UA73140C2 - Isomeric condensed pyrolocarbazoles and isoindolones - Google Patents

Abstract

The present invention is directed to novel fused pyrrolocarbazoles and isoindolones, including pharmaceutical compositions, having activity toward trk kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth factor receptor (VEGFR) kinase, NGF-stimulaied irk phosphoryladon, or tropic factor responsive cells.

Description

Description of the invention

The present invention relates generally to isomeric condensed pyrrolocarbazoles and isoindolones, including pharmaceutical compositions containing them, diagnostic kits, standard tests and reagents, and to methods of their use as drugs. The invention also relates to intermediate compounds and methods of obtaining such new compounds.

The microbially derived substance called "K-252a" is a unique compound that has attracted considerable attention in the last few years due to the diverse functional activity it has. 70 K-252a is an indolocarbazole alkaloid, which was originally isolated from the culture of Mosagaiiosis zr. (Kaze

N. ei aiI., 39 in Apirioiisv, 1059, 1986). K252a is an inhibitor of several enzymes, including protein kinase C (PCK), which plays a key role in regulating cellular functions, and its K tyrosine kinase. Functional activity

The reported activities of K252a and its derivatives are numerous and varied: inhibition of tumors (see patents

US 4877776, 4923986 and 5063330; publication of the European patent 238011 in the name of Motaiys); anti-insecticidal 72 activity (see US patent 4735939); inhibition of inflammation (see US patent 4816450); treatment of diseases related to neuronal cells (see US Patents 5,461,146, 5,621,100, 5,621,101 and UMRO Publication UUO94/02488, published Since February 1994 in the name of Serpa|op Ips., ii Kussha Nakko Koduo So., Tsa); and the treatment of prostate diseases (see US Patents 5,516,771 and 5,654,427). It was also reported that K252a inhibits the production of I! -2 (see Sgome ei a!., Ekhregitepia! Seyi Kezeagsp 193: 175-182, 1991).

The indolocarbazoles that have been reported share several common features. Specifically, each includes three five-membered rings, all of which include a nitrogen moiety; staurosporin (obtained from Zygeriotuses zr.) and

K252a, each additionally includes a sugar fragment attached through two M-glycosidic bonds. Both K252a and staurosporine have been intensively investigated for their use as therapeutic agents. Indolocarbazoles are usually lipophilic, which makes it possible for them to pass through biological membranes quite easily and, unlike protein-like substances, they have a longer half-life of ip mimo. Gee)

Although K252a is usually obtained from the culture medium by an enzymatic process, a total synthesis of the natural (g) isomer and the unnatural (-) isomer was carried out, in which the three chiral carbon atoms of the sugar have opposite configurations (see .Bos, 117:10413, 1995 and ULRO publication МЙ0О97/07081). However, this synthesis is not applicable for practical commercial use. at

In addition to the indolocarbazole alkaloids represented by K252a and staurosporine, "Its synthetic small organic molecules that are biologically active and known as condensed pyrrolocarbazoles (see US patents 5475110, 5591855, 5594009, 5705511 and 5616724) are obtained." --

Condensed isoindolones are also known, which are indole-free molecules that can be chemically synthesized in a new way (see US patent 5808060 and UMIRO publication MU097/21677). Some bis-indolylmaleimide macrocyclic derivatives have also been reported 325 (see, for example, US Pat. Nos. 5,710,145, 5,672,618, 5,552,396, and 5,545,636). Sugar derivatives of indolopyrrolocarbazoles were also reported (see UMIRO publication

MU/098/07433). There is still a need for new pyrrolocarbazole and isoindolone derivatives that have useful properties. This invention belongs to them, as well as to other important points. "

Accordingly, one of the purposes of this invention is to create new compounds that are kinase inhibitors. C 50 In particular, the compounds of the present invention are inhibitors of IgIK kinase, platelet-derived growth factor receptor kinase (ROSEC), vascular endothelial growth factor receptor kinase (VECOR) or

From" MOg-stimulated herK phosphorylation. Another goal of the invention is the development of new compounds that enhance the trophic factor-induced activity of trophic factor-responsive cells.

Another goal of this invention is the development of pharmaceutical compositions that have activity in relation to herK kinase, platelet-derived growth factor receptor kinase (ROSEK), vascular and endothelial growth factor receptor kinase (MESEK), MOB-stimulated herK phosphorylation or respond to trophic cell factor, where the composition includes a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of this invention or a pharmaceutically acceptable salt form thereof.

Another goal of this invention is the development of a new method of treatment or prevention of diseases associated with the abnormal activity of erythrocyte kinase, platelet-derived growth factor receptor kinase (ROSEK), vascular endothelial growth factor receptor kinase (VESEK), MOB -stimulated herKk s phosphorylation or cells responding to a trophic factor, where the method includes administering to a host in need of such treatment or prevention, a therapeutically effective amount of at least one of the compounds of this invention. 29 Another goal of this invention is to develop a method of inhibiting herK kinase, a factor receptor kinase

GF) platelet-derived growth factor (ROSEK), vascular endothelial growth factor receptor kinase (MESEK),

MOg-stimulated herK phosphorylation or increased activity of cells responding to a trophic factor in a body fluid sample, where the method includes treating the body fluid sample with an effective amount of at least one of the compounds of this invention. 60 Another object of the present invention is to provide a kit or container that contains at least one of the compounds of the present invention in an amount effective for use as a diagnostic agent, standard or reagent.

These and other goals, which will become apparent from the following detailed description, were achieved when the authors of the invention discovered the fact that the compounds of formula I: b5

XX,

PROFESSION

K c) So b B (vu vi vi

And stereoisomeric forms, mixtures of stereoisomeric forms or their pharmaceutically acceptable salt forms, where A, oyu B.C,0,E, P, b, 0, X, MU, U, 22, VU, E7 and 2? defined below, are effective kinase inhibitors.

Thus, in the first embodiment, the invention relates to a new compound of formula II

Heh) min in c

I or its stereoisomer or a pharmaceutically acceptable salt, where the ХО ring is selected from phenyl and cyclohexene with a double bond а-п; ring B and ring E, independently, and each, together with the carbon atoms to which they are attached, is selected from: a) a β-linked carbocyclic ring in which 1-3 carbon atoms can be replaced by heteroatoms; and c) a 5-membered carbocyclic ring in which either 1) one carbon atom can be replaced by an oxygen, nitrogen or sulfur atom; c 2) two carbon atoms can be replaced by sulfur and nitrogen atoms, oxygen and nitrogen atoms, or two nitrogen atoms; or

C) three carbon atoms can be replaced by three nitrogen atoms, one oxygen atom and two nitrogen atoms, or one sulfur atom and two nitrogen atoms;

О-Х-М/ selected from: ав a) "А"А?2)С-М(В7)-С(В'В2)-; "c) -СН(К)-с(-0)-М (B.7)- and c) -(A")-c(50)-CH(K M); --

B" selected from: co a) H, substituted or unsubstituted alkyl of 1-6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl; c) -С(О)В , where B" is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic group and substituted or unsubstituted heterocyclyl groups; « 20 c)-ORZ, where BZ is selected from H and alkyl containing 1-6 carbon atoms; ш-в с а) -СК(-оМчНе, "MAV o, "SNoRMAUV o, "("SNoROVU, -FO(SNOROVZ and -"FO(SNO)RMAV U, where p equals 1-4; and where or ; » 1) 29 and K"9 each, independently, selected from H, unsubstituted alkyl of 1-6 carbon atoms and substituted alkyl; or 23 BZ and KO together form a binding group of the formula -(CH 2)5-X!- (СНо)", where X! is selected from -O-, -5- and -| -сСно-; с BA is the same as B; 22, 23, 27 and КЕ? each independently selected from: - a ) H, aryl, carbocyclyl, heterocyclyl, -CM, SEz, -MO", -"OH, -OK", Vg, I, -"F(СНоРМеУвВЯ, -ос(-Ов, и 50 -ос(хОМе УВО . , where B" represents the residue of an amino acid after the removal of the hydroxyl group from the carboxyl group; c) -MvZs(hoMe vo, -Mees(8)Mv Vo, "sov, -c(ho)872, -c(xO)MUVO, -c (58) MeVo, -"CH-MOV, vv "SNEMA", "(СНо)рМАУВО, "(СНо)МНА"! or -СН-ММА'"ВяА, where MK? is selected from H, alkyl from 1 -6 carbon atoms, -OH, 1-6 carbon atoms, -ОС(О)К, -ОС(хОМАУВВ о, -ос (-5)MeUV o, O(SNOIRMeUV o, o(СНО)РОК, substituted or unsubstituted arylalkyl having 6-10 carbon atoms, substituted or unsubstituted heterocyclylalkyl and substituted or unsubstituted carbocyclic group; K'"2A is the same as

IN; a) -(0)уВ и", "СНо)ра(О)уВ 7, -"СН»В(О)УуВ, where у is equal to 0.1 or 2; f) alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, where: 1) each alkyl, alkenyl or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl or alkynyl group is substituted by 1-3 groups selected from aryl with 6-10 b carbon atoms, heterocyclyl, arylalkyloxy, heterocycloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, hydroxyalkylthio, alkoxyalkylthio, E, SI, Bg, I, -CM, -MO", -OH, -OV", -HUSNorRS(OMAUV o, -HU(SNorS

(vche, 0 -ХУ(СНо)проС(ЗО)МАУВ"О, 0 -ХЯсСНорСОоВ, 0 -Х(СНо)ра(ОуВ, 0 "Хо(СНорМА (ОМА В У, -0Ф(-О)К 7, -OS(O)MNe 2, O-tetrahydropyranil, - MEUVO, -MeZSsOv", -MeE8s(xO)Me vo, -MeZs(x5)MA В 9, -mne(-mnmno, -MeZs(-ov, -MAZs (-5)8 7, -MeZ8(-0)87, -(Оо)ув, -с028"2, -С(5О)MeУВ о, -с(-5)МАУВ о, -Ф(2Ф)В" ?. IHOHOV 835, "ОВ! and a monosaccharide of 5-7 carbon atoms, where each hydroxyl group of the monosaccharide is independently either unsubstituted or replaced by H, alkyl of 1-4 carbon atoms, alkylcarbonyloxy of 2-5 carbon atoms, or alkoxy of 1-4 atoms carbon, and X2 represents O, 5 or ME;

О is selected from -MEE, -О- and -5-; 25 selected from Н, 50287, -СО287, -С(2О)В", -С(-О)MEУВ o, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms , and either 1) each alkyl, alkenyl, or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl, or alkynyl group is independently substituted as defined in 22.3, and

B in point e) above;

In selected from a) unsubstituted alkylene with 1-3 carbon atoms;

b) alkylene of 1-3 carbon atoms, substituted "Z, where B3 is selected from B", thioalkyl of 1-4 carbon atoms, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2 -8 carbon atoms, where i) each alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms is unsubstituted; or iii) each alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, independently, substituted as defined for K2, VU, B" and C in item e) above; and c 29 c) functional group selected from -CH-CH-, -CH(OH)-CH(OH)-, -О-, -5-, -8(-50)-, -8(-50)5, -FKVU», Ge) -с-с(8733-, -6(50)-, -б(1-МовВ'У., -сб(ов'ЗвВя, -с(ихо)0сн(ВУ-, -сSN (VU)С(-0)-, -С(-МОК'ЗСсН(В У, -sneЗs(-МОв 72)-, - WHY), -«Ш(В8)С(50)-, -«СН- . o z o A" and A? selected from H, H; H, OB; H, -58727; H, -Щ(2 735; and groups where A" and A? together form a fragment, - - - - 12.; "And selected from 50, -5 and MAK -; and

B' and B? selected from H, H; Н, ОВ"; Н, -8872; Н, -Щ(К 72)"; and groups where В' and В? together form a fragment 7 selected from 50, -З and "МВ; со provided that at least one of the pairs A! and A? or B' and B? forms -0.

In another embodiment, the present invention relates to a new compound of the formula XXII t vu "Fu; Хв « da Св) св (в -о с is в. xx or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein ring 4 is selected from phenyl and cyclohexene with an a-b double bond, ring B and ring EP, independently, and each together with the carbon atoms to which they are attached, selected from: (4) a) b--len carbocyclic ring, in which 1-3 carbon atoms can be replaced by heteroatoms; and with c) a 5-membered carbocyclic ring in which either 1) one carbon atom can be replaced by an oxygen, nitrogen or sulfur atom; 50 of them 2) two carbon atoms can be replaced by sulfur and nitrogen atoms, oxygen and nitrogen atoms, or two nitrogen atoms; or c C) three carbon atoms can be replaced by three nitrogen atoms, one oxygen atom and two nitrogen atoms, or one sulfur atom and two nitrogen atoms;

O-X-M/ selected from: a)-ATAZSMVS(B'B2)-; (F. c) A-сСН(К 77)-с(-0)-М(В. - and о с) -(А")-с(50)-СН(К M);

B" selected from: 60 a) H, substituted or unsubstituted alkyl of 1-6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl; c) -C(O)B, where B" is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbocyclic group and substituted or unsubstituted heterocyclic groups; c) -OE8, where EZ is selected from H and alkyl, which contains 1-6 carbon atoms;

a) -С(С-о)мНее, "МАУ У, "СНОМ УВО, "СНо)РОКУ, "О(СНоИРОВУ and -О(СНо)р MAV У, where p is equal to 1-4; and where or 1) 29 and K"9 each, independently, selected from H, unsubstituted alkyl of 1-6 carbon atoms and substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or 2) BZ and B"O together form a linking group of the formula -(CH 2)5-X!-(СНо)», where X! selected from -O-,-5- and -Sn.-;

BA is the same as B"; 22, VU, 27 and EE? each independently selected from: a) H, aryl, carbocyclyl, heterocyclyl, -CM, CEz, -MO", -"OH, -OK" . -МАЗС(-ОВ or -МАЗС(-5)В 7; 5) -СНОК , where в" represents the amino acid residue after the removal of the hydroxyl group from the carboxyl group; c) -Mebs(хОо)МввВО, -МеЗс(-5Ме во, -soov?, -s(ho)v, -s(xO)MeUvIo, -s(-5)MAUvV o, -SN-MOV I, -sne-MmA 7, "SNo)RMAUA o, "SNO)MNA" or "CH-MMA "B, where B" is selected from H, alkyl of 1-6 carbon atoms, -OH, alkoxy of 1-6 carbon atoms, -OC(OK7, -OC(OMAV o, -ОосС(- 5) IMAUV I, C(SNorMeUV I, C(SNOROU, substituted or unsubstituted arylalkyl having 6-10 carbon atoms, substituted or unsubstituted heterocyclylalkyl and substituted or unsubstituted carbocyclic group; B 72A is the same as B 2; a) -(О)ув ие, "СНо)рв(ОувВ", -"СНоВ(О)УВ", where у is equal to 0.1 or 2; e) alkyl with 1-8 carbon atoms, alkenyl with 2-8 atoms in carbon and alkynyl of 2-8 carbon atoms, where: 1) each alkyl, alkenyl, or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl, or alkynyl group is substituted with 1-3 groups selected from aryl of 6-10 carbon atoms carbon, heterocyclyl, arylalkyloxy, heterocycloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, hydroxyalkylthio, alkoxyalkylthio, E, SI, B, I, -SM, -MO", -OH, -OK", -X(CHnorC(-OMeUVA, -Hu(CHnorC o (-8)MAUV', 0 -ХУ(СНоРОС(ЗОМАУВ, 0 -ХУСНовСОоВ", 0 -ХУ(СНо)ре(О)уВ, 0 -ХО(СНоРМАс(О)МА В, -0Ф(-О) K 7, -OS(O)MNe 2, O-tetrahydropyranil, - MEUVO, -MeZSsOv", -MeE8s(xO)Me vo, -MeZs(x5)MA B 9, -mne(-mnmno, -MeZs(-ov . с(2Ф)В"?, -СНоОовВУ,. "сНАММАВЯ, -снН-МОВ"?, -СН-МА", -СНАММНОСН(М-МНИМН", -5(-0)МА В, "t -P(HOHOV 8)", "ОВ! and monosaccharide of 5-7 carbon atoms, where each hydroxyl group of the monosaccharide is independently either unsubstituted or substituted by H, alkyl of 1-4 carbon atoms, alkylcarbonyloxy of 2-5 carbon atoms, or (57 alkoxy of 1-4 carbon atoms; co

X2 represents O, 5 or ME,

O is selected from -ME5, -O- and -5-; - 25 selected from H, 50287, -СО287, -С(2О)В", -С(-О)MEУВ o, alkyl with 1-8 carbon atoms, alkenyl with 2-8 carbon atoms and alkynyl with 2-8 atoms carbon, and either 1) each alkyl, alkenyl, or alkynyl group is unsubstituted, or "2) each alkyl, alkenyl, or alkynyl group, independently, is substituted as defined for 22.3, and ssh c VZ in item e) above; ц У selected from "» a) unsubstituted alkylene with 1-3 carbon atoms;

b) alkylene of 1-3 carbon atoms, substituted "Z, where B3 is selected from B", thioalkyl of 1-4 carbon atoms, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2 -8 carbon atoms, where -i i) each alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms is unsubstituted; or iii) each alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, - independently, substituted as defined for RK, VU, B" and B" in item y) above; and i" 20 c) functional group selected from -"CH-CH-, -"CH(OH)-CH(OH)-, -O-, -5-, -8(20)-, -5(50 )5, -"С-С(В 3", о -с(50)-, -С-М(К3)-, -с(-МОК3-, -СКОов ЗЛ, -с(ихоО)0сНн(ВУ- . -, -СН?-, -USNo- and -SNYASN"-, where 7 is selected from -С(К23-, -О-, -8-, -сб028"2, -С(-МОВ "2)- and MORE 2)-;

AND! and A? selected from H, H; H, OK"; H, -5872; H, -Щ(К 735; and groups where A" and A? together form a fragment selected from 50, -5 and MV; about B' and B? selected from H, Н; Н, ОВ"; Н, -8872; Н, -Щ(К 72)"; and groups where В' and В? together form a fragment selected from 50, -З and "МВ; provided that at least one of the pairs A" and A? or B' and B? forms -0. 60 In some preferred embodiments of the compounds of formula I, VK "7, KZ and KE? represent H. In some further preferred embodiments, -5-X- U- represents -СН 2М(В)С(50), -С(-ОМЩ(В)СНо- or -С(ОЖМ(В)С(-О).

