UA66362C2 - QUINOLINE AND QUINOXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/ OR p56 - Google Patents

Abstract

This invention is directed to quinoline/quinoxaline compounds which inhibit platelet-derived growth factor or p56lck tyrosine kinase activity, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating apatient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or ' cell activation and proliferation.

Description

Description of the invention

This invention relates to the inhibition of cell proliferation and/or cell matrix production, and/or 2 cell movement (hematoxis), and/or T-cell activation and proliferation by using quinoline and quinoxaline compounds, which are useful protein tyrosine kinase (TPK) inhibitors.

Cellular signaling occurs through a system of interactions that includes cell-to-cell, cell-to-matrix, or extracellular receptor-to-substrate contact. The extracellular signal is often transmitted to other parts of the cell through tyrosine kinase-mediated phosphorylation, which affects 70 substrate proteins behind the cell membrane bound to the signal transduction complex. An example of tyrosine kinase enzymes involved in cellular signaling is a specific set of enzyme receptors, such as the insulin receptor, the epidermal growth factor receptor (EGF-K), or the platelet-derived growth factor receptor (GEF-K). Autophosphorylation of the enzyme is required for efficient enzymatic phosphorylation of substrate proteins containing tyrosine residues. It is known that these substrates are responsible for a variety of 72 cellular acts, including cell proliferation, cell matrix production, cell migration, apoptosis, etc.

It is clear that uncontrolled cell proliferation, matrix overproduction, or poorly regulated programmed cell death (apoptosis) cause many disease states. These disease states affect a wide variety of cell types and include diseases such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, fibrosis, atherosclerosis and restenosis that occurs after coronary, femoral or renal angioplasty, or a fibroproliferative disease such as arthritis , fibrosis of lungs, kidneys and liver. In addition, conditions for cell proliferation with impaired regulation are created after coronary bypass surgery.

It appears that inhibition of tyrosine kinase activity would be useful in regulating uncontrolled cell proliferation, matrix overproduction, or poorly regulated programmed cell death (apoptosis). with

It is also known that some tyrosine kinase inhibitors can interact with more than one type of He) tyrosine kinase enzyme. Some tyrosine kinases are very important for the normal functioning of the body. For example, it would be desirable to inhibit the action of insulin in most normal cases. Thus, compounds that inhibit ROSB-K receptor tyrosine kinase activity at concentrations below those effective in inhibiting insulin receptor kinase could provide valuable tools for the selective treatment of diseases characterized by cell proliferation and/or cellular matrix production, and/ or movement of He cells) (chemotaxis) such as restenosis.

This invention relates to modulation and/or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, regulation of abnormal cell growth and inflammatory response of cells. More specifically, this invention relates to the use of substituted quinoxalines that have the ability to selectively inhibit differentiation, proliferation or mediator release by effectively inhibiting ee, platelet-derived growth factor receptor tyrosine kinase activity (ROSBE-K) and/or tyrosine kinase activity.

In a number of reports in the literature, tyrosine kinase inhibitors that selectively act on "tyrosine kinase receptor enzymes, such as ESBE-K or ROSBE-K, or non-receptor cytosolic tyrosine kinases C 70, such as u-abi, robisk or c-zgso, are described. Recent reviews by Zrada apa Muege (Ehr. Orip. Teg. Raiepiz 1995, 5(8), 805) and Vgiddez (Ehr. Orip. Teg. Raiepiz 1995, 5(12), 1245) provide a brief description of the literature

With" regarding tyrosine kinase inhibitors and inhibitors selective for ESBE-K, respectively. In addition, am apa and udop gave a brief report on the antitumor potential of tyrosine kinase inhibitors (Etegoipud Ogide: Te Rgozresi

Eog Itrgomed Meadisipez 1996, 241-260).

Known inhibitors of tyrosine kinase activity of the ROSB-K receptor include quinoline-based inhibitors, described by Maditsyge and a). (U. Med. Spet. 1994, 37, 2129) and YuoMe ei aiYi. (9. May. Spet. 1994, 37, 2627). Class

Ge») of phenylaminopyrimidine-based inhibitors was recently described by Tgahieg ei ai. in ER 564409 and Lttegtap, ..; apa Tgahieg, R. ei aI. (Viogd. May 5. Spet. Gen. 1996, 6(11), 1221-1226) and Vyspadipdeg, E. ei aYi. (Rhos. Mai. o Asaid. Zsi. 1995,92,2558). Despite progress in this area, there are still no agents in these classes of compounds that have been approved for use in humans for the treatment of proliferative diseases.

The relationship between the multifactorial restenosis disease and ROSE and ROSBE-K is sufficiently described in the scientific literature. However, recent advances in the understanding of pulmonary fibrosis (Apiopiadez, N.M. ei ai. 9. Siip.

