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylate (0.2035g . ""mmol) of potassium trimethylsilanolate is added to the mixture, which is stirred for 30 minutes. The wet solid is dissolved in a ratio of 4:1 (v/v) in a solution of (se) ethyl acetate-methanol (500 ml). The solution is washed with 0.84 M aqueous citric acid (50 Oml), dried

And (M950,) and concentrate in a vacuum until a yellow liquid is obtained. The liquid is re-dissolved in a fresh solution of ethyl acetate-methanol. The solution is washed with brine, dried (Ma5O4), and concentrated in vacuo. The precipitate is re-dissolved in chloroform and re-concentrated to obtain 1.55 g of a viscous, thick yellow precipitate, which consists mainly of citric acid; MS (ARSI-) 191 (M-1, 100). The precipitate is again dissolved in water (5 Oml). The insoluble substance is extracted in 1:1 (v/v) ethyl acetate-diethyl ether (F. (25 Oml). After separation, the aqueous phase remains strongly acidic (pH 0). The organic phase is washed with a fresh portion of water (15 Oml). After partitioning, this solution is only slightly acidic (pH 4.5). The organic phase is dried (Mao9504), concentrated in vacuo and treated with chloroform to obtain a yellow-brown semi-solid substance. The product is triturated with hexane. Vacuum filtration and drying with suction allow obtaining 0 .0839g of a yellowish-brown powder. A part of the product (0.050g) is recrystallized from boiling ethanol (ml). During cooling and scraping with a glass rod, an off-white solid is formed from the inner surface of the flask. This substance is separated by vacuum filtration and dried under high vacuum ( 23"С) to obtain 0.018g of off-white powder; yield 9905; m.p. v5 247 - 248"С РОЗК.; 192-NMR (376MHz; DMSO) δ -132.87 (s);

MS (ARSI k) 412 (M.-1, 100); (ARSI-) 410 (M-1,100);

IV (KVh) 3322, 1689, 1437, 1326, 1218 cm";

Calculated composition/found: Си15Н4и4РИМ30510.61 СоНОп10.59 ННО (91.495 from the starting point) C, 43.30/43.30;

H, 3.55/3.34; M, 9.34/9.15.

Example 2

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethoxyamide (PO 254552) (ARK ISvoh 10pM (p-2); 26 intestinal cells, 1 hour of pretreatment, ISvo-2b0pM) 70 Step a: Preparation of pentafluorophenyl ether of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (RO 254551) (ARC ISvo-120p1M (n-2))

For a stirrable suspension containing / 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

of N-benzoimidazole-5-carboxylic acid (0.844g, 2.05x10mol) in ethyl acetate (4ml), add a solution containing 75 pentafluorophenol (0.375g, 2.04x103mol) in M,M-dimethylformamide (1ml). Then add solid dicyclohexylcarbodiimide (0.415 g, 1.99x107 mol) and stir the reaction mixture for 22 hours. The reaction mixture is filtered under vacuum until a precipitate forms. The filtrate is diluted with ethyl acetate (40 Oml) and this solution is washed with water (3x40O0 ml), dried (Ma95O)) and concentrated in a vacuum to obtain 1.7 g of a spongy yellow substance. The crude product is purified by column chromatography on a layer of pressed quartz glass sand. Elution with a gradient (SNCI»z to 0.595 methanol in SNCIz) allows to obtain 0.69 g of yellow amorphous product; output 6090; "H-NMR (400 MHz; SOCI3) 5 8.54 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.49 (d, 1H, 9-1.7Hz ), 7.36 (dd, 1H, uEB, 2, 1.7Hz), 6.57 (dd, 1H, U-8.4, 6.5Hz), 2.31 (s, ZN); rya 19g- NMR (376 MHz; SOSIz) 5 -132.02 (s), -152.35 (d, 9-18.3Hz), -157.26 (t, 9-21.4Hz), -161.96 (dd, 9-21.3, 18.3 Hz); p

MS (ARSIK) 578 (Mt, 57), 394 (100); o (ARSI-) 576 (M-1, 44), 409 (100), 393 (95), 392 (82), 378 (55), 183 (97), 165 (68), 127 (53);

IV (KVo) 1731 cm"! (S-O strong).

Step p: Preparation of cyclopropylmethoxyamide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 chzo N-benzoimidazole-5-carboxylic acid

To a stirred solution containing 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid pentafluorophenyl ether (0.63 g, 1.09x10 mol) in anhydrous tetrahydrofuran (ml), add solid cyclopropyl-methoxylamine hydrochloride (0.14g, 1.13x10Zmol) and diisopropylethylamine (0.bml, 3.4x10Zmol). The reaction mixture is stirred for one week. --

The solvent is removed and the evaporated solution is treated with a 1095 N hydrochloric acid solution (200 ml) and extracted with diethyl ether (200 ml). The resulting two-phase suspension and sediment are separated by vacuum filtration.

The crude product is recrystallized from absolute ethanol to obtain 0.18 g of a green-yellow powder; output 35905; t. pl. 168 - 17275; "

TN-NMR (400MHz; DMSO) 5 11.48 (s, 1H), 8.37 (s, 1H), 7.50 (width, s, 1H), 7.45 (s, 1H), 7, 24 (s, 1H), 407.07 (d, 1H, 9-8.4Hz), 6.03-5.97 (m, 1), 3.38 (d, 2H, 9-6.5Hz), 2.04 (s, ЗН), 0.85-0.75 (m, 1Н), 0.30-0.22 С s (m, 2Н), 0.00 (s, 2Н); "» 192-NMR (376 MHz; DMSO) 5 -133.23 (s); " MS (ARSI k) 481 (M.-1, 77), 409 (100); (ARSI-) 480 (M, 22), 407 (100); - 75 |V (KVo) 1659, 1632, 1493 cm"!;

Calculated composition/found: SioNivRIMAO20p20.50 NS! (96395 from the original) C, 45.78/45.74; H, th 3.74/3.84; M, 11.24/10.88. sl Example C

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid hydroxyamide Step a: Preparation of O-(tetrahydro-2H-pyran-2- yl)-oxyamide -H 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid

A solution of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid,

O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 equiv.), benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate (1.25 equiv.) and diisopropylethylamine (3 equiv. ) in 11 (v/v) of tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the precipitate (F) is purified by thin-layer chromatography; elution with dichloromethane gives the target product. A substance can

HF be recrystallized with a suitable solvent such as methanol if further purification is required.