In other preferred embodiments, rings B and E are independently substituted or unsubstituted phenyl or pyridyl. In other preferred embodiments, O represents -MK b. where the indicated values for K 9 are H or substituted or unsubstituted lower alkyl. In some preferred embodiments, Y is an unsubstituted alkylene of 1-3 carbon atoms, -C(-0)-, -CHNO-, -5-, -O- or -"CH:CH-.

In other preferred embodiments, isomeric condensed pyrrolocarbazoles are represented by the formula: !

AKA in

AMi1 Av! os vi x s E / u i VE Pi

In some preferred embodiments, isomeric condensed pyrrolocarbazoles are represented by the formula: incl

AKA in!

And Av

Iii p. 5, t v

My in I

In some preferred embodiments, in these formulas, B, C, and B are H. In other preferred embodiments, A and A are selected from H, H; H, OH; 72)"; or groups where A" and A? together form -O or -ME "2; B! and B? selected from Н, Н; Н, ОН; Н, оОСН»У; Н, -МЩ(Б 72)"; or groups where Б" and Б? together form -O and EMV 2; c: represents H, methyl, ethyl, propyl, -OH or methoxy. In other preferred embodiments, the specified values for B? is H or substituted or unsubstituted lower alkyl. In other preferred embodiments, U represents an unsubstituted alkylene with 1-3 carbon atoms, -С(-0)-, -СН 250-, с -8-, -ОО- or -СНАСН-. Still further preferred embodiments are the compounds listed in Tables 1-4. at

In other embodiments, the present invention relates to pharmaceutical compositions containing compounds of formula I! and a pharmaceutically acceptable carrier. In a preferred composition, the compound of formula I is one of the compounds listed in Tables 1, 2, C or 4.

In some preferred pharmaceutical compositions, the composition is intended to inhibit one or ("c") several of its K kinase activity, MESEK kinase activity, or COSEC activity, wherein the composition comprises a compound of formula I and a pharmaceutically acceptable carrier. In other preferred pharmaceutical compositions, the composition is intended to enhance trophic factor or SPAT activity of the spinal cord, where the composition "-- contains compounds of formula I and a pharmaceutically acceptable carrier. co

In other preferred pharmaceutical compositions, the composition is for the treatment or prevention of prostate diseases such as prostate cancer or benign prostatic hyperplasia. In other preferred and - pharmaceutical compositions, the composition is intended for the treatment or prevention of angiogenic diseases, such as solid tumor cancer, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, eye diseases or macular degeneration. In other preferred pharmaceutical compositions, the composition is for the treatment or prevention of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis. In other preferred pharmaceutical compositions, the composition is intended for the treatment or prevention of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, AIDS dementia; epilepsy, multiple sclerosis, peripheral neuropathy, or brain or spinal cord injuries.

In other embodiments, the present invention relates to a method of inhibiting herK kinase activity, which includes providing a compound of formula I in an amount sufficient for effective inhibition. In a preferred embodiment, the compound of formula I is intended for the treatment of inflammation. In yet another preferred embodiment, the receptor of the yKK kinase is yKA.

In other embodiments, the present invention relates to a method of treating or preventing diseases of the prostate, which includes administering to a host in need of such treatment or prevention, a therapeutically effective amount of 50% of a compound of formula I. In a preferred embodiment, the prostate disease is prostate cancer or benign hyperplasia the prostate c2 In other embodiments, the present invention relates to a method of treating or preventing angiogenic diseases where MESEK kinase activity contributes to pathological conditions, and the method includes providing a compound of formula !/ in an amount sufficient to contact the vascular endothelial growth factor receptor with an effective inhibitory amount of the compound . In another embodiment, the present invention relates to a method of treating or preventing angiogenic diseases, which includes administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound of formula I. In a preferred embodiment, the angiogenic disease is cancer of solid tumors, eye diseases , macular degeneration, endometriosis, diabetic retinopathy, psoriasis or hemangioblastoma. 60 In other embodiments, the present invention relates to a method of treating or preventing diseases in which ROSEK activity contributes to pathological conditions, and the method includes providing a compound of the formula ! in an amount sufficient to contact the platelet-derived growth factor receptor with an effective inhibitory amount of the compound. In another embodiment, the present invention relates to a method of treating or preventing pathological disorders, which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of the formula

Y. In a preferred embodiment, the pathological disorder is a neoplasia, rheumatoid arthritis,

pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis or restenosis.

In other embodiments, the present invention relates to a method of treating diseases characterized by abnormal activity of cells responding to a trophic factor, the method includes providing a compound of formula I in an amount sufficient to contact the receptor of cells responding to a trophic factor with an effective activity-inducing amount of the compound. In preferred embodiments, the activity of cells responding to a trophic factor is SPAT activity. In another embodiment, the present invention relates to a method of treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis 7/0, peripheral neuropathy, or brain or spinal cord injuries, which involves administering to a host in need of such treatment or prophylaxis a therapeutically effective amount of a compound of the formula

I. Compounds represented by formula | may also be referred to as Compound I, and the same applies to compounds with other formula numbers.

The following terms and expressions have the meanings indicated. As used herein, "stable compound" or "stable structure" is intended to mean a compound that is stable enough to withstand isolation from a reaction mixture to the desired degree of purity, and is preferably incorporated into an effective therapeutic agent. . This invention relates only to stable compounds. As used herein, "substituted" is intended to indicate that one or more hydrogen atoms of said atom have been replaced by selected groups referred to herein as "substituent", provided that the valency of the substituted atom is not exceeded , and substitution leads to a stable compound.

As used herein, the term "alkyl" means a straight, cyclic, or branched alkyl group containing 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , isoamyl, neopentyl, 1-ethylpropyl, hexyl, octyl, cyclopropyl and cyclopentyl. The alkyl fragment of alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups, has the same meaning as the above-defined alkyl. Lower alkyl groups, which are preferred, are alkyl groups as defined above, which contain 1-4 carbon atoms. and)

Alkyl groups and alkyl moieties contained in substituent groups, such as aralkyl, alkoxy, arylalkyloxy, hydroxyalkyl, alkyloxy, hydroxyalkylthio, alkoxyalkylthio, alkylcarbonyloxy, hydroxyalkyl, and acyloxy, may be substituted or unsubstituted. Substituted alkyl group contains about 1-3 independently selected substituents, preferably such as hydroxy, lower alkoxy, lower alkyloxy, substituted or unsubstituted arylalkyl-lower alkyl, substituted or unsubstituted - heteroarylalkyl-lower alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted " p heterocycloalkyl, halogen, carboxyl, lower alkoxycarbonyl, nitro, amino, mono or di-lower alkylamino, dioxolane, dioxane, dithiolane, dithione, furan, lactone or lactam. i)

As used herein, the term "alkenyl" is intended to include straight, cyclic, and branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, 3-methylbutenyl and cyclohexenyl groups. As used herein, the term "alkynyl" is intended to include straight, cyclic, and branched hydrocarbon chains having at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, 3-methylbutynyl, and cyclohexynyl groups. As used herein, an "acyl" moiety of an acyl-containing group such as an acyloxy group includes a straight, branched, or cyclic alkanoyl group that has 1-6 carbon atoms, such as ;" formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or hexanoyl.

As used herein, the term "carbocyclic" refers to cyclic groups in which ring

The fragment is composed exclusively of carbon atoms. These include, but are not limited to, cyclopropyl, -I cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. The terms "heterocyclo" and "heterocyclic" refer to cyclic groups in which the ring moiety includes at least one heteroatom, such as O, M, or O. Heterocyclic groups include heteroaryl and heteroalkyl groups. - As used herein, the term "aryl" refers to an aromatic ring containing 6-12 carbon atoms, such as phenyl, biphenyl, and naphthyl. Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups. The term "heteroaryl" as used herein refers to an aryl group in which one or more ring carbon atoms are replaced by a hetero (ie, non-carbon) atom such as O, M, or 5.

Preferred heteroaryl groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiaphazolyl groups. The term "heteroalkyl" means a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms such as O, M or 5.

F) As used herein, the term "aralkyl" (or "arylalkyl") is intended to mean a group having from 7 to 15 carbon atoms and consisting of an alkyl group to which an aryl group is attached.

Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, benzhydryl, and naphthylmethyl. Substituted aryl, substituted heterocyclic and substituted aralkyl groups each have 1-3 independently selected substituents which are preferably lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino and halogen .

Preferred heterocyclic groups formed with a nitrogen atom include pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, M-methylpiperazinyl, indolyl, isoindolyl, imidazole, 65 imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole, isothiazole, thiadiazole, triazines, isoxazole, oxindole, indoxyl, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline, isoquinoline and tetrazole. Preferred heterocyclic groups formed with an oxygen atom include furan, tetrahydrofuran, pyran, benzofurans, isobenzofurans and tetrahydropyran groups. Preferred heterocyclic groups formed with a sulfur atom include thiophene, thianaphthalene, tetrahydrothiophene, tetrahydrothiapyran, and benzothiophenes.

As used herein, "hydroxyalkyl" groups are alkyl groups that contain an attached hydroxyl group. As used in this description, "hydroxyalkoxy" groups are alkoxy groups that contain an attached hydroxyl group. As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "heteroarylalkyl" refers to an arylalkyl group that contains a heteroatom in the aryl moiety. The term "oxy" means the presence of an oxygen atom. Thus, "Alkoxy" groups are alkyl groups that are attached through an oxygen atom, and "carbonyloxy" groups are carbonyl groups that are attached through an oxygen atom.

As used herein, the terms "heterocycloalkyl" and "heterocycloalkyl" refer to an alkyl or alkoxy group that contains a heterocyclic group attached to an alkyl moiety, and the term "arylalkyl" refers to an alkoxy group that contains an aryl group attached to an alkyl moiety. As used in this description, the term "alkylcarbonyloxy" means a group of the formula -O-C(-O)-alkyl.

As used in this specification, the term "Alkoxy-Alkyloxy" means an alkoxy group that contains an alkyloxy substituent attached to its alkyl moiety. The term "Alkoxyalkylthio" means an alkylthio group (ie, a group of the formula -5-alkyl) that contains an alkyloxy substituent attached to its The term 2o"hydroxyalkylthio" refers to an alkylthio group (ie, a group of the formula -3-alkyl) which contains a hydroxy substituent attached to its alkyl moiety.

As used herein, the term "monosaccharide" has the conventional meaning of a simple sugar. As used in this specification, the term "amino acid" means a molecule that contains both an amino group and a carbonyl group. Embodiments of amino acids include os-amino acids; that is, carboxylic acids

General formula NOOS-CH(NN")-(side chain). Amino acid side chains include natural and unnatural fragments. The side chains of unnatural (i.e., artificial) amino acids are fragments that are used instead of the side chains of natural acids in the case of, for example, amino acid analogs. See, e.g., Ieppipdeg, Viospetivighu, Zesopa Eaiiop, Uuogii Rybiizpege, Ips., 1975, lines 73-75, incorporated herein by reference. In certain variants, the implementation of a group of substituents for compounds of formulas I, I and Ha")

Include the residue of an amino acid after removing the hydroxyl fragment from its carboxyl group, that is, the group of the formula -С(-0)-СН(МН»)-(chain chain). in

The functional groups present in the compounds of formula I may also contain protective groups. Preferred protecting groups include the benzyloxycarbonyl (Cb2;7) group and the tert-butoxycarbonyl (Boc) group. Other preferred protective groups can be found in the monograph of T.MU Sgeepe. apa M/tsiv R.O.M., Rgoiesiime Sgoumrz ip Ogdapis Zupipevziv and. 3z5 24 Ea., MMpeuye Zopv, 1991, the content of which is included in this description as a reference. uh-

As used herein, it is intended that the terms commonly used to describe the action of therapeutic agents in biological systems, assays, and the like have their meanings generally accepted in the art. As used herein, the term "action" when used to modify the terms "functioning" and "survival" means a positive or negative change or alteration. An action that is positive, "

May be referred to as "enhancement" or "enhancement" and an action that is negative may be referred to as "inhibition" or "attenuation". and As used herein, the terms "enhance" or "enhance" when used to modify the terms "functioning" or "survival" mean that the presence of an isomeric fused pyrrolocarbazole or isoindolone compound has a positive effect on the functioning and/or survival of the corresponding on the trophic factor of the cell compared to the cell in the absence of the compound. For example, and without limitation, -And with respect to the survival of, e.g., a cholinergic neuron, the compound would be an apparent improvement in the survival of a population of cholinergic neurons at risk of death (death due to, e.g., damage, or a diseased state, degenerative state, or natural development) when compared to the population cholinergic - neurons, where such a compound is not present, if the treated population has a relatively longer period of functioning than the untreated population. As used herein, "Inhibit" and "inhibition" mean that a specific response of a labeled substance (eg, enzymatic activity) is comparatively reduced in the presence of an isomeric fused pyrrolocarbazole or isoindolone compound.

As used in this specification, the term "ChK" refers to high-affinity neurotrophin receptors, which 5v5 currently include (KA, KV and (KS, and other membrane-associated proteins to which the neurotrophin can bind. iF) As used as used herein, the term "cancer" and "cancerous" refers to any malignant proliferation of cells in a mammal. Examples include prostate cancer, benign prostatic hyperplasia, cancer of the ovary, breast, brain, lung, pancreas, colon, intestines, stomach, solid tumors, cancer of the head and neck, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized malignant diseases of the hematopoietic system and other types of cancer.

As used herein, the terms "neuron," "cell of neural lineage," and "neuronal cell" include, but are not limited to, a heterogenous population of neuronal types having a single or multiple mAb transmitters or single or multiple functions; mainly, they are cholinergic and sensory neurons. As used herein, the phrase "cholinergic neuron" refers to central nervous system (CNS) and peripheral nervous system (PNS) neurons whose neurotransmitter is acetylcholine; examples are basal forebrain neurons, striatal neurons, and spinal cord neurons. As used herein, the phrase "sensory neuron" includes neurons responsible for feedback to the environment (eg, temperature, movement), for example, from the skin, muscles, and joints; an example is a spinal ganglion root neuron.

As used herein, the term "trophic factor responsive cell" refers to a cell that includes a receptor to which a trophic factor can specifically bind; examples include neurons (eg, cholinergic and sensory neurons) and non-neuronal cells (eg, monocytes and neoplastic cells). 70 As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present invention effective in preventing or treating the symptoms of a particular disease. Such diseases include, but are not limited to, such pathological and neurological diseases associated with abnormal activity of the receptors described herein, where treatment or prevention includes inhibiting, inducing or enhancing their activity by contacting the receptor with a compound of formula |.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, substances, compositions and/or dosage forms that are, within the meaning of medical opinion, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other complications corresponding to a reasonable benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds described above, where the parent compound is modified to give its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or salts of quaternary ammonium bases of the parent compound formed, for example, with non-toxic inorganic or organic acids. high school

For example, such common non-toxic salts include salts derived from inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from (8) organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmic, maleic, hydroxymaleic. phenylacetic, glutamine, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, ozo-oxalic, isethionic and the like.

Pharmaceutically acceptable salts according to the present invention can be synthesized from starting compounds that contain a basic or acidic fragment by conventional chemical methods. Of course, such salts can be obtained - where the interaction of the form of the free acid or base of these compounds with the stoichiometric amount of the corresponding base or acid in water or in an organic solvent, or in their mixture. Usually non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. The list of suitable salts is given in

Ketipdiopye Ripagtaseciisa| Zsiepsev, 177 editions, Magk Rybiizpipd Sotrapu, Eaviop RA, 1985, p. 1418, the content of which is included in this description as a reference.