Ipmevi 1990, 86, 1055), kidney and liver (Reieggop, G.S. Nerayiodu, 1993, 17, 486) showed that ROSE and ROSB-K also play an important role in these diseases. For example, glomerulonephritis is the main cause of 29 kidney failure, and as shown in ZPtsi2 ey a). (At. 9. RPuzioi. 1988, 255, Eb74) and Rioede ei ai. (Siip.

GF) Ex. Etc. 1991, 86, 334), ROSE was identified as a potent mitogen for human mesangial cells.

As reported Trogpiop, V.S.; oh oh oh (Sip. Ehr. Ittyp. 1991, 86, 79), TME-alpha and ROSE (obtained from people with rheumatoid arthritis) are the main cytokines involved in the process of synovial cell proliferation. In addition, specific types of tumor cells have already been identified (see Ziimeg, V.), Viobasiogv. 1992, 60 3, 217) such as glioblastoma and Kaposi's sarcoma, which overexpress the ROSE protein or receptor, leading to uncontrolled growth of tumor cells through an autocrine or paracrine mechanism. Thus, it is expected that the ROSE tyrosine kinase inhibitor will be useful in the treatment of a variety of apparently unrelated disease states that can be characterized by the involvement of ROSE and/or ROSB-K in their etiology.

The role of various non-receptor tyrosine kinases, such as p5b sk (hereinafter "| sk"), in conditions associated with inflammation, which include the activation and proliferation of T cells, was already described by Napke, ei a!. (Pyatt. Kez. 1995, 44,

357) and Voiep apa Vgydde (App. Keu. Ittipoi., 1997, 15, 371). These inflammatory conditions include allergy, autoimmune disease, rheumatoid arthritis, and transplant rejection. Another recent review briefly described the different classes of tyrosine kinase inhibitors, including compounds that have inhibitory activity on IskK (Socpamyeg, ei a). Rgodgezz ip Meadisipai SPpetivighu. 1996, 33, 233). Some natural products that are usually non-selective inhibitors of tyrosine kinases include staurosporine, genistein, some flavones and erbstatin. Recently, there was a report on damnacanthol as a low-NM inhibitor of sc (Rajupek, ey aiYi. Viospetizigu, 1995, 34, 12404). Examples of synthetic IskK inhibitors include: a number of dihydroxyisoquinoline inhibitors, which, as reported (Vygke, et al., 9. 7/0 Me4. Spet. 1993, 36, 425), have activity at low concentrations ranging from micromolar to submicromolar; and a quinoline derivative, which was found to be much less active in relation to IC (IC 5o-61OmM).

Researchers also discovered a number of 4-substituted quinazolines that inhibit Isk at a low concentration ranging from micromolar to submicromolar (Muege et al., MU095/15758 and Muegz et al., Visogd. Med. Speth.

Gay 1997, 7, 417). Researchers from Riga (Napke et al., 9. Biol. Spet. 1996, 271, 695) have discovered two 7/5 bspecific pyrazolopyrimidine inhibitors, known as PP and PP2, which have low nanomolar activity against YsK and Rup. (another kinase of the 5gs family). There are no reports of I/C inhibitors related to quinoline- or quinoxaline-based compounds. Therefore, it is expected that a quinoline or quinoxaline inhibitor of ISK tyrosine kinase activity may be useful in the treatment of a variety of unrelated human disease states that can be characterized by the involvement of signaling through ISK tyrosine kinases in their etiology.

This invention relates to a compound of formula I:

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Kv M , (o) where

X represents I OH or 1 525;

It represents (SE zaKz)g or (SKzaKzv)t-23-(SKzakKze); with

Io represents (SE zaKz)p-74-(SVzaKz)d or ethenyl; "so 714 is CH or M; 7" is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, me) optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl; He 73 is O, MK, 5, ZO or 505;

Zo 74 represents O, MR, 5, 50, 50" or connection; d) t represents 0 or 1; n represents 2 or 3, and pnt-2 or 3; p or 4 independently represents 0, 1, 2, C or 4, and rka-o, 1, 2, C or 4 when 77 represents a bond, " and rna-o, 1, 2 or 3 when 72y is not a bond; r is 2, 3 or 4; o) c Kcha and Kz independently represent optionally substituted alkyl, optionally substituted aryl, "» optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally "substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano,

VBEvM- or acylBM- or one of B.4 and Cl is hydrogen or halogen, and the other is optionally substituted

Me. alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally

He» substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, CoKeM- or acylbiM-; b 20 Kys is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkyloxy, optionally substituted C" cycloalkyloxy, optionally substituted heterocyclyloxy, optionally optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halogen, cyano, K 5KeM- or acyl KBIM-;