Step p: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid hydroxyamide. bo Compound O-(tetrahydro-2H-pyran-2-yl)-oxyamide 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-b-carboxylic acid is dissolved in a suitable solvent, saturated NSI, such as methanol or ethanol. The homogenized solution is concentrated in a vacuum to obtain the target product. The substance may be powdered with a suitable solvent such as chloroform or dichloromethane if further purification is required.

Example 4

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide

Step a: Preparation of O-cyclopropylmethylhydroxylamine hydrochloride

Step i: Preparation of 2-cyclopropylmethoxy-isoindole-1,3-dione.

To a stirred solution/suspension containing M-hydroxyphthalimide (Ayagisp 57.15g, 339.8mmol), cyclopropanemethanol (Ayagisp 25.10g, 341.1mmol) and triphenylphosphine (OEAO", Ayagisn, 91.0g, 344mmol) in 1.0 l of tetrahydrofuran, in a stream of nitrogen and cooled to 6"C (internal temperature of the mixture) with the help of an ice-water bath, add diethyl azodicarboxylate (Alagisia, 5 bml, 35 bmmol) dropwise through an additional funnel for 7/0 20 minutes. The temperature of the reaction mixture is maintained below 20"C during the addition. At the next addition

The OREO water bath is removed and the reaction mixture is stirred for 15 hours. The mixture is concentrated into a paste under reduced pressure. Add chloroform (about ZOOml) and the mixture becomes loose with the formation of a solid phase.

Vacuum filtration allows you to separate the sediment. The filtrate is filtered once more to obtain a white precipitate, which forms again in it, to obtain a clean filtrate. Concentration under reduced pressure /5 allows to obtain pure oil. Rapid filtration through a layer of silicone gel (100956-chloroform) allows to obtain filtrates containing crude product. These filtrates are combined and concentrated under reduced pressure to obtain 127.4 g of pure oil. The oil is dissolved in absolute ethanol (40 Oml) and the solution is cooled for 2 hours. White solid crystals precipitate and are further collected by vacuum filtration. The product is dried in a vacuum oven (607C) to obtain 42.66 bg (5890) of the target product; t. pl. 71-777C; "H-NMR (400 MHz; SOSIZ signal shift up to 5 6.96) 5 7.54-7.43 (m, 4H), 3.74 (d, 2H, 9U-7.6Hz), 1.02-0 .95 (m, 1H), 0.34-0.30 (m, 1H), 0.04-0.00 (m, 1H).

Step ii: Preparation of O-cyclopropylmethylhydroxylamine hydrochloride

To a stirred solution of 2-cyclopropylmethoxyisoindole-1,3-dione (42.64g, 196.3mmol) in 1500ml of dichloromethane under ambient conditions, carefully add methylhydrazine (Aiagisn, 10.7ml, 197mmol). A white precipitate begins to form almost immediately. After intensive stirring for 15 minutes, the suspension is filtered under vacuum. The filtrate is also filtered to remove additional sediment.

The final clean filtrate is carefully concentrated (volatile product) under reduced pressure to a light liquid/solid mixture. Ether is added to the solution and filtered under vacuum, white crystals are removed. The filtrate is acidified with gaseous hydrochloric acid, which instantly forms a white precipitate. The collected solid product is filtered under vacuum and dried in a vacuum oven (5573) to obtain 18.7 g (77905) F of a white powder; t. pl. 165-168; 7TH-NMR (400MHz; DMSO) 5 10.77 (width, c, 2H), 3.57 (d, 2H, 9-7.3Hz), 0.84-0.74 (m, 1H), 0 .31-0.25 (m, - 2H), 0.04-0.00 (m, 1H); 1ZS-NMR (100 MHz; DMSO) δ 75.39, 5.52, 0.00. -

Step p: Preparation of cyclopropylmethoxy-amide 7-fluoro-6-(4-iodo-2-methyl-phenyl-amino)-1

N-benzoimidazole-5-carboxylic acid

A solution containing 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-cyclopropylmethyl-hydroxylamine hydrochloride (1.25 equiv.), hexafluorophosphate Z 50 benzotriazole -1-yl-oxy-tris-pyrrolidine-phosphonium (1.25 equiv.) and diisopropylethylamine (3 equiv.) in 11 s (v/v) tetrahydrofuran-dichloromethane, stirred for 30 minutes. The reaction mixture is concentrated in

From" under vacuum and the precipitate is isolated in diethyl ether. The ether phase is washed with a dilute solution of hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine, dried (Mo5O) and concentrated in vacuo to obtain the target product. The substance can be recrystallized with a suitable solvent such as methanol or chloroform if further purification is required. it. Example 5 - Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxosole-5-carboxylic acid

Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid and similar to Example 1, Step a. (Te) 20 Step p: Preparation of 2,3-difluoro-4-hydroxy-5-nitrobenzoic acid

Solid 5-nitro-2,3,4-trifluorobenzoic acid (1.00 g, 0.00452 mol) is dissolved in 10 wt. 95 aqueous tm of sodium hydroxide solution. A mixture of transparent dark yellow-brown color is obtained. After the mixture is kept under normal conditions for a few minutes, it is quenched with a concentrated aqueous solution of hydrochloric acid until it is strongly acidic (pH 0). The white precipitate is isolated by vacuum filtration and dried by suction to obtain 0.40 g of an off-white solid. This solid is recrystallized from

HF) chloroform (20 ml) to obtain 0.22 g of off-white crystalline powder; output 22965;

M(ARSI-)218(M-1,100). o Step c: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate

Anhydrous gaseous hydrogen chloride is dissolved in anhydrous methanol (5HOml) until a warm 60 solution is obtained. Microcrystalline solid 2,3-difluoro-4-hydroxy-5-nitrobenzoic acid (0.22 g, 0.0010 mol) is dissolved in a methanolic solution of hydrogen chloride. The stirred reaction mixture is refluxed to reflux in a stream of nitrogen for 16 hours. The mixture is concentrated in vacuo to a white solid. The product is dried under high vacuum to obtain 0.213 g of white powder; output 9195; t. pl. 108-109,572; for "H-NMR (400 MHz; DMSO) 5 8.25 (dd, 1H, 9U-7.7.2.2Hz), 3.83 (s, ЗН); (SOCI3) 5 10.83 (s, 1H), 8.66 (dd, 1H,

U-7,0,2,2Hz), 3,98 (s, ZN); 19g-NMR (376MHz; DMSO) δ -127.85 (s), -154.32 (d, uU-19.8Hz); (SOSIz) 5 from -118.31 to -118.37 (m), -152.38 (d, U9-18.3 Gu);

Mk(ARSI-)232(M-1,100);

IV (KVh) 3264, 1731, 1640, 1546, 1307, 1286, 1160 cm".

