UA74024C2 - A method for the treatment of states caused by ??38-kinases, and pyrrolotriazine compounds suitable for use as kinases inhibitors - Google Patents

Abstract

The invention concerns methods for the treatment of one or several states conditioned by ??38-kinase activity, consisting in the incorporation into the body of patient requiring such treatment of at least one compound of the formula (??) or pharmaceutically acceptable salt thereof, prodrugs or solvate, where R3 denotes hydrogen, methyl, perfluormethyl, methoxy, halogen, cyano or NH2, better - methyl, and X, R1-R6 and Z have values according to this description. In the optimal variant of the group ZR4R5, taken together, form N??-substituted aryl.

Description

Description of the invention

The present invention relates to methods of treating conditions caused by pZ8vA and B kinases, as well as 2 pyrrolotriazine compounds, more specifically - carboxamides and benzamides of the pyrrolotriazine series, suitable for treating conditions caused by p3zv kinases.

Many cytokines are involved in the initiation of the inflammatory reaction, including 1-1, 1/-6, /-8 and

TME-A. Overproduction of cytokines such as IL-1 and TME-A has been observed in a wide variety of diseases including, but not limited to, inflammatory bowel disease, rheumatoid arthritis, psoriasis, 70 multiple sclerosis, endotoxin-induced bacterial toxic shock, osteoporosis, Alzheimer's disease, and congestive heart failure 24: 1345-1354 (1999); Zaiyigo ei aYi., Sit. May Spet., 6: 807-823 (1999)). Data obtained as a result of examination of sick people indicate that protein antagonists of cytokines are effective for the treatment of chronic inflammatory diseases, for example, such as monoclonal antibody against TME-A (Eprgei!) |KapKip ey aiY., Vg. U. CPeiytaioi.. 34: 334-342 (1995)) and fusion protein 12 soluble TME-A receptor-Es (E(apegseri) | Mogeiapa ei ai., App. Ipiegp. Med. 130: 478-486 (1999) |.

TME-A biosynthesis occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TME-A production are mitogen-activated protein (MAP) kinases, in particular pZV8-kinase. These kinases are activated in response to various stress stimuli, including, but not limited to, proinflammatory cytokines, endotoxin, UV radiation 20 and osmotic shock. Activation of p38 requires double phosphorylation of threonine and tyrosine in the motif

Tig-Su-Tug, characteristic of rZv isozymes, under the action of 3-5 (irvigeate) kinases MAR-kinase (MKKZ and MKK).

Four isoforms of p3Z8 are known, namely p38-A, pZ38B, pZ8G and p385. Isoforms A and B are expressed in inflamed cells and are key mediators of TMPE-A production. Inhibition of rzZ8A and B enzymes in cells leads to a decrease in TME-A expression levels. When using pZ3vA and B inhibitors in animal models of inflammatory diseases, it was also found that such inhibitors are effective in the treatment of these diseases. Accordingly, riv enzymes play an important role in inflammatory processes mediated by 1-1 and TME-A. The use of compounds reported to inhibit p38 kinase and cytokines such as IL-1 and TME-A for the treatment of inflammatory diseases (described in US Pat. and 5945418 in the name of Mepyeh RnaptasetschiisaYiiv Ips., in Z 30 US patents 6251914, 5977103 and 5658903 in the name of Ztiy-Kipe Veespat Sogr., in US patents 5932576 and Ge 6087496 in the name of 5.0 Zeape So., in international applications MO 00/56738 and MO 01/27089 in the name of Aviga 7epes, in international application MOI 01/34605 issued dopypsop 4: dopypsop, in international applications UMO 00/12497 (quinazoline derivatives as inhibitors of p38-kinase ), MUO 00/56738 (pyridine and pyrimidine derivatives for the same purpose), MMO 00/12497 (the relationship between pZ8-kinase inhibitors is considered) and MO 00/12074 (piperazine and

Z piperidine compounds suitable for use as inhibitors of pZ38)). t

The proposed invention covers methods of treatment of conditions caused by the activity of pZv8-kinase, which consist in the introduction of appropriate pyrrolotriazine compounds into the body of the patient. In addition, the invention covers selected pyrrolotriazine compounds, including compounds of 5-methyl- and "

B-trifluoromethylpyrrolotriazine-b-carboxamides, suitable as inhibitors of kinases, in particular inhibitors of kinases З7З рЗ3ВА and B. Pyrrolotriazine compounds used as tyrosine kinase inhibitors (described in US patent application 09/573829, filed May 18, 2000), assigned to this applicant. Pyrrolotriazine compounds with "with an acid group as a substitute, which - according to reports - are characterized by ZRIA"-inhibitory activity, (described in the international application M/UO 01/14378 Ai1 in the name of Zpiopodi 85 So., (C(4., published on March 1, 2001).

The proposed invention relates to methods of treating one or more conditions caused by p3v8-kinase activity, which consist in introducing one or several pharmaceutically active compounds of the formula (I) into the body of a patient in need of such treatment. g, i (13) , or its pharmaceutically acceptable salt, prodrug or solvate, where (F, Ez means hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano or MH"; where X is selected from such radicals as -O-, -0С(-0)-, -5-, -5(:0)-, -505-, -Щ-0)-, -605-, -МКч1о-, -МКчиос(:9)-, -MAoС( O)MK 44-, -MKioSo»-, -MKio5O»5-, -MKio5O2 MA 44-, -502MKo-, -FSHCHO)MK.o, halogen, nitro and cyano, or because X is absent. 7 is chosen from such radicals as O, 5, M and SK»o, where - if 7 means SKood - the specified carbon atom can form an optionally substituted bicyclic aryl or heteroaryl with K, or Kb;

Kk means hydrogen, -СН», -ОН, -ОСН», -ВН, -ЗСН3, -О0ФШ-О)ка4, -5(-О)Ко», -502Коо, -502МКа24Ков, -СбоКач, -б(5О) MKodKov, -МНО, 0 -МКодКов, 0/«МК245О02МКодКов, 0 -МКойЗО2Ког, 0 -МКодб(тоО)Ков, 0 «МКодСО2 ов, вBo0МКо1Ф(5О)МК а Kov, halogen, nitro or cyano;

E" is selected from a number of such radicals as a) hydrogen, provided that K"o does not mean hydrogen, if X means -5(-0)-, -505-, -МК1оСО»- or -МК410505-; b) alkyl, alkenyl and alkynyl, which optionally has up to four Kov groups as substituents; c) aryl and heteroaryl, which optionally has up to three Co groups as substituents, and d) heterocyclo or cycloalkyl, which optionally has a keto group (50) as substituents, up to three K 27 groups and/or contains carbon - a carbon bridge with 3-4 carbon atoms, or e) K" is absent, if X means halogen, nitro or cyano; (Y) Ku; means a substituted aryl, an aryl having as a substituent MNZO 5-alkyl, a substituted heteroaryl, or an optionally substituted bicyclic 7-11 saturated or unsaturated carbocyclic or heterocyclic 70 ring, and

K5 is hydrogen, alkyl, or substituted alkyl, except when 7 is O or 5, K5 is absent, or (ii) K, and K5 together with 7 form an optionally substituted bicyclic 7-11-ene aryl or heteroaryl;

Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, 75. "MR Ka, -OK; or halogen;

Co and K/4 are independently selected from the group of such radicals as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo and substituted heterocyclo;

KU, Kv, Ko, Kod and Kob are independently selected from a number of such radicals as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo and substituted heterocyclo;

Eoo is hydrogen, lower alkyl, or substituted alkyl, or Kogo may be absent if the carbon atom to which it is bonded is together with Ke. and K5 represents part of an unsaturated bicyclic aryl or heteroaryl;

Co" means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or substituted heterocyclo;

Kob is chosen from a number of such radicals as halogen, trifluoromethyl, haloidalkoxy, keto (50), nitro, cyano, -ZKov, "OKov, "MKovE2o- "MKov3O", -"MKovZO2Kov, -ZO2R29, -ZO2MKovKog, "СОоРov, " С(5О)Нов, -С(-О)Нов о, su 285 ОС(О)Ков, -ОС(О)МКовКоою, «МКовС(О)Ковю, «МКовСОоКоо,-М-ОН, «М-О -allyl; aryl, which optionally has from one to three Co groups as a substituent; cycloalkyl, which optionally has as a substituent a keto group i) (5-0), from one to three Co groups; or contains carbon - a carbon bridge of 3-4 carbon atoms; and a heterocycle, which optionally has a keto group (5-0) as a substituent, from one to three K 5 groups, or contains a carbon-carbon bridge of 3-4 carbon atoms; and each of the radicals Kov and K00 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, C3-7C-cycloalkyl, and C3-heterocycle, or they may together form a C3-heterocycle; and each of the radicals Kod and Koo, in turn, can optionally contain up to two substituents, which are alkyl, alkenyl groups, halogen atoms, haloalkyl groups, haloalkyloxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy and benzyloxy groups; - ! uh-

Co.; are selected from a number of radicals such as alkyl, K 20 and C 10 alkyl, containing as a substituent from one to three K32 groups), and each of the radicals K 20 is independently selected from a number of such radicals as halogen, haloalkyl, haloalkoxy, nitro, cyano, -ZKao, «OKzo, -MKaoKz1, «-MKazozO», -MKzozO»Kz1, -2О02Cazo, -«ЗО2МКzokKai1, -СО2Рzo, -ФЩ2О)Kao, -FЩ-О)МКаовзи -0Ф(-0)Kzo, -OSFS (-О)МКаовзи, -МКзос(-О) Ка, -МКзоСО» 44 and 3-7--lene « 70 carbocyclic or heterocyclic ring, which optionally contains as a substituent alkyl, halogen, - with hydroxy, alkoxy, haloalkyl, haloalkyloxy, nitro, amino, or cyano, wherein each of the radicals K20 and K2/4c is independently selected from the group of such radicals as hydrogen, alkyl, alkenyl, aryl, aralkyl, C2cycloalkyl, and ""heterocycle, or they together may to form a C3/7heterocycle.

In addition, the invention relates to compounds that are characterized by high activity as inhibitors of rZV-kinases A and B and TME-A and are compounds of the formula (II) -I ch vx (1) o and «DA x, va 7 MA.

I" m nya 1 a,

HF) as well as its pharmaceutically acceptable salts, prodrugs or solvates, where K z means methyl or CE"; Kv 7 means hydrogen or alkyl;

U means -С(О)МКоаз-, -МКозС(-О)МА 2з-, -МКоз5О»- or -502МКоз-; in Kv and Kz are selected from a number of such radicals as hydrogen, alkyl, alkoxy, aryl and aryl, containing as a substituent from one to three K./o groups, except for those cases when U means -MK 23505-, then Kud means

S. lalkil, which optionally has from one to three Kch9 groups as a substitute;

Keys and Clio are each, when present, independently selected from the group consisting of alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, 65 alkylsulfonylamine, sulfonic acid, alkylsulfonyl, sulfonamido, and aryloxy, wherein each of the groups,

i.e. Kz and/or Co, may additionally contain hydroxy, alkyl, alkoxy, aryl or aralkyl as substituents; and

X, Ku, B" and Ko correspond to the definitions given above for compounds of formula (1).

Further, the text defines the various terms that are used in the description of the present invention. These definitions apply to the disclosure of terms in all sections of the description provided herein, unless otherwise specified in specific Examples, either individually or as part of a larger group.

The term "alkyl" refers to unsubstituted hydrocarbon groups with a linear or branched chain of 1-20 carbon atoms, preferably 1-7 carbon atoms. The term "lower alkyl" refers to unsubstituted alkyl groups containing 1-4 carbon atoms. If a subscript is placed next to the symbol for a carbon atom of an alkyl or other 7/0 group, such subscript indicates the number of carbon atoms that the group may contain. The term "Colalkyl" includes the bond and alkyl groups, which include 1-4 carbon atoms.

The term "substituted alkyl" refers to an alkyl group having from one to four substituents selected from the group consisting of halogen, hydroxy, alkoxy, oxo (50), alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino , disubstituted amines in which two amino substituents are selected from such radicals as alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthio, arylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. , carbamyl, for example, SOMN", substituted carbamyl, such as, for example,

SOMAlkyl, SOMNaryl, SOMNaralkyl, or two substituents in the position of the nitrogen atom are selected from a number of such 20 radicals, such as alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted or unsubstituted heterocyclo such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. If the substituent in the position of the alkyl group additionally has a substituent, such substituent is alkyl, alkoxy, aryl or aralkyl.

When the term "alkyl" is used in connection with another group, as in the case of heterocycloalkyl or Cscycloalkylalkyl; this means that the defined group is connected directly through the alkyl group, which can be characterized by a linear or branched structure. In the case of the presence of substituents, for example in the case of i) "substituted cycloalkylalkyl", the alkyl moiety of the group - in addition to the presence of a linear or branched chain - may have the substituents given above for the case of substituted alkyl groups, and/or the linked group may be substituted, as listed above for this group. The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups containing 6-12 carbon atoms in the ring fragment, such as phenyl, naphthyl, biphenyl and diphenyl groups. If the aryl is o substituted, each aryl ring may be substituted.

The term "substituted aryl" refers to an aryl group having from one to four substituents "selected from the group consisting of alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, 1-1-hydroxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkylsulfonyl, sulfonamido, and aryloxy. The substituent may also contain hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl as a substituent. "

The term "aralkyl" refers to an aryl group linked directly through an alkyl group, such as benzyl, wherein the alkyl group may be linear or branched. In the case of "substituted aralkyl", the alkyl moiety of the group - in addition to being linear or branched - can be up to ;» the same substituted as listed above for substituted alkyl groups, and/or the aryl moiety may be substituted as listed for substituted aryl. Thus, the term "optionally substituted benzyl" refers to the group 45... ) where each group K can be hydrogen or can also be selected from a number of radicals such as I alkyl, halogen, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, benzyloxy and av! other groups listed above. At least two of these "K" groups should be hydrogen, and preferably at least five of these "K" groups should be hydrogen. The best benzyl group o contains a branched alkyl fragment, marked en, . their

The term "heteroaryl" refers to an aromatic group, for example, a group that is a 4-7-membered monocyclic, 7-11-membered bicyclic, or 10-15-membered tricyclic ring system that contains at least one heteroatom in at least one carbon-containing ring. Each ring of a heteroaryl group containing

F! heteroatom, may contain one or two oxygen or sulfur atoms and/or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. The fused rings comprising bicyclic or tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen 60 or sulfur atoms may optionally be oxidized, and nitrogen atoms may optionally be quaternized.

Heteroaryl groups that are bicyclic or tricyclic must contain at least one fully aromatic ring, but the other fused ring(s) may be aromatic or non-aromatic. A heteroaryl group can be attached at the position of any corresponding nitrogen or carbon atom of any ring. for "Substituted heteroaryl" contains from one to four substituents on any one or more rings,

containing a heteroaryl group. The substituents are selected from the group of substituents listed below for heterocyclic groups.

Examples of monocyclic heteroaryl groups are pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (ie, thiazolyl), thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, and pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, etc.

Прикладами біциклічних гетероарильних груп є індоліл, бензотіазоліл, бензодіоксоліл, бензоксаоксоліл, 70 бензотієніл, хінолініл, тетрагідроізохінолініл, ізохінолініл, бензімідазоліл, бензопіраніл, індолізиніл, бензофураніл, хромоніл, кумариніл, бензопіраніл, цинолініл, хіноксалініл, індазоліл, піролопіридил, фуропіридиніл, дигідроізоіндоліл, тетрагідрохінолініл і etc.

Examples of tricyclic heteroaryl groups are carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

The term "alkenyl" refers to linear or branched hydrocarbon groups containing from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and most preferably from 2 to 8 carbon atoms, and having from one to four double bonds ties

The term "substituted alkenyl" refers to an alkenyl group with one or two substituents selected from the group consisting of halogen, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, 2o alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, as well as substituted and unsubstituted heterocyclo, including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc.

The term "alkynyl" refers to linear or branched hydrocarbon groups containing from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, most preferably from 2 to 8 carbon atoms, and having one to four triple bonds.

The term "substituted alkynyl" refers to an alkynyl group with a substituent selected from the group consisting of halide, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, as well as substituted and unsubstituted heterocyclo, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc.

The term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon c ring system, which optimally contains from 1 to 3 rings with 3-7 carbon atoms in the ring, "3 which can be additionally fused with an unsaturated C" carbocyclic ring . Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and C adamantyl. "Substituted cycloalkyl" has as substituents one or more alkyl or substituted alkyl groups described above, or one or more groups described above as alkyl substituents.

The terms "heterocycle", "heterocyclic" and "heterocyclo" each refer to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example a group which is a "4-7-ene monocyclic, 7-11-ene bicyclic or a 10-15-membered tricyclic ring system containing at least one heteroatom in at least one carbon-containing ring. Thus, the term "heterocycle" includes the heteroaryl groups described above. Each ring of a heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also be optionally oxidized, and the nitrogen heteroatoms may also be optionally be quaternized The heterocyclic group may be attached to any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups are pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, -I pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, tit oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, av! 2-oxazypenyl, azepinyl, 4-piperidonyl, pyridyl, M-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and de tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl , thietanil, thiiranil, triazinil, triazolyl, etc.

Chl» Examples of bicyclic heterocyclic groups are 2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-M-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl , coumarinyl, cinolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo|2,3-c|Ipyridinyl, furo|C,1-b|Ipyridinyl or furo2,3-B|Ipyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as о 3,4-дигідро-4-оксохіназолініл), іФ) бензізотіазоліл, бензізоксазоліл, бензодіазиніл, бензофуразаніл, бензотіопіраніл, бензотриазоліл, ко бензпіразоліл, дигідробензофурил, дигідробензотієніл, дигідробензотіопіраніл, дигідробензотіопіранілсульфон, дигідробензопіраніл, індолініл, ізохроманіл, ізоіндолініл, нафтиридиніл, фталазиніл, піпероніл , purinyl, because pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, etc.

Smaller heterocycles such as epoxides and aziridines are also covered. "Substituted heterocycle" has as a substituent one or more alkyl or aralkyl groups described above and/or one or more groups described above as alkyl substituents.

Unless otherwise indicated, when referring to a specific heterocyclo or heteroaryl, it is assumed that such reference covers those systems with a maximum number of non-cumulative double bonds or with a number of double bonds less than the maximum number. So, for example, the term "isoquinoline" refers to isoquinoline and tetrahydroisoquinoline.

The term "diazepine" refers to a heterocyclic ring that contains at least one seven-membered ring with two nitrogen atoms in the seven-membered ring, including a fully saturated or unsaturated diazepine.

The term "heteroatoms" includes oxygen, sulfur and nitrogen atoms.

The term "haloalkyl" ("haloalkyl") means an alkyl having one or more halogen substituents.

The term "perfluoromethyl" refers to a methyl group with one, two or three fluorine atoms as substituents, namely CNR, SN00 and CE3. The term "perfluoroalkyl" refers to an alkyl group containing from one to five fluorine atoms, such as pentafluoroethyl. 70 The term "halo-alkoxy" ("halo-alkoxy") means an alkoxy group with one or more halo substituents. For example, the term "haloalkyloxy" includes -OCE.

The term "carbocyclic" means a saturated or unsaturated monocyclic or bicyclic ring in which all atoms in all rings are carbon atoms. Therefore, this term covers cycloalkyl and aryl rings. The carbocyclic ring may be substituted; in which case the substituents are selected from the range of substituents listed above for /5 Cycloalkyl and aryl groups.

When the term "unsaturated" as used herein refers to a particular ring or particular group, such ring or such group may be fully unsaturated or partially unsaturated.

Following the text are definitions of various other groups listed above in connection with substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted cycloalkyl, etc.: alkoxy means -OC2, alkanoyl means -C(- O)K2, aryloxy means -OAg, alkanoyloxy means -"OOC(-O)K2, amino means MH", alkylamino means -MNK?, arylamino means -MHAg, aralkylamino means -MH-K-Ag, disubstituted amine or dialkylamino means -MEUVU, alkanoylamino means -MH-C(-o)KU, aroylamino means -MH-C(-O)Ag, aralkanoylamino means -MH-C(-O)KR-Ag, thiol means -ZN, alkylthio means -582 , arylthio means -5Ag, aralkylthio means -5-K2-Ag, alkylthiono means -5(-0)K2, arylthiono means -5(-O)Ag, aralkylthiono means -5(:O)B2-Ag, alkylsulfonyl means -BO(in Kg", arylsulfonyl means Ho) -ZO(duhg, arylsulfonylamine means -МНЗО,uAg, alkylsulfonylamine means -МН5ЗО»К?, aralkylsulfonyl means -BO (in vAg, sulfonamido means -502МН", nitro means -MO» , carboxy means -СО2Н, carbamyl means -СОМН»о, substituted carbamyl means -С(-О)МНЕО or -С(-О)МЕЗОВ9, alkoxycarbonyl means «И b(50)0Ka carboxyalkyl means -ВРСООН, sulfonic acid (sulfonic acid) means -5ОН, сч arylsulfonylamine means -МН6зЗОуАг, guanidino means | , la ureido means . ich and where KZ is still Her. AND GI | "c) n Kk. ; ! " means alkyl as defined above, VC? means alkylene according to the above definition, B and KZ 32 are selected from a number of such radicals as alkyl, aryl and aralkyl, Ag means aryl according to the above definition, and a - a is equal to 2 or 3.

To obtain stable fragments and compounds, experts in the relevant field of technology can choose groups and substituents in them in the description as a whole. "

Compounds of formula (I) can form salts, which are also included in the scope of the present invention. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts may also be used, for example, in the isolation and purification of the compounds of this invention. It is intended that all references to compounds of formula (I) include - without limitation - compounds of formulas (Ia) - (Ii), as well as compounds of formulas (Ii) and (Ma) - (Pp). All references to compounds of formula (II) include - without limitation - compounds of formulas (Ia) - (II).