Eza; Ez Kza and Kz are independently hydrogen or alkyl;

HF) Ku represents hydrogen, alkyl or acyl; and

Kb and Co are independently hydrogen or alkyl, or Kb and Ke taken together with the nitrogen atom to which Kb and Kv are attached form azaheterocyclyl, or its M-oxide, hydrate, solvate, prodrug, or pharmaceutically acceptable salt. 6o This invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. And this invention also relates to intermediate compounds suitable for obtaining compounds of formula I, methods of obtaining intermediate compounds and compounds of formula I! and using a compound of formula I to treat a patient suffering from (or susceptible to) disorders or conditions including cellular differentiation, proliferation, extracellular matrix production, or mediator release.

It should be understood that the following terms used above and throughout the description of the invention have, unless otherwise indicated, the following meanings.

Definition "Patient" includes both humans and other mammals. "Effective amount" is an amount of a compound of the present invention that is effective in inhibiting ROSE-K tyrosine kinase activity and YSK tyrosine kinase activity and therefore providing the desired therapeutic effect. "Alkyl" represents an aliphatic hydrocarbon group, which may be a branched or straight chain group having from about 1 to about 10 carbon atoms. A preferred alkyl is "lower alkyl" having from about 1 to about 6 carbon atoms. A branched chain means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halogen, carboxy, hydroxy or K 5KvM-.

Examples of alkyl are methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, 7/5 butyl, sec-butyl, tert-butyl, amyl and hexyl. "Alkenyl" is an aliphatic hydrocarbon group containing a double carbon-carbon bond, which may be a straight or branched group having from about 2 to about 10 carbon atoms in the chain. Preferred are alkenyl groups having about 2-6 carbon atoms, and more preferably about 2-4 carbon atoms in the chain. A branched chain means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkenyl" is a group having about 2-4 carbon atoms in the chain, which may be straight or branched. The alkenyl group can be substituted with carbalkyl. Examples of alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. LLC "Ethylenil" is a group - "SNASN-". "Cycloalkyl" is a non-aromatic mono- or polycyclic ring system having from about C to i) about 10 carbon atoms. The cycloalkyl group can be substituted by one or more, preferably by one to three, more preferably by one to two, of the following "cycloalkyl substituents": alkyl, hydroxy, acyloxy, alkoxy, halogen, KeKeM-, adylkoM-, carboxy or K5KeMSO-, and more preferred substituents are alkyl, c zo, pydroxy, acyloxy, alkoxy, and KeKeMSO-. In addition, if the cycloalkyl group is substituted with at least two hydroxy substituents, then at least two hydroxy substituents can be ketalized or acetalized with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. co "Hydroxycycloalkyl" is HO-cycloalkyl, where the cycloalkyl may be substituted as indicated above.

If the hydroxyalkyl group is selected from a cycloalkyl group that is also hydroxy substituted, then the specified two ise) hydroxy substituents can be ketalized or acetalized with an aldehyde or ketone with one to six carbon atoms to form the corresponding ketal or acetal. Ketalization of hemdiol leads to the formation of a spirocondensed ring system. A preferred spirocycloalkyl ring is 1,4-dioxaspiro(4,5|dec-8-yl. Preferred unsubstituted or substituted monocyclic cycloalkyl rings include cyclopentyl, hydroxycyclopentyl, fluorocyclopentyl, cyclohexyl, hydroxycyclohexyl, "hydroxymethylcyclohexyl and cycloheptyl; more preferably "hydroxycyclohexyl and hydroxycyclopentyl. y c Examples of polycyclic cycloalkyl rings can be 1-decalin, adamant-(1 or 2-)yl,

And (2.2.1Bicycloheptanyl (norbornyl), hydroxy|2.2.1|bicycloheptanyl (hydroxynorbornyl), 12.2.2|bicyclooctanyl and» and hydroxy|2.2.2|bicyclooctanyl; more preferably hydroxy|2.2.1|bicycloheptanil (hydroxynorbornyl) | and hydroxy|2.2.2|bicyclooctanyl. "Cycloalkenyl" is a non-aromatic monocyclic or polycyclic ring system having

He" is a carbon-carbon double bond and has from about 3 to about 10 carbon atoms.