Step a: Preparation of 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl carbonate

To a solution containing 1-dadamantyl fluoroformate (2.0M) and pyridine (2.0M) in tetrahydrofuran, a solution containing methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate (0.96 eq. ., 0.384M) in anhydrous 70 tetrahydrofuran at ambient temperature. The reaction mixture is stirred for 6 hours and the solution is vacuumed. The residue is dissolved in dichloromethane. The organic solution is washed with dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate, water, dried (Mao y) and concentrated in vacuo to obtain the target product.

Step e: Preparation of 1-adamantyl 4-carboxymethyl-2-fluoro-3-(-2-methylphenylamino)-6-nitrophenyl carbonate

The compound 1-adamantyl 4-carboxymethyl-2,3-difluoro-b-nitrophenyl carbonate is dissolved in an excess of ortho-toluidine. The reaction mixture is stirred at a temperature of 2007C for 6 hours. The mixture is cooled and dissolved in diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, saturated with aqueous sodium bicarbonate, salt solution, dried (Ma5ZO 4) and concentrated in a vacuum to obtain the target product. The product, if necessary, is purified by thin-layer chromatography.

Step 7: Preparation of methyl 3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-5-nitrobenzoate

The compound 1-adamantyl 4-carboxymethyl-2-fluoro-3-(-2-methylphenylamino)-b6-nitrophenyl carbonate is dissolved in an excess of trifluoroacetic acid at ambient temperature. The mixture is stirred for 20 minutes. Trifluoroacetic acid is removed under reduced pressure. The precipitate is subjected to vacuum to remove adamant-1-ol to obtain the target product. with

Step 4. Preparation of methyl 5-amino-3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-benzoate by

The compound methyl 3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-5-nitrobenzoate is processed similarly to Step e

Example 1.

Step n: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate

The compound methyl 5-amino-3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-benzoate is processed similarly to Step i - Example 1. The product can be recrystallized with a suitable solvent such as chloroform or fu ethanol if further purification is required .

Step i: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate IF)

A stirred mixture containing methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate (0.042M), benzyltrimethylammonium dichloroiodinate (Aiagisp, 9595, 0.057M, 1.36 eq. .) and zinc chloride (0.070M, 1.67 equiv.) in glacial acetic acid, refluxed for 15 minutes. The mixture is concentrated under vacuum and the residue is taken up in diethyl ether. The ethereal solution is washed with a dilute solution of aqueous hydrochloric acid, water and brine, dried (MoSO4) and concentrated in vacuo to obtain the target product. The product can be purified by recrystallization with a suitable solvent such as ethanol. "

Step ): Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylic acid

To a stirred solution containing methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-H-benzooxazole-5-carboxylate (0.024M) in tetrahydrofuran, add solid potassium trimethylsilanolate (5.14 eq.). The reaction mixture is stirred at ambient temperature in a stream of argon for 16 hours. An additional equivalent of potassium trimethylsilanolate is added and the mixture is stirred for 30 minutes. The reaction mixture is concentrated in vacuo to obtain a precipitate, which is then treated with 1:1 (v/v) ethyl acetate-diethyl ether. The organic phase is washed with a dilute - and aqueous solution of hydrochloric acid, a salt solution, dried (Mo5O 4), concentrated in a vacuum and - treated with chloroform to obtain a crude product. Recrystallization with a suitable solvent such as ethanol affords the purified target product. 1 Example 6 with 50 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylic acid hydroxyamide

Step a: Preparation of O-(tetrahydro-2H-pyran-2-yl)-oxyamide "m 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylic acid

The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylic acid is treated similarly

Step a of Example 2.

Step B: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylic acid hydroxyamide

The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoxazole-5-carboxylic acid coO-(tetrahydro-2H-pyran-2-yl)-oxyamide is processed similarly to Step 6 of Example 2 .

Example 7 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoxazole-5-carboxylic acid cyclopropylmethoxy-amide

The compound /7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1-H-benzoxazole-5-carboxylic acid is processed similarly to Step 5 of Example 3.

Example 8 65 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid

Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid

Similarly to Example 1, Step a.

Step p: Preparation of 2,3-difluoro-4-hydroxy-5-nitrobenzoic acid

Similarly to Example 4, Step b.

Step c: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate

Similarly to Example 4, Step p

Step a: Preparation of 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitrobenzoic acid methyl ester

A solution of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate in M,M-dimethylformamide is treated with 1 mol equivalent of cesium carbonate and heated to 857C for 30 minutes. Then, to the stirred mixture, 7/0, a solution containing a slight excess of M,M-dimethylthiocarbamoyl chloride in

M,M-dimethylformamide. The reaction mixture is stirred at room temperature for one hour, or it can be heated on a steam bath for one hour. Then the mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with 595 aqueous sodium hydroxide solution, water, brine and then dried with a drying agent such as magnesium sulfate or sodium sulfate. The solvent is then /5 removed in vacuo to give the crude product. The compound is purified by conventional methods such as chromatography or recrystallization from a suitable solvent.

Step e: Preparation of methyl ester of 4-dimethylthiocarbamoyloxy-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid

The compound methyl ether of 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitrobenzoic acid is dissolved in 2o excess of o-toluidine. The stirred mixture is brought to 2007 for one hour. The mixture is then poured into 595% aqueous hydrochloric acid. The aqueous mixture is extracted with diethyl ether. The organic phase is washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by conventional methods such as chromatography or recrystallization from a suitable solvent. with

Their step: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzothiazole-5-carboxylate

The compound methyl 5-amino-3-fluoro-4-mercapto-2-(2-methyl-phenylamino)-benzoate is processed similarly to Step n i)

Example 4.

Step d: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylate

The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-1H-benzothiazole-5-carboxylate is treated similarly to Step and M of Example 4.

Step n: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid Me

The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylate is treated similarly to the step of Example 4.

Example 9 --

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid hydroxyamide

Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide

The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid is treated similarly

Step a of Example 2.

Step p: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid hydroxyamide from Compound O-(tetrahydro-2H-pyran-2-yl)-oxyamide 7 -fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-b5-carboxylic acid is processed similarly to Step p from Example 2.