Compounds of formula (I) can form salts with alkali metals such as sodium, potassium and lithium, with

Alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine, and amino acids such as arginine, lysine, etc. Such salts can be prepared by methods known to those skilled in the art. Compounds of formula (I) can form salts with a number of organic and inorganic acids. Such salts include those formed by the use of hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzene sulfonic acid, toluenesulfonic acid, and other acids (for example, nitrates, phosphates , borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates, etc.). Such salts can be prepared by methods known to those skilled in the art. 52 Salts of the compounds (of the present invention) may be useful in increasing the rate of dissolution of the compounds and thereof

F! bioavailability when administered orally. Mesylates and/or bisulfates have been successfully prepared for selected compounds of formula (I) (see Example 125 herein). Both mesylates and bisulfates were found to be non-hygroscopic, well soluble in water and stable in the solid state. In addition, zwitterions ("internal salts") can be formed. All stereoisomers of the compounds of this invention are contemplated, either in the form of a mixture, or in pure or substantially pure form. The definition of the compounds of this invention covers all possible stereoisomers and mixtures thereof. It includes racemic forms and selected optical isomers, which are characterized by specific activity. Racemic forms can be separated using techniques used in physics, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation of chiral compounds using column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, such as, for example, salt formation using an optically active acid followed by crystallization.

The compounds of formula (I) can also be in the form of prodrugs. Any compound that is immediately converted into a bioactive agent (i.e., a compound of formula I) belongs to the prodrugs that are included in the scope of the present invention and correspond to its essence.

Various forms of prodrugs are well known in the art. For examples of such derivatives-prodrugs, see: a) Oevidp oi Rgodgidv, ediei Bu N. Vypadaaga, (EiIvemieg, 1985), and Meijoaz ip Epgmtoiioam. Moi.42, 70 p.309-396, edigei Bu K. Uuidaeg, ei a. (Asadetis Rgezvz, 1985); b) A Tehirook oi YuOgid YuOezidp apa Oemeiortepi, ediei ru Kgozdaaga-I agzep apa N. Vypadaaga, Sparieg 5, "Oevzidp apa Arriisayop oi Rgodgydvg", Bu N. Vypadaaga, p. 113-191 (1991) and c) N. Vypddaaga, Adumapsed Ogyd Oeiiimegu Kemiyeemuv. 8,1-38 (1992).

In addition, it should be understood that solvates (for example, hydrates) of compounds of formula (I) are also included in the scope of the present invention. Methods of solvation are generally known in the relevant art.

The best options for implementing the invention include the best compounds of formulas (I) and (I) and methods of treating conditions caused by p38-kinase activity, which consist in introducing the best compounds of formulas (I) and (I) into the patient's body. The best compounds are the compounds of the formula (I) "5 V Shchy iga zv Fu c and (o) as well as their pharmaceutically acceptable salts, prodrugs or solvates, where:

Ez means methyl, -CEz or -OSE";

X is chosen from such radicals as -С(-0)-, -СО5-, -МКч1оС(50)- and -ЧЧ(О)МК.о, or X is absent; - 7 means M; high school

Kk means hydrogen, -СН», -ОН, -ОСН», -ВН, -ЗСН3, -О0ФШ-О)ка4, -5(-О)Ко», -502Коо, -502МКа24Ков, -СбоКач, -С(5О) MAoaBov, «МНо, -МА24502МАоаКов, -МАо4502Н22, -МКоаС(тО)Ков, -МКо«СО»Бов, -МКой(б(5О)МАоаВов, halogen, nitro or cyano; "t

Co means hydrogen, C0-alkyl, substituted C-alkyl, aryl, substituted aryl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocycle or substituted heterocycle, or optionally substituted cycloalkylalkyl c. or heterocycloalkyl;

K. means aryl or heteroaryl, which has one K group as a substituent. and from zero to three groups of Kz;

EK" and Co. are independently selected from such radicals as hydrogen and lower alkyl; "

Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, -MK, Pa, -OK, or halogen; o, c Ki" means carbamyl, sulfonamido, arylsulfonamine, or ureido, each of which optionally has up to two "" substituents selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, " substituted aryl and aralkyl, or Ki" means alkylsulfonylamine;

The goat in each case, if it is present, is independently selected from a number of such radicals as alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, -OK.4, -C(xO)alkyl, -OC(-O)alkyl, -MECH5Kuv . »-alkyl,, ZO2MNE7, iz -SOMNA 47 and -MNS(-OMNA.7;

K.4 means hydrogen, alkyl or aryl; ("in K./5 means hydrogen or alkyl; with 50 Kv means hydrogen, alkyl, aralkyl or alkanoyl;

Ku7 means hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl or aralkyl; из» KU, Ka, Kcho, K44, Kaya, Kod, and Kov are independently selected from a number of radicals such as hydrogen and alkyl, and Koo means alkyl or substituted alkyl.

In the compounds of formula (I), in the best version, the Kz group means methyl, trifluoromethyl or methoxy, in an even better version - methyl; X in the best version means -СО5-, -МКиоС(-0)- or -С(-О)МКио, in an even better version -С(«-ОО3)МН; 7 in the best version means M; KK, preferably means substituted aryl or substituted heteroaryl, more preferably phenyl, containing as a substituent at least one group with y such as carbamyl, substituted carbamyl, arylsulfonylamido, substituted arylsulfonylamido, ureido or substituted ureido, and neoob necessarily contains one or two substituents from such a group as C 1-alkyl or halogen. In the best version, K. means phenyl, which has as a substituent at least one of the following radicals, such as -FSH«O)MNO(C .dalkyl) or C(-O)MH (optionally substituted phenyl), and also optionally necessarily has C. .4alkyl as a substituent. Kv is preferably hydrogen or lower alkyl, more preferably hydrogen.

In the best compounds, K. and Co. can be selected from groups of substituents according to the definition given in this description; however, in the best version, they are chosen from a number of such radicals as hydrogen, CH z, OH, OSN", halogen, nitro and cyano, or in the best version, K; and Co represent hydrogen. Co is preferably alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl or substituted heteroaryl, more preferably linear or branched alkyl or optionally substituted benzyl. The best form of salt is mesylate. Accordingly, the best compounds also include compounds of the formula (II) (B What 70 oh !

Fh and also their pharmaceutically acceptable salts, prodrugs or solvates, de

Ez means methyl, CEz or OSN";

X means -С(-О)МА0о-, -МКх1оС(50)-, -С(50)- or -СО»5-;

M means -"F(O)МН-, -МНОС(:О)МН-, -МНЗО"-;

Co means hydrogen or lower alkyl;

Kiv is selected from the group of such radicals as hydrogen, alkyl, alkoxy, aryl and aryl, containing as a substituent from one to three Clio groups, except in cases where U means -MNZO 5-, then K/d means

C. .lalkyl, aryl or aryl having as a substituent the group Co;

C is bonded to any corresponding carbon atom of the phenyl ring A, and when present in each case is independently selected from a number of such radicals as alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, -OK.4, -C (xO)alkyl, -OC(O)alkyl, -MK.5Kiv, ZKiv, -MO», -SM, -СО2Кв, сч -СОоМН», -BOZN, -5(:O)alkyl, -5(-О )aryl, -МНЗО»-aryl-k.7, -3О2МНА47, -СОМНИА.7 and -МНС(-О)МНА.7; Ka, Kv,

Kv and K/7 mean hydrogen or alkyl; at

Clio is in each case selected from the group consisting of alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine , sulfonic acid, alkylsulfonyl, zosulfonamido and aryloxy, and each Co group may additionally have hydroxy, alkyl, alkoxy, aryl or aralkyl as substituents; c n is equal to 0.1 or 2, and o

Ku, EK" and Ko have the values according to the definition given above for the compounds of formula (1).

Preference is given to compounds of formula (Ia) or (NAME) "I 325 "y , Vi | - m E. "oh, . "y yy y y Kk that o 7 y t t s and their pharmaceutically acceptable salts, prodrugs or solvates, where :z" Ez means methyl;

Ku and K/o mean hydrogen or -CH"; 15 Ko is chosen from a number of such radicals as hydrogen, linear or branched C 2g-alkyl; cycloalkyl, which - optionally has a keto group and/or up to two K 257 groups as a substituent; phenyl, which optionally has up to two Co groups as a substituent; a heterocycle, which optionally has a keto group and/or up to two t» Co groups as a substituent; and C-4alkyl, which has as a substituent up to three groups, which are selected from a number of such radicals as o halogen, trifluoromethyl, cyano, OKov, MKovCooyu, СО»оКов, aryl, heterocycle and/or cycloalkyl, where aryl, heterocycle and/or cycloalkyl, in turn, does not necessarily have up to two substituents, which are selected from the group i.e.) 50 such radicals as halogen, hydroxy, alkoxy, haloalkyl, haloalkyl, nitro, cyano and alkyl;

HT» Kv means hydroxy, C1-4 alkoxy, phenyl or phenyl containing as a substituent one or two groups of Co;

Keys and Clio are selected from the group consisting of lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C-alkoxy, nitro, and cyano;

Co.; if it is present, in each case it is independently selected from a number of such radicals as hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy and

HF) benzyloxy;

GF Kov and Koo, if they are present, in each case are independently selected from a number of such radicals as hydrogen, alkenyl, phenyl and benzyl; and n is equal to 0.1 or 2. Because when Ko" means a heterocycle, it is best to choose it from a number of such radicals as diazepinyl, morpholinyl, piperidinyl and pyrrolidinyl, and the specified heterocycle does not necessarily have as a substituent C 4.alkylphenyl and/or benzyl.

Preference is given to compounds of the formula b5 shk oshchi , in which K 4za and Kiz mean hydrogen, CHz3, OH, OSN», CEz, cyano or halogen; Co means Sowalkyl or 70 optionally substituted benzyl; Czz means lower alkyl and n is 0 or 1.

The compounds according to the present invention are selective inhibitors of pZv8-kinase activity, in particular, inhibitors of the activity of isoforms pZ8A and PZ8BB. Therefore, the compounds of formula (I) are used for the treatment of conditions caused by rZv-kinase activity. Such conditions include diseases in which cytokine levels are modulated as a result of intracellular signal transmission by rZ8, in particular diseases caused by 7/5 overproduction of cytokines 1-1, 1I--4, I/-8 and TME-A. As used herein, the terms "treatment" or "treatment" include curative or prophylactic measures, or both, such as measures designed to halt or slow the initial phase of a disease or disorder, to achieve full or partial relief of the symptoms of a disease state, and/or for the relief, mitigation, mitigation or treatment of a disease or disorder and/or its symptoms. When this description refers to the inhibition of "p-38A/B-kinase", this means that it is about inhibition of p38A- and/or rz38B-kinase.

Thus, the reference to the value of IC" for inhibition of p3vA/B-kinase means that the compound is characterized by the corresponding effectiveness in inhibiting at least one or both kinases (rz3vA and/or p38B).

Due to their activity as p-ZVA/B-kinase inhibitors, the compounds of formula (I) are suitable for the treatment of conditions caused by p-38, including, but not limited to, inflammatory diseases, autoimmune diseases of the immune system, bone structural disorders, proliferative disorders , angiogenic disorders, infectious diseases, neurodegenerative diseases and viral diseases.

More specifically, specific disease states or diseases that may be treated with the compounds of this invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis , "Eso rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, active chronic hepatitis, severe pseudoparalytic myasthenia, multiple sclerosis, inflammatory intestinal disease, Crohn's disease, psoriasis, homologous disease, inflammatory reaction caused by endotoxin, tuberculosis, atherosclerosis, muscular dystrophy, cachexia, psoriatic arthritis, - c5 Reiter's syndrome, gout, traumatic arthritis, arthritis as a complication after rubella, acute synovitis, M.

B-cell disease of the pancreas; diseases characterized by a dense neutrophilic infiltrate; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sclerosis, bone resorption, transplant rejection, fever and myalgia secondary to infection, recurrent cachexia secondary to infection, myeloid formation, scarring, ulcerative colitis , pyresis (rugesis), epidemic influenza, osteoporosis, osteoarthritis with c and bone destruction due to multiple myeloma, acute myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, disease;" Parkinson's, cerebral ischemia or neurodegenerative disease caused by trauma; angiogenic disorders, including solid tumors, ocular revascularization, and pediatric hemangiomas; viral diseases, including such infectious diseases as acute hepatitis (including hepatitis A, hepatitis B and hepatitis C), -I HIV infection and SMM-retinitis, AIDS-CACS ("pre-AIDS") or/and the development of malignant formations and herpes; stroke, myocardial ischemia, ischemia in the form of angina pectoris, hypoxia (purosia), vascular hyperplasia, and cardiac and renal damage during reperfusion, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, as well as conditions, due to synthase-2 prostaglandin endoperoxidases. In addition, p38 inhibitors according to this invention inhibit the expression of inducible pro-inflammatory proteins, such as prostaglandin-endoperoxide synthase-2 (РОНЗ5З-2), which is also called "cyclooxygenase-2" (СОХ-2).

Accordingly, other p38-mediated conditions include edema, analgesia, fever, and pain, such as neuromuscular pain, cancer pain, toothache, and arthritic pain. The compounds of the present invention can also be used to treat viral infections in animals, for example lentiviral infections including, but not limited to, equine infectious anemia virus, or retroviral infections including

F) feline immunodeficiency virus, bovine immunodeficiency virus and canine immunodeficiency virus. If in this description the terms "condition caused (caused by) p38" or "disease or disorder caused (caused by) p38" are used, it is understood that each of these terms covers all the conditions defined above (just as if they described in detail), as well as any other condition affected by pZ38-kinase activity.

Thus, the proposed invention covers methods of treating the mentioned conditions, which consist in introducing into the body of a patient who needs such treatment, an effective amount of at least one compound of formula (I) or its salt. Methods of treating conditions caused by pZ38-kinase include the use of compounds 65 of formula (I) alone or in combination with any other compounds of formula (I) and/or other suitable therapeutic agents used to treat such conditions. Examples of such other therapeutic agents include corticosteroids, rolipram, calphostin, SZAIIU, the 4-substituted imidazo|1,2-Alquinoxalines described in US Pat. 4 atipez: And Mom!

Mophapiype A Adeposipe Keseriog Apiadopiviv,", Epgoreap otsgpa! oi Meadisipai Spetivigu Moi. 33. (1998), pp. 943-9551; interleukin-10, glucocorticoids, salicylates, nitric oxide (nitrous oxide) and other immunosuppressants; nuclear translocation inhibitors, such as deoxypergualine (deochuregozapine, U50); non-steroidal anti-inflammatory drugs (NSAIDs3) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; anti-proliferative agents such as methotrexate, leflunomide, EKBOB ( tacrolimus, Rgodgai); cytotoxic drugs such as azatiprine and cyclophosphamide; TME-A inhibitors such as 7/o tenidap, anti-TME antibodies or soluble TME receptor, and rapamycin (sirolimus or rapamune) or its derivatives.

The above-mentioned other therapeutic agents - in the case of their use in combination with the compounds according to the present invention - can be used, for example, in the amounts specified in the doctor's desk reference book; or one of ordinary skill in the art can determine these quantities in any other manner. In the methods of the present invention, said other therapeutic agent(s) may be administered prior to, concurrently with, or after the administration of the compounds of the present invention.

The proposed invention also encompasses pharmaceutical compositions suitable for the treatment of conditions caused by pZ8-kinase, including conditions mediated by TME-A, II/-1 and/or I/-8, as described above.

The compositions of the present invention may contain other therapeutic agents as described above, and may be prepared, for example, using conventional solid or liquid carriers or diluents, as well as pharmaceutical additives appropriate for the intended use (e.g., excipients, binding agents, preservatives , stabilizers, aromas, etc.), according to technologies well known in the relevant field of pharmaceuticals technology.

The compounds of formula (I) may be administered in any manner appropriate to the conditions to be treated, and such manner may depend on the need for site-specific treatment or the amount of drug to be administered. Topical administration is usually preferred for the treatment of cutaneous and) diseases, while systemic treatment is preferred for cancerous or precancerous conditions, although other routes of administration are also contemplated. For example, the compounds can be administered orally in the form of tablets, capsules, granules, powders or liquid preparations, including syrups; locally, for example, in the form of solutions, suspensions, gels or ointments; sublingual way; transbuccally; parenterally, for example, in the form of subcutaneous, intravenous, intramuscular or intrathoracic (intrasternal) injections or by infusions (for example, in the form of sterile aqueous or non-aqueous solutions or suspensions for injections); nasally, for example, in the form of a spray for inhalation; locally, for example, in the form of a cream or ointment; rectal way, for example, in the form of suppositories, or in the form of liposomes. It is possible to apply preparations using dosing devices that contain non-toxic pharmaceutically acceptable carriers or diluents. The compounds can be used in forms suitable for providing rapid action or prolonged action. Immediate (rapid) action or prolonged action can be achieved by using appropriate pharmaceutical compositions, or - in case of need for prolonged action - with the help of special devices, for example, subcutaneous implants or osmotic pumps. "

Examples of compositions for local administration are compositions with a carrier for local application, such as RI AZTIVAZEZ? (mineral oil gelled with polyethylene). Examples of compositions for oral use are suspensions that may contain, for example, "» microcrystalline cellulose to provide volume, alginic acid or sodium alginate as a suspending agent, methyl cellulose to increase viscosity, sweetening or flavoring agents such as, for example, which are

Known in the relevant field of technology; fast-acting tablets that may contain, for example, -I microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binding agents, fillers, substances that promote grinding, thinners and lubricating agents known in the in the relevant field of technology. The compounds of this invention can also be administered orally by sublingual and/or transbuccal administration, for example, in the form of molded, compressed or lyophilized tablets. Examples of compositions include certain compositions with fast-dissolving diluents, such as mannitol, lactose, sucrose and/or cyclodextrin. These preparations may also include high molecular weight excipients, such as cellulose (AMISEI 9) or polyethylene glycols (PEG); an excipient for adhesion to the mucous membrane, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMO), sodium carboxymethyl cellulose (SMCS) and/or maleic anhydride copolymer (e.g. SAMTVE2 U; and 22 release control agents such as polyacrylic copolymer (e.g. SAVVOROY. 934 U), For

F! for ease of preparation and use, lubricating agents, swallowing aids, flavorings, colorings, and stabilizers can also be added. where Examples of compositions for administration by nasal aerosols or inhalations are solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption activators to improve absorption and/or increase bioavailability, and/or other solubilizing or dispersing agents such as which are known in the relevant art.

Examples of compositions for parenteral administration are solutions or suspensions for injection, which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution or others are suitable dispersing or surface-active and suspending agents, including synthetic mono- or diglycerides, as well as fatty acids, including oleic acid.

Examples of compositions for rectal administration are suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at room temperature but become liquid and/or dissolve in the rectal cavity, thereby releasing the drug. substance

An effective amount of a compound of the present invention can be determined by one of ordinary skill in the art; for mammals, it is about 0.05 - 10Omg/kg body weight of the active compound per day; this amount can be administered in the form of a single dose or in the form of several small doses, for example, from 1 to 4 times a day. It should be understood that the level of a specific dose and the frequency of taking doses for each specific patient may vary depending on a number of factors, including the activity of the specific compound used, the metabolic stability and duration of action of this compound, type, age, body weight, general health. I, gender, diet of the patient, method and time of administration, speed of elimination from the body, combination of medicinal substances, as well as the severity of a specific condition. In the optimal version, the objects of /5 Treatment are animals, and mainly the objects of treatment are mammals, for example, humans and domestic animals, such as dogs, cats, horses, etc. Thus, if the term "sick, patient" is used in this description, it is understood that this term covers all objects of treatment, and mainly mammals, whose body is affected by the level of the p38 enzyme.

Testing of the compounds of formula (I) (including the compounds given in the Examples) mentioned in this description is carried out using one or more analyzes described further in the text; these tests indicate the activity of the mentioned compounds as inhibitors of RZVA/B and TME-A enzymes.

Biological tests

Preparation of rZv8-kinase

cDNA of A-, B- and G-isomers of human rZ38 is cloned by PCR (PCR). These cDNAs are subcloned into the expression vector sch VROEX (RNagtavsia). The 55T-p38 fusion protein is expressed in E. Soy and purified from bacterial sediment using affinity chromatography on glutathione-agarose. The p38 fusion protein is activated by incubating with i) constantly active MKKb. Active rZ8 is separated from MKKb using affinity chromatography. Permanently (constitutively) active ICRC is obtained according to the Code of Ethics of Ukraine. (My. SeiI. Vio!., 1247-1255 (1996)).

The production of TMR-A by RHZ-stimulated RVMS «g zo Heparinized undiluted human blood is obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMC) are purified from undiluted human blood by centrifugation in a density gradient based on ficol (RisoI-Nuradtse) and resuspended at a concentration of 5x1O0b/ml in the medium for the analysis of av! (milk-milk medium containing 1095 fetal bovine serum). 5µl of cell suspension is incubated with 5µl of test compound (4X concentration in assay medium containing 0.290 DMSO) in 96-well Z cell culture plates for 5 minutes at room temperature. After that, it is added to the cell suspension. 100 μl of I RZ (200 ng/ml in the initial solution) and the contents of the tablet are incubated for two hours at 372C. After incubation, the cultured medium is collected and stored at -202С. The concentration of TME-A in the environment is quantitatively determined using the standard kit of EGISA (Rpagtipdep, San Diego, State "

California). The concentrations of TME-A and the value of IC 59 of the tested compounds (the concentration of the compound that inhibits the stimulated I P5 production of TMPE-A by 5095) are calculated according to the linear regression equation. - c Analysis p38 c Analyzes are performed in a 96-cell tablet with M-shaped cells. The final volume for the analysis is equal to "bOmcl and consists of three portions of 20 mL each - enzyme, substrates (MVR and ATP) and tested compounds - in the buffer for analysis (500 mM Ttiv, pH7.5, 10 mM MassiO, 50 mM Massi and imm OTT). Activated p38 expressed by bacteria is pre-incubated with the tested compounds for 10 minutes before initiating - I reactions with substrates. The reaction mixture is incubated at 2523 for 45 minutes and the reaction is stopped by adding 1 µl of 0.5 M EOTA to each sample. The reaction mixture is transferred (aspiration) to a pre-moistened filter mat (filter mat) using a ZKaigop Misgo9b Seyi Nagmezieg harvester (ZKaigop, Ips.), after which (a) it is washed with РВ5. Next, the filter mat is dried in a microwave drying cabinet for 1 minute, treated with 7 50 scintillation wax May eh A (UmaiIIias), after which calculations are performed using a scintillation counter Misgoreia tode! 1450 (U/aPyas). Inhibition results are analyzed using nonlinear least-squares regression using Pgi2t (SgarpRadzZoimage). The final concentrations of reagents in the analysis are as follows: ATP, μm; IG-ZR)ATR, ZNM; MVR (Zidta, 2 M1891), 2 μg/cell; pZ38.1onm; and DMSO, 0.395.