The cycloalkenyl group can be substituted by one or more, preferably by one to three, and even more

Me, preferably with one or two cycloalkyl substituents described above. "Hydroxycycloalkenyl" is 2) HO-cycloalkenyl in which the cycloalkyl may be, as indicated, substituted. Preferred unsubstituted or substituted monocyclic cycloalkenyl rings have cyclopentenyl, cyclohexenyl,

Me, hydroxycyclopentenyl, hydroxycyclohexenyl and cycloheptenyl; more preferably "hydroxycyclopentenyl and

Ge hydroxycyclohexenyl. Preferred polycyclic cycloalkenyl rings are composed of (2.2.1|bicycloheptenyl (norbornenyl)) and (2.2.2|bicyclooctenyl. "Aryl" is an aromatic carbocyclic radical containing from about 6 to about 10 carbon atoms. An example of an aryl is phenyl or naphthyl, or phenyl or naphthyl, substituted by one or more substituents of the aryl group, which may be the same or different, and the "substituent of the aryl group" has in iF) its composition hydrogen, hydroxy, halogen, alkyl, alkoxy, carboxy, alkoxycarbonyl or Utu2so -, where they are independently hydrogen or alkyl. Preferred substituents of the aryl group include hydrogen, halogen, and alkoxy. A "heteroaryl" is an approximately 5- to 10-membered aromatic monocyclic or polycyclic hydrocarbon ring system , in which one or more of the carbon atoms in the ring system is an element(s) other than carbon, such as nitrogen, oxygen, or sulfur. "Heteroaryl" may also be substituted with one or d by several of the above "substituents of the aryl group". Examples of heteroaryl groups can be substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, 65 Pyrazolyl, furazanyl, pyrrolyl, imidazo|2,1-b)hiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl , quinolinyl, imidazolyl and isoquinolinyl.

"Heterocyclyl" is a 4-10-membered monocyclic ring system in which one or more atoms in the ring system are element(s) other than carbon and selected from nitrogen, oxygen, or sulfur.

The heterocyclyl group can be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents described above. "Hydroxyheterocyclyl" is HO-heterocyclyl in which the heterocyclyl may be substituted as indicated above. "Azaheterocyclyl" is the above heterocyclyl in which at least one of the ring atoms is nitrogen. Examples of heterocyclyl moieties include quinuclidyl, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl, or 7-oxabicyclo|2.2.1|heptanyl. 70 "Heterocyclylcarbonyloxy" is a heterocyclyl group as described above, which is attached to the parent molecular fragment through a carbonyloxy group (-C(0)0-). The heterocyclyl fragment is optionally substituted by one or more, preferably one to three, more preferably one cycloalkyl substituent, as described above. A typical heterocyclylcarbonyloxy group is 1,41-biperidin-1'-ylcarbonyloxy. "Heterocyclenyl" is a heterocyclyl ring system as defined above, which contains at least one carbon-carbon or carbon-nitrogen double bond. The heterocyclenyl group can be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents, described above. "Hydroxyheterocyclenyl" is HO-heterocyclenyl, in which the heterocyclenyl can be substituted as indicated above. "Azaheterocyclenyl" is the above heterocyclenyl in which at least one of the ring atoms is nitrogen. Typical monocyclic heterocyclenyl groups include 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, C ,4-dihydro-2H-pyran, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, tetrahydrothiophenyl and tetrahydrothiopyranyl, etc. "Acyl" is an H-CO- or alkyl-CO- group in which the alkyl group is as described above. Preference should be given to acyls containing lower alkyl. Examples of acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. i) "Aroyl" is an aryl-CO group in which the alkyl group is as described above. Examples of groups are benzoyl and 1- and 2-naphthoyl. "Alkoxy" is an alkyl-O group in which the alkyl group is as described above. Preference should be given to 3 to 3 alkoxy, which is "lower alkoxy" having from about 1 to about 6 carbon atoms. Alkoxy may be optionally substituted by one or more groups such as amino, alkoxy, carboxy, alkoxycarbonyl, x, carboxyaryl, carbamoyl or heterocyclyl. Examples of methoxy groups can be methoxy, ethoxy, n-propoxy, su isopropoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy, 2-(ethoxy)ethoxy, 2-(4-methylpiperazin-1-yl) ethoxy, carbamoyl, M-methylcarbamoyl, M,M-dimethylcarbamoyl, carboxymethoxy and methoxycarbonylmethoxy. d) "Cycloalkyloxy" is a cycloalkyl-O-group in which the cycloalkyl group is as described above. "at

Examples of a cycloalkyloxy group can be cyclopentyloxy, cyclohexyloxy, hydroxycyclopentyloxy and hydroxycyclohexyloxy. "Heterocyclyloxy" is a heterocyclyl-O-group in which the heterocyclyl group is as described above.