Example 10

Preparation of cyclopropylmethoxy-amide /7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid

The 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5-carboxylic acid compound is processed similarly to Step 5 of Example 3. c Example 11

Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid and Step a: Preparation of 8-fluoro-7-(2-methyl-phenylamino)-quinoxaline-b6-carboxylic acid "M The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (from Step e of Example 1) is dissolved in 2:1:1.2 (volume/volume/ volume) 2.0 M acetic acid - 4 M sodium acetate - methanol. The suspension is heated to 657 (until homogenization) and the clear solution is poured into 0.078 M aqueous sodium glycosal bisulfite (Alagisn, in Monohydrate, 1.05 equiv.), which is heated to a temperature of 707"C. The reaction mixture is carefully stirred at 55-757C for one hour and then cooled to 12"C in a water bath with ice. Granulated sodium hydroxide ground into powder is added to the cold solution (F). The mixture is gently heated to a temperature of 302C and stirred for 45 minutes . The temperature is raised to 70°C for 15 minutes. The mixtures are allowed to cool and treated with ethyl acetate. The two-phase mixture is treated with aqueous hydrochloric acid until pH 0 is reached in the aqueous phase. The organic phase is separated, dried (MoSO4) and concentrated in vacuo to give the target product. The product may be triturated with a suitable solvent such as dichloromethane or recrystallized from a solvent such as ethanol if further purification is required.

Step p: Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b6-carboxylic acid

The compound 8-fluoro-7-(2-methyl-phenylamino)-quinoxaline-b-carboxylic acid is processed similarly to Step 65 of Example 4.

Example 12

Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b6-carboxylic acid hydroxamide

Step a: Preparation of 8-Fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide

The compound 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid is processed similarly to Step a of Example 2.

Step p: Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid hydroxamide

The compound O-(tetrahydro-2H-pyran-2-yl)y-oxyamide /8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid is processed similarly to Step 6 of Example 2. 70 Example 13

Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid cyclopropylmethoxy-amide

The compound 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-b-carboxylic acid is treated similarly to Step

b of Example 3.

Example 14

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid

Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,51-thiadiazole-5-carboxylate

To a stirred solution containing methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (with

Step 1) and diisopropylethylamine (2 equiv.) in a suitable solvent such as diethyl ether or toluene, add a reagent similar to M-thioaniline or thionyl chloride (1.35 equiv.). The reaction mixture is boiled under reflux for 1 hour. The mixture is quenched with dilute aqueous hydrochloric acid. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, dried (Mo5O) and concentrated in vacuo to obtain the target product. The product can be recrystallized with a suitable solvent such as chloroform or ethanol or purified chromatographically if further purification is required. with

An alternative method; Methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate is added to a stirred solution of sulfur monochloride (6 eq.) in M,M -dimethylformamide and the mixture is gradually heated i) to 75-807C. After 5 hours, the mixture is cooled to 10"C, water is slowly added. The mixture is extracted with a solvent similar to diethyl ether or dichloromethane. The organic extract is dried (M9505) and concentrated in vacuo to obtain the target product. The product can be recrystallized with a suitable solvent (M. with similar to chloroform or ethanol or can be purified chromatographically if further purification is necessary. b"

Step p: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5) thiadiazole-5-carboxylate

The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,5|hiadiazole-5-carboxylate is treated similarly

Step and Example 4. --

Step c: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid and

The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylate is treated similarly to Step | Example 4.

Example 15

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo!|1,2,51| of thiadiazole-5-carboxylic acid "

Step a: Preparation of O-(tetrahydro-2H-pyran-2-yl)-oxyamide from 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5 -carboxylic acid

The 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5-hiadiazole-b5-carboxylic acid compound is treated with similar to Step a of Example 2.

Step p: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carbonic hydroxyamide

ACIDS

-I Compound O-(tetrahydro-2H-pyran-2-yl)-oxyamide of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid processed similarly to Step 5 - Example 2. with Example 16

Preparation of cyclopropylmethoxyamide and 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)hiadiazole-5-carboxylic acid

And Compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)| thiadiazole-b-carboxylic acid is processed similarly to Step 5 of Example 3.

Example 17

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)oxadiazole-5-carboxylic acid

Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylate 2-oxide (F) Divysya Takakiv, I.M.; Nadiitinaiakov, R.M., 9. Nefegosusiis Spet., 27,177 (1990). ka A mixture containing methyl 4-amino-33-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (from Step 4 of Example 1) and iodobenzene diacetate (1.76 eq.) in benzene is stirred at ambient temperature medium for 5 hours. The mixture is concentrated in vacuo and the precipitate is purified by column chromatography to give the target product.

Alternative method: A solution containing methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (0.86M) in tetrahydrofuran is diazotized and the diazonium salt is treated with sodium azide as described in stay

R.A.5.; Voueg, U.N., Oho. Zupii., 31, 14 (1951) and sources for references 4 and 8 cited here. Thermolysis 65 of this intermediate product in ethylene glycol at a temperature of 110-1207C for one hour allows to obtain the target product.

Step p: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylate

A solution containing methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylate 2-oxide and sodium azide (1.38 equiv.) in ethylene glycol is heated to 140-150"C for 30 minutes until obtaining the target product after column chromatography.

Step c: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylate

The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo|1,2,5)oxadiazole-5-carboxylate is treated similarly

Step and Example 4.

Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylic acid 70 Compound methyl 7-fluoro-6-(4-iodo- 2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylate is treated similarly to step | Example 4.

Example 18

Preparation of hydroxyamide of 7-Fluoro-6-(4-iodo-2-methyl-Phenylamino)-benzo|1,2,5)oxadiazole-5-carboxylic acid

Step a: Preparation of O-(tetrahydro-2H-pyran-2-yl)-oxyamide 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5- carboxylic acid

The 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylic acid compound is processed similarly to Step a of Example 2.

Step p: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5)oxadiazole-5-carboxylic acid hydroxyamide

The compound O-(tetrahydro-2H-pyran-2-yl)-oxyamide 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylic acid is processed similarly Step

b of Example 2.

Example 19

Preparation of cyclopropylmethoxy-amide 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid

I1,2,5)oxadiazole-5-carboxylic acid

The 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo|1,2,5|oxadiazole-5-carboxylic acid compound is treated i) similarly to Step 5 of Example 3.

Example 20

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid M zo Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1H- benzotriazole-5-carboxylate

The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (from Step e of Example 1) is diazotized according to the standard method. Processing gives the target product. yu

Step p: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylate

The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-TH-benzotriazole-5-carboxylate is treated similarly to Step 77 and Example 4.

Step c: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid

The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1nH-benzotriazole-5-carboxylate is treated similarly

Step | Example 4.

Example 21 "

Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid hydroxyamide from step a: Preparation of O-(tetrahydro-2H-pyran-2-yl)-oxyamide. 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid and? The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid is treated similarly

Step a of Example 2.