As used herein, "prodrugs" are intended to include any covalently bound "carriers that release the active parent drug of formula (I) or other compounds of the present invention 70 ip mimo upon administration of such prodrugs mammals Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, production, etc.), the compounds of this invention can be delivered in the form of prodrugs. Thus, the present invention contemplates prodrugs of the claimed compounds, which include their compositions and methods of their delivery. Prodrugs of the compounds of the present invention, for example, of formula I, can be obtained by modifying the functional groups present in the compound, thus that the modified groups are cleaved either by conventional work-up or ip mimo to yield the parent compound.-I Accordingly, prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or carboxyl group is attached to any group which, when the prodrug administered to a mammal, is cleaved to form a free hydroxyl, free amine, or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters, such as methyl, ethyl, propyl, isopropyl, butyl, e isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl and phenethyl esters and the like.

Synthesis

The compounds of this invention can be prepared by a number of methods well known to those skilled in the art.

The compounds may be synthesized, for example, by the methods described below, or variations thereof, as will be understood by the skilled artisan. All methods that are disclosed in connection with this invention are considered as

F, practically feasible on any scale including milligrams, grams, multigrams, kilograms, co multikilograms or commercial industrial scale.

It is clear that the compounds of this invention may contain one or more asymmetrically substituted boron carbon atoms and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of the structure are meant, unless a specific stereochemical or isomeric form is specifically indicated. It is well known in this field how such optically active forms are obtained and isolated. For example, mixtures of stereoisomers can be separated by standard methods, including, but not limited to, resolution of racemic forms, conventional, reversed-phase, and 65 Chiral chromatography, selective salt formation, recrystallization, and the like, either by chiral synthesis or from chiral starting materials, or by deliberate synthesis of target chiral centers.

As can be easily understood, the functional groups present in the compounds of formula I may contain protective groups during the synthesis process. For example, substitutes for amino acid side chains of compounds of the formula | may be substituted with protective groups such as benzyloxycarbonyl or tert-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively attached and removed from functional groups such as hydroxyl groups and carboxyl groups. Such groups are present in a chemical compound to provide such a function of inertness to the conditions of the chemical reaction to which the compound is subjected. Any of a variety of protecting groups may be used in the present invention. Preferred protecting groups include the 70 benzyloxycarbonyl (Cl;7) group and the tert-butoxycarbonyl (Boc) group. Other preferred groups according to the invention can be found in Sgeepe T.MU. apa MUtsiv, R..M., Rgoiesiime Stgourz ip Ogdapis Zupipevziv, 24, Ea.,

UMieukbopv, 1991.

The compounds of this invention may be prepared as shown generally in the following schemes. Of course, imide compounds can be prepared as shown in Scheme 1.

Scheme I x "KU o o a- u iv N what your

The cycloaddition reaction of maleimide and cyclic-2-vinyl derivative (II) gives tetrahydrocarbazole compounds of the general structure (II), which can be dehydrogenated by methods well known in the field (Scheme 1). The cycloaddition reaction can be carried out in the absence of a solvent at temperatures from d) about 150 to about 2002C, or in a solvent such as toluene, xylene or chlorobenzene at elevated temperatures with or without the addition of a Lewis acid as a catalyst. Dienes of the general structure (II) can be obtained by adding 2-lithiindole derivatives, substituted or unsubstituted, to a cyclic hetero(aryl) 1-ketone, for example, 1-indanone, 1-tetralone, 4-chromanone, - 4-keto-4, 5,6,7-tetrahydrothianaphthalene, substituted or unsubstituted, as described, for example, in Teigapedop "I

I ek, 1985, 26, 5935, the description of which is incorporated herein by reference.

Scheme 2 shows in general terms the general approach to obtaining lactam isomers, that is, compounds where - в-Х-М/ represents -С(-0)-М(В7)-С(В'В2) or -С(АА ?)-M(B 7)-C(50)-. co

Scheme 2

З5 ms sozh vo sm - t u v sh Y u ku m

OD po « sh u ve m v. ms sov fights sn - s w-- y y

IN; k z» s, o,

M n k "Tv ish

M. ko bi -I s "zh u o shi it - e u v Za z. iz 50 ih x o The reaction of cycloaddition of dienes of the general structure I to ethyl cis-p-cyanoacrylate under the conditions described for imides in Scheme 1 gives regioisomers cyano-ester tetrahydrocarbazole of the general structure M and MI.

Standard methods such as recrystallization or chromatography can be used to separate the resulting M and MI regioisomers. Tetrahydrocarbazole cyano esters can readily be dehydrogenated according to conventional methods, for example with 2,3-dichloro-4,5-dicyano-1,4-benzoquinone, to give

HF) aromatic carbazoles of the general structure MI! and MI! (Scheme 2). Lactams of the general structure of IX and X can

HF can be obtained separately or in the form of a mixture by reductive cyclization of nitrile esters using reducing agents, for example, nickel Raney/H»o, RaO and Ra or on activated carbon. The imide derivative IM can easily be reduced to the lactam isomers IX and X by conventional methods, such as using zinc-HCI II amalgam, 2p in acetic acid, or treatment with hydride reducing agents such as lithium aluminum hydride.

The resulting lactam regioisomers can be separated by standard methods such as recrystallization or chromatography.

Compounds in which C-X-M/ represents -CH(B. 77)-C(-0)-M(B.)3- or -M(K7)-C(-0)-CH(B Y) , as well as those in which 65 O-X-M is a lactam or an imide can be prepared by the methods described, for example, in US patents 5,616,724 and 5,801,190, the description of which is incorporated herein by reference in its entirety.

Scheme From about

Are you in -- - what are you and,

Ve ya hi n i yi

Oky chyo Oschey ho y HO zh | and Tues

Ko Ve hi M ho

Compounds that contain heteroaryl groups in rings B or E can be prepared using the methods described, as shown in schemes C and 4. The phenyl indole ring can be a heterocycle, for example, but not limited to, 7-azaindole.

Scheme 4 and U s vo

IN; 5 W ke sh hu i se b y Osy cho o de h y M o h gya 5 Gya iv ke

ХУ ХМ ХМ (ав)

Although the resulting alcohol derivative of general structure (I) shown in Scheme 17 can be dehydrogenated to g compounds of general structure (I) using conditions known in the art, such as HCl in acetone or p-toluenesulfonic acid in benzene , dienes of the general structure (I) can also be obtained 77 using the palladium-catalyzed cross-coupling method. For example, the coupling of the corresponding bromine, iodine or trifluoromethanesulfonate derivative with 2-stannyl- or 2-boronic acid - an indole derivative, as shown in Scheme 5. -

Scheme 5 8 ee | in; "

B - 70 C owls tv Her - and shchi Her dream I: ;" ate V i i plfu, pf -i

Mami KU Z ttn--yuya Ku g iz» 50 U ke

In the river

What? (NO to o (Shv) Y

Tetrahydrocarbazole adducts of cycloaddition I can easily be dehydrogenated according to conventional methods using, for example, 2,3-dichloro-4,5-digyano-1,4-benzoquinone, giving aromatic carbazoles of the general structure IM (Scheme 1). name) 60 b5

Scheme 6 pod ono,

Her 7- ; zhk, y, z pa Be zhk o khushch Y in o / o- o. Ge; SM I pozvodiovo, s / 7 M

That's the spirit of them

EUJ. SM

A o, "KI SHE ho "A 78 (X V on y scho ha sch

Scheme 6 shows in a general form an alternative method of obtaining a lactam isomer of the general structure X. A diene of the general structure II, substituted or unsubstituted, reacts with oxalyl chloride and alcohol, i) giving ketoesters of the general structure XIX. Olefinization reactions known to specialists in the field of organic synthesis, for example, the interaction of ketone XIX with diethylcyanomethylphosphonate, easily give cyano-ether XX. The closure of the aromatic ring under palladium-catalyzed or oxidizing conditions gives the cyano-ether-carbazole of the general structure XXI (Scheme 6) or MI (Scheme 2). Reductive cyclization gives lactams of general structure X (schemes 2, 6). -

The compounds of this invention, where the compounds of the general structures IM, IIX or X contain X-CH", can additionally be (u substituted, as shown in scheme 7.

Scheme 7 Geo)

Her

OM s-o oh che

I (with 1ZhMeX or SSO, and with m g M (3 IX or VSNO mih r Sinya B h o v - "

The decision-making group for them - ' ' : s OO Oi o. x "» o oz k dosh: Yi ma ha

With t? Of course, compounds in which KZ is hydrogen can be alkylated in the presence of a base (for example, hydrides, alkoxides, hydroxides of alkali or alkaline earth metals, or organolithium compounds) by treatment - B, where I. is a leaving group, such as a halogen The obtained pyrrolocarbazole can have an alkyl group, 1"50 substituted or unsubstituted, connected to the indole nitrogen, for example, IM-20, 41. Compounds of the general formula IM, IIX or

X, in which B? represents M-hydrogen, can be subjected to a Michael reaction using a base such as DBU and a (ze) Michael acceptor such as an acrylic acid derivative or acrylonitrile to give compounds IM-20-22. Reactions of this type can further be understood with reference to scheme 8.

Scheme 8 h n o. o basis - KH or

ГФ) snysnsM v snySNSOV v s Y ko tirnyh i y 60 general structure IM, IX or X IU-19-22, 4 1x-4,6, X-7

Halogen derivatives, such as the bromo-substituted compound IM-9, can be used to further modify the indole ring, as shown in Schemes 9 and 10. b5

Scheme 9 and about M gv) M ve Me and Her

N nn / 1u-9 / IU-32 n (y oh R oyu

M trnn (o;

IUt F u it n n 1u-33 zbotu

M n. 5 I

M. H. Ootsi ro

M mn shk 7 add,

Mouth! at

IU-35

A palladium-catalyzed Heck reaction using IM-9 and a coupling partner such as a vinylaryl or heteroaryl derivative, an acrylic acid derivative, or acrylonitrile gives vinyl derivatives d)

IM-37, 37, 39, 43. The vinyl derivative can be reduced to alkane derivatives such as IM-38, 40 using reduction conditions such as palladium-on-carbon in a hydrogen atmosphere.

Shhsma!0 .

Her oi Fo o M o o v "

VI. -

M p y / M (ze) 13 TU-36, 37, 39, 43 u i o. M o i: "

M - s N ;" Other distinctive features of the invention will become clear in the course of the following description of examples of implementation. These examples are given to illustrate the invention and are not intended to limit it.

Examples - and Some abbreviations used in this specification are defined as follows: "THF" for tetrahydrofuran, "Vy"c for butyllithium, "MMP" for M-methylpyrrolidinone, "DMSO" for dimethylsulfoxide, "SOCI3" for deuterated chloroform, "Cami" for nickel Raney, "TLC" for thin layer chromatography, "EUAc" for ethyl acetate, "TVAE" for tetrabutylammonium fluoride, "sa" for approximate value, "kt" for room temperature, "psi" 1 » 50 for pounds per square inch, "mm" for millimeters of mercury (Na), 72" for degrees Celsius, "d" for doublet, "dd' for doublet of doublets, "t" for triplet, "m' for multiplet, "eq" for equivalents, "g" for (42) gram or grams, "mg" for milligram or milligrams, "ml" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hour" or "g" for hour or hours, "m' for multiplet, "M" for molarity, "min" or "x" for minute or minutes, "MHz" for megahertz, "mp" for melting point, "Mass spectrum" for mass spectroscopy , "'yamr" or "NMR" for nuclear magnetic resonance spectroscopy.

Example 1

F) R

Compound IM-1 o Stage 1: Intermediate compound I-ia (M-СНо, Б7-К-Н, К9-Н (2-(1-Hydroxy)indanyl)indole))

To a solution of indole (4.0 g, 34.1 mmol) in THF (200 ml) at -782C in a nitrogen atmosphere, Vi and 60 (34.1 mmol, 13.7 ml of a 2.5 M solution in hexanes) were added dropwise over 15 minutes. After stirring for 3 minutes, CO 5" (g) was passed through the solution for 10 minutes, after which the clear solution was left to warm to ambient temperature, then concentrated to half the volume under reduced pressure. The volume of THF was adjusted to approximately 200 ml and cooled to -782C. Tert-Vy and (34.1 mmol, 20 ml of a 1.7 M solution in hexanes) was slowly added while maintaining the temperature below -682C with further stirring for 2 hours at 62 -78oC. 1-indanone (5.0 g, 37.4 mmol) was added to THF (25 ml), the mixture was stirred for 1 hour, quenched by adding water (5 ml), then poured into a saturated solution of MH.CI (250 ml). The mixture was extracted with simple ether (1 x 200 ml), washed with 100 ml of a saturated solution of MNACI, dried (MazO,) and concentrated under reduced pressure to obtain an oil. Recrystallization from a mixture of EsgoO-hexane gave 5.1 g (6396) of I-i-a, m.p. 123-12420. "YAN YMR (SOSIZU: 5 2.3-2.5 (m, 1H), 2.55-2.7 (m, 2H), 2.9-3.05 (m, 1H), 3.1- 3.2 (m, 1H), 6.15 (s, 1H), 7.05-7.4 (m, 7H), 7.5 (d, 1H), 8.5 (s, 1H).

Stage 2: Intermediate compound Na (U-CH", B2-K7-H, K9-H (2-(1-Indenyl)indole))

2N HC (bml) was added to a stirred solution of Ia (4.0 g, 16 b, 1 mmol) in acetone (5 bOml). After stirring for 15 minutes. at room temperature water was added and the solid was collected by filtration, washed well with water and dried to give 3.7 g (10090) of intermediate Pa as a white solid. IN NMR (SOSvB): 5 3.6 (s, 2H), 6.75 (s, 1H), 6.95 (s, 1H) 7.1-7.5 (m, 5H), 7.6 (d, 1H), 7.7 (d, 1H), 7.9 (d, 1H), 8.35 (width, 1H). Mass spectrum (EB") t/e 254 (M.23).

Stage 3: Intermediate compound Ia, (M-CH», B2-7-H, K9-H) 75 A mixture of intermediate compound Ia (6bOmg, 2.9mMol) and maleimide (55Omg, 5.7mMol) in a 10cm sealed reaction ampoule was heated with stirring at 180-190 during ZOkhv. After cooling to about 50-60 °C, Meon (Zml) was added and the product was collected after trituration to give 88mg (92905) of Sha as a white solid; t.pl. 210-214°C. "H NMR (DMSO-iv, ZOOMHC): 5 3.1-3.4 (m, 2H), 3.8 (m, 2H), 3.95 (t, 1H), 4.35 (d, 1H ), 6.9-7.4 (m, 7H), 7.75 (d, 1H), 11.05 (s, 1H), 11.25 (s, 1H). Mass spectrum (EV): t /e 327 (t-1).

Stage 4: Compound IM-1

Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (865 mg, 3.81 mmol) was added in one portion to a suspension of intermediate compound Sha (500 mg, 1.52 mmol) in toluene (boOml). The solution was kept at 60-65 for 6 hours. After cooling in an ice bath, the solids were collected by filtration, suspended in MeonN (20 mL) and the product was collected by filtration. Recrystallization from acetone gave 3500 mg of He (71965) of compound IM-1 as a yellow solid, m.p. 23002С. "H NMR (DMSO-av, ZOOMHz): δ 4.38 (s, 2H), He) 7.38 (t, 71), 7.45-7.5 (m, 1H), 7.6-77 (m, 2H), 7.8 (m, 2H), 8.6 (d, 71H), 8.95 (d, 1H), 11.15 (s, 1H), 12.15 (s, 1H) Mass spectrum (GAV): t/e 324 (t"). Elemental analysis, calculated for C 24H42M20270.7H20: C, 74.86; N, 4.01; M, 8.31. Found: C, 74.85; H, 3.62; M, 8.52.

Example 2 Fr

Compound IM-2 "I

To the stirred solution of compound IM-1 in MMP (2ml) was added Man (1mg of 9595) at room temperature. The reaction mixture changed color from orange to green. After 0.5 hours, water was added and the resulting red solid was collected, washed with water and dried. "H NMR (DMSO-iv, ZOOMHz): 5 7.34 so zv (t, 1H), 7.45(t, 1H), 7.6-7.75 (m, 4H), 8.35 (d , 1H), 8.95 (d, 1H). Mass spectrum (E5"): t/e 337 (t-1). them-

Example C

Compound IX-1

Stage 1: Intermediate compound Ma (U-СНо, 2-К7-Н, К9-Н)

Intermediate compound Pa (2.0 g, 8.7 mmol) and ethyl cis-p-cynoacrylate (3.3 g, 26, 00 mmol) were heated in a round-bottom flask in a stream of nitrogen at 19023 with stirring for 1 h. As it cooled to room temperature, MeonN (10 ml) was added and stirring was continued for 0.5 h. The solution was left overnight in the refrigerator and the separated solid was collected to give 88mg (2890) of intermediate Ma as a white solid. IN nMR (DMSO-av, ZOOMHz): 5 1.28 (t, U-6.9HzC, ZN), 3.00-3.08 (m, 1H), 3.30 (m, 1), 3, 47-3.51 (m, 1H), 3.62 (m, 1H), 4.26 (kv, 9U-7.0Hz, 2H), 4.54 (m, 1H), 4.72 (m, 1H), 6.97-7.09 (m, 2H), 7.16-7.24 (m, ZH), 7.31 (d, 9U-7.8Hz, 1), 7.50 (d, 9-7.5Hz, 1), 7.82 (d, 9-7.0Hz, 1H), 11.04 (s, 1H).