Production of TME-A in the body of GRO-stimulated mice. Mice (female VaiYir/s, age 6-8 weeks, Nagpap iare; p-v8/treated group) were injected intraperitoneally with lipopolysaccharide (5Omkg/kg) (GRO; E. soy, strain 0111:84, 5idta), suspended in a sterile physiological solution. Ninety minutes later, the mice are put to sleep with CO.:O" and a blood sample is taken. Separate the serum and analyze by determining the concentration of TMP-A using an industrial EGISA assay according to the manufacturer's instructions (K 50 Zuvietv, Minneapolis, MN 60).

The compounds are administered orally, at different time points, before the injection of I P5. A dose of the compound is administered either as a suspension or as a solution in various carriers or solubilizing agents.

Abbreviation

For ease of use in this description, including methods of obtaining and Examples, the following abbreviations are used:

Ri is phenyl

B2 - benzyl

I1-Vy is tertiary butyl

Me - goals

Rg - propyl

Ivo-R. - isopropyl meon - methanol

Eon - ethanol

EtOAc - ethyl acetate 70 Vos - tert-butyloxycarbonyl

CB2 - carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

OSM - methylene chloride

ОСЕ - 1,2-dichloroethane

OME, DMF - dimethylformamide

OM5O, DMSO - dimethylsulfoxide

TEA, TFC - trifluoroacetic acid

TNE, THF - tetrahydrofuran

NATI-O-(7-azabenzotriazol-1-yl)-M,M,M',M'-tetramethyluronium hexafluorophosphate

KOH g potassium hydroxide

KoSoO»z - potassium carbonate

ROSI»z - phosphorus chloride

KoiVy - potassium tert-butoxide

ES or EOSI - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

OPIREA: diisopropylethylamine sch

NEW - 1-hydroxybenzotriazole hydrate t-SRBA - m-chlorobenzoic acid i)

Mann :- sodium hydride

Mmaon -: sodium hydroxide

Ma"52O"53 - sodium thiosulfate "g zora - palladium

Ra/s - palladium on coal with tip, min. - minute(s) o

Y, l: liter ml - milliliter « μl - microliter y- g E gram(s) mg - milligram(s) mol - moles mmol - millimole(s) « mEq - milliequivalent with c CT or gi - room temperature . gays y, time t.- HPLC holding time (minutes) y? nas/zai or zaga) - saturated water, ad. - water

TLC, TI C - thin-layer chromatography - and HPLC - high-performance liquid chromatography

OO(ER) HPLC - reversed-phase HPLC and IS/mM5 - high-performance liquid chromatography/mass spectrometry o M5 - mass spectrometry

NMR - nuclear magnetic resonance o.p. pl (tr) - melting point i" In the Examples, the expression "HPLC, conditions A" means: ballistic column UMO 55 005 4.6x50 mm, flow rate 4 ml/min., 4 min. linear gradient elution (initial solvent 95 V-O; final solvent 96 V-100), solvent

A-1095 MeoOn/ZObo NiO/0.295 NzRO,.

Methods of obtaining

Compounds of formula I in general can be obtained according to the schemes below and described in the special iF) literature by technologies known to specialists in the relevant field of technology. On the diagrams of groups K 4-Kv, Ko, Kz, Kv, ko Koz, X and 7 have characteristics corresponding to the definition for compounds of formula (1).

Scheme 1 60 b5

NOT dh and ko z. и бе и клиш m. chne V Ya ny sob. n her and 1 of ; same as me ! 70 07 "XX -- "In 4 a with 3 - I pvh -O til; "5 I K, ; there are 7

Optionally substituted 2-formylpyrrole (1) reacts with an aminating reagent, such as hydroxylamine-O-sulfonic acid, in aq. solvent at room temperature followed by treatment (on cooling) with a base such as KOH to form compound (2).

Compound (2) reacts with aq. solution of a base, such as KOH, at room temperature to form compound (3). Compound (3) reacts with an adilating agent, such as formic acid, in aq. solvent to form compound (4). Compound (4) is cyclized by a base such as sodium methoxide in Meon to form compound (5) on heating. Compound (5) is halogenated, for example, with oxybromide (bromide) of phosphorus at elevated temperature to form compound (6). Compound (6) reacts with an amine such as aniline in an organic d) solvent such as acetonitrile to form product (7) in Scheme 1.

Compound (7) in scheme 1, where Ku. means halogen, can be prepared from compound (7) in Scheme 1, where K is hydrogen, by reaction with a halogenating reagent, for example, bromine, in a suitable solvent, for example, acetic acid. "

Compounds (1) can be obtained from substituted pyrroles by formylation, for example, in the presence of phosphorus oxychloride in DMF. Methylpyrrole can be obtained by reducing formylpyrrole, for example, using lithium aluminum hydride. at

Scheme 2 "g

Scheme 2 i - ne e 5 i i vka ----k sn -4 I i

And what? in : k -i shi Kei sini v a gy - i- M t («c) E- electron-accepting group, such as an ester, nitro- or keto group mo X'- halogen

The reaction of tosylmethylisocyanide (To5MIS) anion (1) with a Michael acceptor, such as ethyl crotonate, allows it to obtain disubstituted pyrrole (2). Treatment of pyrrole (2) with a reducing agent, for example, trichloroacetyl chloride, in the presence of a Lewis acid, for example, aluminum chloride, at a temperature from room to 502, followed by treatment with sodium methoxide allows to obtain trisubstituted pyrrole (3). Compound (3) can be prepared by heating an aldehyde, for example acetaldehyde, with 2 equivalents of ethyl isocyanoacetate in the presence

GF! base, such as OVO, in an organic solvent, such as THF. As an option, compound (3) can be obtained by the technology of M. 5y2ikKi, M. Miuovpii apa K. Maivitoiyo 9. Oga. Spent 1974, 39 (1980). o Pyrrole (3) can be aminated with an aminating reagent such as diphenylphosphorylhydroxylamine in the presence of a base such as MaH at room temperature in organic solvents such as DMF to give 60 M aminated pyrrole (4). Compound (4) is cyclized when heated to 120-19592C with formamide to form 1,2,4-triazine (5). Treatment of compound (5) with a halogenating reagent such as phosphorus oxybromide at 60-11590. in the presence or absence of another solvent, such as OSE, affords compound (6).

Compound (6) reacts with an amine such as aniline in an organic solvent such as DMF to give compound (7). Alternatively, compound (7) can be prepared by reacting compound (b) with an anion of a heterocyclic compound such as oxindole in an organic solvent such as THF.

TozMIS anion (1) can be obtained by treating its solution in DMSO with a base such as Mann at room temperature or after reacting its solution in THF with lithium hexamethyldisilazane at -7890.

Scheme Z

I'm a schemer. ov p o.:. WE and schsogvv p-ooeo Ho them. with with i eat ? with - ; si chuk v i de R" - protective group, KR-KZ by definition (see above in this description)

A glycine ester with a suitable protecting group in the position of the M atom, for example, with a benzyl group, can be added to dialkyl methylene malonate at room temperature to 802C, obtaining compound (1). Compound (1) is cyclized to form pyrrole (2) upon treatment with a strong base such as lithium hexanedisilazane at -782 to room temperature in an organic solvent such as THF.

Pyrrole (2) is alkylated by treatment with an alkylating agent such as iodomethane or dimethyl sulfate in the presence of a base such as KCO'' in an organic solvent such as acetone or DMF to give compound (3). high school

If in the compound (3) the optional protective group is a group such as benzyl, its removal can be carried out by hydrogenation in the presence of a catalyst such as Pa and ammonium formate. Compound (4) is converted to compound (5) by cyclization as described for compound (5) in Scheme 2.

Hydrolysis of the ester group in compound (5) can be carried out by treatment with a base such as aq. KOH solution. The acid formed can be condensed with an amine in the presence of a condensing agent such as Res or RuBhor.

Scheme 4 p

Scheme 4 ("c") "

I am 35. . wow

Os y y N /not i. and . » And mon " Her about her 1 th « vo. juo vh 2 - n yiv s i and p z 4

I» ' where XM "9, MA'OsSO, Me 'cSsOMe ", Mviesoo, Me "950»5, MA 9502ME ", as indicated above in this description 15 Compound (5) in scheme C can be converted into a carboxylic acid (1) (where Kz means methoxy or has another meaning as defined in this description) by treatment with a base such as aq. KOH solution.

This acid undergoes a Curtis rearrangement with diphenylphosphoryl azide in the presence of an alcohol such as t" benzyl alcohol in an organic solvent such as 1,4-dioxane to give compound (2). o If the carbamate group of compound (2) is optionally protected by groups such as CB7, the protection can be removed by hydrogenation in the presence of a catalyst such as Pa to form compound (3). The amino group of compound (3) can be acylated to form compound (4), for example, by treatment with carboxylic acid in

HT" in the presence of a condensing agent such as OSS, or a sulfonated compound can be obtained, for example, by treatment with sulfonyl chloride. Alternatively, the amino group of compound (3) can be alkylated with alkyl halides or subjected to reductive amination with aldehydes in the presence of a reducing agent such as sodium cyanoborohydride.

Scheme 5 has) 60 b5

It's still OK, Monday, June 4, 2020! AH AKdryuui V, zha om I 4 i o 70 n, mk z what in

And Rishazh Shchu. N ! --n--Zho Ko 5 kr

EE in where P" is a protecting group; VO, B9-85: and E'-H or SOOK, as indicated above in this description

Accordingly, the protected compound (1) (iminodicarboxylate) can be cyclized by treatment with a dialkyl oxalate in the presence of a base such as sodium methoxide in an organic solvent such as MeOH.

Compound (2) after selective removal of protection, for example, under the action of TFC in the presence of an optional protective tert-butyl ether group, undergoes decarboxylation, which allows to obtain compound (3), where K'-H. This stage is skipped during the formation of compound (3), where ВЕСООВ 7,

The hydroxyl group of compound (3) can be esterified by reaction with an alkylating agent such as dimethyl sulfate. Compound (4) can be deprotected by hydrogenation when the optional protecting group is a benzyl group to give compound (5). Compound (5) is then converted to compound (6) using procedures similar to those described for compound (4) in Scheme 3 and compounds (4) - (7) in Scheme 2. c

Scheme 6 in ve in voos And in them se brus -in ch

M xy "7 3o o Vishomy 2 1 1 p

KU ОР in ОР жи | y o r schi M o eru - 0 -3 h

Moz in h M. and m 8 4 MORE: in water "

Compound (6) in scheme 2 can be esterified (simple ether) in position 4, for example, by treatment with phenoxide anion to form compound (1). Reduction of compound (1) with a reducing agent, such as OIVAG, in an organic solvent, such as toluene, allows obtaining alcohol (2). Oxidation of alcohol (2) can be carried out by treating MpO 5 at an elevated temperature in an organic solvent, such as toluene, while 1" is formed compound (3).Treatment of compound (3) with an oxidizing agent such as t-SRBA in an organic solvent such as methylene chloride, followed by hydrolysis using water in the presence of a base such as potassium bicarbonate (α) affords the hydroxy compound (4) ).

I" can be performed using an acid such as aq. NOSI solution, at elevated temperature, thus obtaining compound (6). Compound (6) can be converted to compound (7) by methods similar to those described in the notes to Scheme 2.

Scheme 7

F) name) 60 b5 in OB. and with )

Compound Z 1 from scheme 6 70 I En, I F) and a A 2 Z

M

Ky. you stump re: and KOSA 4. where B", B9-K2 according to the above definition in this description

Compound (3) in Scheme b can undergo a Wittig reaction, for example, with phosphonates such as methyldiethylphosphonoacetate in an organic solvent such as OSE in the presence of a base such as Mann to give compound (1). The double bond of compound (1) can be hydrogenated with hydrogen in the presence of a catalyst such as Pa. Compound (2) can be converted to compound (3) by the methods described for Scheme 2.

Hydrolysis of the ester described above, followed by reaction of the resulting acid with an amine in the presence of a condensing agent such as OCC, affords compound (4).

Scheme 8 p

Schemav about no. what ; n nose N ; I Ira force Ben oo un vin i KA tsa h what a with sch

Industrially produced compound (1) reacts with oxalyl chloride on heating, after which the product is evaporated under vacuum and reacted with the amine KieMmNo in the presence of a base such as diisopropylamine in (a) an organic solvent such as methylene chloride to give the compound ( 2). Compound (2) can react with hydrogen in the presence of a catalyst, such as Pa, in an alcoholic solvent, for example, in EUN, at room temperature, which makes it possible to obtain compound (3). Compound (3) can then be used in scheme 9 to obtain compounds (b) in scheme 9.

Scheme 9

Scheme 9 « - p p. and. n in 4

With metypyropo» 2 Aedivtylester

ЧК» t - How and ; I E I: with 50 with -" and 7 bo Foch.

Ka RA od - nn o 4, 2);

Ф) ny 60 Her You and in : ve I 65 3-methyl-1-pyrrole-2,4-diethyl ester can react with chloramine in ether, which makes it possible to obtain compound (1). The reaction of compound (1) in formamide with acetic acid allows to obtain compound (2). Compound (2) can react with PIREA and ROSI" in toluene, which makes it possible to obtain compound (3). Compound (3) can react with OIREA and compound (4) in DMF to give compound (5). Compound (5) can react in THF with Mahon to form an intermediate acid, which upon treatment with NOVI, EOSI and the corresponding amine (MK»oKcho) in DMF allows to obtain compounds (6).

Compound (4) can be obtained 1) by the reaction of industrial 4-amino-3-methylbenzoic acid and

of M-(tert-butoxycarbonyl)anhydride in THF with the formation of intermediate BOC-protected aniline, 2) by reaction of intermediate aniline with (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, NOVI and DMF followed by the addition of methoxyamine hydrochloride and OIREA, thereby forming intermediate BOC-protected M-methoxyamide, and 7/0 C) by the reaction of this intermediate methoxyamide in a solution of HCl in dioxane with the formation of compound (4) in the form of hydrochloride. Alternatively, compound (4) can be prepared as shown in Scheme 8.

Scheme 10

Scheme/0 5 We are an oiler, in U anyun. go Rol s PI anna " n 1 2 "uh NATI, basis of Hiuonig: F. , ! vigin ia y

From the truth of the investigation "shk --k iy pe mya i EY" with And her sch

Substituted hydroxamate (1) can react with an acid such as HCl in anhydrous MeonH to form compound (2). Compound (2) can react with aq. with a solution of a base such as KOH when heated to form compound (3). Compound (3) reacts with amine K/8MH»e in the presence of a condensing agent such as NaTU and a base such as diisopropylamine in an organic solvent such as M-methylpyrrolidinone to form compounds (4). Alternatively, compounds (4) can be prepared in the manner shown in Schemes 8 and 9.

Scheme 11: p

Scheme 11 "c) o.,0 m sh Y 1 vach siv veya -leya chE iv | 2 of | yi- va s - ny vve var re y shiv 4 (compound Z 8 « . of scheme 9) ож De, -о s vodi: KON nn show connection a ; in and

Lk Yan, and Shk University of and? In the village

Compound (Ta) - a technical product - can react with a sulfonyl chloride in the presence of a base such as TEA (TEA, triethylamine) in an organic solvent such as methylene chloride to give compound (2). The reaction of compound (2) with hydrogen in the presence of a catalyst, such as Ra, in a solvent, for example, in Meon, allows them to obtain compound (3). Compound (6) is obtained by reacting compound (3) with chloride (5) (compound C in Scheme 9) in an organic solvent such as DMF at room temperature. o By reacting compound (6) with aq. with a KOH solution upon heating, compound (7) is obtained. Compound (7) can be reacted with the amine CoMNO in the presence of a condensing agent such as EOSI and a base such as isopropylamine in an organic solvent such as DMF to form compound (8). Scheme 12

F) name) 60 b5 cSchemal2. ve the tower and I where the water. NaOH. veyuu ni -sh- - є c) earthly z ni to penne code, Nove voshch p ni eh

SYA van in: 2 4 -69 o -,, louse zone in Y in nok . Mr.

Chloropyrrolotriazine (1) (compound C in Scheme 9) can react with aniline (Ta) (eg, compound Ta in Scheme 11) in anhydrous DMF at room temperature to give compound (2). The reaction of compound (2) with aq. with a solution of a base, such as Mahon, when heated, allows compound (3) to be obtained. Compound (3) can be reacted with an amine CoMn" in the presence of a condensing reagent such as NOVI with or without a base such as diisopropylamine in an organic solvent such as DMF to form compound (4). Compound (4) can react with hydrogen in the presence of a catalyst such as Pa/C in an organic solvent such as MeonH to give compound (5). The reaction of compound (5) with isocyanate in an organic solvent, such as 1,2-dichloroethane (OCE), allows to obtain compound (b). at

Scheme 13

Scheme of TK: vek chiv - podevichateo and "Kuka z Sean Mk. then Vin, o NYA I s ate and 1 report a o oveshniko, with "Not Ere tizh sew it- g 4 (compound Z from Scheme 9) vevi ne What "KA " g MOM svodn,naOn and ny - tou- U и-и I с и и ' . ;" ; o "Communication: ve i N vya -1 ton, from ach ne y" n 7 . o Serially produced compound (1a) (compound Ta in Schemes 11 and 12) reacts with carbonyldiimidazole and amine K/vMH»o in an organic solvent such as OSE to form compound (2). ko 50 By reacting compound (2) with hydrogen in the presence of a catalyst such as Pa in an alcoholic solvent such as

HT" as ЕЮН, compound (3) is obtained. By reacting compound (3) with chloride (4) in an organic solvent such as

DMF, compound (5) is obtained. By reacting compound (5) with aq. with Mahon's solution upon heating, product (6) is obtained. The product (6) reacts with the amine K».MnO in an organic solvent such as DMF, which makes it possible to obtain the compound (7).

Scheme 14

Ф) име) 60 b5 scheme v'bos is VM. osoov? in 2; Ov Shche nterov shchi

The basis of She Ehp; Sandmeyer is the same person from VRoos in OO sk

ИХ loe --o in ІХ soju with H MMP 4 M x means halogen

XX" means halogen

Glycine ethyl ester is added to alkyl alkoxymethylene cyanoacetate at a temperature from room to 802C, obtaining compound (1). Compound (1) is cyclized to form pyrrole (2) upon treatment with a strong base such as lithium hexamethyldisilazane at a temperature from -782C to room temperature in an organic solvent such as

THF. Pyrrole (2) is converted to the halide in the presence of sodium nitrite in an organic solvent such as

DMF, and a halogen-containing compound (source of halogen), such as SiHg, to give compound (3). Compound (3) can be converted to compound (4) using SiCM in an organic solvent such as MMP at elevated CM temperatures. Alternatively, compound (2) can be directly converted to compound (4) using (5) sodium nitrite in an organic solvent such as DMF and a source of cyanide such as SISM. Compounds (3) and (4) can further be used as shown in the previous schemes (e.g. as a compound

C in scheme 2), to obtain compounds of formula (I), where Kz means halogen or cyano.

In addition, other compounds of the formula | can be obtained by methods generally well known to those skilled in the art. In particular, the following Examples describe additional methods of preparing the compounds of this invention. high school

This invention is described below with the help of working examples, which represent the best options (and) of the implementation of the invention. Purification by HPLC is carried out on columns with reversed phase (CR) C18, using Meon and TFC mixtures as a buffer solution. These examples are provided for illustrative purposes only and do not in any way limit the scope of the present invention. There are other possible implementations of this invention, which correspond to its essence and are included in its scope, which are determined by the attached formula of the invention.

Example 1 1-(2,3-dihydro-6-(pyrrolo|2,1-411,2,A)griazin-4-ylamino)-1H-indol-1-yl|ylIethanone "dk-s HYU" and . :z» sia z sn, : - A. 4-bromopyrrolo|2,1-t1(1,2,Cgriazine

A mixture of 5Omg (0.37mmol) pyrrolo|2,1-7(1,2,triazin-4(Z3H)-one (obtained by the method described in 5.A. Raii, t» V.A.ONeg apa k.5 .Kieip, U. Nei Speth., 31, 781-786 (1994) and 0.5 g of phosphorus oxybromide are heated for 20 minutes at 602 in an argon atmosphere. First, a transparent orange melt is obtained, which upon further heating for 5 minutes forms a solid yellow. Ice is added with vigorous stirring. The mixture is extracted twice with EOAc. The combined extracts are washed with saturated Manceau with and

T» with saline solution, dried (MazO)) and the solvent was removed, obtaining 10 mg of crude compound A as an orange oil, which crystallized on settling. (MAN) -1987, 2007.

B. Example 1 5B A bomg solution (0.3 mmol) of compound A and 1-acetyl-b-aminoindoline in 1.5 ml of acetonitrile is stirred overnight at room temperature under argon. A white precipitate is obtained, this precipitate is filtered. The precipitate on the (F) filter is suspended in a mixture of 1095 isopropanol/methylene chloride for extraction. Saturated Manso solution is added, and the mixture is stirred until a solution is formed. The organic layer is separated, washed with saline solution, dried (Ma5O)) and the solvent is removed. Purification by means of chromatography on silica gel with ЕХOAc gives 490 compounds according to Example 1 in the form of a white solid. (Mn) -294.

Example 2

Methyl ester of 4-(2,3-dihydro-1H-indol-1-yl)-5-methylpyrrolo|2,1-4(1,2,A)griazine-6-carboxylic acid b5 ne i i 9 Sha I

A. Methyl pyrrole-3-carboxylic acid methyl ester

To a 1.0 M solution of lithium hexamethyldisilazide in THF (41 ml, 41 mmol) at -782C dropwise over 45 min. then add a solution of tosylmethylisocyanide (8.1g, 4A1mmol) in THF. After stirring the reaction mixture for another 45 min. add a solution of methylcrotonate in THF for 40 minutes. The reaction mixture is heated to 252C and stirred for 2 hours. The reaction mixture is diluted with E(OAc) and washed with a saturated aqueous Manso solution.

The aqueous layer is extracted three times with EtOAc, dried (Ma»3O)), evaporated and purified by chromatography on silica gel with elution in a gradient of 20-3096 EtOAc in a mixture of hexanes, obtaining compound A.

B. Dimethyl ester of 3-methylpyrrole-2,4-dicarboxylic acid

Trichloroacetyl chloride (89ml, 798mmol) was added dropwise to a suspension of aluminum chloride (106.4g, 79O8mmol) in OCE (700ml) at -409C under nitrogen. Add a solution of compound A (37 g, 26 mmol) in OCE (200 Oml).