Examples of heterocyclyloxy groups include quinuclidyloxy, pentamethylene sulfidoxy, tetrahydropyranyloxy, "tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy or //7-oxabicyclo-(2.2.1I)heptanyloxy, pt") with hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo-(2.2.1|Iheptanyloxy. . "Aryloxy" is an aryl-O-group in which the aryl group is as described above. and?" "Heteroaryloxy" is a heteroaryl-O-group in which the heteroaryl group is as described above. "Acyloxy" is an acyl-O-group in which the acyl group is as described above "Carboxy" is a HO(O)C-(carboxylic acid) group.

Ge" "KBK'K-M-" represents a substituted or unsubstituted amino group, in which K 5 and Kv are as defined above.

Examples of groups can be amino (Noichm-), methylamino, ethylmethylamino, dimethylamino and diethylamino.

Me, "KBKeMSO-" is a substituted or unsubstituted carbamoyl group, in which K 5 and Kb are as defined in 2) above. Examples of groups are carbamoyl (HMCO-), M-methylcarbamoyl--"Memnoo-) and M,M-dimethylaminocarbamoyl (MeMCo-).

Me, "AcylKeBM-" is an acylamino group in which Kb and acyl are as defined above.

"Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred, and more preferably - fluorine or chlorine. "Prodrug" is a form of the compound of formula I, suitable for administration to the patient without excessive toxicity, irritation, allergic reaction and the like, and effective in its purpose; these forms include ketal, ester and zwitterionic forms. The prodrug is transformed ip past y

F) parent compound of the above formula, for example, by hydrolysis in blood. The full description is given by T. ka Nidispi and M. B(eya in Rgo-dgydz az Mome! YuOeiimegu Zuvietv, Moi. 14 oii (pe A.S.5. Butrozisht begiev, and Ezhmaga

V. Kospe, eid., in Viohemegvirbie Saitiege ip Ogyd Oevidp, Ategisap RIagtaseciisa| Avzosiayop apa. Regdatop in Rgezv, 1987; both materials are incorporated herein by reference. A "solvate" is a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bond formation, including hydrogen bond formation. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" represents 65 both solvates in the solution phase and solvates that are released. Typical solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate in which the solvent molecule(s) is H2O.

Preferred options

A preferred compound of the present invention is a compound of formula I, wherein:

It represents (SE zaKz)t- 23 (SEKzaKzev);

It is (SK zaKz)r-24-(SKzakKz)d; 72 is optionally substituted hydroxycycloalkyl or optionally substituted hydroxyheterocyclyl; 74 represents O and ME; t is 0; 70 n is 2 or 3; rna-o or 1;

Ka and Ki independently represent optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy or K 5KeM- or one of

Ka, and K/j represents hydrogen or halogen;

Ks represents hydrogen, optionally substituted alkyl or optionally substituted alkoxy;

Ezza; Kz, Kza and Kuz are independently hydrogen or lower alkyl;

Cu is hydrogen; and

Kb and Eb taken together with the nitrogen atom to which Kb and Ke are attached form azaheterocyclyl, or its M-oxide, hydrate, solvate, prodrug, or pharmaceutically acceptable salt.

Another preferred compound of the present invention is a compound of the formula and wherein:

X represents 1,525;

Y" represents (SK zaKz)r-24-(SKzaKz)d; 7" is optionally substituted hydroxycycloalkyl; 74 represents C and ME; c p is 0; d is 0 or 1; (8)

Kia and Ki are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, or optionally substituted heterocyclyloxy, or one of Ka and Kyl is hydrogen or halogen and the other of Ka and K/u - optionally substituted alkyl, optionally substituted alkyloxy, c zo optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy;

Ks is hydrogen; X,

Kza and Kz independently represent hydrogen; and

Cu is hydrogen; or its M-oxide, hydrate, solvate, prodrug, or pharmaceutically acceptable salt. ise)

Another preferred compound of the present invention is a compound of formula I, wherein Ka and K are independently optionally hydroxy-substituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy, or one of Ka, and K is hydrogen or halogen , and the other with K 44, and K/j - optionally substituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy.

The next preferred compound according to the present invention is a compound of formula I, in which Ka and K are independently heterocyclylcarbonyloxy or optionally substituted lower alkoxy, and more preferably in lower alkoxy is methoxy or ethoxy. . The next preferred compound according to the present invention is a compound of formula I, in which Ka and K are independently y? is lower alkyl, and more preferably lower alkyl, which is methyl or ethyl.

A further preferred compound of the present invention is a compound of formula I wherein one of C and R is lower alkoxy and the other of C and R is halogen, more preferably the lower alkoxy being methoxy or ethoxy and the halogen - chlorine or bromine.

The next preferred compound according to the present invention is a compound of formula I, in which one of Ka and K/j represents

Me. is lower alkyl, and the other from Ka and Cl1 is lower alkoxy, and more preferably lower alkoxy oo is methoxy or ethoxy, and lower alkyl is methyl or ethyl.