Step p: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1nH-benzotriazole-5-carboxylic acid hydroxyamide

The compound O-(tetrahydro-2H-pyran-2-yl)-oxyamide - 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid is treated similarly to step p c of Example

Example 22 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carbonate cyclopropylmethoxy-amide

And acids

The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzotriazole-5-carboxylic acid is treated similarly

Step 5 of Example 3.

Example 23

Cascade analysis of MAP kinase inhibitors

F, The introduction of ZR into myelin basic protein (MBP) is analyzed in the presence of glutathione 3-transferase of a chimeric protein containing p44MAP kinase (VO5T-MAPK) and glutathione 3-transferase of a chimeric protein containing ri5MEK (O51-MEK). The solution for analysis contains 20 mM NEREB5, pH 7.4, 10 mM MosiI, 1 mM ESTA, 50 µM 6o | Z2P)ATP, 10 μg of О5T-MEK, 0.5 μg of О5T-MARK and 40 μg of MVR in a volume of 100 μl. The reaction is stopped after 20 minutes by adding trichloroacetic acid and filtered through a layer of SB/C filter. C2P retained on the filter layer is determined using a 1205 Veilariae device. The compounds are evaluated at 1O0μM for the ability to inhibit the introduction of Z2R.

In order to verify whether the compounds really inhibit ZZI-MEK and O5T-MARK, two additional protocols (analysis) are used. In the first analysis, compounds are added to test tubes containing ZZT-MEK with the following additive

OZ51T-MARK, MVR and ((G2RIATR. In the second analysis, the components are added to test tubes containing both Z5T-MEK and

O5T-MARK, with the following supplement of MVR and (GRI ATR.

Compounds that show activity in both assays are recognized as MAPK inhibitors, while compounds that show activity only in the first assay are recognized as MEK inhibitors.

Example 24

Analysis of MAP kinase ip migo

Inhibitory activity can be confirmed in a direct assay. For MAP kinase, 1 kg of Z5T-MARK is incubated with 40 µg of MVR for 15 minutes at a temperature of 30 °C in a total volume of 5 µM containing 5 µM TRIS (pH 7.5), 70.10 µM Mdsi, 2 µM ESTA and 10 µM (GR ) ATP The reaction is stopped by adding model buffer 505

Laemmli, and phosphorylated MVR are resolved using electrophoresis on a 1095 polyacrylamide gel.

The radioactivity included in the MVR is determined both autoradiographically and by scintillation calculation of the selected range.

Example 25

Analysis of MEK ip migo

To determine the direct activity of MEK, 1 µg of Z5T-MEKIi is incubated with 5 µg of glutathione 5-transferase of a chimeric protein containing p44MAP kinase with lysine, until the alanine mutation in position 71 (Z5T-MARK-KA). This mutation eliminates the kinase activity of MAPK, as the kinase activity remains attributed to the addn

MEC. Incubation is carried out for 15 minutes at a temperature of 30"C in a total volume of 5 Ωcl containing

BOMM Tris (pH 7.5), 10 µM Mosi", 2 µM ESTA and 10 µM (G2RIATR. The reaction is stopped by adding model buffer 5ZO5 Laemmli. Phosphorylated MVR is resolved by electrophoresis on a 1095 polyacrylamide gel. Radioactivity included in Z5T-MARK-KA , are determined both autoradiographically and by subsequent scintillation calculation of the selected range. In addition, artificially activated

MEK containing serine to glutamate mutations in positions 218 and 222 (55TI-MEK-2E). When these two sites are phosphorylated, MEK activity increases. Phosphorylation of these two sites can be simulated by mutations d) serine residues to glutamate. For this analysis, μg of Z5T-MEK-2E is incubated with 5 μg of Z5T-MARK-KA for 15 minutes at a temperature of 30°C in the same reaction buffer as described above. The reaction is terminated and the analysis is carried out similarly to that described above.

Example 26 -

Analysis of MAR kinase of healthy Fo cells

To determine whether compounds block activation of MAP kinase in healthy cells, the following assay is used. Cells are placed in multiwell tubes (Petri dishes) and grown until confluent. Serum is removed from the cells overnight. Cells are exposed to the necessary concentrations of the compound or solvent (DMSO) for 30 minutes, followed by the addition of a growth factor, for example, ROSE (1OOng/ml). After 5 minutes of treatment with the growth factor, the cells are washed with PB5 and lysed in a buffer containing 70 mM Masi, 10 mM NEREZ (pH-7.4), 500 mM glycerol phosphate and 190 Triton X-100. Lysates are clarified by centrifugation at 13,000 rpm for 10 minutes. Protein from 5 to 15 μg, which floated to the surface as a result, is subjected to ZOB/RACE analysis and Western blotting for phosphorylation of MAP kinase steps. "

Example 27

Cells are placed in multiwell test tubes (Petri dishes) from 10,000 to 2,000 cells/ml. 48 hours "» after their seeding, test compounds are added to the cell growth medium and incubation is continued for two " additional days. Then the cells are removed from the nests by incubation with trypsin and counted with a counter

Coulter.

Example 28

Soft Agar Cultivation - Cells are seeded in Zoml dishes at 5000 to 100OO cells/dish using a growth medium containing 0.395 agar. After freezing the agar to a solid state, the cells are transferred to an incubator at a temperature of 377°C. After growing for 7-10 days, visible colonies are counted manually using

Ge) 20 dissecting microscope.

Example 29 tm Collagen-induced arthritis in mice

Collagen-induced arthritis (CIA) type II in mice is an experimental model of arthritis that shares a number of pathological, immunological, and genetic features with rheumatoid arthritis. This disease 22 is caused by immunization of OVA/1 mice with 1O0Omkg of collagen type II, which is the main component of articular cartilage,

F! injected subcutaneously with Freund's auxiliary kit. Susceptibility to the disease is regulated through the MHC class II gene locus, which is analogous to the association of rheumatoid arthritis with NI A-OKA. o Progressive and inflammatory arthritis will develop in most of the immunized mice, and is characterized by an increase in paw width up to 10095. The test compound is administered to mice in various amounts such as 20, 60, 100 and 60 200mg/kg body weight per day. The duration of the trials can be from several weeks to several months, for example, 40, 60 or 80 days. To assess the development of the disease from erythema and edema (phase 1), combined distortion (phase 2), to combined ankylosis (phase 3), a clinical calculation index is used. The disease progresses in such a way that it can affect one or all paws in animals, therefore the total possible score for each mouse is 12. Histology of an arthritic joint reveals synovitis, pannus formation and erosion of cartilage and bone. All deformities in mice that are susceptible to SIA have a high antibody response to type II collagen and there is a clear cellular response to SIA.