The temperature of the reaction mixture is gradually brought to room temperature and this mixture is stirred during the period of time 20 from Friday to Monday (b hours, "meeKepa"). To the reaction mixture is added a pre-prepared cooled mixture of aluminum chloride (53.2g) and trichloroacetyl chloride (44.6g) in OCE (4500ml). After another 24 hours, the mixture is carefully poured into ice water (2 L) and the pH of the solution is adjusted to 2.0. The organic layer is separated, and the aqueous layer is extracted with OCM. The combined organic extracts are washed with 3M HCl and brine, dried (Ma»2O)) and evaporated in vacuo to give a dark oil. This oil is dissolved in 25 ml Meon (40 Oml), and the resulting solution is cooled to 02 under nitrogen. Sodium methoxide (2595 solution in Meon) is added to this solution, bringing the pH of the solution to 10. After 1 hour, the mixture is evaporated, after which it is diluted with with ice water (1 l) and the pH of the mixture is brought to 6. The mixture is extracted with methylene chloride (3 x 1 l). The combined hoods are washed with MnSO, brine, dried (MnSO)) and evaporated in vacuo. The resulting brown solid is purified by chromatography on silica gel eluting with EtOAc in a 30% mixture of hexanes, obtaining 44.3 g (8495) of compound B. M8: |MAN) -196.

C. Dimethyl ester of 1-amino-3-methylpyrrole-2,4-dicarboxylic acid cm

To a suspension of Man (60905 in oil, 33 mg, 0.8 mmol) in DMF (5 ml) at 09C is added compound B (46 g, 213 mmol) in (Z

DMF (Zml). After 10 minutes pure diphenylphosphoryl hydroxyl amine (0.19g; 0.83mmol) is added at 0°C, after which DMF (3ml) is added. The reaction mixture is stirred for 2 hours at 252C, after which phosphate

Zo buffer with pH7 (15 ml). The mixture is extracted using EtOAc (4x20ml). The combined extractions are dried - (Ma»ZO),) and after purification by chromatography on silica gel using the eluent EtOAc (25-30905) in a mixture of hexanes, 38g (84965) of compound C are obtained as a white solid. EBI (M5 with electrospray ionization) (MANI 213.1. "

Or. Methyl ester of 5-methylpyrrole|2,1-Ш(1,2,triazine-(ZH)-one-6-carboxylic acid Z7Z

Compound C (38 g, 179 mmol) was mixed with formamide (40 mL) and heated at 16593 for 1 h. The reaction mixture was diluted with water (bml), extracted with EtOAc (3 x 10 ml), dried (Ma22O)) and evaporated. The crude product was purified by washing with ether/hexane mixture (7/3) to give 33.4 g (9095) of compound 0 as a white solid. EBI M: (M-NO -206.0.

E. 4-chloro-5-methyl-6-carbomethoxypyrrolo|2,1-PC(1,2,triazine) 50 Phosphorus oxychloride (2.5 ml) is mixed with compound Y (10 mg; 0.48 mmol) and overnight heated at 1002C. The melt was cooled to room temperature and dissolved in E(Ac. The mixture was neutralized with aqueous Manso solution and extracted twice using E(OAc). The combined organic extracts were dried (NaCl) and evaporated, obtaining 101 mg (93905) compounds E. M8: (MH) -226.6.

E. Example 2

The mixture of compound E (20mg; 0.09mmol) and indoline (21mg; 0.177mmol) in SNUSM (Iml) is shaken for 4 hours

F! After that, DMF (0.2 ml) was added and the crude mixture was purified by preparative HPLC to give 12.2 mg (4595) of the compound of Example 2 as a white solid. MANI 7-309.2; "H NMR o (SOSIS): 6 8.06 (p, 1H); 7.91 (s, 1H); 7.20 (m, 1H); 7.01 (m, 1H); 6.93-6 .91 (m, 2H); 4.15 (t, U-7.8Hz, 2H); 3.81 (s, ЗН); 3.09 (t, U-7.8Hz, 2H); 2.35 (c, ZN). 60 Examples 3-6 b5 pa): / Compounds of formula (Id), where the group K. has the values given in Table 1, are obtained by the method described in

Example 2, using in stage E the appropriate selected amine instead of indoline.

Table 1

IABLYTSYA i

I (ex. Iv 33333777 I Names compounds 77777 | compounds. that Den ("9 n piperazinocarbonylrenipieninoi- chem fomneu B tla i zrnnn oon arvyunoiy (Ko NI acid gu, chn), 7523 (in is, g); 3.76 (6. ZNU , 2.57 (c, ZN) 1 - and Methyl ester MB: Manu zh 340.2;

I n (acetylaminoquenikivininoin 6. m yame foosxh in tv (is i sno 0 | About riaain-ya carboxylic NC uk o acid (s; ЗН), 2.84 (s; ЗН), 1.80 (s; ЗН) one IN NMR (BOSV i am

Y Z-D, o 1nAndop-v- "N YAM i): 6 8.14 (d,

Zyl)amino)-5-methylpyrrolo |(2,1-0 |y-8i6 Hz, 18), 7:95 (s; TN),

ХО 0 ofenetne ee (t, 27.8 Gu; 2Н), 3.81. (6, kt at 8); Sv (t, a-7 8 Hz, ZNU, sa 2.67 (s: ZN). 2.19 (s, ZN)

Methyl ester 5-methia:4-(2- Me: nt so voie i) ! on about Kmethyleulfonylianinoipheniya |bhshsh. with. TM), 795 E, NU pov. By triazine o herbonov |Z), AB" (2, ZNO, 300 but acid zn 289 is, ZN); 2.28: (c; "

Example 7

Methyl ester of 4-(1H-indazole-b-ylamino)-5-methylpyrrolo|2,1-4(1,2,4)triazine-6-carboxylic acid

Fe her to K « and zF : і-

A mixture of compound E from Example 2 (20mg; 0.09mmol) and b-aminoindazole (18mg; 0.1mmol) in CH3SM (Tml) and DMSO (0.5ml) is shaken for 4 hours. The mixture was filtered, washed with HPLC, and the crude product was purified by preparative HPLC to give the compound of Example 7 as a white solid with 3 c (13 mg, 4595). MAN) -323.1; "NN NMR (SOSI3): 5 8.37 (p, 18); 7.99 (s, 1H); 7.94 (d, 9U-7.4Gu, 1H); 7.68 (d, :z" 3-4.2Hz, 1H); 7.00 (dd, 9-7.4; 4.2Hz, 1H); 3.83 (s, ZN); 2.91 (s, ZN).

Example 8 15 Methyl ester of 5-methyl-4-((Z--"methylsulfonyl)amino|phenylI|amino|pyrrolo|2,1-P(1,2,4)triazine-6-carboxylic acid bo" ZD ma 70 4 you

T" And that Mr.

Compound E from Example 2 is dissolved in DMF (2 ml), after which 3-(methylsulfonylamino)aniline (54 mg; 0.03 mmol) is added. The reaction mixture was stirred for 4 hours at 2523 in an argon atmosphere. The crude reaction mixture is purified by preparative HPLC. The obtained product is obviously a salt of the given compound.

The substance is dissolved in EtOAc and washed with a saturated Manso solution. After evaporation of the solvent (F. 24 mg (4095) of the compound from Example 8 are obtained. M8: MAN) -376.2; "H NMR (4-DMSO): δ 8.89 (s, 1H); 8.14 (s, ka 1); 7.95 (s, 1H); 7.55 (s, 1); 7.38 (s , 1); 7.34-7.32 (m, 2H); 7.01 (d, U-8.0Hz, 1H); 3.81 (s, ЗН); 3.02 (s, ЗН); 2.82 (c, ЗН). in Example 9 Methyl ester of 4-((3--aminosulfonyl)|phenyl|amino|)-5-methylpyrrolo|2,1-4(1,2,triazine-6-carboxylic acid b5

/Fo, nn i same o ud -K 4 t ;

Compound E from Example 2 (20 mg; 0.09 mmol) was mixed with 3-aminobenzenesulfonamide (2 mg, 0.13 mmol) in DMF (1 mL) and shaken for 4 hours. By evaporating the solvent and purifying with preparative 710 HPLC, 8.bmg (58956) of the compound of Example 9 is obtained as a solid. MO: MANI -362; "H NMR (4DMSO): δ 9.08 (s, 1H); 8.18 (s, 2H); 7.98 (s, 1H); 7.91-7.89 (m, 1); 7, 62-7.58 (m, 2H); 7.42 (s, 2H); 3.81 (s, ZN); 2.84 (s, ZN).

Examples 10-15

Ie pe gy (is)

And U

Compounds of formula (Ie), where the groups 7, K, and K5 together have the values listed in Table 2, are prepared by the method of Example 9, except that instead of 3-aminobenzenesulfonamide, the corresponding se amine is used. at

Table 2: TABLE 2

Best: 01 day « 1st Methyl ester 4-(3-Me: IMANI" 418.2; ! and no IbusylaninosulfoniIfenyldeninoi (A YMe (siusK vo sc ne ra 5-methylpyrroloi|2, 1-Щ(1,2,4)griazine -v- (c, 1H), 784-782 (m, 183, ts 758 a-58.0 Gu, 1H), ie: carbonic acid tats (m, onu zvo o

ZNU 293-289 (m; 28); 2.81 (c; ZN), 144-118 (m,

ZNU" 084 (vol. 9-74 Gu, and zn and "I 11 Na Methyl ester 4-3" M; (MENI - 376.2; ; (aminosulfonyluche tn YaMe (soshkh 5 805

From Unit meimaphenylamitnoi-5-methylpyrrolog 1" lived you, zveuche te - (P11,2,4)triazine-b-carboxylic acid. 1 without - 8 pe 2), 3:84 (s, -ZN), 2.84 (t,

Ж-рпфо2Н), 2.85 (with the meaning of methyl ester 4-P6-(acetylamino)-|M5: Meni a 342; « where lvndino ns metvrnovy methe rrmeoch is. 2.8) triazine-v-voi "|иH). 8.53 (p, 1), 814-

What is your paroanvnot (m, zn 1nu 8 --- | 3.80 (s, ZM), 2.83. (s, ZN), s and nak - 232ie, zn

Metypic ester 44(3,4-M; IMen) - 3432; . in the dimethoxyphenylamines of Ksrsv 5, these and more than methylpyrrolo(2,1-P11:2,4)griazine-b- (E 1n), t. (dd; 3e8 6, and same 2.8. Hz, 1НU 8.82 ( d, as carboxylic acid 1-86 Hu, tv zva

Z, 9H), 2.88 (c, ZNI

Methyl ester 44(2,3-dihydro-3-M: (MH) with 3242, and background "NYAM? (SOS): 5 98 in and oxo-1H-indazol-2-yl-5- is. Janv and sn , 555 - I and methylpyrrolo|2,1-P(1,2,4) triizin-- c, H), tav: le82 Gu,

YAN", 742-737 (m, 2H),

J of carboxylic acid (m. tn vv i t» ! - Z, 2.84 (6, ZN.

Y Methyl ester 445- Me: (mn) - 386. o | we o (minocarbonip)-2 З-dithydrochoch» Z ste tyu - 7 enandol-Z-ip|b-methylpyrroloi 2, 1- 1), 7.48. (where 3-80. HC, ply, NAP of 2x4triazine-b-carboxylic acid is in

Kk and ZNU 2 os, zn, and "r" Example 16

Methyl ester of 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo|2,1-4(1,2,)triazine-6-carboxylic acid ime)' and In a solution of oxindole (5.32 g; 40 mmol) in THF (150 ml) and DMF (35 ml), oxygen is removed by blowing argon through it. This mixture is placed in an ice bath and Mann (6095 in oil; 1.7g; 42mmol) is added. Through ЗОхв. add 4-chloro-5-methyl-β6-carbomethoxypyrrolo|2,1-P(I1,2,|triazine (compound E from Example 2) (3.38 g; 15 mmol).

The resulting mixture is left for 1 hour at room temperature, after which it is neutralized with acetic acid.

The solvent is removed in vacuo. The residue is dissolved in methylene chloride, washed with saline solution and dried (M950). The solution was evaporated to give a solid residue, which was triturated with methylene chloride and diethyl ether to give the title compound as an orange solid (3.5 g; 7290).

M8: ME -323.1; "H NMR(SOSI"): δ 7.86 (p, 1H); 7.74 (s, 1H); 7.37 (s, 1H); 7.19 (d, 9-7.6Hz, 1H) ; 7.11 (t,

U-7.6Hz, 1H); 7.10 (t, U-7.6Hz, 1H); 7.06 (d, 9U-7.6 Hz, 1H); 3.84 (c, ZN); 2.34 (c, ZN).

Example 17

Methyl ester of 4-(2,3-dihydro-3-oxo-1H-indazol-1-yl)-5-methylpyrrolo|2,1-P(1,2,4)triazine-6-carboxylic acid "Us in U in

The above compound from Example 17 is obtained according to the method of obtaining the compound from Example 16, according to /5, with the exception that instead of oxindole, 3-indazolinone is used. MANI)" -324; "H NMR (SOSI"): 5 8.16 (p, 1H); 8.02-7.99 (m, 2H); 7.83-7.81 (m, 1H); 7.58-7.54 (m, 1H); 7.46 (s, 1H); 3.87 (c, ZN); 2.66 (c, ZN).

Example 18

Methyl ester of 4-(2,3-dihydro-1-methyl-2-oxo-1H-indol-3-yl)-5-methylpyrrolo|2,1-P(1,2,)triazine-b6-carboxylic acid

K. A i ze sh e (8)

M-methyloxindole (22mg; 0.15mmol) was added to Mann (60595; 5mg; 0.10bmmol) in DMF (0.5ml) at 023. The reaction mixture is stirred for 1 min. at 0C. Add compound E from Example 2 (22 mg; 0.100 mmol) in DMF (ml).

The reaction mixture is stirred for 45 minutes. at 2592C, after which phosphate buffer with pH 7 is added. The mixture is extracted using EtOAc. The combined extracts were dried (Ma 25503) and purified by preparative HPLC to give the compound from Example 18 as a yellow solid. M5: see

IMYANI"-337.2; "H NMR (SOCIz): 85 7.90 (p, 1H); 7.40 (c, 1H); 7.16 (m, 2H); 7.02 (t, 9-7.6Hz, 18); 6.90 (d, 3-7.6 Hz, 1H); 5.28 (s, 1H); 3.86 (c, ZN); 3.36 (c, ZN); 2.37 (c, ZN). "

Examples 19-24 and -

Wat pe) and n « | e c) c and av;" and Compounds of formula (I), where groups 7, Ku; and K5 together have the values listed in Table C, obtained by the method described in Example 18, except that instead of oxindole, a correspondingly substituted -1 15 oxindole is used, and in Examples 19 and 20, 2,3-dihydro is used instead of oxindole, respectively -2-oxo-1H-benzimidazole (40.2mg; 10 mmol) and ((methylsulfonyl)(amino|-2-oxo-1H-indole (9Omg;

ChK» O.4 mmol). After purification by preparative HPLC, the given product can be collected, evaporated and neutralized with aq. solution of ManNnsSoO" or desilylate with tetrabutylammonium fluoride.

Table With name) s»

F) name) 60 b5

. TABLE C

Benyuk 7777 fNueasyulyu 00 be

Methyl ester 4-(2,3-dihydro- |H NMR (SOC); 6 8:37.

NK 2-okbo-THN-benzimidazop-1-ip)-5-py in TE 2 ve, , methylpyrroloi2:1-01K2.Iadtriazine- 17.10 (m, 4H), 388 (s, « (v-carboxylic acid ЗН) . (d, 1-88 Hz, IN), and b: methyl pyrolog? "PI, 2,4 ze "be Fi 67. (with triazine-b-carboxylic acid. ! n 21 o Methyl ester 4-(5- ME: IMANI -400.1; 1 wolf aminosulfonium)-2.Z-dihydro-2-chi i s 2

E tZh oxo-THN-indolazchyl)nv- IN 765 (B, 582 Hz, і methylpyrroloi2,1-ІІ1 2 AIgriazin-vn ey g z z

I b-carboxylic acid. (c/Zn). " shk 22 Methyl ester 4-(2,3 -dihydro- |М8: МН) - 446.2; on you" "I and NMR in: Hto m Y SHY (sosustOnu 5. 7:84

Mr. hydroxyethyl)aminosulfonyl)2-Ce, 1NU 755 (c, 1NH ! ozhxo-1NandoleZ-yl)-5-methylpyrrolo 7 (I 7 NE (2A-it 2, ernazine-v-carbonov (3-66 Hz, 18) , 3.78 (U

ZN), 3.60 (t; o«74 Gu. acids. nu zt ty p i shi 24), 2.20 (s, ZA. 23 | - zn st Methyl ester 4-|5- Mo: IMNI - 430; no. 9 them, (dimethylamino)sulfonipr 2.3 is the same 5 c and dihydro-2-oxo-1Nindol-Z-yl)-b- 17.65-7.54 (m, ZNU, 7.15, ear methylpyrolog2; 1-011.2; griazine- (e With its composition of β-carboxylic acid 2.43 (s, ZN)

I Metypic ester 4-12;3-dihydro-5". MBeIM-Nu with at; vn--5 9 yn 1(quetylamino)sulfonyl|-?2-oxosostyu nu 5'7vv o i 1n-indol-3-yl)-5-methylpyrrolo|2,1-s; JAN) 7:76. (c, Nu. r pealtnannechayuenyu SVT, MS and cm

And: acids; ate hc, n), va. her

And immediately is, ZNU 221 Ge)

Example 25

Methyl ester of 5-methyl-4-(1,2,3-4-tetrahydro-3-oxo-1-quinoxalinyl)pyrrolo|2,1-P(1,2,4(htriazine-b-carboxylic acid) ! " and -

Compound E from Example 2 (23mg; 0.mmol) was mixed with 1,2,3,4-tetrahydroquinoxalin-2-one (44.4mg;

O, Zmmol) in DMF (0.5 ml) for an hour. at 5020. Water is added and the solid product formed is collected, washed with water and dried. The product was triturated with Meon, filtered and dried again to give 20 mg 400 (5995) of the title compound as a white solid. "H NMR (4-DMSO): 5 8.30 -8.25 (m, 2H); - s 7.12-7.03 (m, 2H); 6.83 (us. s, 2H); 4 .38 (c, 2H); 3.73 (c, ЗН); 2.49 (c, ЗН), 1.72 (c, ЗН). "from Example 26 and 4-(2,3-dihydro-2 -oxo-1H-indole-3-yl)-5-methylpyrroloi|2,1-P(1,2,4triazine-b6-carboxylic acid b and -I y and ime)

HT" To a solution of the compound from Example 16 (3.3g; 10.2mmol) in MeonH (b0Oml) is added KOH (1M aqueous solution, 200ml), and the mixture is purged with argon to remove oxygen from it. Heat to 60 C for 20 hours, then cool and evaporate to a volume of approximately 500 ml. The residue is acidified with concentrated NOSI to pH4i. The yellow precipitate was collected, washed with water and dried in vacuo to give the title compound (2.9 g; 92905).

M: IMeANI -307.1; "H NMR (CO500): δ 7.94 (p, 1H); 7.71 (s, 1H); 7.18-7.10 (m, 2H); 6.94-6.86 (m, 2H ); 2.45 (c, ZN).

F) Example 27 ko 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo|2,1-4(1,2,A)triazine-6-carbonate ethyl ester acids because what In 65 ; ;

A. Diethyl ester |(2-ethoxy-2-oxoethyl)xphenylmethyl)amino|methylene) propanedioic acid

M-benzylglycine ethyl ester (5.79g; ZOmole) is mixed with diethylethoxymethylene malonate (6.48g; ZOmole) and for 1 hour. stir at 1202. The crude product is directly used in the next reaction.

B. Diethyl ester of 1-phenylmethyl-3-hydroxypyrrole-2,4-dicarboxylic acid

To a suspension of Mann (6095 in oil, washed with a mixture of hexanes; 500mg; 12.5mmol) in toluene (LOml) at 5090, add compound A (3.63g; TOmmol) in toluene (ZOml) dropwise. In 2 hours the mixture is poured into ice water and acidified with 1M aq. NSI solution. Extracted three times using E(SO4. The combined organic extracts were dried (Ma53O)) and evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 5095 E(OAc) in a mixture of hexanes to give 2.70 g (8595) of compound B as a pink oil.

C Diethyl ester of 1-phenylmethyl-3-methoxypyrrole-2,4-dicarboxylic acid

Compound B (634 mg; 2 mmol) was stirred in acetone for 1 hour. at room temperature with methyl iodide (300 mg; 2.1 mmol) and K»CO3 (500 mg). The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 3395 solution of EAs in a mixture of hexanes to give 47mg (71905) 75 of compound C as a gel.

O. Diethyl ester of 3-methoxypyrrole-2,4-dicarboxylic acid

Compound C (27g; 81.5mmol) is mixed with Ra/s (1095.4g) and ammonium formate (28g) in EUN (Tl) and hydrogenated at a pressure of 4 bar (275.79kPa) and a temperature of 90°C for 18 hours. The reaction mixture is cooled to room temperature, filtered and evaporated. The crude product (brown oil) was purified by chromatography on silica gel eluting with 2595 EtOAc in a mixture of hexanes to give 13 g (66905) of a yellowish-brown solid.

E. Diethyl ester of 1-amino-3-methoxypyrrole-2,4-dicarboxylic acid

To a suspension of Man (6095 in oil; 1.76 g; 7 mmol) in DMF (35 mmol) with stirring under nitrogen at 09C, add the compound OY (13 g; 54 mmol) in DMF (200 mmol) dropwise. Through ЗОхв. DMF (/50ml) is added to the mixture, CM after which diphenylphosphorylhydroxylamine (15.7g; 67.4mmol) is added, and the reaction mixture is brought to room (5) temperature. After 6 hours, the mixture is evaporated and the residue is diluted with water (1 L) and extracted using

EUAs (Хх1л). The combined organic extracts were dried (Mo 5 O 5 ), evaporated and purified by chromatography on silica gel eluting with 2095 EtOAc in a mixture of hexanes, obtaining 13 g (9395) of a solid.