The next preferred compound according to the present invention is a compound of formula I, in which one of Ka and K/j represents

Me. is lower alkoxy, and the other with Ka and K/l is cycloalkyloxy, and more preferably lower

Alkoxy is methoxy or ethoxy, and cycloalkyloxy is cyclopentyloxy or cyclohexyloxy.

The next preferred compound of the present invention is a compound of formula I in which one of Ka and Kl is hydrogen and the other of Ka and Cl is lower alkoxy, cycloalkyloxy or heterocyclyloxy, and more preferably lower alkoxy is methoxy or ethoxy, cycloalkyloxy - cyclopentyloxy or cyclohexyloxy and heterocyclyloxy - furanyloxy.

F) The next preferred compound according to the present invention is a compound of formula I, in which K a and K i are lower o-alkoxy, optionally substituted by alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. A further preferred compound of the present invention is a compound of formula I, wherein one of Ka and Kl is unsubstituted lower o-alkyloxy and the other of Kia and Ki is optionally substituted heterocyclylcarbonyloxy or lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl.

The next preferred compound of the present invention is a compound of formula I in which one of Ka and K is methoxy, and the other of Kia and K is 1,4-bipiperidin-1-ylcarbonyloxy, 2-(ethoxy)ethoxy, 2 -(4-morpholinyl)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carboxymethoxy, methoxycarbonylmethoxy,

aminocarbonylmethoxy, M-methylaminocarbonylmethoxy or M,M-dimethylaminocarbonylmethoxy.

A further preferred compound of the present invention is a compound of formula I, wherein C is hydrogen, lower alkyl, or lower alkoxy, with more preferably lower alkoxy being methoxy or ethoxy.

The next preferred compound of the present invention is a compound of formula I wherein 74 is CH.

The next preferred compound of the present invention is a compound of formula I wherein 74 is M.

The next preferred compound according to this invention is a compound of formula I, in which the 7th is an optionally substituted hydroxycycloalkyl.

The next preferred compound of the present invention is a compound of formula I in which r and d are 0. 70 The next preferred compound of this invention is a compound of formula I in which r is 1.

The next preferred compound of the present invention is a compound of formula I wherein 74 is 0.

The next preferred compound of the present invention is a compound of formula I wherein 24 is 0 and 24 is 0.

The next preferred compound according to this invention is a compound of formula I, in which 74 is 0, and rnd-1.

The next preferred compound of the present invention is a compound of formula I wherein 74 is MCU.

The next preferred compound of the present invention is a compound of formula I wherein 74 is MK, and R and d are 0.

The next preferred compound according to this invention is a compound of formula I, in which 74 is MK", and species-1.

The next preferred compound of the present invention is a compound of formula I wherein 74 is 5.

The next preferred compound of the present invention is a compound of formula I wherein 74 is 5 and 11a is 0.

The next preferred compound according to this invention is a compound of formula I, in which 74 is 5, and the species is 1.

The next preferred compound according to this invention is a compound of formula I, in which 25 is hydroxy- or alkyl-substituted hydroxycycloalkyl, more preferably (lower alkyl) hydroxycycloalkyl. high school

The next preferred compound according to the present invention is a compound of formula I, in which Ka and Kl is lower alkoxy. optionally substituted by alkoxy, heterocyclyl, carboxy. alkoxycarbonyl or carbamoyl. and)

Preferred compounds according to this invention are selected from the following: trans-4-(7-Chloro-6b-methoxyquinoxalin-2-ylamino)cyclohexanol; trans-4-(6-Chloro-7-methoxyquinoxalin-2-ylamino)cyclohexanol; c zo trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol; cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol; ise) (2endo,bexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo-(2.2.1|)heptan-2-ol; c (2exo,bexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo-(2.2.1)heptan-2-ol; (2endo,Zexo,bexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|heptane-2,3-diol; d) cis-2-(6-Methoxyquinoxalin-2-ylamino)ucyclopentanol; "o trans-2-(6-Methoxyquinoxalin-2-ylamino)cyclopentanol; trans-4-(6-Methoxyquinoxalin-2-ylamino)cyclohexanol;

Izak,45,6K,base|1|-6-(6,7-Dimethoxyquinoxalin-2-ylamino)-2,2-dimethyltetrahydrocyclopenta|1.3|dioxol-4-carboxylic acid ethylamide; « 2-(1,4-Dioxa-spiro|(4.5|dec-8-yloxy)-6,7-Dimethoxyquinoxaline; with c 4-(6,7-Dimethoxyquinoxaline-2-yloxymethyl)cyclohexanol; 3-(6, 7-Dimethoxyquinoxalin-2-yloxy)cyclohexanol; » 4-(6,7-Dimethoxyquinoxalin-2-yloxy)cyclohexanol; 5-(6,7-Dimethoxyquinoxalin-2-yloxy)bicyclo|2.2.1)heptane-2, 3-diol; (2exo,Zexo,bexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|heptane-2,3-diol;