She Mass spectrum (EB") t/e 357, 379 (M--1, M.n23).

Ge) Stage Ib. The methanol layer from the stage was concentrated under reduced pressure to oil, and excess cyanoacrylate was removed by Kideigoig distillation (furnace temperature 802C, 1MM). The residue was triturated with ether to give a yellow solid which was collected. "H NMR showed a 2:1 mixture of Ma and Mia isomers (U-CH"); Mass spectrum (EB") 45 70 tue 357, 379 (M, Ma23). o Stage 2: Intermediate compound Miia (U-СНо, В2-В7-Н, В9-Н)

Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.05 g, 4.6 mmol) was added to a suspension of intermediate Mia from step 1 (b5Omg, 1.9 mmol) in toluene (bbOml) in the form one portion The solution was placed in an oil bath at 652C for 1 hour. After cooling to freezer temperature, the solids were collected by filtration, suspended in MeonN (20 mL) and the product was collected by filtration to give 62Omg (98965) of a yellow

F) solid matter. IN NMR (DMSO-ab, ZOOMHC): 5 1.44 (t, 9-7.0Hz, ZN), 4.36 (s, 2H), 4.45 (a, 9-7 18Hz, 2H), ko 7.38 (t, 1), 7.44 (t, 1H), 7.54-7.63 (m, 2H), 7.71-7.78 (m, 2H), 8.55 (d, 9U-7.5Hz, 71H), 8.63 (d, 9U-8.0Hz, 1H), 12.22 (s, 1H). Mass spectrum (EB") t/e 353, 375 (M--1, M-23). 6o0 Stage C: Compound IX-1

The product from step 2 (intermediate Ma) (500 mg, 14 mmol) in DMF (40 mL) and Cami catalyst (1 small spatula) was hydrogenated at 60 psig. inch in a Parr apparatus for 24 hours or until TLC data (2:11, EtOAc:Hexanes) indicated completion of the reaction. The solvent was filtered through celite to remove the catalyst, then concentrated under reduced pressure. The solid was triturated with Meon, 65 was collected and dried, yielding 325 mg (7195) of compound IX-1 as a white solid, m.p. » 3002S. NN NMR (DMSO-α, ZOOMHC): δ 4.30 (s, 2H), 4.93 (s, 2H), 7.32-7.42 (m, 2H), 7.52-7.56 ( m, 2H), 7.72-7.716 (m, 2H),

8.05 (d, 1H), 8.51-8.54 (m, 2H), 11.92 (s, 1H). Mass spectrum (EAV): t/e311 (t).

Example 4

Compound X-1

Stage 1: Intermediate compound Mina (U-СНо, В2--Н, К9-Н)

Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1 ,3g, 5,bmMol) in the form of one portion. The solution was placed in an oil bath at 652C for 6 hours. After cooling to freezer temperature, the solids were collected by filtration, suspended in Meon (20 mL), and the product collected by filtration to give 700 mg (8895) of the product as a mixture of two isomers of the cyano ester carbazole in a ratio of approximately 2.1 (MI:MIMa) according to "H NMR. Mass spectrum (E58") t/e 353 (M.--1). The mixture was directly used in the next stage.

Stage 2: Compound X-1

A mixture of the cyano ester isomers of MIMA and MIA from stage 1 (70Omg, 2.0 mmol) and Kami catalyst (one 75 full spatula) in DMF (40 mL) was hydrogenated at 60 psig. inch in a Parr apparatus for 24 hours or until TLC data (2:1, EoAc:Hexanes) indicated completion of the reaction. The solvent was filtered through celite to remove the catalyst, then concentrated under reduced pressure. The product was triturated with Meon, collected and dried to give 55mg (8996) of a white solid. According to H NMR data (DMSO-γ, ZOOMHCc) it was shown that the product was a 2:1 mixture of compounds X-1: IIX-1. Compound X-1 was isolated by column chromatography (silica gel) 20 and eluted with a mixture of toluene: THF, increasing THF content from 3095 to 5095. Fractions containing the pure product were combined and concentrated under reduced pressure. The product was collected after trituration with meon, mp » 3002C. "YAN NMR (DMSO-iv, ZOOMHz): 5 4 .08 (s, 2H), 4.59 (s, 2H), 7.20 (t, 9-7.5Hz, 1H), 7.37-7.46 (m, 2H), 7.54 (t , 9-7.5Hz, 1H), 7.64-7.71 (m, 2H), 8.53-8.56 (s, 2H), 9.18 (d, 9U-7.8HzC, 1H) , 11.71 (c, 1H). Mass spectrum c 25 (EB5B"): m/e 311 (M.n1).

Example 5 o

Compound PI-1

Stage 1: Intermediate compound I-IB (/-CsH»o, B7-27-H, E9-H). (1-Methyl-2-((1-hydroxy)indanyl)|indole))

You (9.bml, 24.1mmol) was slowly added to 1-methylindole (3.0g, 22.9mmol) in ether (200ml). "3 30 The solution was stirred at reflux for 4 h, cooled to room temperature, followed by the addition of 1-indanone in 1 Oml of ether. After stirring at room temperature for 2 hours, the solution was poured into a saturated solution of MH SI (3 mL). The ether layer was washed with water (2 x 20 ml), Masi solution (2 x 20 ml) and dried (Ma95O,). Trituration with a mixture of simple ether-hexane (2:1) gave 3.7 g (62965) IB. "H NMR (DMSO-α , ZOOMHz): 5 2.5-2.6 (m, 1H), 2.7-2.8 (m, 1H), 2.9-3, (m, 1H), 3.1-3.2 at 35 (m, 1H), 3.95 (s, ЗН), 6.0 (s, 1H), 7.05-7.30 (m, 2H), 7.45-7.5 (m, 7H ).-

Stage 2: 1-Methyl-2-(1-indenyl)indole (Intermediate PPB)

To a stirred solution of the intermediate compound I-IIB (500 mg, 1.9 mmol) in acetone was added slowly at room temperature 2N HC. After 2 hours, water was added and the precipitate was collected by filtration, washed well with water and dried, obtaining 445 mg (9696) of intermediate compound IB as a white solid, m.p. » 25020. /H 40 NMR (SOCI5): 5 3.66 (s, 2H), 3.8 (s, ЗН), 6.65 (s, 1H), 6.70 (s, 1), 7, 15-7.4 (m, 2H), 7.5-7.6 (m, 2H), o) c 7.75 (d, 1H). Mass spectrum (EB") t/e 245 (M-Y).

From" Stage-3. Compound 1-1 (Intermediate compound PI-B, M-СНо, В2-К7-Н, К9-Н)

A mixture of IB (ZvOmg, 1.6 mmol) and maleimide (190 mg, 1.9 mmol) in a 10 cm sealed reaction ampoule was heated at 1802 for 30 minutes. After allowing the mixture to cool below 602C, Meon (3ml) was added and the product was collected after trituration to give 45mg (8296) of a white solid, m.p. 205-2102p. NN NMR (DMSO-av, ZOOMHC): 5 2.9-2.95 (m, 71Н), 3.05-3.15 (m, 2Н), 3.5 (m, 71Н), 3.9 ( s, ЗН), 7.0-7.3 (m, 5Н), 7.45 o (d, 1Н), 7.55 (m, 1Н), 7.85 (d, 1Н), 11.05 (c, 1H). Mass spectrum (EB) t/e 341 (M-1). - Example 6

Compound IM-3 ve To a suspension of compound 1-1 from example 5 (333Omg, 1.0 mmol) in toluene (5Oml) was added solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (55O0mg, 2 .5 mmol) in the form of one portion. The solution was kept under reflux for 4 hours. After cooling in an ice bath, the solids were collected by filtration, suspended in Meon (2Oml) and the product collected by filtration to give 280Omg (8695) of a yellow solid, m.p. » 262-26590. IN nMR (DMSO-ab, ZOOMHC): 5 3.4 (s, ZN), 4.2 (s, 2H), 7.35-7.5

GF! (m, 4H), 7.6-7.8 (m, 2H), 8.3 (d, 1H), 8.95 (d, 1H), 11.1 (s, 1H), Mass spectrum ( E5U t/e 337 (M-1).

Example 7 o Compound IM-4

Stage 1: Intermediate compound Ps (M-CH»o, B?-H, K7-5-Vg, K9-H) 60 This substance was obtained using a similar general method of examples Ia-Pa, using indole (10.0g, 85.3mMol) and 5-bromo-1-indanone (19.0g, ZOmMol), obtaining crude alcohol intermediate Is. The obtained crude alcohol in the form of a dark oily residue was dissolved in acetone (2500 ml) with the subsequent addition of 2N NOSI (25 ml) and water (50 ml). After stirring for 2 hours at room temperature, the mixture was poured into water and extracted with EtOAc. EIUAs were washed with water and saturated salt solution, dried over MozO), then concentrated under reduced pressure. The product was triturated with ESO and collected to give

8.7 g of the intermediate compound Is. "H NMR (SOCI3): 5 3.56 (s, 2H), 6.68 (s, 1H), 6.90 (s, 1H), 7.12-7.25 (m, ЗН), 7, 4O (d, 1H), 7.52 (d, 1H), 7.66-7.74 (m, ЗН), 8.26 (s, 1H). Mass spectrum (EB"): t/e 311 (m'-1).

Stage 2: Intermediate compound Che (M-CH», B2-H, K7-5-Vg, E9-H)

This substance was obtained by means of a similar general procedure to Example 1 using Ps (300mg, 0.97mmol) and maleimide (30mg, 3.1mmol), obtaining 210mg (5795) of the intermediate compound Shs in the form of a white solid. IN YAM (DMSO-av): 5 3.72-2.80 (m, 1), 3.17-3.26 (m, 2H), 3.53 (m, 1H), 4.4 (m, 2H), 6.95-7.206 (m, 2H), 7.27 (d, 1H), 7.41-7.46 (m, 2H), 7.66-7.75 (m, 2H), 10 .69 (c, 1H), 11.33 (c, 1H). Mass spectrum 0 (EB7): t/e 407 (t).

Stage 3. Compound IM-4

This substance was obtained using a similar general technique for compound IM-1 using

She (16Omg, 04mMol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (228mg, 1.0mMol) to give 158mg (10095) of compound IM-4 as a yellow solid. "H NMR (DMSO-iv): 5 4.34 (s, 2H), 7.36 (t, 1H), 7.62 (t, 75. 1H), 7.73-7.82 (m, 2H), 7.98 (s, 1H), 8.52 (d, 1H), 8.93 (d, 1H), 11.18 (s, 1H), 12.18 (s, 1H). spectrum (EB'): t/e 402 (t-1).

Example 8.

Compound IM-5

Stage 1: Intermediate compound I-ia (M-СНХСН», В2-К7-Н, К9-Н (2-(1-Hydroxy-1,2,3,4-tetrahydronaphthyl)indole))

This compound was prepared using a similar general procedure to compound Ia, using indole (15g, 132mmol) and 1-tetralone (20g, 139mmol), yielding 18g (4695) of intermediate compound Ia as a white solid. IN nMR (SOS): 5 1.84-1.93 (m, 1H), 1.97-2.03 (m, 1H), 2.17-2.35 (m, 2H), 2.36 ( s, 1), 2.88-2.92 (, 2H), 6.10 (s, 1), 7.07 (t, 1H), 7.13-7.19 (m, ЗН), 7, 23-7.28 (m, 71H), 7.33-7.36 (m, 2H), 7.51 (d, 1H), 8.42 (s, 1H). p 29 Stage 2: Intermediate compound Id (M-CHNoCHn", B2-K7-H, B9-H (2-11-(3,4-dihydronaphthyl)) indole)) o

To a solution of alcohol I-ia (15g, 57mmol) in acetone (1500ml) was added 2n NOSI (3ml). After stirring at room temperature for 1 hour, water was added to initiate precipitation of the solid. The product was collected by filtration and dried to give 14 g (10095) of the intermediate as a white solid. "H NMR (SOSIv): 5 2.39-2.46 (m 2H), 2.82-2.87 (m, 2H), 6.38 (t, 1H), 6.59 (s, 1H) , 7.09-7.25 (m, o

From BN), 7.34-7.40 (m, 2H), 7.61 (d, 1H), 8.11 (s, 1H). Mass spectrum (EB") t/e 246 (M.-1). "

Stage 3: Intermediate compound Sha (М-СнНоСсН»о, В2-в7-Н, В9-Н) «-

A stirred mixture of diene Ia (330 mg, 1.4 mmol) and maleimide was heated at 19023 for 1 hour. The mixture was cooled, dissolved in ethyl acetate (bH0ml) and washed several times with hot water to remove i.

Зз5 of excessive maleimide. The EtOAc layer was dried (Mo5O)), concentrated, and the resulting solid was dried under vacuum at 8023, obtaining 425 mg (8995) Sha. Mass spectrum (EB'") t/e 341 (M-1).

Stage 4: Compound IM-5

2,3-dichloro-5,6-dicyano-1,4-benzoquinone (16 mg, 0.7 mmol) was added to the imide intermediate compound Sha suspended in toluene (1 Oml) in one portion with subsequent heating at 70 60-6590 within 16 hours. The suspension was concentrated and the product was purified by column chromatography - with (silica gel, E(OAc:hexane; 1:1), obtaining 9Omg of a yellow solid. "IN YAME 5 2.81 (m, 2H), 3.16 (m, 2H), 7.27 (t, 1H), 7.40-7.54 (m, 4H), 7.67 (m, 1H), 8.12 (d, 1H), 8.88 (d, 1H ), 11.10 (s, 1H), 11.85 (s, 1H). "Mass spectrum (EB") t/e 337 (M-1).

Example 9.

Compound IM-6 - Stage 1: Intermediate compound II. (y-cHn oCH», t2-5-OSH», ven, vb-n (95) (2-(1-Hydroxy-1,2,3,4-tetrahydronaphthyl)-5-methoxyindole)) - Intermediate compound I -ie was prepared using a similar general procedure for compound I-ia using 5-methoxyindole (5.0g, 34AMmMol) and 1-tetralone (5.3g, 34AMmMol), yielding 6.2g (6296) of intermediate 50 of compound I- i.e. in the form of a white solid. IN NMR (SOS): 5 1.84-1.90 (m, 1H), 1.96-2.03 (m, 1H), oz 2.16-2.33 (m, 2H), 2.36 (s, 1H), 2.90 (m, 2H), 3.80 (s, ЗН), 6.03 (s, 1H), 6.82 (m, 1H), 6.97 (s, 1H) , 7.13-7.25 (m, 4H), 7.32 (d, 1H), 8.31 (s, 1H).

Stage 2: Intermediate compound Pe (y-cHn oCH», t2-5-OSH», ven, vb-n v8BoO(2-11-(3,4-Dihydronaphthyl))|-5-methoxyindole))

2n NOSI (ml) was added to a solution of alcohol I-ie (ZOOmg, 1.0mmol) in acetone (10ml). After mixing at

F) water was added at room temperature for 1 hour to precipitate the product, which was collected by filtration and co-dried to give 200 mg (7395) of He as a red solid. "H NMR (SOSIV): 5 2.41-2.45 (m, 2H), 2.81-2.86 (m, 2H), 3.86 (s, ЗН), 6.35 (m, 71Н ), 6.52 (s, 1H), 6.83 (m, 71), 7.08 (s, 1H), 7.12-7.25 (m, 4H), because 7.39 (m, 1H ), 8.01 (s, 1H). Mass spectrum (EB") t/e 276 (M'-1).

Stage 3: Intermediate compound She. (U-СНоСН», К2-5-ОСН», В7-Н, К9-Н)

This substance was obtained using a similar general technique for compound Sha using

He (15mg, 0.54mmol) and maleimide (105mg, 1.1mmol) to give 10mg (5095) She as a white solid. Mass spectrum (EB") t/e 373 (M'n1). because Stage 4: Compound IM-6

This substance was obtained using a similar general procedure for compound IM-1 using She imide from stage C (8Omg, 0.22mMmol) and 2,3-dichloro-5,b-dicyano-1,4-benzoquinone (10Zmg, 045mMol) in dioxane (Zml), yielding 75 mg (95965). "H NMR (DMSO-ydv): δ 2.82 (m, 2H), 3.2 (m, 2H), 3.84 (s, ЗН), 7.15 (m, 51), 7.36- 7.59 (m, ZN), 7.57 (d, 1H), 8.11 (d, 1H), 8.46 (s, 1H), 11.09 (s, 1H), 11.69 (s , 1H).Mass spectrum (EB') t/e 367 (M-1).