ER. Ethyl ester of 4-hydroxy-5-methoxypyrrolo|2,1-7(1,2,triazine-6-carboxylic acid "

Compound E (100mg; 0.39U9mmol) was mixed with formamide (Iml) and heated at 1809 for b hours. high school

The reaction mixture is cooled to room temperature and water (ml) is added. The precipitate formed is collected, washed with water and dried. 7Omg (7695) of compounds B. about b are obtained. Ethyl ester of 4-chloro-5-methylpyrrolo|2,1-1(1,2,triazine-6-carboxylic acid)

Phosphorus oxychloride (ml) is mixed with compound E (23.7mg; 0.Tmmol) and refluxed at 70°C for 2 hours. The melt is cooled to room temperature, and phosphorus oxychloride is removed on a rotary evaporator. with N. Example 27

To a suspension of Man (6095; 44mg; 1.1mmol) in THF (ml) add oxindole (1333mg; Tmmol). The reaction mixture is stirred for 20 min. at room temperature and add compound C (0.1 mmol). The mixture is stirred at -1 75 for 2 hours. at 2523. The crude product is purified by preparative HPLC followed by chromatography on silica gel with EtOAc as eluent. 5.5 mg (1695) of the compound according to Example 27 are obtained as a yellow solid. MO: MANI -353; "NMR (SOSIv): δ 8.42 (p, 0.4H); 8.10 (s, o O, 6H); 7.79 (s, 1H); 7.75-6.88 (m, 4H ); 4.33 (m, 2H); 3.57 (s, ЗН); 1.37 (m, ЗН).

Example 28: Methyl ester of 5-methyl-4-(4-methyl-3-(methylsulfonyl)amino|phenyl|amino|pyrrolo(2,1-P(1,2,triazine-b6-carboxylic acid) |il about 0000 KO

60 g of d-methyl-3-((methylsulfonyl)aniline) (4.4 µl; 87 µmol) is added to a solution of the compound from Example b (1 mg; 1 µmol) in pyridine (ml) at 09Cb. The reaction mixture is stirred for an hour. at 02C, then heated to 252 and stirred for 4 hours. Water (5 mL) was added, and the mixture was extracted with EtOAc (3 mL). The combined organic extracts were washed with water (1 mL) and brine (1 mL) and dried (Ma»25O4). The crude product was purified by chromatography on silica gel with elution in 5 295 MeOH in chloroform. 6.9 mg (3095) of a solid are obtained. c, 1H); 7.77 (c, 1); 7.35 (d, U-82Hz, 1H); 7.27 (c, 1), 7.18 (d, U-8.2Hz, 1H) 6.25 (c, 1H),

3.82 (c, ZN); 3.03 (c, ZN); 2.86 (c, ZN); 2.24 (c, ZN).

Example 29

Phenyl methyl ester

I4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrroloi|2,1-PC(1,2,triazine-b6-carbamic acid)

Go

Sneao 70 h/ h and

To a solution of the compound from Example 26 (29mg; 0.09mmol) in 1,4-dioxane (0.bml) in the presence of powdered molecular sieves (4A) under argon, add TEA (1µl; 71µmol), diphenylphosphorylazide (15µl; 7/Tµmol) and benzyl alcohol (12 μl; 0.12 mmol). The reaction mixture is heated at 5023 for 15 hours. The mixture was evaporated in vacuo and immediately chromatographed on silica gel eluting with a gradient of 2-5906 Meon in chloroform to give 8 mg (5095) of the intermediate as a white solid. Phosphorus oxybromide (bq.) is mixed with this intermediate (1 mg; 0.054 mmol) and heated to 602 for 20 min. The melt was poured into ice water and extracted using E(OAc (4 x 5 ml). Extracts were washed with aqueous Manso solution, dried (Ma»3O)) and evaporated in a vacuum. The residue is dissolved in a mixture of CHZSM (0.5 ml) and DMF (0.1 ml), after which 5-amino-o-cresol (10 mg; 0.081 mmol) is added. The reaction mixture was stirred overnight under argon at 259C. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel eluting with 295 Meon in chloroform to give the title compound as a yellow oil (5 mg; 13965). M: MANI 414; "H NMR (SOSIV5): δ 7.94 (p, 1H); 7.82 (s, 1H); 7.41-7.34 (m, 5H); 7.17-7.14 (m, 1H ); 7.04-7.02 (m, 1H); 6.93-6.90 (m, 2H); 6.44 (s, 1H), 5.23 (s, 2H); 2.12 ( p., ZN).

Example 30 o

Methyl ester 4-(2,3-dihydro-6-methyl-2-oxo-1H-pyrazolo|2,3-4|pyrimidin-3-yl)-5-methylpyrroloi|2,1-P(1,2, 4-triazine-6-carboxylic acids

ШИ н - n ; And about school C "

Mch i-

A. 6b-methyl-5,7-diazaoxindole

To a solution of ethyl (4-amino-2-methylpyrimidin-5-ylluacetate (international application MUO 99/10349, 0.975g; 5mmol) in "

Potassium tert-butoxide (1M in THF, 5ml) is slowly added to THF (30ml). After 1 hour, the mixture is neutralized with acetic acid to pH5. Volatile components were removed in vacuo and the residue was purified by flash column chromatography (silica gel, 5-8956 MeOH in methylene chloride) to give a yellow solid (68Omg; 9195). "» B. Methyl ester of methyl pyrrolo|2,1-Y(1,2,triazine-6-carboxylic acid

To a solution of b-methyl-5,7-diazaoxindole (b7mg; 0.45mmol) in DMF (2ml) and THF (ml) add Mann (60595 in oil, 2Omg; O0.5mmol). After twenty minutes of stirring, add compound E from Example 2 (34 mg; 0.15 mmol). -i The mixture is stirred at room temperature overnight, after which it is neutralized with acetic acid. 1» Methylene chloride (1 Oml) is added, and the resulting precipitate is filtered off and washed with small amounts of methylene chloride and water, then dried in vacuo to give the title compound as an orange solid (a) (32 mg; 6390). M: (M.-N)-359. t 50 Example 31

Methyl ester chz» 4-(2,3-dihydro-2-oxo-1H-pyrazolo|2,3-b|Ipyridin-3-yl)-5-methylpyrroloi|2,1-4(1,2,Agriazin- b-carboxylic acid from KO

Pe) si ey 60 To a solution of 7-azaoxindole (see Teigapedhop. Hey. Moi. 28 (1987), p. 4027) (bOmg; 0.45 mmol) in DMF (2 ml) and

Man (60595 in oil; 20mg; O0.5mmol) is added to THF (ml). After twenty minutes of stirring, the compound is added

E from Example 2 (334 mg; 0.15 mmol), and the mixture is stirred at room temperature overnight. The solution is neutralized with acetic acid, after which methylene chloride (1 Oml) is added to the mixture. The resulting precipitate is filtered off, washed with small amounts of methylene chloride and water and dried in a vacuum, obtaining a yellow solid (35mg; 7290). And C-M8: (M-H)-324.

Example 32

Methyl ester of 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)pyrrolo|2,1-4C(1,2,triazine-6b-carboxylic acid 70 I | o

The compound is obtained according to the method described in Example 2, using 2-methoxycarbonylpyrrole as a starting compound to obtain 4-chloro-6-carbomethoxypyrrolo|2,1-4(1,2,)griazine, which is then converted into the compound from Example 32 , using the same or similar technology as in Example 31.

Examples 33-36 (9. in c x s schi 6)

Compounds of formula (II), where K/5 have the values listed in Table 4, are obtained by the technology of Example 32, using reagents known from special literature (see international application UUO 97/42187). h » (33 | P Methyl ester of 4-I(b-fluoro-2-hydroxy-AN-indol-3-yl)-5--methyltrolo|2,1-P(1,2,)triazine-b-carbon acid c (34 | Vg Methyl ester of 4-(6-bromo-2-hydroxy-AN-indol-3-yl)-5-methylpyrrolo(2,1-4(1,2,A)triazine-b-carboxylic acid av) (35 | SEZ Methyl ester 4-(2,3-dihydro-2-oxo-6-trifluoromethyl)-1H-indol-3-yl|-5-methylpyrrolo(|2,1-P(1,2 ,)triazine-b-carboxylic acid « 36 |8OzMe Methyl ester 4-(2,3-dihydro-6-(methylsulfonyl)-2-oxo-1H-indol-3-yl|-5--methylpyrroloi(2,1 -4(1,2,Atriazine-b-carboxylic acid m.

Examples 37-49 60 g po) "ch an KO Y. -I y" To the compound from Example 26 (50 mg; 0.1 mmol) in DMF (ml) and methane chloride (0.5 ml) is added RuVhor (113 mg; 0 .24 mmol) and SIREA (0.08 ml; 0.5 mmol). After 10 minutes add the appropriate amine. After 15 hours the reaction av) mixture is purified using preparative reversed-phase (QR) HPLC, obtaining compounds of formula (Id) 50 (see above), where K» and K.o have the values given in Table 5.

Table 5 "from"

F) name) 60 b5

TABLE 5 ekt 76 ee 0 37 J Hist. 44022. 3-dihydro-2-oxo-THN-indoleZ-yl)4M,5-dimethyl-M2- and po (1-pyrrolidinyl)ethyl|pyrrolo(2,1-0(1,2,4)griazine-b - carboxamide ts 7TYA23-dihydro-o-oxo-ANANDoliZ ip) B.letiya KI. 4 koe pyrrolidinyl)stil|pyrrolo(2.1-0(1.2,4)griazine-in-

Ii |carboxamide 39 o A (23-dihydro-2-ocoo-1Neindol-3-yl)-b-methyl-M-(3-(4-.

M m scha morpholinilupropylIpyrrolo(2. 1-41 2.4 ) griazine-b- and carboxamide) What Y Y ach Z: dihydro-ogoxo-Tn-indol-z-iya)-b-methyl- Ma: s zh morphopinyl)vtilpyrogo( 2,4-2(1,2,4)triazine-in-carboxamide 4-(2,3-dihydro-2-oxo-1H-indop-3-ip)-5-methyl-M-(3 (4- I Mmethyl-1-pliperazinyl) propyl Ipyrroloi2,1-71,2 4) griazine- and situ, b-carboxamide: - (a-(2,3-dihydro-2-oxo-1Hlndol-Z-ip p b -methyl-KAZYAN- 75 not J; pra: i 12,3-triazol-1-yl)prolya|pyrrolo(2,15011 2,4Itriazin-6b-

M carboxamide 4-(2.3-dihydro-2-oxo-1H-indol-3-yl)-b-methyl-M-132H-c 1,2.3-triazol-g-yl)propyl|pyrologg, 1-0 (11.2.2triazine-b-

M carboxamide - 442.3-dihydro-2-oxo-1 "Nandol-yl)-5-methyl-MAZ g which Kk ra: 1/di-triazop 1 ilypropypipipopoga, 1-2 2, phytrniavinev" carboxamide h scha Y 4-02 ,3-Dihydro-2-oxe-1 Nlndop-Z4l)-5-Methyl-Mo: !zi metyp-iNimidazol-y-yl)propyp)pyrolo2,1-sna PA 4 |griazine-8-carboxamide, and

And 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methyl-M-(4-(4-

Her Yeullya morpholinyl)butyl|pyrrolo2, 1-1 1:2,4)hryvzina-

And carboxamide Hα o sn 4-(2,3-dihydro-2-oxo-1 NAindol-3-yl)-M,5-dimethyl-MU(3"

M i z (morpholinyl propylpyrrolo2,1-P1;2,utriazin-v- o - A carboxamide; n Yn 4-(2.3-dihydro-2-oxo-1H-indol-3-yl)-5-methiapyrrolo|2 ;1-

I0(1.2.4|griazine-b-carboxamide

N. And there is 4-(2,3-dihydro-2-oxo-TN-dol-ZL)-M, 5

Idimethylpyrologg, 1-Я11,2,4)triazine-b-carboxamide ch;E

Examples 50-52 (t) («c») and ee g M. izhof o « - s Compounds of formula (II), where K.va and K/5j have the values listed below in Table 6, are obtained by the following method with application to stage C of the corresponding substituted oxindole.

A. 5-methylpyrrolo|2,1-4(1,2,4)griazine-6-carboxylic acid

To a solution of 5-methylpyrrolo|2,1-4(1,2,Agriazine-4(ZH)-one-6-carboxylic acid methyl ester (compound Y-I from Example 2; 1.035g; 5.00mmol) in a mixture of THF /MeOH/water (5Oml, 3:1:1) add lithium hydroxide (2.062g; 49.1mmol). The reaction mixture is stirred at 5523 for 12 hours, cooled to 02C and neutralized with МС and НОИ. The organic solvents are removed and, adding 1M NOI, the pH of the aqueous solution is brought to 4. The resulting precipitate is filtered off, washed with cold water and dried in air. Compound A is obtained as a grayish-white solid substance (0.965g; 10090). Co. B. 4-chloro-5-methyl -M-I(3-(4-morpholinyl)propyl|pyrrolo(2,1-P(1,2,4)triazine-6-carboxamide) Suspension of compound A (2.00 g; 10.4 mmol) in phosphorus oxychloride (ml) stir at 1002 for 4 hours.

The solvent is removed in vacuo, adding toluene to aid in the removal. The resulting green solid is suspended in acetonitrile (20 ml) at 02С and treated with a sufficient amount of TEA (5 ml) in order to bring the pH of the solution to 10. 4-(3-aminopropyl)umorpholine (1.5 ml; 10.3 mmol) is added, and the solution stir at room temperature for an hour. The reaction mixture is poured into a saturated solution

F, sodium bicarbonate and extracted using EtOAc. The organic layer was dried (Mo 5 O /), and the volatile components were removed in vacuo to give compound B as a yellow solid (1.75 g; 50905).

C. Examples 50-52 in To a solution of the corresponding substituted oxindole, i.e., 5-fluorooxindole in Example 50 (Zbmg; 0.24 mmol) in

DMF (Tml), add Mann (5.9mg; 0.23mmol). The mixture is kept for ЗОхв. at room temperature, a solution of compound B (24 mg; 0.072 mmol) in DMF is added, and the resulting mixture is stirred at room temperature for 1 h. The solvent is removed in vacuo, and the mixture is purified by reversed-phase (RP, CR) HPLC. Meon in the required HPLC fractions is distilled off in a vacuum, and the formed aq. solution 65 is neutralized with a saturated solution of sodium bicarbonate, after which it is extracted using EtOAc.

The organic layer was dried (M9504) and the volatile components were removed in vacuo. The resulting solid is dissolved in a mixture of acetonitrile/MeOH and treated with 1M HCl in diethyl ether. The mixture was stirred at room temperature for 1 h, and the solvents were removed in vacuo. The NSI salt of the main compound is obtained as an orange solid (18 mg; 51905).

Acknowledgment К Кк Name of the compound. Data ко По пони ПЕ --АБ3

St. GE morning in antidro o eye IN nat via) B metit MV morpholinipipipirioloio 1-12 prizes in harbokyamia 1 o Plans WHAT

MN

2

Example 53

Methyl ester of 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo|2,1-4(1,2,Agriazine-b-propanoic acid vch u c

A. 4-phenoxy-5-methyl-b-carbomethoxypyrrole|2,1-C(1,2,triazine

To a solution of phenol (705mg; 7.5mmol) in a mixture of THF (10ml) and DMF (10ml) add Mann (6090 in oil; ZOOmg; c 7.Bmmol). Through ЗОхв. add 4-chloro-5-methyl-β6-carbomethoxypyrrolo|2,1-ShC(1,2,triazine (675 mg; 3, mol - about compound E from Example 2). After 1 hour, the solvent is removed and the residue is poured into 595 aq. CoCOz solution.

The precipitate was collected, washed with water and dried in vacuo to give compound A as a white solid (800 mg; 94965). M5: (MAN) -284.

B. 4-phenoxy-5-methyl-6-hydroxymethylpyrrolo|2,1-4(1,2 A)griazine "I

OIVAG (1.5M in toluene; bmmol) was added to a solution of compound A (700mg; 2.47mmol) in toluene (20ml) at -602С. high school

The mixture is stirred at 09 for 1 hour, add aq. solution of 1M CARRIER (ZOml), and the mixture is stirred for ЗОхв. After that, methylene chloride is added to the mixture. The organic layer is separated, dried over (Mo95O,) and evaporated. The residue was purified by flash column chromatography (silica gel, 296 MON in "E methylene chloride) to give compound B as a solid (61Omg; 9695). M8: (MAN) -256. 3o C 4-phenoxy-5-methylpyrrolo|2,1-1(1,2,triazine-6-carboxaldehyde in

A mixture of compound B (500 Ωg; 1.9 bmmol) and MpoO»5 (Z,Og) in toluene (30 ml) is heated at 602 for 1 h. After cooling to room temperature, the mixture is filtered through a layer of silica gel and washed with EtOAc. After evaporation in a vacuum, compound C was obtained as a white solid (420 mg; 8596). M5: « 20 (Man) -254 z

Or. 4-phenoxy-5-methylpyrrolo|2,1-P(1,2,4)triazine-6-propenoic acid methyl ester To a solution of compound C (bOmg; 2.37mmol) and methyldiethylphosphonoacetate (1.74ml; 9.4ummol) in OSE (20 ml) :z" add YUOVY (1.42 ml; 9.49 mmol). The mixture is stirred at room temperature overnight, the reaction mixture is diluted with methylene chloride and washed with 295 aq. citric acid solution, saline solution, 15 is dried (MazO),) and evaporated. The organic extracts were evaporated and the residue was purified by chromatography on silica gel, eluent 20956 EtOAc/OSM, to give a white solid (71mg, 9790). M5: (MAN) -310. ve E. Methyl ester of 4-hydroxy-5-methylpyrrolo|2,1-4(1,2,)triazine-b6-propanoic acid o To a solution of the compound OO (71O0mg; 2.3Omol) in a mixture of solvents EUAs/ meon/gHF /AcOonNn (10Oml/100ml/2o0ml/2ml) add Ra/C (1095, 7Omg). The suspension is stirred for 2 hours. under hydrogen i.e.) The reaction mixture is filtered through a layer of celite, the celite is washed with MeOH, and the filtrate is evaporated under vacuum,

Their" receiving a raw product. Treatment (grinding) with a mixture of hexanes allows obtaining compound E as a white solid (43Omg; 88965). M8: (MAN) -236.

E. Methyl ester of 4-chloro-5-methylpyrrolo|2,1-4(1,2,A)griazine-b6-propanoic acid

A mixture of OIREA (0.24 ml; 1.4 mmol), compound E (220 mg; 0.94 mmol) and ROSI" (3 ml) is heated in a sealed ampoule at 802C. In 2 hours the mixture is cooled to room temperature and evaporated in vacuo. Received balance

F, distributed between methylene chloride and aq. MansSoOz solution. The OSM layer is separated, dried (MazoO)) and co-evaporated in vacuo to give a dark green solid. Purification by chromatography on silica gel and elution with 2095 ЕХАСС/ОСМ allowed to obtain compound E as a yellow solid (220mg; 9295). M8: (MN) -254. b. Methyl ester of 4-(2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo|2,1-Y(1,2,triazine-b-propanoic acid

Man (60595 in oil; 28mg; 0.71mmol) was added to a solution of oxindole (94mg; 71mmol) in DMF (2ml) under argon.

The mixture is stirred for 1 hour. and compound E (bOmg; 0.24 mmol) is added. The mixture is kept for 1 hour at 65 room temperature, and the reaction is stopped by adding acetic acid and diluting OSM. The organic solution is washed with water, dried (Ma95O)5) and evaporated in vacuo to obtain a crude product. Purification by chromatography on silica gel and elution with 2095 EtOAc/OSM afforded the title compound as a pure yellow solid (78 mg; 94965). M5(MN) 351

Example 54 1,3-dihydro-3-(5-methoxy-6-(phenyl methoxy)-pyrrolo|2,1-C(1,2, A|triazin-4-yl|-2H-indol-2-one

In and "5

A. 4-hydroxy-5-methylpyrrolo|2,1-411,2,4)triazine-6-methanol

The ethyl ester of 4-hydroxy-5-methoxypyrrolo|2,1-4(1,2,4)triazine-6-carboxylic acid (compound E from Example 75. 21; 3.56 g; 15 mmol) is mixed with tri-tert-butoxyaluminum hydride lithium (1M solution in THF; bOml; bomol) and reflux overnight. The reaction mixture is cooled to room temperature and 1M aq. NSI solution. The mixture is evaporated in order to remove volatile components, the residue is mixed with 100 g of silica gel and purified on a column using flash chromatography with E(OAc) elution. 2.65 g (9095) of compound AM are obtained: (MAN) -196. 20 V. I (b-hydroxymethyl)-5-methoxy-4-oxopyrrolo|2,1-4(1,2,Agriazin-3(4H)-yl|methyl ester of 2,2-dimethylpropanoic acid

Compound A (195 mg; TIMmol) was dissolved in 1.5 ml of DMF. Add Mann (60595 in oil; 48mg; 1.2mmol) and the reaction mixture for 0.5h. stir at room temperature. Chloromethyl pivalate (181 mg; 1.2 mmol) was added and the mixture was stirred for 1 hour. Water was added and the mixture was extracted with EtOAc (3 x 10 mL). c 25 The combined extractions are dried (Ma 2505), evaporated in vacuo and purified on a column by flash chromatography on silica gel eluting with 3390 EOAc in a mixture of hexanes. 26b0mg (84905) of the compound are obtained

In the form of a solid substance. M5: (M.--N) -310.

C. 16b-formyl-5-methoxy-4-oxopyrrolo|2,1-P(1,2,4Itriazin-3(4H)-yl)|methyl ester of 2,2-dimethylpropanoic acid « 30 of Compound B (74Omg; 2 .3ummol) is suspended in toluene (TOml) with manganese dioxide (835mg; 9.bmmol) and heated at 1002 during The reaction mixture is cooled to room temperature, filtered, and the precipitate is washed with E(Ac. The filtrate is evaporated in a vacuum, obtaining bbOmg (9095) of compound C in the form of a solid substance. M5: (Ma-H) -308. "I r. Ib- formyloxy-5-methoxy-4-oxopyrrolo|2,1-4(1,2,triazin-3(4H)-yl|methyl ester of 2,2-dimethylpropanoic acid in ser r « t0 Compound C (6bOmg; 2, 15 mmol) is dissolved in CHCl (1 Oml). Add m-chloroperoxybenzoic acid (5790; not with 745mg; 2.46bmmol) with Ma5zO, (2.0g), and the reaction mixture is stirred for 5h. at room temperature. "from Mixture filtered, and the filtrate was washed twice with aqueous MnSO 3 , dried (MazO)) and evaporated to give 6b8Omg (9895) of compound O as a solid. M5: (MH) 324.