Example 30

ZSMU-induced monoarticular arthritis

Arthritis is induced as described in Zspmab, et al., IpTesiop apa Ittipyu, 59:4436-4442(1991), with minor modifications. Rats would receive mcg of ultrasound-dispersed ZSMU (in 1 μl of the YushShBesso reagent

RVB (ORV5)) by intra-articular injection into the joint of the right lower leg on the 0th day. On the 21st day, OTN initiates 1OOmkg of ZSMU (25O0mcl), which is introduced with an increase. For oral compound studies, compounds are suspended in a solvent (0.595 hydroxypropyl methylcellulose/0.29o Tween 80), dispersed in 7/0 sonication, and administered daily twice daily (1 Oml/kg body weight) starting in 1 hour to reactivation with

ZSMU The compounds are administered in amounts from 10 to 50 Ωg/kg body weight/day, for example 20, 30, 60, 100, 200 and

ZbOOmg/kg/day. Swelling measurements are obtained by determining baseline measurements of the sensitized hindpaw prior to reactivation on day 21 and comparing them to measurements at later time points, such as day 22, 23, 24, and 25. Paw sizes are determined using mercury plethysmography.

Example 31

Mouse ear-heart transplantation model

Eeu T.A. etc. describe the method of transplanting neonatal heart grafts into the auricle of mice and rats (U. Rpagt. Apa Tohis. Mei. 39:9-17(1988)). The compounds are dissolved in a solution containing a combination of absolute methanol, 0.295 hydroxypropyl methylcellulose in water, propylene glycol, cremophor, and dextrose or other solvent or suspending diluent. Mice are dosed orally or intraperitoneally once, twice, or three times daily from the day of transplantation (day 0) until day 13 or until the graft is removed. Rats were dosed once, twice, or three times daily from day 0 to day 13. Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the dorsal epidermis and dermis. The incision is extended down to the cartilage parallel to the heart and wide enough to allow the appropriate tunneling tool for the rat or insertion tool for the mouse.

A newborn mouse or rat pup less than 6 hours old is anesthetized and subjected to cervical i) displacement. The heart is removed from the chest, washed with saline, cut in half lengthwise with a scalpel and washed with sterile solution. A fragment of the donor heart is placed in a previously prepared tunnel with an inserted instrument, and air or residual liquid is carefully squeezed out of the tunnel under a low pressure of 3 M. No suture, adhesive bandage, bandage, or antibiotic treatment is required. Me

Implants are checked at 10-20 times magnification on a stereoscopic microscope for anatomy without anesthesia. Recipients whose grafts have no obvious damage can be anesthetized and assessed for electrical activity using Sgazv E-2 contact subcutaneous platinum microelectrodes, -- z5 placed either in the auricle or directly in the graft, and a tachograph. Implants can be checked 1-4 times a day for 10, 20, 30 or more days. The ability of the test compound to improve the symptoms of transplant rejection can be compared with control compounds such as cyclosporine, tacrolimus, or orally administered leflunomide.

Example 32 "

Egg albumin-induced eosinophilia in mice with c Female C57VI/6 mice were obtained from The Jackson Laboratory (Bar Harbor, Maine). All animals receive food and water at will. Mice are sensitized with a single subcutaneous injection of OMA (Grade M, ;" by Bidt Spetis! Sotrapu, San Luis, Missouri), adsorbed on alum (1 µg of OMA and µg of alum in 200 µl of saline) or a control diluent (dUmg of alum in 200O0μl of physiological solution) on the 0th day. On the 14th day, the mice are stimulated with a 12-minute inhalation of an aerosol containing 1.596 OMA (weight/volume) in -I physiological solution obtained in a nebulizer (small particle generator, model 5RAS-2; ISM company

RINagtasecisaivie, Costa Mesa, California). Groups of 8 mice are dosed with an oral solution (0.595 - hydroxypropylmethylcellulose/0.2595 Tween-80) or the studied compound at 10, 30 or 100 mg/kg in an oral solution, 200 μl per mouse orally. Dosed administration is carried out once a day, starting from the 7th or 13th day, and 5p continues for 16 days. ik To determine pulmonary eosinophilia, three days after the first administration of OMA in the form of an aerosol (17th "M day) mice are anesthetized with the help of an intraperitoneal injection of an anesthetic (Ketamine/Acepromazine/Xylazine) and the tracheas are isolated and cannulated. Lungs and upper respiratory tracts are washed twice with 0.5 ml of cold RVZ (phosphate-saline buffer). A portion (200 μl) of bronchoalveolar lavage fluid (VAG) is counted using a Coulter counter model 281 (Sosheg Eiesigopisv company, Khivele,

Florida). Residual weight. the liquid is then centrifuged at 300 x d for 5 minutes and the cells are resuspended in iF) 1 ml HB55Z (bibso VK) containing 0.595 fetal calf serum (NusSiope) and 10 mm NEREZ (Sirso VK). The cell suspension is centrifuged in a cytospin (Zpapdop Zoshcipegp Ipvigitepiv, Sewickley, PA) and counterstained using the Oi Otis (Ategisap Zsiepiyis Rgodisiv, McGray Park, IL) device to distinguish VAI. leukocytes in the set of neutrophils, eosinophils, monocytes and lymphocytes. The number of eosinophils in VAG. fluid is defined as an increase in the percentage of eosinophils in relation to the total number of cells.

Example 33

Study of Saso-2 cells

The study of cell transfer is carried out with Saso-2 cells grown on ZparueiYv between 22 and 28 days after b5 seeding. Usually, 10 mm MEZ buffer (pH 6.5) with 5 mm KSI, 135 mm Massi and 1.6 mm Sasi is used for the upper side and 10 mm MORZ (pH 7.5) with 5 mm KSI, 132.5 mm Masi and 1.8 mm Sasi » with 5mM O-glucose is used for the side located at the base. After washing the monolayers, the applied buffer is pipetted into the appropriate chamber and the cells are pre-stabilized at 37"C for at least 15 minutes. On the day of the experiment, the growth medium is removed and the cell monolayers are pre-stabilized with the applied buffers at 37"C for at least 15 minutes. TEEK measurements are then performed to confirm the integration of the monolayers. Measurements of transepithelial flux are performed by collecting cell monolayers in an adjacent diffusion chamber system (Rhesiziop Ipzigitepi Oevzidp, Tahoe City,

California). The temperature of 377°C is maintained by circulating water through the water shell. The solutions are mixed with a circulating gas containing 95 95 oxygen and 5905 carbon dioxide. Donor solutions with 70 PO compounds, "SI mannitol (a leak marker), and "NO metoprolol ( the reference compound) is added to the upper chamber. Donor and received samples are combined at selected time intervals of up to 3 hours. Radioactively labeled mannitol and metoprolol are analyzed using a scintillation counter (firm TorSoshpi, RasKaga Ipvigitepiv,

Downers Grove, Illinois). PO compounds are analyzed using the I C/M5/M5 method. Apparent permeability coefficients are calculated using the following ratio:

Rarr-(U'YASZHKA.So.ayu, where M is the volume of the obtained solution in ml, A is the surface area in cm? So. is the initial concentration of the donor in MM and as/a is the change in the drug concentration in the recipient cavity over the entire time.