Example 10

Compound IM-7

Stage 1: Intermediate compound I-ie (/-CH CH», vo-Hn, and -6-OSH», vo-n 70. (2-(1-Hydroxy-1,2,3,4-(b- methoxy)tetrahydronaphthyl)-2-indole))

Prepared by a similar general procedure for intermediate I-ia using indole (7.0 g, 59.8 mmol) and b-methoxy-1-tetralone (11.6 g, 65.8 mmol), yielding 12.7 g (73905) of intermediate compound I in the form of a white solid. IN NMR (SOS): 5 1.83-2.01 (m, 2H), 2.16-2.25 (m, 2H), 2.86 (m, 2H), 3.80 (s, ЗН) , 6.12 (s, 1H), 6.67-6.73 (m, 2H), 7.04-7.17 (m, 2H), 7.23 (m, 1H), 7.34 (d , 1H), 7.50 (d, 1H), 8.40 (width, 1H). 9 Stage 02:00 Intermediate compound 1 o (m-CHO osn, BN, 0 Vi-6osCHnU BN (2-(6-Methoxy-(3,4-dihydronaphthyl))-2-indole))

This substance was prepared using a similar general procedure for compound Ia, using intermediate compound I-its (300 mg, 1.03 mmol) and 3 ml of 2n HCl, yielding 280 mg (10096) of IC as a white foam. "H NMR (SOCI3): 5 2.37-2.43 (m, 2H), 2.78-2.85 (m, 2H), 3.82 (s, ЗН), 6.12 (s, 1 ), 6.25 (m, 1H), 6.57 (s, 1H), 6.70 (d, 1), 6.79 (s, 1H), 7.09-7.18 (m, 2H) , 7.33-7.35 (m, 2Н), 7.61 (d, 1Н), 8.10 (width, 1Н).

Stage 3: Intermediate compound PE (y-СНоСсН», В2-Н, К7-6-ОСН», В9-Н)

This substance was prepared using a similar general procedure for compound Sha, using He intermediate IR (250 mg, 0.91 mmol) and maleimide (265 mg, 2.7 mmol), yielding 225 mg (67905) PC as a white foam. "H NMR (SOSI): 5 1.60-1.72 (m, 2H), 2.70-2.9 (m, ЗН), 3.62 (m, 1Н), 3.80 (s, ЗН ), 4.20 (m, 1H), 4.30 (m, 1H), 6.7 (s, 1H), 6.9 (m, 1H), 7.1-7.35 (m, 4H) , 6.60 (s, 1H), 6.80 (s, 1H), 8.0 (d, 1H). Mass spectrum (EB') t/e 371 (M-).

Stage 4: Compound IM-6 o

This substance was obtained using a similar general procedure for the compound IM-1, using the imide of ShPZh from stage C (ZBmg, 0.094 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (54 mg, 0.237 mMol), yielding 31 mg (8596) of compound IM-6 as a yellow solid. "H NMR (DMSO-α): δ 2.80 (m, 2H), 3.2 - (m, 2H), 3.83 (s, ЗН), 7.03 (m, 2H), 7.27 (t, 71H), 7.50 (t, 71H), 7.66 (d, 1H), 8.06 (d, 1H), 8.87 (d, 1), "o 11.05 (s, 1H), 11.76 (s, 1H). Mass spectrum (E5") mp 369 (M-H1), 391 (M.n23). them

Example 11

Compound IM-8

Stage 1: Intermediate compound I-id (M-СНоCH», В2-6-ОСН», В7-5-(2-ethoxy)ethoxy, К9-Н)

It was obtained using a similar general procedure for intermediate I-ia, using β-methoxyindole (1.5 g, 9.8 mmol) and 5-(2-ethoxy)ethoxy)|-1-tetralone (2.35 g, 10, 0 mmol), obtaining 1.8 g (4795) of the intermediate compound I-id as a white solid. "H NMR (SOSIv): 5 1.23 (t, ЗН), 1.83 (m, 1Н), 1.94 (m, ц 1Н), 2.10-2.32 (m, 4Н), 2 ,74-2.83 (m, 2H), 3.64 (q, 2H), 3.83 (s, ЗН), 4.15 (m, 2H), 6.02 (m, tn), 6, 72-6.80 "» (m, ЗН), 7.00 (d, 1H), 7.12 (d, 1H), 7.25 (s, 1H), 7.36 (d, 1H), 8 ,41 (width, 1H).

Stage 2: Intermediate compound Pd (M-СНоСН», 82-6-ОСНЗ, К7-5-(2-ethoxy)ethoxy, B 9-Н)

This substance was obtained using a similar general procedure for compound Ia, using intermediate compound Id (200 mg, 0.52 mmol) and 2 ml of 2N NOSI, obtaining 175 mg (9595) of intermediate compound Id as a white powder. "H NMR (SOSI): 5 1.25 (t, 3H), 2.32-2.40 (m, 2H), 2.85 (m, 2H), 3.65 (q, 2H), 3, 81-3.85 (m, 2H), 3.82 (s, ЗН), 4.15 (m, 2H), 6.33 (m, 1H), 6.49 (s, 1H), 6.76 -6.86 (m, ZH), 7.02-7.15 (m, 2H), 7.45 - (m, 1H), 7.97 (width, 1H). Mass spectrum (E5" ) t/e 364 (М'Н1). of them 70 Stage 3: Shu intermediate compound. (M-СНоСН», 1-2-6-ОСН», В7-5-(2-ethoxy)ethoxy, В9-Н) o This substance was obtained using a similar general procedure for the intermediate compound Ša, using the product of example Id (10mg, O.29mMol) and maleimide (55mg, 0.58mMol) to give 55mg (4190)

Sha in the form of white foam. 1 Mass spectrum (EB") t/e 459 (M-1).

Stage 4: Compound EM-8

This substance was obtained using a similar general procedure for compound IM-1, using (F; imide Sha from stage C (5Omg, 0.11 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( 54 mg, 0.24 mmol), yielding 45 mg (90965) of compound IM-8. "H NMR (DMSO-iv): δ 1.13 (t, 3H), 2.77 (m, 2H), 3.2 ( m, 2H), 3.51 (q, 2H), 3.74 (m, 2H), 3.84 (s, ЗН), 4.17 (m, 2H), 6.88 (m, 1H), 7.10-7.16 (m, 2H), 7.42 (m, 1H), 7.72 (m, MH), 60 8.7 (d, 1H), 1.04 (s, 1H), 11.65 (s, 1H). Mass spectrum (E5") t/e 455 (M-1).

Example 12

Compound 1-9

To the compound IM-4 (500 mg, 0.15 mmol) in DMF (2 ml) was added MV5 (Zimg, 0.18 mmol) with further stirring at room temperature for 2 hours. The solution was concentrated under reduced pressure. 65 The residue was triturated with Meon (3 ml) and the solid was collected and washed with Meon to give 55 mg (89905) of compound IM-9 as a yellow solid, m.p. » 3009; IN NMR (DMSO-av, ZOOmHz): δ 2.82 (m, 2H), 3.12

(m, 2H), 7.43-7.53 (m, AN), 7.68 (s, 1H), 8.14 (d, 1H), 9.06 (s, 1H), 11.24 ( c, 1H), 12.05 (c, 1H). Mass spectrum (E5BU) t/e 416 (M-1).

Example 13

Compound X-2

Stage 1: A mixture of intermediate compound II (2-(1-(3,4-dihydronaphthyl)|ndol) (1.0g, 4, mmol) and ethyl cis-(3Z-cyanoacrylate) (2.0g, 16.0mmol) ) was heated at 19027 with stirring for 1 hour. As it cooled to room temperature, Meon (10 mL) was added and stirring was continued for 0.5 hour. The solid that separated was collected to give 1.2 g (7990) of a white solid. Solid The substance 70 was a 1:1 mixture of 2 isomers and had a melting point of 3002C. Mass spectrum (EB") mp 371 (M'-1). This intermediate compound was directly used in the next stage.

Stage 2: To a mixture of isomers from stage 1 (500 mg, 1.35 mmol) in toluene (5 mL) was added solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (678 mg, 3.0 mmol) as one portions The mixture was heated at 60-652C for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained substance was dissolved in EtOAc (7Bml), washed with 2N Mahon (2x5Oml), water (2x50ml), saturated Massi solution (2x5O0ml), dried (MaozO,) and concentrated, obtaining 480Omg (9795) of the product in the form of a 1:1 mixture of Z- cyano and 4-cyano isomers. This intermediate compound was directly used in the next step.

Step C: A 1:1 mixture of isomers (45Omg, 1.2mMole) from Step C in DMF:MeOH (1:11, 1Oml) and 1 full spatula of CaMmi was hydrogenated at 55 psi for 18 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The solid substance was triturated with ether, obtaining 35Omg (9095) of a mixture of isomers of lactam IX-2: X-2 in a ratio of 1:1.

Stage 4: Compound X-2

Triethylamine (19mg, 0.25ml) and tert-butyldimethylsilyl chloride (285mg, 1.9mmol) were added to the lactam isomers from stage C (300mg, 0.93mmol) in DMF (10ml). The solution was stirred for 1 hour at room temperature, according to SM data by TLC (silica gel, simple ethertexane; 1:11) the reaction had proceeded to about 5095 at this time. DMF was removed under reduced pressure and the residue was dissolved in EtOAc, washed with water and Massey solution and dried (Mo950,). The solvent was removed and the resulting solid was triturated with ether. Compound X-2 was collected and dried, m.p. » 3002S. "H NMR (DMSO-iv, ZOOMHz): 5 2.8 (width, 4H), 4.5 (s, 2H), 7.21 (t, 1H), 7.37-7.51 (m, 4H), 7.65 (d, U-8Hz, 1H), 8.23 (d, U-7.6HzC, 1H), 8.63 (s, 1H), 9.14 (d, 9U-7, 7HzC), 11.48 (s, 1H) Mass spectrum (E5) at 371 (MA).

Example 14

Compound IX-2 -

The ether solution from Example 13 stage 4 was concentrated and THF was added, followed by TVAE (2ml, 1M in THF). The solution was stirred at room temperature for 4 hours, after which the solvent was removed and the resulting solid was triturated with water and collected. The product was washed with ether and dried (602С, mm), obtaining compound IX-2 in the form of a white solid, m.p. » 300 «S. "H NMR (DMSO-4yv, ZOOMHC): 5 2.77-2.81 (m, 2H), 3.49-3.52 (m, 2H), 4.83 (s, 2H), 7.23 -7.36 (m, 2H), 7.42-7.51 (m, ЗН), 7.70 (d, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 8.46 (s, 1H), 11.61 (s, 1H). Mass spectrum (EB'") t/e 371 (M'-1). "

Example 15 - c Compound ХІІ ц Stage 1: Intermediate compound ХІ (Б2-7-К5-Н) "» To a solution of 7-azaindole (5.2 g, 44 mmol) in dry THF (120 ml), cooled to -782С, in the atmosphere of nitrogen was slowly added to Vii and (46.2 mmol, 18.5 mL of 2.5 M solutions in hexanes). After stirring for 30 minutes

CO(g) was passed through the solution for 10 minutes, after which the clear solution was concentrated to approximately two-thirds of the original volume under reduced pressure. The volume of THF was adjusted to approximately 125 ml and cooled to -782C. Slowly added the third-you! and (44mmol, 2bml 1.7M solutions in hexanes), maintaining the temperature below -682C, followed by stirring for 2 hours at -782C. 1-tetralone (6b, 8g, 46.2mmol) in THF (10ml) was added dropwise to the orange solution. The mixture was stirred for 1.5 hours, then poured into 20 2N NOI (150 ml), extracted with EtOAc (1x150 ml), and the HCl layer was stirred for 18 hours. The NSI solution was alkalized with 2N Mahon and the resulting precipitate was collected, yielding 6.7 g (63905) of intermediate compound XII. "H NMR (DMSO-iv): δ 2.35 (m, 2H), 2.74 (m, 2H), 6.41 (s, 1H), 6.52 (m, 1H), 7.02 ( m, 1H), 7.17-7.24 (m,

ЗН), 7.35 (m, 1Н), 7.88 (m, 1Н), 8.15 (m, 1Н), 11.76 (s, 1Н). Mass spectrum (E5") t/e 247 (M.-1).

Stage 2: Intermediate compound XII (Н7-27-29-Н)

A mixture of intermediate compound X! (100 mg, 0.41 mmol) and maleimide (79 mg, 0.8 mmol) in xylenes (8 ml) (F) were kept under reflux for 14 hours. The reaction mixture was cooled to room temperature and the separated solid was collected, washed with ether and dried to give 390 mg (6495) of compound XII as a yellow-brown solid; Mass spectrum (EB") t/e 341 (M-1). in Stage C: Compound XII

Solid UBO (45 mg, 0.2 mmol) was added to a suspension of XII (35 mg, 0.1 mmol) in dioxane (3.5 ml). The reaction mixture was stirred at room temperature for 12 hours. Methanol (ml) was added and the mixture was cooled in a freezer. The light golden precipitate was collected and dried to give 200 mg (5895) of the compound

XII. "NN NMR (DMSO-iv): δ 2.88 (m, 2H), 3.2 (m, 2H), 7.39-7.48 (m, 4H), 8.17 (d, 1H), 8.62 (d, 1H), 9.14 (d, b5 1H), 11.25 (s, 1H), 12.48 (s, 1H). Mass spectrum (Eb5"): t/e 338 ( t-1).

Example 16

Compound P1I-2

Stage 1: Intermediate compound Id (y-5, K2-K7-859-H (2-(3-Benzotieno)indole))

To a solution of 1-carboxy-2-tributylstanylindole (9.5 g, 21.0 mmol) and 33-bromobenzothiophene (3.0 g, 14.1 mmol) in

Dichlorbis(bistriphenylphosphine)palladium(II) (771 mg, 1.1 mmol) was added to EUN (75 ml). The mixture was stirred at reflux under nitrogen for 16 hours, cooled to room temperature and concentrated under reduced pressure. The resulting dark oil was rinsed with ether-hexane (1:11) and decanted (2x) to give a brown solid. The solid was recrystallized from hot MeonH to give 3.2 g (6596) of a golden brown solid. "H NMR 70 (DMSO-α): δ 6.94 (s, 1H), 7.04 (t, 1H), 7.15 (t, 1H), 7.43-7.62 (m, 4H) , 8.04 (s, 1H), 8.09 (d, 1H), 8.29 (d, 1H), 11.55 (s, 1H). Mass spectrum (EB"): t/e 250 ( t'1).

Step 2: Compound PI-2 2-(3-Benzothieno)indole (Po, step 1) (10mg, 0.4mmol), maleimide (77mg, 0.8mmol) and trifluoroacetic acid (ca. 10 drops) in toluene (10ml) were kept at boiling under reflux for 75 12 hours. The reaction mixture was cooled to room temperature and the solid was collected, washed with toluene and ether to give 75 mg (5495) of compound IP-2 as a golden brown solid. "H NMR (DMSO-iv): δ 3.73 (m, 1H), 4.47 (m, 1H), 4.90 (m, 1H), 4.96 (m, 1H), 6.96- 7.06 (m, 2H), 7.17-7.30 (m, ЗН), 7.68 (m, 1H), 7.77 (m, 1H), 10.45 (s, 1H), 11 ,38 (s, 1H). Mass spectrum (E5"): m/e 345 (t-1).

Example 17

Compound IM-10

To a suspension of compounds 1-2 (Sha) (ZOmg, 0.09 mmol) in dioxane (4 ml) was added solid OBO (bomg,

Oh, 26 bmMol). After heating at 652 for 12 hours, the mixture was concentrated, the product was triturated with methanol, collected and dried, obtaining 24 mg (7895) of IM-10. "H NMR (DMSO-iv): δ 7.38 (t, 1H), 7.56-7.82 (m, 4H), 8.23 s (d, 1H), 8.92 (d, 1H) , 9.00 (d, 1H), 11.32 (s, 1H), 12.37 (s, 1H). Mass spectrum (EB"): t/e 341 (t-1).

Example 18 i)

HMIYA compound

Stage 1: Intermediate compound KHIM (K2-H)

This substance was obtained using a similar general procedure for the intermediate |I-ia, (ав) starting from indole (3.5 g, 29.9 mmol) and 4-keto-4,5,6,7-tetrahydrothianaphthalene (5.0 g, 32.9mMol), obtaining «b.5Bg (8195) CHEM in the form of a white solid. IN NMR (SOSIv): 5 1.93-2.09 (m, 2H), 2.16-2.24 (m, 2H), 2.33 (s, 1H), 2.86-2.93 ( m, 2H), 6.16 (s, 1H), 6.87 (d, 1H), 7.05-7.18 (m, ЗН), 7.35 (d, 1H), 7.52 (d , 1H), 8.44 (s, 1H). --

Stage 2. Intermediate compound ХМ (К2-Н) so

This substance was obtained using a similar general technique for compound Ia, using

KHM (200mg, 0.74MmMol), obtaining diene HM as a white unstable glassy substance. IN NMR - (SOCI3): 5 2.52-2.59 (m, 2H), 2.89-2.95 (m, 2H), 6.13 (m, Ш), 6.61 (s, 1H ), 7.08-7.22 (m, 4H), 7.35 (d, 1H), 7.60 (d, 1H), 8.14 (s, Sh). Mass spectrum (EB") t/e 252 (M.--1).