E. (5-methoxy-4-oxo-6-(phenylmethoxy)pyrrolo|2,1-4(1,2, Atriazin-3(4H)-yl methyl ester of 2,2-dimethylpropanoic acid

Compound O (68Omg; 2.10mmol; Teq) was dissolved in acetone (1Oml), after which benzyl bromide (43OmgHg; t" 2.5mmol) and KSO" (1.0g; 7.25mmol) were added. The reaction mixture is stirred at 602C for 10 hours, cooled to room temperature and filtered. The filtrate is evaporated and purified using flash chromatography on silica gel with elution of 2595 E(OAc in a mixture of hexanes. 485 g (6095) of compound E are obtained in the form of a gel. ko MM NI -386. i» ER. 5-methoxy-6-(phenylmethoxy )pyrrolo|2,1-C(1,2,4A)triazine-Z(4H)-one

Compound E (b5 mg; 0.17 mmol) was stirred at room temperature in a mixture of MeOH (ml) and ammonium hydroxide (0.2 ml) for 2 h. The mixture is evaporated under vacuum, dissolved in CHCl and purified using 5B flash chromatography on silica gel eluting with 3395 ЕюdAs in a mixture of hexanes, obtaining 45 mg (9795) of compound E as a solid. M5: (MANI 5272. iF) Fr. 4-chloro-5-methoxy-6-(phenylmethoxy)pyrrolo|2,1-411,2,4)griazine to Compound E (44mg; 0.1bmmol) was stirred with ROSI" (0.5ml) at 602С during The mixture is evaporated in vacuo, dissolved in Si2Si0 (2 mL) and stirred with solid MnSO2O3 for 1 h. The mixture is filtered and evaporated. 60 4 mg (9995) of compound C are obtained as a solid. M: (MAN) "-286 (substitute SI when defending v

Meon can be replaced by OSN"). Retention time (K.T.)-3.265 min. (column UMO 55 005, 4.6x5 Ohm, 10-9095 aqueous MeonN solution, which after 4 minutes contains 0.295 phosphoric acid, 4 ml/min, monitoring at 220 nm); "H NMR (SOSI"): δ 8.01 (p, 1H); 7.45-7.30 (m, 6H); 5.15 (s, 2H); 4.03 (s, ЗН).

H. 1,3-dihydro-3-(5-methoxy-6-(phenylmethoxy)-pyrrolo|2,1-4(1,2,AZtriazin-4-yl|-2H-indol-2-one) To suspension Man ( 6090 in oil; 19.2mg; 048mmol) in DMF (0.5ml) add oxindole (63.4mg; 0.48mmol).

The reaction mixture is stirred for an hour. at room temperature. Add compound o (38mg; 0.1bmmol;

Current), and the mixture is stirred for 1 hour. Add water and filter the mixture. The resulting solid was triturated with MeOH and dried to give 38 mg (6296) of the title compound. M: |MANI-387; "H NMR (4-DMSO): δ 12.83 (s. s, 1H); 10.64 (s. s, 1H); 7.78 (s, 1H); 7.60 (s, 1H); 7.50-7.31 (m, 6H); 7.02-6.94 (m, 1); 6.89-6.82 (m, 2H); 5.10 (s, 2H); 3, 55 (c, ZN).

Examples 55-60 and (I) and:

Compounds of formula (II), where Kuva, Kchv and K/vs have the values given in Table 7 (see below), are obtained by the technology described in Example 54, but using a different phenylamine.

Table 7

Po ki OM p polyn moi

E Y Snu | Methyl ester 445-fluoro-2- (MeNu 315; (methyphenyl)amino|p5- TOK vd methypyrrolo|2;1-ShSHh4,2,4) (EX 7. ZV);

Itriazin-b:carboxylic acid 1 be t 7 53 ha, ShCHA 387 (p. p.

ZNU 2:82 (c, ZN) 23 zn her

H n CH» | Methyl ester 44(5- (meni - 368.23; Ho) g; from Eethylaminosarbonyl i: in Nut d i Zmethylphenyleimino-5- (E, TN), 7:83 (c, 1H), methylpyrrolo (2, 4-P(1254) its tt of triazine-b-carboxylic acid |; 1), 3-82 (s, ЗН); 3.40-(m, 2-13, 2.88(s, "I

ZN), 2.30 (s. ZN), - and - 1.85 (m, 34; t) CH» 2,1-P(11,2,41 1nu.7. 66. tush, p, 1), ytryvzin-b-carboxylic acid Kt ie (c; (ав)) and 231(c,3Н i no Methyl ester 42K4- Me" "301; chI

Iftorfevilyaminoivt. with ve methylpyrrolo|2,1-0(1:2,4) 1, 754 im, 2); and triazine-v-carboxylic acid Iv and. be zva 5a n H SN". |Methyl ester 4-15-4C3- (Meni "4462 rod and methoxyphenyl)amino|ycarbonyl-. 2-methylphenylamino-5-methypyrrolo|2, pi 2.4). « ytriazine-in-carboxylic acid. And SN. Methyl ester b-methyl-4-1 (MH) 3551 shsh i; M 2-methyp-5-s Cosna (methypaminojarbonyl. - phenoxy|pyrrolo 2; 1- ; » ) (1,2, Aeriazin-bcarboxylic acid. Y Y

Example 61 - M-cyclobutyl-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|)-5-methylpyrrolo|2,1-4(1,2,A)griazine-6-carboxamide what

NO

Well; ko I and 2 I « and SE

I" NO g -

Compounds from Example 61 are obtained according to the above description according to scheme 9, where compounds (A)-(E) o are characterized by the following structures.

A. name).

K.. 60. g - tsk

KE Ha b t y y

To a solution of 3-methyl-1-pyrrole-2,4-diethyl ester (100 mg) (M. Neyegosusis Spet. MoiI. 34 (1997),

177-193; Neyegosudez MoI.50 (1999), pp. 853-866; BZupipeziz (1999), pp. 479-482) in DMF (044M) at room temperature add either Man or KOIIIIVy (1.2 equiv.). This solution is stirred for 30-45 minutes.

Using a syringe, inject a solution of chloramine in ether (about 0.25 M; Current). The solution is stirred for 1.5 hours. to the conversion of the starting compound into a product (HPLC analysis). After that, an aqueous solution of Ma»5Z2Oz is added to the reaction mixture, and the mixture is extracted using E(Ac or EO. The organic extracts are washed with water and brine and dried using sodium sulfate. Compound A is obtained with a yield of 29095. МН»оСИ in ethers are obtained according to the technology (Mipp, y.) Spect. os. (S) (1971), p.

V. v. ! To

Acetic acid (2095 by weight) is added to a solution of compound A (2g) in formamide (v8ml), and the mixture is heated at 12022 for 24 hours. The reaction mixture is cooled and water (32 ml) is added to precipitate the product. The precipitate was filtered off and washed with EtOAc to give compound B as a yellow solid (9096). with. b where SHY: » rthe ?

To a solution of compound B (10g; 45.2mmol) in toluene (150ml) add OPIREA (6.31ml; 36.2mmol; 0O, eq.) and ROSI»z (B.OBml; 54.2mmol; 1.2eq.) , and the reaction mixture is heated at 120-125 (oil bath temperature) for 20 hours. The reaction mixture is cooled, poured into an ice-cold mixture of a saturated solution of MaHsSO»z-water-toluene with (450ml-45О0ml-15О0ml) and intensively stirred in order to ensure the complete disappearance of RUSSIA with. The layers are separated (if a suspension is formed, filter through a layer of celite), and the organic layer is washed again with a saturated solution of ManHsSO»z. The organic layer was dried over NaCl, filtered and evaporated in vacuo to give compound C as a yellowish-brown solid (9.9g; 9590). r. and - o. sg zro 2 s o ts A mixture of serially produced 4-amino-3-methylbenzoic acid (100g; 0.bbmol) and "» M-(tert-butoxycarbonyl)anhydride (15O0mg; 0.b6b8mol) in THF (1000ml) is slowly heated to 502 overnight.

The resulting mixture is cooled to room temperature, and the solvent is removed on a rotary evaporator.

The resulting solids were triturated with a mixture of hexanes and dried in vacuo to give 151g (9195) of crude and intermediate BOC-protected aniline as a light pink solid. iz To this light pink solid is added EOSI (127g; 0.6bmol), NOVI (90g; 0.6bmol) and DMF (1000ml), and the resulting mixture is stirred at room temperature for 30 minutes, after which (av) is added one portion of methoxylamine hydrochloride (55g; 0.bbmol). After stirring for 1 min. the yuyu 50 mixture is cooled in an ice bath. OIREA (25 Oml; 1.4 mol) is added at such a rate as to maintain the temperature of the reaction mixture below 2520. After the addition is complete, the ice bath is removed, and the mixture

I" stir overnight. The reaction mixture is divided between 0.5 L of water and 1.5 L of E(OAc) and the layers are separated. The aqueous layer is extracted with an additional amount of EAC (40 Oml x 3), and the combined organic extracts are washed with water (30 O0 ml x 3), cold 0.5 M aqueous solution of HCl ( 400 ml x 2 ) and water (50 ml). The product is then extracted with cold 0.5 M aqueous Mahon solution (Z00 ml x 3 ) and the combined basic aqueous extracts are treated with aq.

HF) alkali with the slow addition of cold aq. 0.5M solution of NSI, neutralizing them to pH-8. The precipitate formed is filtered and washed with cold water. The crude solid product is decolorized in hot EUN and activated carbon, obtaining 106 g of a white solid BOC-protected M-methoxyamide intermediate.

To a suspension of this solid intermediate (91g; 0.32mol) in 1.4-dioxane (4000ml) at room temperature 60 was added a 4M solution of HCl in dioxane (400ml), and the resulting mixture was stirred at room temperature overnight. Diethyl ether (1000 ml) is added, and the solid precipitate is filtered off and treated with a hot mixture

EUN/NYO (4/1 by volume). The resulting solid was dried under vacuum to obtain 53 g of pure hydrochloride (compound 0) as a white solid. "H NMR (DMSO-aiv): 5 9.5-9.9 (ss. s, 1H); 7.75 (s, 1H); 7.55 (d, 1H); 7.36 (d, 1H ); 3.70 (s, ZN); 2.38 (s, ZN). b5 E.

E., 4th century

OPIREA (33.ml; 180./mmol; 0.95 eq.) is added to a solution of compound O (41.2g; 190mmol) in DMF (230ml), and the reaction flask is heated to 552C (oil bath temperature). Solid compound C (45.6 g; 190 mmol) was added in several portions over 10 min., the flask was washed with DMF (1500 mL) and this compound was poured into the reaction mixture.

The reaction mixture is heated for 1 hour. at 55922 and cooled to room temperature. After that, the mixture for 10 minutes. slowly pour into 1.5 liters of water, the volume of which is brought up to 2.2 liters with ice. The pH is adjusted to b, and the solids are stirred for an hour. The precipitate is filtered off, washed with water (2 x 20 Oml) and dried on a filter, obtaining 71.9 g of crude ester. After that, the precipitate is suspended in acetonitrile (4500 ml) and heated for an hour. with stirring at 5020. The mixture is cooled and filtered, obtaining 64.2 g of product (purity 29995). After that, these solids are dissolved in hot EN (2.87/) and charcoal for decolorization (6b.4g) is added, after which it is boiled under reflux for 15 minutes. The mixture was filtered through a pad of celite, and the reaction flask was washed with hot EN (Tl). The hot filtrate is evaporated by distillation to -1 l of EN, while the product begins to crystallize, falling out of the solution at a volume of 2.b5l. The solution is cooled and placed in a cold room, leaving with stirring for 40 hours. The precipitate is filtered off and washed with a mixture of EN/EBO (1/1; 500 ml), obtaining 58.5 g of compound E as a white solid (8095). Mr. E. Example 61

To a solution of the ester of compound E (22.5 g; 58.7 mmol) in THF (205 ml) is added 1 M Mahon (205 ml), and the reaction mixture (o) is heated at 502 for 1 h. THF is removed in vacuo, the mixture is acidified to pH 4-5 by adding 1M aq. NSI solution in order to precipitate the product. The heterogeneous mixture is stirred for 1 h, filtered and washed with water (150 Oml) and ether (15 Oml). The combined sediments are partially dried on a filter, obtaining a crude acidic intermediate in the form of a wet white solid, which is used further without further purification. with

NOVI (11.9g; 88.0mmol), EOSI (16.9g; 88.0mmol) and 1.Sq. o (117 mmol) of cyclopropylamine in the form of a free base or in the form of a hydrochloride. The mixture is stirred for 30 minutes, while the precipitate dissolves, it is placed in a cold water bath and with the help of a syringe, slowly add PIREA (20.4 ml; 117 mmol). The reaction mixture is stirred for an hour. at room temperature and with vigorous stirring, pour into ice and water (1.2 l), while a precipitate falls out. The mixture is stirred for 10 minutes, the precipitate is filtered off under vacuum, washed with water (150 ml) and ether (2 X 100 ml), dried under vacuum in air, obtaining the compound from Example 61 (92-9890) as a white solid.

Examples 62-115 « shi s more. (Ps) c.

I what

See and - and M, (Pe) sh» o Compounds of the formula (Is), where Ko and Ko have the values given in Table 8, are obtained by the methods given above in scheme 9 and in Example 61, using at the last stage various amines (MCoKcio). In addition, each compound can be crystallized from a mixture of Eo»H/water (7/1), thus obtaining an analytically pure compound in

GT" in the form of a white crystalline substance.

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Examples 116-119 -and r:Ke (pa) with 50 ? and t - apa s"

Compounds of formula (Id), where the Co groups have the values given in Table 9, are prepared by the methods described above using Scheme 9 and Examples 62-115.

Table 9 where We EVvayvro-ketiv Not a Kivnevyn" M 1 they re |dnrboninanivtyutirooeiny oaerannny" pbazhe. for Mr. DRINK Verse set t tva TT i

OMA. reorfelnyasvrovanyuvnog prying (weight b5 kp p Co S i o t Oma it yo Ions Motives NO

She is in Tvireitinnyicarboviv pyrrolach Z orKokitemannin" DeMVy

Examples 120-124 (pe)

Ru | Z. tuya і to и и и

Compounds of the formula (Pe), where X and Kz have the values listed in Table 10, are obtained by the same methods as those shown in Scheme 9 and in Example 61, or by similar methods, except that in the first stage, instead of 3-methyl -1-pyrrole-2,4-diethyl ester is used serially produced

3-trifluoromethyl-1-pyrrole-2,4-diethyl ester.

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And the Russian Federation still | ovinrtorivv vonna ran I chi II iy mane b carboxamide. i (av) 11 i jan Pdteafeniikyyu ne vav 1 i nya "Fo ovechv sv TEMNO KVN eagle urenyu ! t 1. THAT t of anl wn s s « nm in NY she - s Example 125; z» M-ethyl-4-I((5-(methoxyamino)carbonyl)|-2-methylphenylI|amino|-5-methylpyrroloi|2,1-4(1,2,Agriazine-6-carboxamide methanesulfonic acid) ns . and -i : their m" t; sh zl: m) vo ): zd a ik

T» To the compound from Example 97 in the form of a free base, add acetone (1Oml/g, Pr. 106) and heat the shell to 50-602С. Boiling begins at 55-57 "С, and the mixture is stirred during ЗОхв. at 50-602С. Add methanesulfonic acid (1.2 eq.) and observe a weak exothermic reaction. The suspension is stirred at 59 50-602C until O5C (extrusion chromatography) of two consecutive samples shows complete conversion

HF) of the free base (m.p. 2200-2222) to mesylate (m.p. 259-26122). Suspension for approximately ЗОхв.

GI is cooled to 20-2592С, after which it is stirred for at least ЗОхв. at temp. 20-252S. The suspension is filtered, the sediment on the filter is washed with acetone and dried in a vacuum at 40-502С to 00-0.595, obtaining the compound from Example 125 in the form of a white crystalline substance (yield 90-9595). (MANI 478.4. The above technology can be used to prepare mesylates or other compounds of formula (I) and formula (II) according to this description.

Example 126

M-ethyl-5-methyl-4-(2-methyl-5-((3-("trifluoromethyl)phenylamino|-carbonyl|phenylI|amino|pyrroloi|2,1-P(1,2,tri 65 zin- 6-carboxamide)

A. To the suspension of compound (1) (2.0g; 4.2mmol) in scheme 10, where Ko means ethyl, in 12ml of anhydrous MeOH solution at room temperature, add 18ml of a 4M solution of anhydrous NOSI in dioxane. The resulting clear 7/0 solution was stirred at room temperature for 16 hours, and the reaction mixture was evaporated under vacuum. The obtained oil is dissolved in 1 bml of 1.5M aq. of KOH solution and heated during Acc. at 502C. After cooling to room temperature, the mixture is diluted with 5 Oml of water and 1095 aq. HCl solution, bringing the pH to about 3 or 4. The precipitate formed is filtered off under vacuum, washed with 5 Oml of water and dried under vacuum.

1.47 g (9995) of compound (3) from Scheme 10 are obtained. An analytical sample of this product is obtained by 75 recrystallization from 1095 aq. acetonitrile solution. "H NMR (СО500): δ 8.21 (ss. s, 1H); 8.11 (ss. s, 1H); 7.89-7.91 (m, 2H); 7.67 (ss. s . SM5 (MAN) - 354.2. HPLC (conditions A): 2.24 min.

B. A mixture of compound A (40 mg; 0.1 mmol), NATO (b5 mg; 0.17 mmol), diisopropylamine (2 μM; 0.11 mmol) and

C-trifluoromethylaniline (Zbmg; 0.22 mmol) in 0.3 ml of M-methylpyrrolidone is heated at 802C for 16 hours, and the reaction mixture is purified using preparative reversed-phase HPLC. 41 mg (74965) of the compound from Example 126 are obtained as a yellowish-brown solid. "H NMR (SOZOOs/t FC): δ 8.28 (s, 1H); 8.19 (s, 1H); 8.16 (d, 1H); 8.11 (d, 1H); 7.84 (c, 1H); 7.71 (d, 1H); 7.58 (t, 2H); 7.47 (d, 1H); 3.44 (q, 2H); 2.94 (s, ЗН) ; 2.47 (s, ZN); 1.26 (t, ZN). I SM5(MAN)-497.47. HPLC (conditions A): 3.3 Occurrence of shrya Examples 127-129 (8) c. (tyu ni Y M. vyv ni v - zo v sho sch

Compounds of formula (II) are obtained according to the technology described in Example 126, except that the appropriate substrates and amines are selected in order to obtain such compounds in which K o and Kv would have the values given in ch;E

Tables 11.

From Table 11 - reerk 7 (feeni6S « pev g. ii t g shk sia 0 rianobenimivninorvani KN 40. LO |neinvvnidvninonsniyuen varna in sh-v her oeeiinnivanaem re ave (; s ! E NO orvy beeyarbechvyaniya KKZ WAK TJH ch i i o aniuchnoh і і - щ : ! I ey an I і і - пі Epevtnya zayvnya Tena, I so ob nn -i | shin 00 UNVINIVYAYIN Ve ObKoVn u shi she ; ha ČesMe usvadi about і і Shi tiv. rek I

POV evanine neni I: o nn SHY . DNbidnitsnezyanny karbeknakd; . Example 130

T» M-ethyl-4-I((5-(3-fluorophenyl)|sulfonyl|amino|-2-methylphenyl|amino|-5-methylpyrroloi|2,1-P(1,2,4)triazine-6 - carb oxamide

A. zv Z ae di o Z A yo) ime) man | and in A. 65 3Z-fluorobenzenesulfonyl chloride (5.00g; 25, 7mmol), after which TFC (7.0ml; 50.2mmol) was added using a syringe. The resulting mixture was stirred for 20h, and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (bbOml), washed with saturated aqueous MansSoOz solution, and dried using sodium sulfate, filtered and evaporated in vacuo.

8.00 g of a dark solid were obtained, which was triturated with methylene chloride to give 5.46 g of a yellow solid. Part of this solid substance (1.63 g) is dissolved in 10 ml of 1M aq. of Masn solution and 20 ml of THF, and the solution is stirred at room temperature for 20 hours. The solvent is removed under vacuum and the residue is acidified with ZM NSII to pH. The formed precipitate is filtered, obtaining 1.02 g (9495) of a light yellow solid compound A. HPLC (conditions A) - 2.99 min. "H NMR (SOSIv) 5 7.67 (5, 70.1); 7.59 (dd, 1H); 7.49 (m, 2H); 7.32 (m, 1H); 7.28 (m, 2H ); 2.54 (c, ZN).

V. v. "Tru

To compound A (0.20g; 0.b4mmol) in MeonH (10ml) was added 1095 Pa/sC (200mg), and the mixture was stirred for 2h. at room temperature in a hydrogen atmosphere from a cylinder. The solution was filtered through a pad of celite and the solvent was removed in vacuo to give 0.18g (10095) of compound B as a colorless glassy solid. 720 HPC (conditions A): 1.77 min. | SMI3MAN (t/2)281. with. b. s 25 now (o)

Compound B (0.18g; 0.b4mmol) and 0.15g (0.64mmol) of 4-chloro-5-methylpyrrolotriazine-b-ethylcarboxylate (compound 8t in scheme 11) in anhydrous DMF are stirred at room temperature for 20 hours. The reaction is stopped by adding cold water and saturated aq. solution of MaHsSoO»z. The precipitate is filtered off, washed with water and dried under vacuum, obtaining 0.27 g (9195) of compound C as a light yellow solid.

HPLC (conditions A: 3.49 min. CM5 MN" (t/z) 484. « r. i - r. y ee ov them 7 - I I U shs s i z Solution of 0.27g (5bmmol) of compound C in ml 0.1M aq.Mason and Zml MeonH are heated at 6023 for 12h. Meon is removed in vacuo and the aqueous layer is acidified with 1M aq.hydrogen chloride to pH 2.

The formed precipitate is collected, washed with water and dried in a vacuum, obtaining 0.25 g (9895) of compound O in the -I form of a pale yellow solid. HPLC (conditions A): 2.93 min. | CM5 MAN" (m/2) 456.