He»cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)cyclohexyl ester of acetic acid; cis-(6b,7-Dimethoxyquinoxalin-2-yloxy)cyclohexanol;

Me, 4-(6,7-Dimethoxyquinoxalin-2-yloxy)cyclohexyl ester of dimethylcarbamic acid; 2) trans-4-(6,7-Dimethoxy-4-oxyquinoxalin-2-ylamino)cyclohexanol; trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexyl ester of acetic acid;

Me, (2exo,bexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo (2.2.1)heptan-2-ol;

Ge (2endo,bexo)-5-(6,7-Dimethoxyquinolin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol; (2exo,bendo)-6-(6,7-Dimethoxyquinolin-2-ylamino)bicyclo|2.2.1| preferably heptan-2-ol; 4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (-3-(2trans,А4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol;

F) (-)--2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; ka (2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (2cis,4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; in (2cis,A4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; 4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol and (15,2K,45,5K)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo-(2,2LIheptan-2-ol).

The following compounds are more preferred: trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol; 65 cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol; 4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol;

(-)--2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (2exo,bexo)-5-(6,7-Dimethoxyquinolin-2-ylamino)bicyclo|2.2.1|-heptan-2-ol; trans-4-(7-Chloro-6b-methoxyquinoxalin-2-ylamino)cyclohexanol; 4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol and (15,2K,45,5K)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1)heptan-2-ol.

It is to be understood that this invention encompasses all suitable combinations of special groups and preferred groups mentioned in this description.

The compounds of this invention can be obtained using methods known from the literature, from known 7/0 compounds or from easily obtained intermediate compounds. Examples of common methods are given below.

In addition, compounds of the formula | are obtained according to the following schemes 1-X, where the variables are as described above, except for those variables that one skilled in the art of chemistry would consider incompatible with the method described.

Scheme I

Sun nom ven

Kk M. s v rec: woolen - clean "4

Ka M Ka

Scheme P

As Nh. t ke s y t I shchih se l cho o

Man, tnE and

Riv He Oabob5 k,y

Scheme Sh s n (Se) where s is an excess of "x "o Ge)

Man, tNE And I (Se)

Yi Yi (Se)

Scheme I that Vs « t Mo» DK meon ry nn

Virgo XX (2) pt s Ka M she Via y 4 . and?

Scheme U (o) (o) (95)

FO

Ko) ime) 60 b5

Scheme I

Ne nom v st M. s 5 tv M tro --- x

It is pure T and Z

Ka M Ka

Scheme P

As o Vske si t h shen My e ;oI nya ;ve a liv He Oabob5 k,y

Scheme Sh

N yo z) si excess Z "o ; man, tnE e chu s

The scheme of the IU about

Rice Vs

V. oon voby s leads

M Z you se (ze)

Scheme U i-th (Se) « shi s z (o) (o) (95) o 50 what)

F) ko 60 65

Scheme I

Ne nom v st M. s 5 tv M tro --- x

It is pure T and Z

Ka M Ka

Scheme P

As o Vske si t h shen My e ;oI nya ;ve a liv He Oabob5 k,y

Scheme Sh

N yo z) si excess Z "o ; man, tnE e chu s

The scheme of the IU about

Rice Vs

V. oon voby s leads

M Z you se (ze)

Scheme U i-th (Se) « shi s z (o) (o) (95) o 50 what)

F) ko 60 65

Scheme Y

As nm Ve N ve. tla Zv "S U UZ ro clean

M "

Ka Ka

Scheme P

Yais to Ya te s v x pt vllnvtr , We ;ofI t of iz pi. ХХ: Oabo5 du,

Scheme I n pi ve se surplus "xx "8 stand

Man, TNE co

І І сч 29 Scheme ІХ (о)

Re Rice

Viv MO 1)noU RIS V y z Mask Meon " Z ZyN ra XX (z) sia

Gee -

Ma M TZ you in (se) (ze)

Scheme U (Se)

Scheme U (Se) pe v na, MI Nivah: ycha and what 21NOZH Nana and Ge!