Stage 3: Compound HMI (K2-H) «

This substance was obtained using a similar general procedure for compound Sha using - with diene XM (250 mg, 1.0 mmol) and maleimide (194 mg, 2.0 mmol), obtaining 225 mg (6695) from a mixture of MeOH-simple ether. Mass spectrum (E5") t/e 347 (M-1). ,» Stage 4: Compound CHMI

A mixture of HMI (7Omg, O2mMol) and OO (13bmg, O,bmMol) was heated at 659C for 40 hours. The mixture was concentrated and the product (CI 0.4) was isolated by column chromatography (silica gel, E(Ac:hexane; 2:1) in the form of a yellow solid. IN NMR (DMSO-a5, ZOOMHz): 5 7.43 (t, 1H), 7.63 (t, 1H), 7.96 (d, 1H), 8.33 (d, 9) 1nH), 8.43 (d, 1H), 8.96 (d, 1H), 9.07 (d, 1H), 9.13 (d, 1H), 11.25 (c, 1H), 12.21 (c, 1H). Mass spectrum (EV") t/e ЗА1(М-1). -3з Example 19

Compound IM-11 of 70 Stage 1: Intermediate compound I-ip (M-CHНО, K2-в7-9-Н) o This substance was obtained using a similar general procedure for compound I-ia using indole (7.0 g, ZomMol ) and 4-chromanone (9.74 g, 65.8 mmol), yielding 12.5 g (7995) of crude oil. The sample was recrystallized from a mixture of ether and hexane. "H NMR (SOSI): 5 2.30-2.49 (m, s, ЗН), 4.26-4.43 (m, vv 2H), 6.25 (s, 1H), -6.86 -6.93 (m, 2H), 7.07-7.27 (m, ЗН), 7.35 (d, 1H), 7.54 (d, 1H), 8.39 (s, 1H).

Stage 2: Intermediate compound In (y-CHO, K2-K-KH) and F) The oil from stage 1 was dissolved in acetone (125ml) and 2N HC (20ml) was added with further stirring for 1h at room temperature. The precipitate was collected, washed with water and dried, obtaining 11 g (76905 2 stages) of the substance. "H NMR (SOCI3): 5 4.82 (d, 2H), 6.06 (m, 1H), 6.64 (s, 1H), 6.93-6.97 (m, 2H), 7, 11-7.25 (m, ZN), 60 7.36-7.A3 (m, 2H), 7.62 (d, 1H), 8.13 (s, 1H). Mass spectrum (EBB") t/e 248 (t1).

Stage 3: Intermediate compound IIi (U-СНоО, Кг-к7-в9-Н)

This substance was prepared using a similar general procedure for compound Pa, using diene IV (300 mg, 1.2 mmol) and maleimide (235 mg, 2.4 mmol). After cooling to room temperature, the residue was dissolved in EtOAc (5Oml) and washed with hot water (3x5Oml), dried (Mo5O/) and concentrated to give a yellow solid. Mass spectrum (EB") mp 343 (M- 1).

Stage 4 Compound IM-11

UBO (684 mg, 3.00 mmol) was added to the product of stage C (IIN) in toluene (1 Oml) and heated at 659 for 16 hours. The mixture was cooled to room temperature and the precipitated solid was collected, washed with Meon and dried to give 290 mg (7190 2 stages) of crude solid. The product was purified by column chromatography (silica gel, toluene:THF; 1095-3096 THF)". "H NMR (DMSO-a6, 30 MHz): δ 7.24 (m, MH), 7.33-7-38 (m, 2H), 7.59 (m, 1H), 7.62 (m, 2H ), 7.80 (m, 1H), 8.38 (d, 1H), 8.98 (d, 1H), 11.30 (s, 1H), 12.08 (s, 1H). Mass spectrum (E5") t/e 339 (M-1).

Example 20

Compound IX-3

Stage 1: A mixture of diene IN (88Omg, 3.bmMol) and ethyl cis-p-cyanoacrylate (1.8g, 14.4mMol) was heated at 190222 with stirring for 1 hour. While the mixture remained hot, methanol (15 ml) was added, followed by stirring at room temperature for 3 hours. The separated solid was collected and dried in vacuo to give 55mg (41965) of the 4-CM isomer (intermediate M, M-CHO, K2-B7-H). in the form of a yellow solid. "H NMR (DMSO-av, ZOOMGhC): δ 1.33 (t, ЗН), 3.11-3.17(m, 1Н), 3.81-3.84 (m, 1Н), 4.00 -4.08 (m, 1H), 4.31-441 (m, 4H), 4.77 (d, 1H), 6.87 (d, 71H), 7.04-7.15 (m, ЗН ), 7.23 (t, 1H), 7.42 (d, 1H), 7.57 (d, 1H), 7.64 (d, 1H), 10.69 (s, 1H). Mass spectrum (EB") t/e 373 (M-1). The meonH layer was evaporated under reduced pressure to half the volume and a simple ether was added to initiate precipitation. After cooling at the temperature of the freezer during the night, 325 mg of a solid substance was isolated in the form of a mixture of isomers M in a ratio of 1:11 (М-СНО, К?-К-Н)- and MI (U-СНоО, К?-К-Н) according to according to "H NMR.

Stage 2: The 4-CM isomer from stage 1 (500Omg, 1.3mMol) and 00O (74Omg, 3.3mMmol) in toluene was heated for 18 hours at 602C. The solution was concentrated and the residue was dissolved in EtOAc, washed with 2N Mahon (2x), water, saturated salt solution and dried (Ma5O,)). After concentration of the solvent, the product was triturated with Meon, Ge to give 320 mg (6795). "H NMR (DMSO-av, ZOOMHz): δ 1.43 (t, ЗН), 4.48 (q, 2Н), 5.37 (s, 2Н), 7.20 (d, (5) 1нН) , 7.36-7.49 (m, ЗН), 7.65 (t, 1Н), 7.81 (d, 1Н), 8.25 (d, 1Н), 8.58 (d, 1Н), 12.12 (s, 1H). Mass spectrum (EVB") t/e 369 (Mt).

Stage 3: Compound 1X-3

To the cyano ester product from step 2 (300mg, 0.82mmol) in DMF:MeOH (20ml, 1/1) was added about a full Cami spatula and hydrogenated at 55 psi in a Parr apparatus for 14 hours. The solution was filtered through celite and concentrated. The product was recrystallized from MeOH to give 20mg (75905) as a white solid. IN NMR (DMSO-av, ZOOMHz): 5 4.90 (s, 2H), 5.75 (s, 2H), 7.15 (d, 1H), 7.29-7.38 -- (m, ZH), 7.52 (t, 1H), 7.75 (d, 1H), 8.02 (d, 1H), 8.22 (d, 1H), 8.62 (s, 1H), 11, 73 (p. 1H). Mass spectrum (EZ") t/e 326. DCC"F"O zv (MU. and -

Example 21

Compound X-3

A mixture of isomers from stage 1 of example 20 (30mg, 0.9mmol) was oxidized using OBO (boO7mg, 2.7mmol) using a similar general procedure to example 20, stages 3-15, obtaining ZbOmg (90965) « 70 product. The isomers were dissolved in a mixture (1:11, 30 ml) and hydrogenated using a similar general procedure - from example 20 stage 4, obtaining 175 mg. Compound X-3 was obtained from MeOonH. "H NMR (DMSO-4dv, ZOOMHz): δ 4.58 c (s, 2H), 5.25 (s, 2H), 7.15-7.50 (m, 6H), 7.70 (d, 71H), 8.30 (d, 1H), 8.60 (s, 1H), 9.20 (d, 1H), 11.60 (s, is" 1H). Mass spectrum (EB") t/ e 326 (M).

Example 22

Compound X-4 and Stage 1: Intermediate compound XM (B2-82-H) soman (325 mg, 8.2 mmol, 60905 dispersion in oil) was added to a solution of diene Pa (1.0 g, 4 1 mmol) in dry DMF (40 mL ). After stirring at room temperature for 1 hour, mesyl 2-benzyloxyethanol (1.9 g, 8.2 mmol) was added. The reaction mixture was heated to 7092C in an oil bath for 18 hours, cooled to room temperature and poured into water (100 ml). The product was extracted with EAs (2x100ml), followed by washing with water (2x100ml), sodium chloride solution (2x100ml) and dried (Mo950 5). The solution was concentrated under reduced pressure and the resulting product was triturated with a solution of simple ethertexane (1:11), obtaining 1.45 g (9595) of a reddish-brown solid. "H NMR (SOCI5): δ 2.38 (m, 2H), 2.86 (t, 2H), 3.59 (t, 2H), 4.12 (t, 2H), 4.31 (s, 2H), 6.20 (t, 1H), 6.47 (s, 1H), 6.74 (d, 71H), 7.02 (t, 1H), 7.10-7.25 (m, 9H ), 7.38 (d, 1H), 7.62 (d, 1H). Mass spectrum (EB") t/e 380 (t'n1). (F. Stage 2: Intermediate compound XIXH (K2-22-H) co To the product of stage 1 (65mg, 1.7mMol) in SNCI" (25ml) was slowly added oxalyl chloride (0.15ml, 1.7mMol) at the temperature of an ice bath The solution was stirred for 0.5 g, then anhydrous Meon (2 ml) was added with further stirring at room temperature for 0.5 g. The solution was concentrated, dissolved in EtOAc and washed with 2 N Meon (2x), water (2x), sodium chloride solution ( 2x) was dried (Mao5O)) and concentrated to a dark oil. Purification by column chromatography (silica gel, EtOAc:hexane; 1:11) gave 0.5 g (6395) as an oil. "H NMR (SOSIS): 5 2.35-2.42 (m, 2H), 2.83-2.89 (m, 2H), 3.23 (s, ЗН), 3.51-3.68 (m, 2H), 3.96-4.06 (m, 1H), 4.10-4.24 (m, 1H), 4.31 (s, 2H), 6.11 (m, 71H), 6.70 (d, 1H), 7.04-7.09 (m, 2H), 7.18 (m, 65 2H), 7.24 (m, 4H), 7.32-7.39 (m , 2H), 7.40 (m, 1H), 8.45 (m, 1H). Mass spectrum (EVB") t/e 466 (t1).

Stage 3: Intermediate compound XX (В2-87-Н)

A mixture of diethylcyanomethylphosphonate, intermediate compound XIX (16bOmg, 0.34mMol) and Ma»oCO» (4Zmg, 0.41mMmMol) in dry THF (25ml) was stirred at reflux for 4h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (50 ml), washed 2x 2N

Mahon, water, saturated salt solution, dried (MaSO)) and concentrated to give 15O0mg (9095) of a yellowish solid. TN nMR (SOS): 65 2.40 (m, 2H), 2.80-2.87 (m, 2H), 3.20 (s, ЗН), 3.5-3.65 (m, 2H) , 2.95-4.05 (m, 7H), 4.15-425 (m, 1H), 4.3 (s, 2H), 5.95 (s, 1H), 6.05 (m, 1 ), 6.65 (d, 71Н), 7.05-7.1 (m, 2Н), 7.18 (m, 2Н), 7.2-7.4 (m, 6Н), 7.45 ( m, 1H), 7.7 (m, 1H). 14cm"! 2240 (CM). Mass spectrum (EVB") t/e 489 (m'n1).

Stage 4: Intermediate compound XXI (К2-Е7-Н)

Intermediate XX (500mg, 1.1mmol), chloronil (27mg, 1.2mmol) and palladium acetate (24mg, 1.1mmol) in dichlorobenzene (40ml) were stirred at reflux under nitrogen atmosphere for 24h. The solution was concentrated, the residue was dissolved in EtOAc and extracted with a 2M solution of Ma 2CO3 (3x) and dried (Mao).

The product was purified by column chromatography (RI 0.5, silica gel, EOAc: hexane; 1:1). Mass spectrum (EB") t/e 487 (tya1), 509 (t23).

Stage 5: Compound X-4

A full Kami spatula was added to the product from stage 4 in a mixture of DMF-MeOH (10ml.eB5ml) and hydrogenated in the apparatus

Parra for 14 hours. The solution was filtered to remove the catalyst, then concentrated under reduced pressure. The residue was dissolved in a mixture of OME-MesSnH (1:1.15 ml), added RY(OH)2 (5Omg, 20905/C) and hydrogenated in the apparatus

Parra for 12 hours. The solution was filtered and concentrated under reduced pressure. The product was triturated with a mixture of EBO-hexane and collected to give IX-4. IN nMR (SOS): 5 2.95-3.0 (m, 4H), 4.20 (m, 1H), 4.4-4.5 (ext., 6H), 7.21 (m, 1 ), 7.28-7.46 (m, AN), 7.57 (d, 1H), 7.66 (d, 1H), 8.60 (s, 1H), 9.18 (d, 1H) . Mass spectrum (EB") t/e 369 (t'-1), 391 (t23).

Additional compounds IM-12-IM-44, IX-4, IX-5, X-5 and X-b6 were obtained according to the methods corresponding to examples 1-22. Such compounds, as well as those presented in the examples above, may be further referred to by reference to Tables 1-4, which are presented for illustrative purposes, where each entry corresponds to the (o) accompanying structure.

Table I

IJ

OM - o ; about "

IN

KU che

Her friend 5. schi tt t sne v V tires sne g 10-Vx H « ss OO HO ny -8 СНоСН» t z -

From" IM nose. 2-osB opy n

OSNoSNz shu nyny pn a Z A i I p y - ik sh Moi i ut - ; th

SNY pis zhyn ns salt ny posa Vo

IU-17 SNISN»OSNoSN» n N N - Z PON Piy NBN POM NO 1-21 Spasy; p n sSpesSNeSO VE

F) name) 60 b5

Stm-22 SnoSnison iU-94 SM2SE N ri SnoSvoSchNe

О2СНз т1у-25 СНоСК; n gi sSNnIsnesnnNo

OSN; iU-26 SNoSNe N I StoSNoSpoMNo

ZMNSNz

1st sVosV; r Pi SYUSNOMNo

OMERA tu-28 sys; n Kk There is respect; with

I1Uu-29 СНоСЕ; n n in kAI u po: ne yn po i oo about p kAKY” because in

IU-3 СН;СНе E IT I kA 0 00osn,

T/-35 Snisne G3-sm ni N stu-33 sNsN Goz-siunn; Mr. N

IU-34 SNoSN; And 3- N

IU-35 SS; 1 8-SNoMNOVNN- n GI sn. tu-36 SNoSV; : 3rd I gsnesnsomry posa Y Half SIX ---- 17-39 pi nn: nn p i i

His hands flow from the world | to cattle tu-42 snesa; K Й K Голекизой о стаз Снист с-снесно Ги ! IS

Table 2 (ав) and

OM o "I and "-- her so i

What?

AND:

Compound U Kk di vo rtltp-i se E i SN ; ; ; h

Table 3. Residential complex about;" n 2-3 in Sao. 5 oh

Kk o Yeoluka in Be | Em - hsh cTsn; SS li n 2

E 50 M

ХупП снесн С и н с 2 | 5 60 65

Table 4

AB and () and 6.

FOR

IN

76 Compound вк ві,В2 в в? and Vb

Mr. Wo Nyvy wrote them too? the burrow will bear | Н Н н я не прови вия обо н н - 1 ny sne н ня ше тр тясне тітр х-3 хо 1в,н sСнго гн н

OWL POVY PASI NIZ UN SANA NOSY PO

SHY in OZ SOMNSNe svo petrvoryuteyuayutt yur novo, TET

The isomeric fused pyrrolocarbazoles and isoindolones of the present invention may be used, inter alia, as therapeutic agents. In particular, the compounds can be used to inhibit kinza. It has been shown that isomeric condensed pyrrolocarbazoles and isoiindolones inhibit, for example, one or more ik kinases, platelet-derived growth factor receptor c kinase (ROSEK), vascular endothelial growth factor receptor kinase g) (MESEK) or MOgB-stimulated HERK phosphorylation.

The properties of the compounds of this invention are useful for therapeutic regulation. The activity of condensed pyrrolocarbazoles and isoiindolones in relation to some enzymes can be used to combat the harmful effects of these enzymes. In particular, inhibition of the vascular endothelial growth factor receptor (VESF) involves its use, for example, in diseases in which angiogenesis plays an important role, such as solid tumor cancer, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, as well as in other eye diseases and types of cancer. Inhibition of iiiK involves - use, for example, in diseases of the prostate, such as prostate cancer and benign prostatic hyperplasia, and for the treatment of inflammatory pain. Inhibition of platelet-derived growth factor receptor

Zo (ROSREB), provides for use, for example, in various forms of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, diseases that lead to cardiovascular failure, such as atherosclerosis, restenosis, restenosis after angioplasty, etc. similar

It was also shown that the activity of isomeric condensed pyrrolocarbazoles and isoiindolones also has a positive effect on the functioning and survival of cells responding to the trophic factor by promoting the survival of neurons. With respect to cholinergic neuron survival, for example, a compound can preserve the survival of a cholinergic neuron population at risk of death (eg, death due to injury, disease, degenerative condition, or natural development) compared to a cholinergic neuron population in which the compound is not present. , in the case where the treated population has a relatively longer period of functioning than the untreated population.