E. Example 130 e The mixture of compound O (3mg; bbµmol), EOSI (19mg; 98µmol), NOVI (1µg; 98µmol) and Hunig's base (43µmol; av) 0.25mmol) is stirred at room temperature for 00.5h. Ethylamine hydrochloride (1 mg; 0.1 mmol) was added, and the mixture was stirred for 1 h. The crude product is purified by preparative reversed-phase HPLC to give the compound from Example 130. HPLC (conditions A): 2.83 min. | CM5 MAN" (m/7) 483. "from" Examples 131-132

The compounds of Examples 131 and 132, as shown in Table 12, are prepared from compound XX of Example 130 and the corresponding amine as described in Example 130, step E.

Table of 12 superlatives "Zh V zh sebemnev vino NKY Vyy" lenyi Y bo

Examples 133-141

Ves (in) sh "Fr: "y Hey svi , y y y no

Compounds of the formula (Pd), where X and Co have the values given in Table 13, are obtained from serially produced diethyl-2,4-dimethylpyrrole-3,5-dicarboxylate according to the technologies described above for the preparation of 5-dimethylpyrrolotriazine, or according to similar technologies .

Table 13 and 75 of the Russian Federation.

Er rya agave TE es in ZO! Baked non-corbeniauach Zah, her HER Zdnneetalti rotor, YAN oo grassy y and Я Nova Я | ; I roar 000800 eketevkineooeniakya; BY FIGHTS; etiliyenip|amini Bk biy, I BEN nen NE renny Tent sveta she di t tt put dove "I i s eettnoiireninivminoi y dizhnetalvi a Nabyaviy. shi pdni vyv ey dniro vi ! day sch ee chic shi p tv 5 TV

Dini r Vs aivijvnynV

Te ten and GEN onetokiyannonrenya java ny ny 325 - 1 lyn Bookworm melons in iodimyetn ne: biy -

With I and coeurides vip pyrenoe E

Ii | Damn it! 8

Essay t NAVY o p shk p V EE ts GT oi trays of ereny in vov" more;" AND! nmetyryairono and Od dtrnakhiny"

Example 142 -I 4-C(5-(I(ethylamino)carbonylamino|-2-methylphenyl|amino|-5-methyl-M-propylpyrrolo|2,1-4(1,2,Agtriazine-6-carboxamide o in and

Fo "ko - i x, vy

T» A. Ethyl ester of 5-methyl-4-((2-methyl-5-nitrophenyl)amino|pyrrolo|2,1-7(1,2,triazine-6-carboxylic acid

A suspension of chloropyrrolotriazine (compound 1, scheme 12) (2.03 g; 847 mmol) and 3-nitro-5-methylaniline (1.41 g; 9.3 mmol) in DMF (25 ml) was stirred at room temperature for 24 hours. Through ЗОхв. water 60 (125 ml) is added, and the solution is stirred for an hour, after which the pH value of the medium is brought to neutral by adding a saturated aqueous solution of ManHCO3. The precipitate was filtered, washed with water and dried to give compound A (2.589 gH; 85965 yield) as a pale brown solid.

B. 5-methyl-4-(2-methyl-5-nitrophenyl)amino|pyrrolo(2,1-4(1,2,triazine-6-carboxylic acid b5 is

To a solution of compound A (825mg; 2.32mmol) in THF (2ml) and MeonH (ml) was added 1M Maon (bml), and the reaction mixture was heated at 602 for 24h. The mixture is cooled, the organic solvents are evaporated and - by adding 1M carrier - the pH of the medium is brought to neutral. The precipitate is filtered, washed with water and dried, obtaining compound B. I CM5 (MAN")-328.1. HPLC (conditions A): 3.4 Ohv. to C. 5-methyl-4-((2-methyl-5- nitrophenyl)amino|-M-propylpyrrole|2,1-P(1,2,4)triazine-6-carboxamide

With that

A solution of compound B (2.32 mmol), EOSI (489 mg; 2.55 mmol) and NOVI (345 mg; 2.55 mmol) in DMF (bml) was stirred at room temperature for 1 h, after which p-propylamine (0.38 ml; b, 4 mmol). The reaction mixture is stirred for 4 hours. and water is added to precipitate the product. The precipitate was filtered off and purified by silica gel column chromatography (3395 ethyl acetate/hexanes mixture) to give compound C (0.79g; 9395) as a white solid. "H NMR (SOSI»c): δ 9.11 (p, 1H); 7.92 (m, 2H); 7.71 (s, 1H); 7.36 (d, U-8.4HuC, 1H); 5.82 (ear m, 1H); 3.34-(sq, 9U-6.7Hz, 2H); 2.86 (s, ЗН); 2.41 (s, ЗН); 1.58 (m , 2H); 1.16 (t, U-7.5Hz, ZN). And CM5(MH)-369.3. HPLC (conditions A): 3.42 min.

Or. 4-K5-amino-2-methylphenyl)amino|-5-methyl-M-propylpyrrolo|2,1-4(1,2,Agriazine-6-carboxamide c

And tsde and 7 et and in

A flask with a solution of compound C (794mg; 2.16mmol) and 1095Ra/C (25Omg, wet) in MeOHN (20ml) is filled with hydrogen, after which its contents are stirred for 2 hours. The solution was filtered and evaporated to give compound Y (691 mg; yield 9595). "H NMR (SOSIv): δ 7.94 (p, 1H); 7.73 (s, 1H); 7.53 (s, 1H); 7.23 (m, 1H); 7.06 (d, U-8.1Hz, 1); 6.53 (dd, 9-81, 2.2Hz, 1H); 5.86 (ear m, 1H); 3.43 (square, 9U-6.6Hz, 2H ); 2.91 (s, F

ZN); 2.27 (c, ZN); 1.68 (m, 2H); 1.02 (t, 9-7.3 Hz, ZN). I SM5 (MR ")-339.2. HPLC (conditions A): 2.39 min. "I

E. Example 142 3o To a suspension of compound OO (25.6g; 0.07bmmol) in OZml OSE at room temperature, add 22μl of ethyl isocyanate. The reaction mixture is heated at 502 for 12 hours, after which it is cooled and isopropanol (IU) is added. The resulting precipitate was filtered off under vacuum, washed with ml of isopropanol and dried under vacuum to give 19.bmg (63965) of the pure title compound. "H NMR (С0500): δ 7.94 « 20 (r. 71); 7.70 (s, 1H); 7.60 (s, 1H); 7.23 (ush. s, 2H); 7, 44 (d, 1H); 3.23 (q, 2H); 2.84 (s, ЗН); 2.24 (s 7Z with ЗН); 1.66 (m, 2Н); 1.16 (t, ZN); 1.02 (t, ZN). CM (MAN)-410.2. HPLC (conditions A): 2.82 min.

Examples 143-148. and? : o (pp) «ХА и на 8) и и M -ity Fk («c) with 50

Compounds of the formula (II), where K/v has the values listed in Table 14, are obtained by the technology given

CH" in Example 142, using various other isocyanates in the final stage.

Table 14 does not exist

STILL Perevtana in renrooniozvni they rvnne (voya. y ro still y A b-ka chav sid!

And oh well in and rent CHI etsivnogfrenigiuvk zezkarbon her) av. Yii

And stupid zuvopineiro: KD zh trnazinov y h NBVEVVBBeNeGI KA akvyvannna"! rya I IF TWO: Yauve V rod MO in gazavtin-Mnvopiinivovo E shchi "Kene pen led G ! to her t V, ""DY killed but VAV IV" Y and 70 | and PE and kriabyn- b iavoksamiy. T

Examples 149-152

The compounds listed below are prepared by methods that are analogous to the methods given above in this description: 149) 759.1,3-dihydro-3-(5-methoxy-6-((4-(4-methyl-1-piperazinyl)butyl|amino) |pyrrolo|2,1-4(1,2,triazin-4-ylI|-2H-indol-2-one; 150). 1,3-dihydro-3-I(5-methoxy-6-((4 -(4-morpholinyl)butylamino|pyrrolo|2,1-4(1,2,A)griazin-4-ylI|-2H-indol-2-one; 151) 1-I3-(4-(2,3 -dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrroloyl2,1-P11,2,4Atriazin-6-yl|-1-oxopropyl)4-methylpiperazine; and 152) 2-methyl-5- ((5-methyl-6-I3-(-2H-1,2,3-triazol-2-yl)upropoxy|pyrroloi|(2,1-Y(1,2,griazin-4-yl|amino|phenol .

Claims (30)