Example 34

Metabolic stability in human and rat liver microsomes

The compounds are individually incubated (bmcl, solution in DMSO) with human and rat liver microsomes (0.5mg/ml protein) in 5HOMM KHPO4 buffer at 37"C in the presence of 1.0mM MAORN. At 0, 10, 20 and 40 minutes, 10Omcl are taken aliquot and add to 300µl of acetonitrile. Standard curves have the same character for each compound at concentrations: 7.5µl, 3.75µl, 2.50µl, 1.25µl. Samples are analyzed for initial concentration by method I C/M5/M5. Determination of period metabolic half-transformation of ip migo is carried out according to the graph of the titrated solution using the UMUipMopiiip program. The data of ip migo represent the degree of oxidative and o hydrolytic metabolism.

E. other implementation options

From the above and the examples, as well as from the claims below, it follows that the essential advantages of the invention are obvious. The scope of the invention also includes various modifications and adaptations within the limits of the ordinary skill in the art. what

Examples include a release compound modified by addition of a transfer protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of the release compound. The publications cited herein are incorporated by reference in their entirety. Io)

Claims (34)

- The formula of the invention m 1. Benzoheterocycles of the formula (I) . what are you and where MI - oku, MRgOnu, MeAK in, MKOMAAK in, O(СН»)» AMAAK in or MA (СН2)» and MAV in; - Ku - H, C. Cd-alkyl, C3 c-alkenyl, C3 c-alkynyl, C3 c-cycloalkyl, phenyl, (phenyl)C. /-alkyl, (phenyl)C3-6-alkenyl, (phenyl)C3-alkynyl, (C3-6-cycloalkyl)C 4-alkyl, (C3-8-cycloalkyl)C3 4-alkenyl, (C3-8-cycloalkyl )Cz z-alkynyl, Cz 8 - heterocyclic radical, (Cz.8 heterocyclic radical)C. -alkyl, (C3.8 heterocyclic radical)C3 -alkenyl, sl (C3.8 heterocyclic radical)C3.-alkynyl or (CH2)» AMC; P» - H, C. d-alkyl, phenyl, C3-c-cycloalkyl, C3-c heterocyclic radical or (C3-c-cycloalkyl)methyl; (Ce) Ka - H, C6-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl, phenyl, (C3-8-cycloalkyl)C. d-alkyl, -h (C3 c-cycloalkyl) C3/-alkenyl, (C3 c-cycloalkyl) C3-4-alkynyl, C3 c-heterocyclic radical, (C3 c8 heterocyclic radical)C. /-alkyl, (aminosulfonyl)phenyl, (Caminosulfonyl)phenyl|S. /-alkyl, (aminosulfonyl)S. β-alkyl, (aminosulfonyl)C with. 6d-cycloalkyl, Caminosulfonyl)C3 6-cycloalkyl)|C 4,4-alkyl or (СНо)». and MKsVo; Ev - H, C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, C6-cycloalkyl or phenyl; o - one of the following formulas (I1)-(iii): Ф) here, blackberry barks (Iii), ime) Ez Ez 60 in Ez - H or E; Kk - halogen, MO», ZO»MCo(CH»)» AMKEK ee, ZOoMKEKeE or (SOT; 65 T - Su. c-alkyl, C3.c-cycloalkyl, (MKeEKe)Si.4-alkyl, OKe, - MKO(SN")".AMKeEKe or MKeRe; 2 - one of the following formulas (im)-(miii): top tsretote M M M.Kh; OH» I AM she wines in "vv V, V; V; SHTY YOU (mii), pt shi (mii), M.M M. .-M YAM yu Z 00ove M one of Kb and Kb; - H or methyl and other from Kb and Kv - H, C..v-alkyl, C.v.-alkenyl, C.v.-alkynyl, phenyl, benzyl or -M-E-O; M -O, CO, 505, MK), (SOOMEn, MEN(CO), MeEN(ZO"), (5025)MEN or CH"; E - (СН2) 4.4 or (СНо)пО(СНо)р, where 1 x (for each ter) 5 312 "5 (ter) 5 4; or E - absent; o - Kk, OK, or MK)uKk, under the condition that if p - 1, then C - H; K; - H, C, C-alkyl, C-alkenyl, C-alkynyl, C-C-cycloalkyl, phenyl, 2-pyridyl, C-pyridyl, 4-pyridyl, (CH»)/2Ag, where Ag - phenyl, 2-pyridyl, Z-pyridyl or 4-pyridyl, 50О2МКН(СН»)» АМАКвКк, (СОХСН»)»АМК вк or (СОМ Н(СН2г)» АМЕКК; Хи - О, 5, MK8 or СНК»; X" - 0, 5 or SNK"9; and Xz - O or 5; where, if X; or Xo - CHCo, the mentioned compound can also be a tautomerized indole; Kv - H, C. d-alkyl, phenyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, (CH»)/.2Ag, where Ag is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, Co -alkenyl, C» /-alkynyl, C3.6-cycloalkyl or (Co-alkyl)/MK, Km; provided that K7 and Ka together have no more than 14 carbon atoms, with the exception of K,, Ku, K. and Kk. Ko - Si.4-alkyl, phenyl, 2 -pyridyl, 3-pyridyl, 4-pyridyl, C3.4-alkenyl, C3.4-alkynyl, C3.6-cycloalkyl, (CO)OC», with (Co l-alkyl/MK., Km, (SOMAMSN» )". A MA, Km, (SOM, Km, (SOHCHN")". A-MA., Km or (CH"). 2Ag, where Ag is phenyl, He) 2-pyridyl, Z-pyridyl, 4- pyridyl; Co - C..4-alkyl, phenyl, 2-pyridyl, C-pyridyl, 4-pyridyl, C» d-alkenyl, Co /-alkynyl, C3 6-cycloalkyl, (COOCr, (Co d-alkyl/MCu, Km, (CO)MKMSHN")" And MK, Km, (CO)MEK, Km, (CO)(CH")". A-MK, Km or (CH»)42Ag, where Ag is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; - Ker - H, C1-6-alkyl, phenyl, C3-1-alkenyl, C3-6-alkynyl, C3-6-cycloalkyl or (CH0)". 4 ME. km; Fo Co - H, methyl, halogen or MO"; Ku - H, methyl, halogen or MO"; Io) each of Ks, Ko, Ke, Ke, K, K,, Kk, Ki, and Km is independently selected from H, C. ./-alkyl, C.sub.3-alkenyl, "- C3-alkynyl, C3-6-cycloalkyl and phenyl; each of MKoCo, MKeEKe, MKK, and MKIiKu may also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl; and - each of Kn, Km, Ko - independently H, methyl or ethyl; where, each above hydrocarbon radical or heterocyclic radical is optionally substituted with 1-3 substituents independently selected from halogen, C-4-4-alkyl, C3-6-cycloalkyl, C3-alkenyl, C3-alkynyl, "phenyl, hydroxyl . hydroxyl, amino and MO"; h or their pharmaceutically acceptable salts or C. 7-esters. » 2. The compound according to claim 1, where OO) represents the formula (Her). 