Many neurological diseases are characterized by neuronal cells that are in a state of death, damage, and that are functionally at risk, that undergo axon degeneration at the risk of death, and 2) others. These diseases include, but are not limited to, Alzheimer's disease, motor neuron diseases (eg, amyotrophic lateral sclerosis), Parkinson's disease, cerebrovascular diseases - (eg, stroke, ischemia), Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, their 20 peripheral nervous system diseases (for example, damaging eye neurons in chemotherapy-related peripheral neuropathy), including diabetic neuropathy; diseases induced by excitatory amino acids; and diseases associated with concussion or penetrating brain or spinal cord injuries.

The compounds are not only useful for enhancing the trophic factor-induced activity of trophic factor responsive cells, such as cholinergic neurons, but may also act as agents promoting

HF) survival of other types of neuronal cells, for example, dopaminergic or glutamatergic. The growth factor can regulate the survival of neurons in the direct sequence of signaling cascades of small GTP-bound proteins o gas, gas and sas42 (Oepnagai O.T., Viospet. ., 1996, 318, 729). Specifically, gas activation leads to phosphorylation and activation of intercellular receptor-activated kinase (ECK), which is associated with biological 60 growth and differentiation processes.

Stimulation of gas/sas42 leads to increased activation of UMK and p38, corresponding responses associated with stress, apoptosis, and inflammation. Although the corresponding growth factor reactions primarily proceed through

EKK, the impact on these later processes can lead to an alternative mechanism of neuron survival, which can mimic the growth factor's survival-enhancing properties (Hia eyi a!., Zsiepse, 1995, 270, 1326). Bo compounds may also function as survival-promoting agents for neuronal and non-neuronal cells through a mechanism related to, but also distinct from, growth factor-mediated survival, such as inhibition of the MK and p38 MAPK pathways, which can lead to survival through inhibition processes of cell death due to apoptosis.

These compounds are also useful in the treatment of diseases associated with reduced SPAT activity or death, damage to motor neurons of the spinal cord, and can also be used, for example, in diseases associated with apoptotic death of cells of the central and peripheral nervous system, the immune system and in inflammatory diseases. SPAT catalyzes the synthesis of the neurotransmitter acetylcholine and is considered an enzymatic marker for functional cholinergic neurons. A functional /0 neuron is also capable of survival. Neuronal survival is analyzed by quantifying the specific uptake and enzymatic conversion of a dye (eg, calcein AM) by living neurons. The compounds described herein may also find use in the treatment of disease states involving the proliferation of malignant cells, such as many types of cancer.

Due to their various useful properties, the distinctive features of isomeric condensed pyrrolocarbazoles and isoindoles can be applied in other activities such as scientific research.

For example, the compounds can be used to develop models of survival, function, identification of neuronal cells in the human brain, or to screen other synthetic compounds that have activity similar to that of the isomeric fused pyrrolocarbazole and isoindolone compounds. Thus, the compounds developed in this invention can be used as standard or reference compounds for use in 20 tests or assays to determine the activity of an agent in pharmaceutical research programs.

The compounds can also be used to study, identify and establish molecular targets (targets) associated with functionally relevant reactions. For example, if an isomeric fused pyrrolocarbazole or isoindole compound labeled with a radioisotope is associated with a specific cellular function (e.g., mitogenesis), then the target to which the derivative binds can be identified, isolated, and purified to , to characterize it. As a further illustration, the compounds can be used to develop assays and models to further understand the role played by i) inhibition of a serine/threonine or tyrosine protein kinase (eg, PKC, herK tyrosine kinase) in mechanistic aspects of related diseases and disease states. Thus, the compounds of this invention may be useful as diagnostic reagents in diagnostic assays such as those described herein. o o o Inhibition of enzymatic activity by means of the isomeric condensed compounds of pyrrolocarbazole and isoindolone according to the present invention can be determined using, for example, the following assays: - 1. Assay of inhibition of vascular endothelial growth factor kinase (MESEK) "- 2. Assay of inhibition of itsKA tyrosine kinase activity 3 .Analysis of inhibition of the activity of PKS and me) 4. Analysis of inhibition of the growth factor receptor obtained from platelets. uh-

Descriptions of these analyzes follow, but the results obtained here are not considered as limiting the scope of the disclosure of the invention. For convenience, some abbreviations defined in the main text are used to present the results. Other abbreviations are defined as follows: "μg" for microgram, "mg" for milligram, "g" for gram, "μl" for microliter, "ml" for milliliter, "l" for liter, "NM" for nanomolar concentration, "μM" for micromolar, "MM" for millimolar, "M" for molar and "nm" for nanometer, "BSC" with c for benzenesulfonic acid, "ATP for adenosine triphosphate and EDTC for 1,2-di(2-aminoethoxy)ethane-M ,M,M'M'-tetraacetic acid. ;" Inhibition of herKA tyrosine kinase activity

Selected isomeric fused compounds of pyrrolocarbazole and isoindolone were tested for their ability to inhibit the human cytoplasmic domain KA kinase activity expressed by baculovirus using the -I assay based on EGISA as previously described (Apdeiez ei ai., ApaI. Viospet. 236: 49-55, 1996). Briefly, a 96-well microtiter plate was covered with a substrate solution (fusion protein recombinant phospholipase o human C-/y/glutathione Z-transferase (Koiip ei ai. EMVO 3., 11:559-567, 1992). Inhibition studies were carried out in 100 μl assay mixtures containing 50 mM Nerez, pH 7.4, 40 μM ATP, 10 mM MacIi 2, 0.196 BSK, 275 DMSO, and various concentrations of inhibitor. The reaction was initiated by the addition of IgKA kinase and allowed to proceed for 15 minutes at 372. Then an antibody to of phosphotyrosine (VI) followed by the addition of a secondary enzyme-conjugated antibody, alkaline phosphatase-labeled goat anti-mouse Ids (Vio-Cad).

The activity of the bound enzyme was measured using an amplified detector system (BIRSO-VKI). Inhibition data were analyzed using a sigmoidal dose-response equation (variable slope angle) in

SgarpRai Rgizt. The concentration that led to 5095-fold inhibition of kinase activity is indicated as "IS v5or" - o The results are summarized in Table 5.

HerKA kinase 60 - century

IM-5 15 pn nn p o py ti PO 5

Inhibition of vascular endothelial growth factor receptor kinase activity

The isomeric condensed compounds of pyrrolocarbazole and isoindolone were tested for their inhibitory effect on the kinase activity of the baculovirus-expressed MESE domain of the receptor kinase (human YAK-1, COC, MESEKZ) using the method described in the EI IZA assay for IgKA kinase disclosed above. The kinase reaction mixture, which consists of 5 mM Nerez, pH 7.4, 40 μM ATP, 10 mM Maps, 0.190 BSK, 296 DMSO and different concentrations of the inhibitor, was transferred to RI C-u/Z5T coated tablets. MESEK kinase was added and the reaction was allowed to proceed for 15 minutes at 37 °C. Detection of the phosphorylated product was carried out by adding an anti-phosphotyrosine antibody (VI). A secondary enzyme-conjugated antibody was added to capture the antibody-phosphorylated RI C-uU complex (5T. The activity of the bound enzyme was measured using an amplified detection system (SIRSO-VKI). Inhibition data were analyzed using the sigmoidal dose-response equation ( variable angle of inclination) in SgarpRai Rgizt. The results are summarized in Table 6.

IM-30 (1 o and cm 5 o

F

3 o'clock

Inhibition of the kinase activity of the platelet-derived growth factor receptor Isomeric condensed compounds of pyrrolocarbazole and isoindolone were investigated for their inhibitory effect on the kinase activity of the receptor kinase domain expressed by the baculovirus ROSER using the EG IZA assay for IgKA

From the kinase described above. Analyzes were carried out on 96b-well microtiter plates coated with the substrate of RIS-USZT. Each 100 μl reaction mixture contained 500 mM Nerez, pH 7.4, 20 μM ATP, 10 mM Massi", 0.195 BSK, 2965

DMSO and different inhibitor concentrations. The reaction was initiated by the addition of a previously phosphorylated recombinant human enzyme (1 ng/ml ROSECr) and allowed to proceed for 15 minutes at 37 20.

Pre-phosphorylated enzyme was obtained before use by incubating the kinase in buffer C 70 containing 20 μM ATP and 10 mM MacIi for 1 hour at 420. Detection of the phosphorylated product was performed by adding horseradish peroxidase (HPR)-conjugated anti-phosphotyrosine antibody (OPI). Later, NKR substrate solution containing 3,3-5,5-tetramethylbenzidine and hydrogen peroxide was added, and the tablets were incubated for 10 minutes at room temperature. The reaction was quenched with acid, and the resulting absorbance was read at 4500 nm using a Vio-kipeiisv microplate reader (Vio-Tek Ipsvigitepi EI 312e). The 395 inhibition data were analyzed using a sigmoidal dose-response equation (variable slope angle) in iv. SgarpRaai Rgizt. The results are summarized in Table 7. (95) in 20 pyrrolocarbazoles and isoindolones.

IXh-1 (23)

Dosage and composition

For therapeutic purposes, the compounds of this invention can be administered by any method that brings the active agent into contact with the site of action of the agent in the mammalian body. The compounds can be administered by any conventional means available for use in combination with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. Preferably, they are administered as a single active agent in a pharmaceutical composition, but alternatively, they can be used in combination with other active ingredients, for example, other growth factors that /5 facilitate neuronal survival or axonal regeneration in diseases or disorders. The compounds are preferably combined with a pharmaceutical carrier based on the chosen route of administration and conventional pharmaceutical practice.

The compounds can be incorporated into pharmaceutical compositions, for example, by mixing with pharmaceutically acceptable non-toxic excipients and carriers. Such compositions can be obtained for oral use by parenteral administration, in particular, in the form of liquid solutions or suspensions; or oral administration, in particular, in the form of tablets or capsules; or intranasally, in particular in the form of powders, nasal drops or aerosols; or through the skin, using, for example, transdermal patches.

The composition can be conveniently administered in the form of a unit dosage form and can be prepared by any methods well known in the field of pharmaceuticals, for example, as described in Ketipdiop'z ch 25 Rpagtaseciisa! Zsiepsez (MagkRyb.So., Eaviop, RA, 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as (o) polyethylene glycol, vegetable oils and oils, hydrogenated naphthalene, and the like. In particular, a biocompatible, biodegradable lactide polymer, lactide, glycolide copolymer, or copolymers of polyoxyethylene and polyoxypropylene can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. -

Formulations for inhalation contain as excipients, for example, lactose, or can be aqueous solutions that contain, for example, polyoxyethylene-B-lauryl ether, glycocholate and deoxycholate, or oil solutions for administration in the form of drops for the nose or in in the form of a gel for intranasal application. Formulations for parenteral administration may also include glycolate for buccal administration, salicylate for rectal administration, or citric acid for vaginal administration. Compositions for transdermal patches are mainly lipophilic emulsions.

Compounds of the formula | and their pharmaceutically acceptable salts can be administered orally or non-orally, for example, in the form of an ointment or injection. The concentrations of the compounds of this invention in the therapeutic composition may vary. The concentration will depend on factors such as the total dose of the drug to be administered, the chemical characteristics (for example, hydrophobicity) of the compound used, the routes of administration, the age, body weight and symptoms of the patient, etc. The compounds of this invention can be prepared in the form of an aqueous physiological buffer solution containing from about 0.1 to 1095 wt/vol of the compound for parenteral administration. Typical dosage ranges range from about mg/kg to about 1 mcg/kg body weight per day; the preferred dosage range is from about 0.01mg/kg to 10Omg/kg of body weight per day and, preferably, from about 0.1 to 2Omg/kg one to four times per day. The preferred dosage of the medicinal product for administration will accordingly depend on such variables as the type and degree of development of the disease or disorder, the general health of the particular patient, the relative biological effectiveness of the selected compound, the composition of the excipients, and the route of administration.

Pharmaceutical compositions according to the present invention can be obtained by homogeneous mixing - an effective amount of the compound of the formula | or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. The carrier can take a wide range of forms according to the forms of the composition suitable for administration. Preferably, such pharmaceutical compositions are provided in a unit dosage form suitable for oral or non-oral administration. Forms for / Non-oral administration include ointment and injection.

Tablets can be prepared using excipients such as lactose, glucose, sucrose, mannitol and (F) methylcellulose, disintegrating agents such as starch, sodium alginate, calcium carboxymethylcellulose and

GI crystalline cellulose, lubricants such as magnesium stearate and talc, binders such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose and methylcellulose, because surfactants such as sucrose and fatty acid esters and sorbitol esters and fatty acids and the like in the usual way. It is preferable that each tablet contains 15-300 mg of the active ingredient.

The granules can be prepared using excipients such as lactose and sucrose, disintegrating agents such as starch, binders such as gelatin, and the like in a conventional manner. The powders may be prepared using excipients such as lactose and mannitol and the like in a conventional manner.

Capsules can be obtained using gelatin, water, sucrose, gum arabic, sorbitol,

glycerin, crystalline cellulose, magnesium stearate, talc and the like in the usual way. It is preferable that each capsule contains 15-30Omg of the active ingredient.

Syrup compositions can be obtained using sugars such as sucrose, water, ethanol and the like

In the usual way.

The ointment may be prepared using an ointment base such as petrolatum, liquid paraffin, lanolin and macrogol, emulsifiers such as sodium lauryl lactate, benzalkonium chloride, monosorbitan fatty acid esters, sodium carboxymethyl cellulose and gum arabic, and the like in a conventional manner.

Injectable preparations may be prepared using solvents such as water, saline 7/0, vegetable oils (eg, olive oil and peanut oil), ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate, and urethane , isotonic agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoic ester and chlorobutanol, antioxidants such as ascorbic acid and sodium pyrosulfite, and the like in a conventional manner.

It will be apparent to those skilled in the art that numerous modifications and variations of the present invention are possible in accordance with the foregoing. Thus, it is to be understood that within the scope of the appended claims, the present invention may be practically implemented other than as specifically set forth in this description, and it is intended that the scope of the invention encompass all such variations.

Claims (1)