The formula of the invention 1. A method of treating one or more conditions caused by pZ8-kinase activity, which consists in introducing at least one compound of the formula (I) into the body of a patient in need of such treatment through a vein of SHO; zt t o where "Ez means hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano or MH"; X is chosen from such radicals as -O-, -0C(-0)-, -5-, -5(:0)-, -5O 25-, -FSH-0)-, -С05-, -МК410о- . halogen, nitro and cyano, or X is absent; 7 is chosen from such radicals as O, 5, M and СКоо, and if 7 means СКобд, the specified carbon atom "can form with ЕК. or K is optionally substituted bicyclic aryl or heteroaryl; in. means hydrogen, -СН»У, -СН, -ОСН», -ЗН, -ЗСНЗз, -О0ФЩ-О)ka, -ШЧО)Ко», -502К2о, -502МК ав, -Сбжач, - с -б(5О )MKodKov, -MNO, 0 -MKodKov, 0/«MK245O02MKodKov, 0 -MKoiZO2Kog, 0 -MKodb(tO)Kov, 0 «MKodSO2 ov, and -MAK24C(O)MA 24 Rv, halogen, nitro or cyano; is" E" is selected from a number of such radicals as a) hydrogen, provided that Ko does not mean hydrogen, if X means -5(-0)-, -505-, -МК1оСО»- or -МК1о50»5-; b) alkyl, alkenyl and alkynyl, which optionally has up to four Kob groups as substituents, or pentafluoroalkyl; - and c) aryl and heteroaryl, which optionally has up to three groups of Co»7 as substituents, and i» d) heterocyclo and cycloalkyl, which optionally has a keto group (50) as substituents, up to three groups of K27 and/ or contains a carbon-carbon bridge with 3-4 carbon atoms, or (a) d) Co is absent if X is halogen, nitro or cyano; 7 50 KE. means a substituted aryl, an aryl having as a substituent MNZO" alkyl, a substituted heteroaryl or an optionally substituted bicyclic 7-11--len saturated or unsaturated carbocyclic or heterocyclic ring, and iz" K5 means hydrogen, alkyl or substituted alkyl, except those cases when 7 means O or 5, then K5 is absent, or KE, and K5 together with 7 form an optionally substituted bicyclic 7-11-membered aryl or heteroaryl; Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, o -MA7Rav, -OK". or halogen; Co and K/4 are independently selected from the group of such radicals as hydrogen, alkyl, substituted alkyl, aryl, substituted im) aryl, cycloalkyl, substituted cycloalkyl, heterocyclo and substituted heterocyclo; KU, Kv, Ko, Kod and Kob are independently selected from a number of such radicals as hydrogen, alkyl, substituted alkyl, aryl, because substituted aryl, heterocyclo and substituted heterocyclo; Eoo is hydrogen, lower alkyl, or substituted alkyl, or Co may be absent if the carbon atom to which it is bonded is together with C, and C5 is part of an unsaturated bicyclic aryl or heteroaryl; Co" means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or substituted heterocyclo; Kob is chosen from a number of such radicals as halogen, trifluoromethyl, haloidalkoxy, keto (50), nitro, cyano, 65 -ZKov, "-OKov, -"MKovKov, "MKovZO", -MKovZO2Kov, -ZO2Kov, -ZO2MKovKov, "СО Kv, "S(O)Kov, "S(O)MKovK o, -OS(Ok zv, -OS(O)MKovKoo, "-"MKovS(O)Koo, -"MKovSO"Kov, "M-OH, -M-O-alkyl; aryl, which optionally has from one to three Co groups as a substituent; cycloalkyl, which optionally has a keto group (50) as a substituent, from one to three Co groups; or contains carbon- a carbon bridge with 3-4 carbon atoms; and a heterocycle, which optionally has a keto group (50) as a substituent, from one to three K 2 groups; or contains a carbon-carbon bridge with 3-4 carbon atoms; and each of the radicals Cod and Coo are independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C3-7-cycloalkyl, and C3-7-heterocycle, or they may together form a C3-heterocycle; and each Cod and Coo, in turn, may optionally contain up to two substituents, which are alkyl, alk enyl groups, halogen atoms, haloalkyl groups, haloalkyloxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy and benzyloxy groups; 70! Co.; are selected from a number of such radicals as alkyl, K 20 and C.i.dalalkyl, containing as substituents from one to three groups Kz", and each of the radicals Kz" is independently selected from a number of such radicals as halogen, haloalkyl, haloidalkoxy, nitro, cyano, -ЗКао, -ОКзо, -МКзоКа4, "-МКзозО", -МКазозО»оКа1, -2502Кз30, -23О2РзоКа1, -СОоКзо, -ФЧО)Кзо, -ФЧО)МAZокКз1, -OF(О)Кзо, - ОС(О)МКзокз1, -МКазос(-О) Кз, МЕКзоСО» 34 and 3-7--lens carbocyclic or heterocyclic ring, which optionally contains as a substituent alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloidolkoxy, nitro, amino or cyano, and each of the radicals Kzo and Kzi is independently selected from a number of such radicals as hydrogen, alkyl, alkenyl, aryl, aralkyl, C with 7cycloalkyl and heterocycle, or together they can form C3.7heterocycle; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 2. The method according to claim 1, which differs in that at least one compound of formula (I) is introduced into the patient's body, where Ez means methyl, -SEz or -OSH"; X is selected from such radicals as -С(-0)-, -СО5-, -МКчо-, -МК1ос(:9)-, -МК1оСО»-, -МК1озО»-, - ЧОМА 4о- and -ФШЧО)МК 40, or X is absent; сч 7 means M; EK" means hydrogen, C-alkyl, C-alkyl, having as substituents up to four K groups, pentafluoroalkyl, or (8) aryl or heteroaryl, optionally having as substituents up to two K groups; KE. means phenyl having one K group as substituents. and from zero to three groups of K.z; EK" and Co. are independently selected from such radicals as hydrogen and lower alkyl; "g zo Ky" means carbamyl, sulfonamido, arylsulfonamine, or ureido, each of which is optionally substituted with up to two groups selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, C aryl, substituted aryl and aralkyl or alkylsulfonylamine; o Kiz, if present, in each case is independently selected from a number of such radicals as alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, -OK.4, -C(xO)alkyl, -OC(O)alkyl, -MK.5Kiv , -ZKiv, -MO", -SM, " call 7 SOZHIV, "SOMN", -5OZN, -5(O)alkyl, -5(xO)aryl, -MNZO"-aryl-k.7, -MNZO"-alkyl, -Z0O2MNK.47, "SOMNK; and ka -MNSesomMny 47; K.4 means hydrogen, alkyl or aryl; Kv means hydrogen or alkyl; Kv means hydrogen, alkyl, aralkyl or alkanoyl; and " Ku7 is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl; with c or its pharmaceutically acceptable salt, prodrug or solvate. 3. A method of treating one or more conditions caused by p38-kinase activity, which differs;" which consists in introducing into the body of a patient who needs such treatment at least one compound of the formula о) щ SE ОЙ - I ж и5» koh poshee NM, ud o ka Жх тм я и ko 50 ke и» where Ez means hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano or MH"; X is chosen from such radicals as -O-, -0C(-0)-, -5-, -5(:0)-, -5O 25-, -FSH-0)-, -С05-, -МК410о- . , nitro and cyano, or X is absent; (Ф; 7 means 0, 5, M or SK»ao; ka Kk. means hydrogen, -CH», -OH, -ОСН», -ВН, -ЗСН3, -О0ФЩ-О)ka4, -5(-О )Ko", -502Koo, -502MKa24Kov, -SboKach, -F(5O)MKodKov, "MN", -MK24502MKoaKov, -"MKo1ZO2Koo, -MKoo(tO)Kov, -MKoaSO" ov, "MK21S(O)MK od Kov, in halogen, nitro or cyano; Co is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, or heterocycloalkyl or substituted heterocycloalkyl, or, if X is halogen, nitro, or cyano , K» is absent, provided that Ko does not mean hydrogen, if X means -5(-0)-, -505-, -МКчоСО»- or -МК10505-; 65 K. means a substituted aryl, an aryl with a МН5ЗО»-alkyl group as a substituent, a substituted heteroaryl or an optionally substituted bicyclic 7-11-lene saturated or unsaturated carbocyclic or heterocyclic ring system; K is hydrogen, alkyl or substituted alkyl, but in those cases where 7 is O or 5, then K 5 is absent; Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, -MA7Rav, -OK". or halogen; КУ, Ка, Ко, Кч4, К2й, Код and Ков are independently selected from a number of such radicals as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo and substituted heterocyclo; Eoo is hydrogen, lower alkyl or substituted alkyl; and 70 Ko" means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or substituted heterocyclo; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 4. The method according to claim 3, which differs in that at least one compound of the formula (I) is introduced into the patient's body, where K and K5 together with 7 form Gal C where Ki" is connected to any available carbon atom of the phenyl ring And it is selected from the group of such radicals as carbamyl, sulfonamido, arylsulfonylamine, and ureido, each of which optionally has as a substituent one group that is selected from the group of such radicals as hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl and aralkyl, or C. alkylsulfonylamine; Kiz is connected to any available carbon atom of the phenyl ring A and, if it is present, in each c 29 case it is independently selected from a number of such radicals as alkyl, substituted alkyl, halogen, trifluoromethoxy, (U trifluoromethyl, -OK. ;, -C(xO)alkyl, -OC(-O)alkyl, -MK./5Kiv, -ZKiv, -MO», -SM, -СО2Kiv, -СОМН», -503Н, -5(O)alkyl, -5(:O)aryl, -MNZO»-aryl-c.7, -MNZO»C.g-alkyl, -5302MNK47, -SOMNA.7 and -MHC(-O)MNA.7; K.4 means hydrogen, alkyl or aryl; K./5 means hydrogen or alkyl; C Kv means hydrogen, alkyl, aralkyl or alkanoyl; Ge Ku; means hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl or aralkyl; and n is 0, 1, 2 or 3; - or a pharmaceutically acceptable salt, prodrug or solvate thereof. "Her 5. The method according to claim 3, which differs in that at least one compound of formula (II) 5 is introduced into the patient's body where - Ez means methyl or CE"; their X means -C(-O)MA0o-, -MCH1oC(50)-, -C(50)- or -CO»5-; Ku means hydrogen, -CH»z, -OH, -OSN", halogen, nitro or cyano; o U means -С(:О)МН-, -"МНС(-О)МН-, -МНЗО"- or -502МН-; ma 70 Vo means hydrogen or lower alkyl; Kv is selected from the group of radicals such as hydrogen, alkyl, alkoxy, aryl and aryl, containing as substituents y" from one to three groups K.o, except for those cases where U means -MNZO"-, then Kw is C. alkyl, aryl, or aryl substituted with Co; C is bonded to any appropriate carbon atom of the phenyl ring A and, whenever present, is independently selected from the group consisting of alkyl, substituted alkyl, halogen, HF) trifluoromethoxy, trifluoromethyl, -OC.;, -C(xO)alkyl, -OC(xO)alkyl, -MKi5Kiv, -ZKiv, -MO», -SM, -SOKchv, -SOMNo, -ZO3H, -5(-0O)alkyl, -5(-O)aryl, -MNBO»-aryl-kK.7, -MNZO»-alkyl, -502MNK.7, -SOMNEK.7 and where - MNO ("OMNV 17; Ka, KUB, Kv and K47 mean hydrogen or alkyl; 60 Kio, if present, in each case is selected from the group of such radicals as alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono , arylthiono, arylsulfonylamine, sulfonic acid; alkylsulfonyl, sulfonamido, and aryloxy, wherein each Co group may additionally have hydroxy, alkyl, alkoxy, aryl, or aralkyl substituents; and because n is equal to 0, 1 or 2; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 6. The method according to claim 3, which differs in that at least one compound of the formula (Ia), (IV) or (Ic) is introduced into the patient's body V. se Rv(v), . Ba y Ka bitim Vshtr S K M iy 70 h..vi eI EC. T V. Rv IV), tu tv Z Sheik EK) same, and; Mu t. M 00 Input (VU in m х НЯ i in E o Ez means methyl or CE"; Eoa and Cos are independently selected from a number of such radicals as hydrogen, C ovalalkyl, substituted C..dalalkyl, aryl, substituted aryl, benzyl and substituted benzyl; "Her Eo is heterocycle or substituted heterocycle; and Co is hydrogen or lower alkyl; c or a pharmaceutically acceptable salt, prodrug or solvate thereof. av! 7. Compound of formula (II) (Eli (1, in. Rv. all in | washed 3. shh! "where Ez means methyl, CEz or CH"; K»5 means hydrogen or alkyl; -I U means -С(О)МКоаз-, -МКозС(-О)МА 2з-, -302МКоаз- or -МКозЗО»-; Kv and Coz are selected from a number of such radicals as hydrogen, alkyl, alkoxy, aryl and aryl, having as a substituent o from one to three Co groups, but in those cases where U means -MK»z5O»5-, Kivo means C .i.dalkyl or aryl, which optionally has from one to three K 9 groups as a substituent; X is chosen from such radicals as -O-, -0C(-0)-, -5-, -5(:0)-, -5O 25-, -FSH-0)-, -С05-, -МК410о- . , both of which are missing; Chl» Kk. means hydrogen, -СН», -ОН, -ОСН», -ВН, -ЗСН3, -О0ФШ-О)ка4, -5(-О)Ко», -502Коо, -502МКа24Ков, -СбоКач, -б(5О) MKodKov, -МНО, 0 -МКодКов, 0/«МК245О02МКодКов, 0 -МКойЗО2Ког, 0 -МКодб(тО)Ков, 0 «МКодСО2 ов, -МАК24С(О)МА 24 Rv, halogen, nitro or cyano; 5B EC" is chosen from the group of such radicals as a) hydrogen, provided that K"o does not mean hydrogen, if X means -5(-0)-, -505-, -МК1оСО»- or -МК410505-; F) b) alkyl, alkenyl and alkynyl, which optionally has up to four Cob or pentafluoroalkyl groups as substituents; ka c) aryl and heteroaryl, which optionally has up to three Co»7 groups as substituents, and d) heterocyclo or cycloalkyl, which optionally has a keto group (50) as a substituent, up to three K27 groups and/or contains carbon-carbon bridge with 3-4 carbon atoms; Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, -MA7Rav, -OK". or halogen; Co means hydrogen or alkyl; Keys and Clio, if present, in each case are independently selected from the group of such radicals as alkyl, b5 Halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, Si dalalkylsulfonylamine, sulfonic acid; alkylsulfonyl, sulfonamido and aryloxy, and each of the Kz and/or Co groups may additionally have hydroxy, alkyl, substituted alkyl, alkoxy, aryl or aralkyl as substituents; KU, Ka, Co, Cod, and Cob are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle; Co" means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or substituted heterocycle; Kob is selected from the group of such radicals as halogen, trifluoromethyl, haloidalkoxy, keto (5-0), nitro, cyano, -ZKov, OKov, -MKovKov, -MKovZO", -"MKov5ZO2Kov, -ZO2Kov, -5O2MKovKov; "СОоКов, "С(2О)Ков, -С(О)МКовКо, -ОС(Ок зв, -ОС(О)МКовКо, "-"МКовС(О)Коо, -"МКовСО"Ков, "М-ОН, -M-O-alkyl; aryl, optionally having as /o Substituents from one to three Co groups; cycloalkyl, optionally having as a substituent a keto group (50), from one to three Co groups; or containing carbon - a carbon bridge with 3-4 carbon atoms; and a heterocycle, which optionally has a keto group (50) as a substituent, from one to three K 2 groups; or contains a carbon-carbon bridge with 3-4 carbon atoms; and each of radicals Cod and Coo are independently selected from the group of such radicals as hydrogen, alkyl, alkenyl, aryl, aralkyl, C3-7-cycloalkyl, and C3-7-heterocycle, or they may together /5 form a C3-7-heterocycle; and each of the radicals Kov and Koo, in turn, may optionally contain up to two substituents, which are alkyl groups, alkenyl groups, halogen atoms, haloalkyl groups, haloalkyloxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy and benzyloxy groups ; Co.; is selected from the group of such radicals as alkyl, K 20 and C..alkyl, containing as substituents from one to three groups Kz", and each of the groups Kz" is independently selected from a number of such radicals as halogen, haloalkyl, haloalkoxy, nitro , cyano, -ЗКао, -OKао, -МезоКая4, -МКзозО»5, -МКзозО» Ка, -502Као, -502МКзокКзі1, -Сбо зо, -ФЧО)Као, -СЧО)МКаокКз1 , -О0Ф(О)Као, - OF(-)МКаоК 4 , -М Кзос(-О) Ка , МЕКзоСО» 44 and from 0 3-7-ene carbocyclic or heterocyclic ring, which optionally contains as a substituent alkyl, halogen, hydroxy, alkoxy, haloalkyl, halidolkoxy, nitro, amino or cyano, and each of the radicals Cz0 and Cz1 is independently selected from the group of such radicals as hydrogen, alkyl, alkenyl, aryl, aralkyl, C3/cycloalkyl and heterocycle, or together they can form a C37heterocycle ; and n is equal to 0, 1 or 2; (8) or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 8. The compound according to claim 7, which differs in that it has the formula (Pa) or the formula (PID) and ex 8) "t shk. du m : sh "A. bachelor's degree Zk as with zvo a z SHE NN, " GI I g I - y to Y i gg 18 "ob y; te iz ve vi o pe Ku and K/o mean hydrogen or -CH"; co 20 Kis means lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-6 decoxy, nitro or cyano; HT» Kv means hydroxy, C1-4 alkoxy, phenyl or phenyl having as a substituent one or two Kch9 groups; Koz means hydrogen or lower alkyl; and n is equal to 0, 1 or 2; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 59 9. The compound according to claim 7, which differs in that in it ГФ) X means -С(-0)-, -СО5-, -МК1оС(50)- or -С(5О)МА0о-; 7 U means -С(-О)МН-, -МНОС(-О)МН- or -МНБЗО»-; KB and K/o mean hydrogen or -CH"; Keyes and Co., if available, in each case, are independently selected from the group of such radicals as lower alkyl, 60 halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C. 4 alkoxy, nitro and cyano; KU, Kv, Ko, Kod, and Kov are independently selected from such radicals as hydrogen and lower alkyl; Who does lower alkyl mean; and n is equal to 0 or 1; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. for 10. The compound according to claim 7, which differs in that in it X-Ko mean ked or is; same vd: ve in Eoa is chosen from the group of such radicals as a) hydrogen; b) linear or branched C» valkyl; 70 c) cycloalkyl, which optionally has a keto group and/or up to two Co groups as a substituent; d) phenyl, which optionally has up to two Co groups as substituents; e) a heterocycle, which optionally has a keto group and/or up to two Co groups as a substituent; e) pentafluoroalkyl or C.., alkyl having as substituents up to three groups, which are selected from a number of such radicals as halogen, trifluoromethyl, cyano, OK ov, MKovKoe, COoRov, aryl, heterocycle and/or cycloalkyl, where / 5 aryl, heterocycle and/or cycloalkyl, in turn, can optionally have as substituents up to two groups, which are selected from a number of such radicals as halogen, hydroxy, alkoxy, haloalkyl, haloalkyloxy, nitro, cyano or alkyl; and Co means a monocyclic or bicyclic heterocycle, optionally having up to two Co groups as substituents; Co.; if present, in each case independently selected from such radicals as hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy and benzyloxy groups; and Kov and Koe, if present, are in each case independently selected from such radicals as hydrogen, alkyl, alkenyl, phenyl, and benzyl; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. high school 11. The compound according to claim 7, which differs in that in it Eoa is chosen from such radicals as a) linear or branched Co alkyl; b) phenyl, which optionally contains up to two substituents, which are selected from such radicals as halogen, C 1 hydroxy and trifluoromethyl; "c) C3.vcycloalkyl, which optionally contains up to two C..lalkyl and/or hydroxy groups as substitutes; d) linear or branched C...alkyl, which has as substituents up to three groups, which are selected from a number of such radicals, such as o Y) halogen, i) trifluoromethyl, « iii) cyano, iich) Si. lalkoxy, m) phenyloxy, mi) benzyloxy, mii) MH", MH(C..d)alkyl and/or M(C..dalalkyl)", "20 mii) phenyl, which, in turn, has as substituents up to two halogen atoms and/or up to two methoxy groups, w-in them) a heterocycle selected from such radicals as pyridinyl, indolyl, thiophenyl, furanyl, thiazolyl, thienyl, morpholinyl, tetrahydrofuranyl, triazinyl, piperazinyl, indenyl and piperidinyl , and the indicated "c" heterocycle does not necessarily have as a substituent from one to two C..alkyl groups, x) C. c. cycloalkyl; and 415 Koh means a five-seven-membered monocyclic heterocycle selected from such radicals as - diazepinyl, morpholinyl, piperidinyl and pyrrolidinyl, and the specified heterocycle optionally has a dalalkyl, phenyl and/or benzyl group as a C substituent; - or a pharmaceutically acceptable salt, prodrug or solvate thereof. at 12. The compound according to claim 7, which differs in that in it K. and Ko independently mean hydrogen or CH"; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. name) 13. The compound according to claim 7, which differs in that in it Ko means hydrogen; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 14. The compound according to claim 7, which differs in that in it U stands for -МНС(-О)МН- or -МНЗО»-; Kid means aryl or aryl substituted with alkyl, OCH 5 , CEz, cyano or halogen; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 15. The compound according to claim 7, which differs in that in it ХУ means -С(-О)МКоз-, Коз means hydrogen or lower (F. alkyl, and Kv means C1-alkoxy or aryl, optionally having as a substituent alkyl, OSH z, CEz, cyano or GI halogen; or a pharmaceutically acceptable salt, prodrug or solvate thereof. 16. The compound according to claim 7, which differs in that it has the formula 60 b5 same, comma: ШИ НЕЙ у. For example, Ta yu de Kzz means lower alkyl. 17. The compound according to claim 16, which differs in that Kz and Kzz mean methyl, K,; and Co are hydrogen, and Co is linear or branched alkyl or optionally substituted benzyl; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 18. The compound according to claim 7, characterized in that it is selected from the group consisting of () M-(2,2-dimethylpropyl)-4-(5-(methoxyamino)carbonyl|-2-methylphenyl|amino|) -M,5-dimethylpyrrolo|2,1-4(1,2,Agriase n-6-carboxamide; 3-(6-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl)| -5-methylpyrrolo|2,1-41(1,2,griazin-4-yl|iamino|-M-methoxy-4-methylbenzamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|- 5-methyl-N-(1-methylethyl)pyrrolo|2,1-Y(1,2,triazine-6-carboxamide; 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5 -methyl-M-(2-methylpropyl)pyrrolo|2,1-4(1,2,Agriazin-6-sch carboxamide; M-(2,2-dimethylpropyl)-4-(5-(methoxyamino)carbonyl|- 2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,Agriase i) n-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5- methyl-M-propylpyrroloi|2,1-P(1,2,triazine-b-carboxamide; IM-(1,1-dimethylethyl)-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino| -5-methylpyrroloi|2,1-P(1,2,triazine-"gzo b-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-M-(2-meth (siethyl)-5-methylpyrrole|2,1-P(1,2,4)triazine-6-s carboxamide; o M-methoxy-4-methyl-3-((b-methyl-6-(4-morpholinylcarbonyl)|(pyrrolo(2,1-P(1,2,4)triazine-4-ilyamino|benzamide; M- cyclohexyl-4-|((5-((methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrroloi|2,1-4(1,2,Agriazine-6-carb « oxamide; и- 4-Ц (5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(1K)-1-phenylethyl|pyrrolo|2,1-4(1,2,griazine-6-carboxamide; 4-C (5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-((15)-1-phenylethyl|pyrrolo|2,1-C(1,2,triazine-6-carboxamide; " M -C4-fluorophenyl)methyl|c-4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrroloi2,1-4(1,2,griase with c in-6-carboxamide; 4 -C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-N-(2-methoxyphenyl)methyl|-5-methylpyrroloi|2,1-ShC(1,2,Atriazine-6-carboxamide 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-N-(4-pyridinylmethyl)pyrrolo!|2,1-4(1,2,griazine-6-carboxamide; - And 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2-(4-pyridinyl)ethyl|pyrrolo|2,1-4(1,2,griazine -6-carboxamide, and 4-C(5-Cmethoxyamino)k carbonyl|-2-methylphenyl|amino|-5-methyl-N-(2-(1-piperidinyl)ethyl|pyrrolo|2,1-4(1,2,Agr o yazine-6-carboxamide; 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2-(4-morpholinyl)ethyl|pyrrolo|2,1-P(1,2,4Ctridesazine -6-carboxamide; -methylpyrrolo|2,1-91,2,A)griazine-6b-carboxamide; M-K15,2K)-2,3-dihydro-1H-inden-1-yl)|-4-C(5-(methoxyamino )carbonyl|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-91,2,A) griazine-6b-carboxamide; M-methoxy-4-methyl-3-((b-methyl-6-((4-(phenylmethyl)-1-piperidinylcarbonyl|pyrrolo|2,1-47(1,2,griazin-4-yl)|a ( F) mino|Senzamide; ka M-cyclopropyl-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrroloi|2,1-4(1,2,Agriazine-6-carb oxamide ; in M-cyclopentyl-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,)triazine-6-carb oxamide; IM-( 2-(4-fluorophenyl)ethyl-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,griazine-6-carboxamide; M -(cyclohexylmethyl)-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,Agriazine 65 -6-carboxamide; 4-C(5 -Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(tetrahydro-2-furanyl)methyl|pyrrole|2,1-P(1,2 -BO0- "And griazine-6b-carboxamide; IM-(2-1nH-indol-3-ylethyl)-4-((5-(methoxyamino)carbonyl)|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,griazine -6-carboxamide; M-butyl-4-((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrole|2,1-P(1,2,triazine-b-carboxamide; M-( cyclopropylmethyl)-4-((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,Agriazine-6-carboxamide; 4-C(5-Kmethoxyamino) carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2-methylbutyl)pyrrolo|2,1-4(1,2,Agriazine-6-k arboxamide; 70 M-(2-furanylmethyl)-4 -I((5-(methoxyamino)carbonyl)|-2-methylphenyl|amino|-5-methylpyrroloi|2,1-4(1,2,Agriazine-b-carboxamide; 4-C((5-Cmethoxyamino)carbonyl |-2-methylphenyl|amino|-5-methyl-M-(2-thienylmethyl)pyrrolo|2,1-4(1,2,Agriazine-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2 -methylphenyl|amino|-5-methyl-N-(2-phenoxyethyl)pyrrolo!|2,1-P(1,2,4)triazine-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2 -methylphenyl|amino|-5-methyl-M-(2-methylcyclohexyl)pyrrolo|2,1-4(1,2,griaz yn-6-carboxamide; M-ethyl-4-I((5-(methoxyamino) carbonyl)|-2-methylf enylI|amino|-M,5-dimethylpyrroloi2,1-4(1,2,Agriazine-b-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2,2,2-trifluoroethyl)pyrrolois|2,1-4C(1,2,triase n-6- Carboxamide; IM-(2,3-dihydro-1H-inden-2-yl)-4-(5-Cmethoxyamino)carbonyl|-2-methylphenylamino|-5-methylpyrrolo!|2,1-4(1,2, sc 4|griazine-6b-carboxamide; M-ethyl-4-((5-(methoxyamino)carbonyl)|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1,2,Agriazine-6- carboxamide; and) 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2,2,3,3,3-pentafluoropropyl)pyrrole|2,1-P( 1,2, 4|griazine-6b-carboxamide; 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5,7-dimethyl-M-(1-methylethyl)pyrrolo|2,1- 4(1,2,Agriazine-«gzob-carboxamide; M-(4-fluorophenyl)-4-I((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrrole|2,1 -4(1,2,Agriazine-6-ca c rboxamide; o 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-M-(2-methoxyphenyl)-5-methylpyrrolo|2,1- 4(1,2,Agriazine-b-carboxamide; " 4-C((5-Kmetok siamino)carbonyl|-2-methylphenyl|amino|-N-(3-methoxyphenyl)methyl|-5-methylpyrroloi|2,1-ShC(1,2,Atri-iazin-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-III-"trifluoromethyl)phenyl|pyrrolo|2,1-4Х(1,2,triazine-6-carboxamide; -K2,6-dichlorophenyl)methyl)-4-((5-(methoxyamino)carbonyl|-2-methylphenylamino|-5-methylpyrroloi|2,1-4(1,2,ACt « ryazine-6b-carboxamide; with with M-K15)-1-cyano-2-phenylethylic-4-I((5-(methoxyamino)carbonyl|-2-methylphenyl|amino|-5-methylpyrroloi|2,1-4(1,2,4 . Hygrazine-6b-carboxamide; 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-N-(2-phenylethyl)pyrrolo|2,1-4(1,2 ,)triazine-6-carboxamide; M-methoxy-4-methyl-3-((b-methyl-6-(1-pyrrolidinylcarbonyl)pyrrolo|2,1-4(1,2,)griazine-4-ilyamino |benzamide; -I 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(2-pyridinylmethyl)pyrrolo!|2,1-4(1,2,griazine-6 -carboxamide; and 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(phenylmethyl)pyrroloi|2,1-4(1,2,Agriazine-6-car o boxamide 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(4-methyl-2-thiazolyl)pyrrolo|2,1-4(1,2,griase de in- 6-carboxamide; 4-C((5-Kmeto xyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-N-(1K)-1-methylpropyl|pyrrolo|2,1-4(1,2,triazine-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(15)-1-methylpropyl|pyrrolo|2,1-4(1,2,triaz 5B yn-6- Carboxamide; carboxamide; ka IM-(1-(4-fluorophenyl)ethyl-4-((5-(methoxyamino)carbonyl|-2-methylphenylI|amino|-5-methylpyrrolo|2,1-4(1,2,griazine -6-carboxamide; in -K2,4-difluorophenyl)methyl-4-(5-(methoxyamino)carbonyl|-2-methylphenyl|amino)-5-methylpyrrolo|2,1-4(1,2, Atriazin- 6b-carboxamide and -K2,6-difluorophenyl)methyl-4-(5-(methoxyamino)carbonyl|-2-methylphenyl|amino)-5-methylpyrrolo|2,1-4(1,2, Atriazin-6b- carboxamide; 4-((5-((4-cyanophenyl)amino)carbonyl|-2-methylphenyl|amino|-M-ethyl-5-methyl-pyrroloi|2,1-P(1,2,4)triazine- 6-carb 65 boxamide; 4-((5-((4-cyanophenyl)amino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-K15)-1-phenylethyl|pyrrolo|2,1-4 (1,2,41 triazine-6b-carboxamide; 4-((5-(((4-cyanophenyl)amino|carbonylamino|-2-methylphenyl|amino|-5-methyl-M-propylpyrrolo|2,1-P (1,2, Ctriase in-6-carboxami d; or (i) a pharmaceutically acceptable salt, hydrate, or prodrug thereof. 19. The compound according to claim 7, which is characterized in that it is selected from the group consisting of M-ethyl-4-((5-(methoxyamino)carbonyl)|-2-methylphenyl|amino|-5-methylpyrrolo|2, 1-4(1,2,Agriazine-6-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-N-(1-methylethyl)pyrrolo|2,1-Y (1,2,triazine-6-ca 70rboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-propylpyrroloi|2,1-P(1,2,triazine -b-carboxamide; 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(/1-phenylethyl|pyrrolo|2,1-P(1,2,4)triazine -6b-carboxamide and 4-C((5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(1-methylpropyl|pyrrolo|2,1-P(1,2,4) triazine-6-carboxamide, as well as its pharmaceutically acceptable salt. 20. Compound of formula (II) (ball Z Shchy 7. qui in ; ev vm me and . . . se from Shchi | ; and Mem, o vi: where Ez means methyl or SE"; "30 K5 means hydrogen or lower alkyl; U means -С(О)МКоаз-, -МКозС(-О)МА 2з-, -МКоз5О» or -50О2МН»-; c Kv and Kz are selected from the group of such radicals as hydrogen, alkyl, alkoxy, aryl and aryl having as substituents o from one to three Clio groups, except when M means -MK 23505-, Kv means C. alkyl or aryl optionally having one to three Co groups as substituents; " 35 X is chosen from such radicals as -O-, -0C(-0)-, -5-, -5(50)-, -50 5-, -(-0)-, -605-, -MKcho -, -MKcho-C(-0)-, ich- -MKcioS(-O)MA 4 -, -MKcioSO»-, -MAchozO»5-, -MAKcho5O2 MK .4-, -302MKo- and -FSHCHO)MK .oh, both are absent; Kk means hydrogen, -СН», -ОН, -ОСН», -ВН, -ЗСН3, -О0ФЩ-О)ка4, -5(-О)Ко», -502Коо, -502МКа24Ков, -СбоКач, -Ф(5О) MKodKov, "МН", -МК24502МКоаКов, -"МКо1ЗО2Коо, -МКоо(тО)Ков, -МКоаСО" ов, "МК21С(О)МК od Kov, halogen, nitro or cyano; " Co means alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heterocycloalkyl or c substituted heterocycloalkyl; :z" Ke means hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, -MA7Rav, -OK". or halogen; Keys and Clio, if present, in each case are independently selected from the group of such radicals as alkyl, - halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, Alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, - Si lalkylsulfonylamine, sulfonic acid; alkylsulfonyl, sulfonamido and aryloxy, and each of the groups K413 o and/or Co may additionally have hydroxy, alkyl, alkoxy, aryl or aralkyl as substituents; KU, Ka, Ko, Kod and Kob are independently selected from the group of such radicals as hydrogen, alkyl, substituted alkyl, aryl, imo) substituted aryl, heterocyclo and substituted heterocycle; T"Co" means alkyl, substituted alkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; and n is equal to 0, 1 or 2; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 21. The compound according to claim 20 of the formula is sent to the other side. СЕ 60 ше ИЙ и и-я бе и s MK Yan where it is 65 R. another 7 which differs in that in it K/d means alkoxy, aryl or aryl with the K group." as a substitute; Ku and K/o mean hydrogen or -CH"; and Keys means lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-6 decoxy, nitro or cyano; or a pharmaceutically acceptable salt, prodrug, or solvate thereof. 22. The compound according to claim 20 of the Bida OV formula! and. shk: iz yu a se ni ne i: lo ; he in -. which differs in that in it E" means a linear or branched C" alkyl or optionally substituted benzyl, and K.za and K/z are selected from such radicals as hydrogen, C.-4 alkyl, hydroxy, halogen, cyano and trifluoromethyl; or a pharmaceutically acceptable salt, hydrate, or prodrug thereof. 23. The compound according to claim 20, which differs in that it is M-ethyl-4-((5-(methoxyamino)carbonyl)|-2-methylphenyl|amino|-5-methylpyrrolo|2,1-4(1, 2, Agriazine-6-carboxamide; or a pharmaceutically acceptable salt thereof, which is a methanesulfonate of this compound. 24. The compound according to claim 20, which differs in that it is 4-(5-Mmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(1-methylethyl)pyrrolo|2,1-P( 1,2,triazine-b-carboxamide, or a pharmaceutically acceptable salt thereof. 25. The compound according to claim 20, which differs in that it is o 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-propylpyrrole|2,1-P(1,2 ,triazine-b-carboxamide; or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 20, which differs in that it is "4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(1-phenylethyl|pyrrolo|2,1- P(1,2,4|triazine-6b-carboxamide; or its pharmaceutically acceptable salt. c 27. The compound according to claim 20, which differs in that it is o 4-C(5-Cmethoxyamino)carbonyl|-2-methylphenyl|amino|-5-methyl-M-(/1-methylpropyl|pyrrolo|2,1 -4(1,2,)griazine-6-carb oxamide; or its pharmaceutically acceptable salt. 28. A pharmaceutical composition containing at least one compound according to claim 7 and a pharmaceutically acceptable carrier or diluent. 29. A pharmaceutical composition comprising at least one compound according to claim 20 and a pharmaceutically acceptable carrier or diluent. 30. The method of treating an inflammatory disorder, which consists in introducing the pharmaceutical composition according to claim 28 into the body of a patient who needs such treatment. 31. The method according to claim 30, which differs in that the inflammatory disorder is selected from the group of disorders , which include asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic inflammation of the lungs, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, homologous disease, atherosclerosis and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic rubella-related arthritis, gouty arthritis, and osteoarthritis. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits", 2005, M 10, 15.10.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with 50 s» F) ime) 60 b5