3. The compound according to claim 2, where Kz represents H or fluorine. 4. Compound according to claim 3, where K; is fluorine, chlorine or bromine. -and 5. The compound according to claim 1, where C/o is hydrogen, methyl, fluorine or chlorine. - 6. The compound according to claim 1, where K/4 represents methyl, chlorine, fluorine, nitro or hydrogen. 7. Compound according to claim 6, where K/4 is H. at 8. The compound according to claim 6, where K/4 is fluorine. at 20 9. The compound according to claim 5, where each of Co and K/1 represents fluorine. 10. The compound according to 1, where K/ represents H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, "C3-6-alkenyl, C3-6-cycloalkyl, (C3-5-cycloalkyl)C. - »-alkyl, (C35 heterocyclic radical)C.o-alkyl or (CH2)2AMesCo, 11. The compound according to claim 10, where Ku is H or (C3.4-cycloalkyl)C4.2-alkyl. 25 12. The compound according to claim 1, where Co" represents H or methyl. Gee! 13. The compound according to claim 1, wherein KA has at least one hydroxyl substituent. 14. The compound according to claim 1 e Ka is H, methyl, ethyl, isobutyl, hydroxyethyl, phenyl U d A " " " U " dr " " where 2-piperidin-1-ylethyl, 2,3-dihydroxypropyl, 3-I4 -(2-hydroxyethyl)-piperazin-1-yl|-propyl, 2-pyrrolidin-1-ylethyl or 2-diethylaminoethyl; and Kv represents H; or where Kv is methyl and KA is phenyl. for 15. The compound according to claim 1, where MU is MKACv or MKoMCACv. 16. The compound according to claim 1, where MU is MKa(СН»)» and MEARv or О(СН»)»zMEAEv. 17. The compound according to claim 1, where the MU is the MCoOK). 18. Compound according to claim 1, where MU is OK). 19. The compound according to claim 1, where 7 represents the formula (hm). 65 20. The compound according to claim 19, where Xi is MKva, and K»7 is N. 21. The compound according to claim 1, having the structure of 7-fluoro-6-(4-iodo-2-methylphenylamino)-1H-benzoimidazole-5-carboxylic acid. 22. The compound according to claim 1, selected from the group of 7-fluoro-6-(4-iodo-2-methylphenylamino)-1H-benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)benzoxazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)benzothiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)benzo|1,2,5)hiadiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)benzo|1,2,5|oxadiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)-2-(2-hydroxyethyl)-1H-benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methylphenylamino)-2-(2-dimethylaminoethyl)-1H-benzoimidazole-5-carboxylic acid; 70 7-fluoro-6-(4-iodo-2-methylphenylamino)-1-acetylbenzoimidazole-5-carboxylic acid; 8-fluoro-7-(4-iodo-2-methylphenylamino)quinoxaline-6-carboxylic acid and 7-fluoro-6-(4-iodo-2-methylphenylamino)-1H-benzotriazole-5-carboxylic acid; and the corresponding hydroxamic acids and cyclopropylmethylhydroxamates. 23. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable carrier. 24. A method of treating a proliferative disease in which a pharmaceutically effective amount of a composition containing a compound according to claim 1 is administered to a patient in need of such treatment. 25. The method of claim 24, wherein said proliferative disease is selected from psoriasis, restenosis, autoimmune disease, and atherosclerosis. 26. A method of treating cancer, in which a pharmaceutically effective amount of a composition containing a compound according to claim 1 is administered to a patient in need of such treatment. 27. The method according to claim 26, wherein said cancer is MEK-induced. 28. The method according to claim 26, where the cancer is rectal cancer (colorectal cancer), cervical cancer (cervical cancer), breast cancer, ovarian cancer, brain cancer, acute leukemia, stomach cancer, non-small cell lung cancer, pancreatic cancer or kidney cancer. high school 29. A method of treating or alleviating the effects of a stroke or heart failure, in which a pharmaceutically effective amount of a composition containing a compound according to i) is administered to a patient in need of such treatment claim 1. 30. A method of treating or reducing the symptoms of xenograft rejection, in which a pharmaceutically effective amount of M Zo Composition containing the compound according to claim 1 is injected into the transplanted organ, limbs, skin or bone marrow of the patient. 31. A method of treating osteoarthritis or rheumatoid arthritis, or a viral infection, or cystic Me fibrosis, or hepatomegaly, or cardiomegaly, or Alzheimer's disease, or complications of diabetes, or septic shock, or asthma, in which it is administered to a patient in need of such treatment, a pharmaceutically effective amount of the composition containing the compound according to claim 1. -- 32. A method of treating cancer, in which (a) a pharmaceutically effective amount of a composition containing a compound according to claim 1 is administered to a patient in need of such treatment and (b) therapy selected from radiation therapy and chemotherapy is administered. 33. The method of claim 32, wherein said chemotherapy includes a mitotic inhibitor. 34. The method according to claim 33, where said chemotherapy includes a mitotic inhibitor selected from the group: paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine and vinflunine. etc. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrals;" microcircuits", 2004, M 12, 15.12.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. -I - 1 o 50 that F) has) 60 b5