The formula of the invention 1. The compound of the formula UC s b uv o 20, KK v v? it "- or its stereoisomer or a pharmaceutically acceptable salt, where c ring a is selected from phenyl and cyclohexene with a double bond a-p; ring B and ring E, independently, each together with the carbon atoms to which they are attached, selected from: - a) a b--linked carbocyclic ring in which 1-3 carbon atoms can be replaced by heteroatoms; and c) a 5-membered carbocyclic ring in which either 1) one carbon atom can be replaced by an oxygen, nitrogen or sulfur atom; "2) two carbon atoms can be replaced by sulfur and nitrogen atoms, oxygen and nitrogen atoms, or two nitrogen atoms; or - c C) three carbon atoms can be replaced by three nitrogen atoms, one oxygen atom and two nitrogen atoms, or one sulfur atom and two nitrogen atoms; ," О-Х-М/ selected from: 4) "ATAIS-M(В 7)-С(ВВ2-; e) -"СН(В")-с(50)-М(В 7)- and B. 9 -(7)-(50)-CH(in M); (9) B" selected from: - a) H, substituted or unsubstituted alkyl with 1-6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or t" 50 unsubstituted heteroarylalkyl; -C(-O)B, where B" is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic group and substituted or unsubstituted heterocyclic groups; c) -OKZ, where KZ is selected from H and alkyl, which contains 1-6 carbon atoms; a) -SS-OMNe, -"MEUV o, "(Sno)rmA UVO, "(SNorOva, -b(snorov and o -O(SNo)r MAU U, where p equals 1-4; and where or 1) 9 and KO each, independently, selected from H, unsubstituted alkyl with 1-6 carbon atoms and substituted de alkyl; or 2) BZ and БЕ" together form a binding group of the formula -(CH 2)5-X!-(СНо )", where X is selected from -O-, -5- and 60 -sne-; BA is the same as B; 22, 83, 27 and KZ are each independently selected from: a) H, aryl, carbocyclyl, heterocyclyl, -"SM, SEz, -MO", "OH, "OK, Ve, I, "(СНОМ -ос(Ов, ве Оос(хО)МАУВ о, "О(СНо)рОУ, Р, SI, " CHO, -"MeUv o, "MAb8(-0)оА 7, -МАЗС(-ОВ or -"МА8С(х5)В 7; Б) -СНоОВ", where В" is the residue of an amino acid after removal of the hydroxyl group from the carboxyl groups; c) -MA с-m o, -MeZs(-8)IMe vo, -соо8?, -с(хО)В, -С(ОМАУВ TO, -с(-5)MeV o, "-сСН- МОВ Я, -сн-маА 7, "СНОМ ВЯЯ, "СНо)МНА" or -СНА-ММА'ЯВяВ'А, where B? is selected from H, alkyl with 1-6 carbon atoms, -OH, alkoxy with 1- 6 carbon atoms, -оФ(хоВВ", -ос(хОо)МАУвВя, -ос(-8)МАУВЯ, o(СНо)рМвУВо, о(СНо)рОКУ, substituted or unsubstituted arylalkyl having 6-10 carbon atoms, substituted or unsubstituted heterocyclylalkyl and substituted or unsubstituted carbocyclic group; B 724 is the same as B 2; a) -(Оув 2, "СНо)ра(О)ув", -СНЬВ(О)УВ ", where у is equal to 0, 1 or 2; f) alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, where: 1) each alkyl, alkenyl or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl or alkynyl group is substituted by 1-3 groups selected from aryl with 6-10 carbon atoms, heterocyclyl, arylalkyloxy, heterocycloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, 18 hydroxyalkylthio, alkoxyalkylthio, E, Si. W, Her, -SM, -MO" OH, -ov7 -HUSNorsS( ОМА, -Х"(СНо)рс(-8)MA UVO, -Х(СнНоррОосс(хОМА В У, -Х(СНорСОВ, -ху( snorB(OuV, -X"(Sno)rmv s(xO)MA V I, -OS(-0)8 7, -OS(OMNA 2, O-tetrahydropyranil, MAV U, -mEZsoov 7, -MmvZs(-OMe vo, "Mmees(-5)Me vo, "Mmne(c-MnMNn", -MeU(-ОВ 7, -mv8s(x8)A 7, -MAb8(-0)"87, -(OUA, "SO, "С(хО)МАУв о, "С(х8)МАУв о, "с(-О)В Я, -snoov8, "СНАММА ВА, "СН-МОвВ 2, "СН-MAT, "СН-ММНеН(М- МНИМН», -5(20)DMV BA, -Р(-OKHOKU», -08"!) of a monosaccharide with 5-7 carbon atoms, where each hydroxyl group of the monosaccharide is independently either unsubstituted or replaced by H, alkyl with 1-4 atoms carbon, alkylcarbonyloxy with 2-5 carbon atoms or alkoxy with 1-4 carbon atoms; X2-O,5 or Me8; c O selected from -MEE, -O- and -5-; He) 2? selected from H, 50287 , -СО»Б7, -С(О)Б7, -С(5О)MAУВ o, alkyl with 1-8 carbon atoms, alkenyl with 2-8 carbon atoms and alkynyl with 2-8 carbon atoms, and or 1) each an alkyl, alkenyl, or alkynyl group is unsubstituted, or o zo 2) each alkyl, alkenyl, or alkynyl group rupa, independently, is substituted, as defined for 22.3, and VZ in item is) above; M U is selected from "-- a) unsubstituted alkylene with 1-3 carbon atoms; B) alkylene with 1-3 carbon atoms substituted by K"Z, where KZ is selected from "2, thioalkyl with 1-4 carbon atoms, halogen, alkyl with 1-4 carbon atoms, alkenyl with 2-3 carbon atoms and alkynyl with 2-3 carbon atoms, where i) each alkyl with 1-8 carbon atoms, alkenyl with 2-38 carbon atoms and alkynyl with 2-8 carbon atoms is unsubstituted; or "j) each alkyl with 1-38 carbon atoms, alkenyl with 2-8 carbon atoms, and alkynyl with 2-38 carbon atoms, independently, substituted as defined for B, KU, B" and БЕ? in item e) above ; and - c c) functional group selected from -CH-CH-, -CH(OH)-CH(OH)-, -O-, -5-, -8(-50)-, -8(-50 )5. )-, -СН(ВУ)с(-0)-, -С(МОВ'ЗСН(ВУ-, -снЕ8с(-Мов 72)-, - (ОВ), -Ш8)С(-0); -« СН»?2-, -2СНо- and -СНоСН»-, where 7 is selected from -С(К72)-, -О-, -8-, 415 -сб028"2, -С(-МОВ "2) - and OTHER 2)-; - A! and A? selected from H, H; H, OK"; H, -5872; H, -Щ(К 735; and groups where A" and A? together form a fragment, selected from 50, 5 and "MV 2; and about B' and B? selected from H, H; H, OK"; H, -58727; H, -Щ(К 735; and groups where B' and B? together form a fragment - selected from 50, -Z and "MV; iz 70 provided that at least one of the pairs A" and A? or B' and B? forms 50. 2. The compound of the formula XXII c x ikh o A MU (F) , E E wo u bo v B or its stereoisomer or a pharmaceutically acceptable salt, where the ХО ring is selected from phenyl and cyclohexene with a double bond а-п; ring B and ring E, independently, and each, together with the carbon atoms to which they are attached, are selected from: a) a b-linked carbocyclic ring in which 1-3 carbon atoms can be replaced by heteroatoms; and 65 c) a 5-membered carbocyclic ring in which either 1) one carbon atom can be replaced by an oxygen, nitrogen or sulfur atom; 2) two carbon atoms can be replaced by sulfur and nitrogen atoms, oxygen and nitrogen atoms, or two nitrogen atoms; or C) three carbon atoms can be replaced by three nitrogen atoms, one oxygen atom and two nitrogen atoms, or one sulfur atom and two nitrogen atoms; O-X-M/ selected from: a) CHATAZS-M(B 7)-C(B'VZ-; c) -CH(K)-c(-0)-M(B .7)- and c) -"Ш(К 3-С(503-СН(В 72)-; В" selected from: a) H, substituted or unsubstituted alkyl with 1-6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl; c) -C(O)B, where B" is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, 19 substituted or unsubstituted aralkyl, substituted or unsubstituted carbocyclic group and substituted or unsubstituted heterocyclic groups; c)-OB8, where EZ is selected from H and alkyl, which contains 1-6 carbon atoms; a) -С(хо)мНнА?, "MAV У, "СНОМ в о, "СсНо)рОове, "Ф(СНо)рОве and -"С(СНО)рМАУВ , where р equals 1-4; and 20. Be or 1) 9 and KO each, independently, selected from H, unsubstituted alkyl with 1-6 carbon atoms and substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or 23 VZ and KO together form a binding group of the formula -(CH 2)5-X!-(СНо)», where X! selected from -O-, -5- and -Sno-; c BA is the same as B; o 22, 83, 27 and KZ each, independently, selected from: a) H, aryl, carbocyclyl, heterocyclyl, -"CM, SEz, -MO", "OH, "OK, Be, I, "(СНОМ -ос (Ов, -ос(:оМме УВО, -Ф(СНо)роМе, Е, СИ, -СНоокУ, -МЕ?В "9, -МЕ885(-0)58 7, -МЧЕЗС(-ОВ 7 or -МАЗС( -5)8 7; zo B) -SNOV 7", where BK"! represents the amino acid residue after removal of the hydroxyl group from the carboxyl group; , -с(хо)872, -с(хО)MUVO, -с(58)MeVo, -"СН-МОВ , - -сн-маА 7, "СНОМ ВИЯ, "СНо)МНА" or -СНА-ММА' YByaA, where B? is selected from H, alkyl with 1-6 carbon atoms, -OH, alkoxy with 1-6 carbon atoms, me) -оФ(хов", -ос(хОо)МАУвВія, -ос(-8 )IMAUV"Y, o(SNo)rMvUvo, o(SNo)rOKU, substituted or unsubstituted arylalkyl having 6-10 carbon atoms, substituted or unsubstituted heterocyclylalkyl and substituted or unsubstituted carbocyclic group; B 724 is the same as B 2; a) -в(О)ув У, "СНо)рВ(О)уУ, -"СНоВ(О)УВ ", where у equals 0, 1 or 2; « f) alkyl with 1-8 carbon atoms, alkenyl with 2-8 carbon atoms and a alkynyl with 2-8 carbon atoms, where: 1) each alkyl, alkenyl or alkynyl group is unsubstituted, or t c 2) each alkyl, alkenyl or alkynyl group is substituted with 1-3 groups selected from aryl with 6-10 "with by carbon atoms, heterocyclyl, arylalkyloxy, heterocycloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, "hydroxyalkylthio, alkoxyalkylthio, E, Si. W, Her, -SM, -MO" OH, -ov7 -HUSNorsS( ОМА, -Х"(СНо)рс(-8)МА УВО, -Х"(СНо)рОоС(хОМА В Е, -ХУ(СНо) pSOV, -xu(snorB(OuV, - 15 -X"(SnNo)rmv s(xO)MA UVO, -OS(-0)8 7, -OS(OMNA 2, O-tetrahydropyranil, MAV U, -meZsoov 7 . ", -с028е"2, -Ф(хОМеУВ Я, -«С(-8)МАУв о, -С(-О)В2, - -снгов8, "сСН-ММе в А, "сНАМОвВ"?, "-" CH-MeT, "SNAMMNen(М-МН)МН", (50) B, "Р(ИЗХОХОВУ", 1) 50 units of monosaccharide 3 with 5-7 carbon atoms, where each hydroxyl group of the monosaccharide is independently either unsubstituted or replaced by H, alkyl with 1-4 carbon atoms, alkylcarbonyloxy with 2-5 carbon atoms or 62 alkoxy with 1-4 carbon atoms; X2-O, 5 or ME; O selected from -ME5, -O- and -5-; 2? with Н, 50287, -СО»Б7, -С(О)Б7, -С(5О)MAУВ o, alkyl with 1-8 carbon atoms, alkenyl with 2-8 carbon atoms and alkynyl with 2-8 carbon atoms , and or where 1) each alkyl, alkenyl or alkynyl group is unsubstituted, or 2) each alkyl, alkenyl or the alkynyl group, independently, is substituted as defined for 22,3, and in VZ in item y) above; In selected from a) unsubstituted alkylene with 1-3 carbon atoms; B) alkylene with 1-3 carbon atoms substituted by K"Z, where KZ is selected from "2, thioalkyl with 1-4 carbon atoms, halogen, alkyl with 1-34 carbon atoms, alkenyl with 2-3 carbon atoms and alkynyl with 2-3 carbon atoms, where i) each alkyl with 1-8 carbon atoms, alkenyl with 2-38 carbon atoms and alkynyl with 2-8 carbon atoms is unsubstituted; or i) each alkyl with 1-38 carbon atoms, alkenyl with 2-8 carbon atoms and alkynyl with 2-38 carbon atoms, independently, substituted as defined for K2, EZ, 27 and RE in item e) above; and c) a functional group selected from -СНАСН-, -СН(ОН)-АСН(ОН)-, -О-, -5-, -5(50)-, -8(50)5, -С(К9 )о-, -с-с(8733-, -6(50)-, -б(1-МовВ'У., -сб(ов'ЗвВя, -с(ихо)0сн(ВУ-, -сSN(ВУ )С(-0)-, -С(-МОК'ЗССН(В У, -сСнеЕ Сс(-МОв 72)-, - (ОМ), -«ШЧЭ8)С(50)-, -«СН»Я- . and A? selected from H, H; H, OB"; H, -8872; H, -Щ(К 72)"; and groups where A" and A? together form a fragment selected from 50, 5 and "МВ 2; and B' and B? selected from H, H; H, OK"; H, -58727; H, -Щ(K 735; and groups where B' and B? together form a fragment selected from 50, - C and "MV; provided that at least one of the pairs A" and A? or B' and B? forms -0. 3. The compound according to claim 1, where B", VZ and B? are N. 4. The compound according to claim 3, where -0-X-U- represents -"СНоМ(В )С(О), -С(5ОМ(В )СН"- or -С(С-О)М(В ) C(-0). 5. The compound according to claim 1, where rings B and E are independently substituted or unsubstituted phenyl or pyridyl. 6. The compound according to claim 1, where CO is -ME, and K59 is H or substituted or unsubstituted lower alkyl. 7. The compound according to claim 1, where M is an unsubstituted alkylene with 1-3 carbon atoms, -С(-0)-, -СН2О-, -5-, -О- or -СНАСН.-. 8. The compound according to claim 1, which has the formula: in! . 1 / cm is V (o) (di 2 -- and V i 4 "y - where is v? "- 9. The compound according to claim 8, where rings B and E represent phenyl. with 10. The compound according to claim 9, where B", VZ and E? are N. 11. The compound according to claim 9, where A" and A? are selected from H, H; H, OH; H, OSN"; H, -Щ(К 77)"; or groups where A" and A? together - form -O or -MEA "2; B! and B? selected from H, H; H, OH; H, OSN"; H, -Щ(К 77)"; or groups where B' and B? together they form 50 and -MV2; and 72 - H, methyl, ethyl, propyl, -OH or methoxy." 12. The compound according to claim 9, where KZ is H or substituted or unsubstituted lower alkyl. 13. The compound according to claim 9, where U is an unsubstituted alkylene with 1-3 carbon atoms, -С(-0)-, -СН2О-, -5-, -0- or -СНА:СН-. - p 14. The compound according to claim 1, which has the formula: з» и , В , в , " , " Kk M M M Ogky tvo o o o o o OO Yu datzivatotse x Fo a is OO oo N ; ; ! - B: Eh! ; N Nna iz 70 y , s , y , y , o o eO o o Oko o Oo- o 25 ep ovtotshva o U kh M yk M o sn, y y v: ki Gesn, : bo b5 N ' sh ' 2) they o ono OM no DNO 5 Fi, veni NI Fi, gi tsi N «/ osn, Ye i zhi nin pn O---o o- M. no o M no Ve, I and F. o, - (7 - m Fi 4 | o, F F. ts Ho FO, y c) SO) y Kk y zny nyn pi OO On o o- zho On cho F o, 5 u 5 F u 24 Y cho o sch M F M y | M shield -claim 7 (o) V N he H 5.5 N cho, N ' N ' N ' n ' M o o M ok o "jo o - i " Fu 5 o FI losi still M M M i schi " I so N o, N y u I o) - N o ( o SN Vo. o them s 7 o tro o o o o o i o Z z Z (7 F and F fi. o 8 cv. that 7 shi in F t s i de son Mo Sm MN, - in Н N ' N iz o o "vo oo oo de cho o - 2 ooo, pine s05-o 7 f / /7 F is hy d- F goiter Zh KO bo b5 N N N N on chno ono o "ro OO 5dya ; - ooo Os sho sh to o on nya ne o i a a 000 OO they o O- S o 7 cholo Za - Falo a 59589 8 nk sh М M sh o o 5 ) s Soie an i zo 0; M o me O- o ny o "I nos - Mt F u Z F LV, gi u / her y FV F i- M o Go) o o " - o nm sy MS s - s sn,O,MN F 5 snnn is SHHI. Kk Fe Ff and F - te her o o o d 50 nos o o ms. oto Ho o on o eto o Fa V Ff i i Y still o (F. - K , k , n , with C i; (v; ono o-k no tya u 0 5 ot i on Fa z Fa A Fa; V N b5 o M o Ot -o Oz v; on sr Wed SON yu Osy still n , N I G o y o (0) M GI on boss Ff Her same s s I n O IF N N x 15. Pharmaceutical composition, which includes a compound according to claim 1 or claim 2 and a pharmaceutically acceptable carrier. 16. Pharmaceutical composition according to claim 15, which includes a compound according to claim 14. 17. Pharmaceutical composition according to claim 15 for the treatment or prevention of prostate diseases. 18. Pharmaceutical composition according to claim 17, where the prostate disease is prostate cancer or benign prostatic hyperplasia. 19. Pharmaceutical composition according to claim 15 for the treatment or prevention of angiogenic diseases. high school 20. Pharmaceutical composition according to claim 19, where the angiogenic disease is cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, eye diseases and macular degeneration. 21. Pharmaceutical composition according to claim 15 for the treatment or prevention of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis or restenosis. 22. Pharmaceutical composition according to claim 15 for the treatment or prevention of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, dementia with AIDS, epilepsy, multiple sclerosis, peripheral neuropathy or brain or spinal cord injuries "- brain 23. A method of inhibiting herK kinase activity, which includes providing the compound according to claim 1 or claim 2 in an amount sufficient for effective inhibition. uh- 24. The method according to claim 23, where herK kinase is herK A. 25. The method according to claim 23, where the compound according to claim 1 or claim 2 is intended for the treatment of inflammation. 26. A method of treating or preventing prostate diseases, which includes administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound according to claim 1 or claim 2. 27. The method according to claim 26, where the prostate disease is prostate cancer or benign prostatic hyperplasia. 28. A method of treatment or prevention of angiogenic diseases, which includes the introduction of a host that;" in need of such treatment or prophylaxis, a therapeutically effective amount of the compound of claim 1 or claim 2. 29. The method according to claim 28, where the angiogenic disease is solid tumor cancer, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, eye disease or macular degeneration. -I 30. A method of treatment or prevention of diseases in which ROSEK activity affects pathological conditions, which includes providing the compound according to claim 1 or claim 2 in an amount sufficient to contact the platelet-derived growth factor receptor with an effective inhibitory amount of the compound . - 31. A method of treating or preventing neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis, which includes administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound according to claim 1 or claim 2. 32. A method of treatment or prevention of diseases characterized by abnormal activity of cells responding to a trophic factor, which includes providing the compound according to claim 1 or claim 2 in an amount sufficient to contact the cell receptor of the trophic factor with an amount of the compound that induces effective trophic factor activity . 33. The method of treatment or prevention of Alzheimer's disease, amyotrophic lateral sclerosis, F) Parkinson's disease, stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy or brain or spinal cord injuries, which includes the introduction of the host, in need of such treatment or prevention, a therapeutically effective amount of the compound of claim 1 or claim 2. 60 Official Bulletin of Industrial Property. Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 6, 15.06.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5