I'll see the uri, p on ' in y

Te) ta - s ve in h 1)na. What is your race? и зав и" MO zUNOMO, To wear In o

ZR, OVAYU S Za s tnnnvno ur tk M no Y - vh o (o) (o)

Scheme MI (95) b) Ve vs yav By 1) MabE! tik to ie iz I 2) Kg as: Zh

Basis, or ka M RON, RizR, OBAR or in g ss where at least one of K.; Kv and Kv); Represents where at least one of Ka; Cyrus and Ks -

ГФ) is lower alkoxy and ХХ" is as defined above, and where X' is d) HOR" or 127", where P" is a self-protecting ILOR, the protecting group P" then the group suitable for protection is removed to obtain /- OH in the hydroxyl fragment in the presence of a base and an alkylating agent

In the schemes MI, MI and MIK is a group that precedes K 44, Ki and Ks - as already defined above, in 65 which the interaction of KVg, KOH or KSOSI with an aromatic hydroxy group under the conditions described in the schemes MI, MI! and MI, leads to the formation of Ka, Kl or Kub.

The composition of a typical KVg includes bromoacetic acid and methyl or ethyl bromoacetate. Typical KOH includes 2-ethoxyethanol, 2-(4-morpholine)ethanol and 3-(4-methylpiperazinyl)propanol.

A typical KSOSI is (|1,4bipiperidin-1'-ylcarbonyl chloride.

Sema WE howl ah

ZkNa, I - n in 2) stilglyoxalate.,., KaOH I su that; ZE ROO Nshi y y vo, n vo Pskava, KBh 459 1n 19 DON, RR, REAYU zbo med

KO tah vo

She shen tt pyati o

As described in the diagrams

I, P, Sh or their es

In

ЧОР or и», with dere is a group suitable for protection of a thidroxyl fragment in the reaction conditions described in schemes I, CP, ОХ

Scheme MY s » asks r F moz tn y in ZI ZHAN, 0 snyovtmetu aton n (ze) 3 ROS - nyu da o Oouvazh , in I Te 7 (Se)

R My o dvzh" Or" or og",

Where Р" Р" is also a group, appendage for the protection of "st styutny nkk pdroxylny frapaient in pc descriptive In mo. Хих - conditions of the reaction, described by hyvshchak IJ, Shatkz IJ ve and schemes I, M, SHO 1X. - with not "» we che she -------- n

Ge") Pevgolla Fr. KVK in "OEASt" ny nn vi oh oo A "n

FO 50

Co.)

Ф) име) 60 b5 re Ka odeh"- ОР" or Gog», where Р" and Р" is

May M groups suitable for protecting the ------- hydroxyl moiety in as described in Vol

Meow. (7 under the reaction conditions described in schemes 1, M, Shabo and X and T schemes of I.P, SHYH r

M ke ef y

HELL

Basis. . HV abs

KON, tt, OBAO for. in -

Pe M

Scheme of IH in with B,

HeMoh", p

Kv Zh rak Mi catalyst Hch pe h u he - si, Vk or I v - 24 --- - ----- - 1a ХА iyuR'or oto, Ka M de P" - a group suitable for When X"- COR, the protection of the hydroxyl, the OR' fragment can be a fragment in the presence of a fragment transformed into the corresponding Grignard reagent OH fragment with the use of the corresponding protective He fragment about

Scheme X

I . s nesu she As meo M (in) eru" about "so meo M Meo M

And activate Gran 2. On RShS o 'Ve 2) 72 - GU nucleophile and catalyst 2 s

Mmeo 2 V. che uuuya in her in sho. in mo M Mei M meo (Se) and M

Mechi tyu: Yi Viting mz

You - and Ve

Mei 2,.sNo oon Chveey meo M meo ki " "Amen for obtaining 171) basis shsh gg: y y M | canon t change of Go 7" - electrophile with ! '

Ve Yake

Meo g meo 7 He) and MA, » oo obi " meo and Y meo re

In general

And not e and)

AND

F web

Me, Y. General operations: 2) 1. Interaction of 2-chloro-substituted quinoxaline and amines or anilines

A mixture of 2-chloro-6,7-dimethoxyquinoxaline (Eq.) and amine (approximately 1-eq.) is heated at

Me, about 160-180" for a period of time from about three hours to overnight. The dark brown residue is dissolved in a mixture of methanol-methylene chloride (0905-1095) and chromatographed on silica gel eluting with a mixture of hexane-ethyl acetate or methanol-methylene chloride ( 095-10095), resulting in the target product. The target product can be further purified by recrystallization in methanol, methylene chloride, or a methanol-water mixture. 2. Interaction of 2-chloro-substituted quinoxaline and alcohols or phenols

F) A suspension of alcohol or mercaptan (Eq.) and sodium hydride (approximately 1-Eq.) in anhydrous DMF/THF ka (0960-5090) is heated under reflux for 1 hour, after which 2-chloro-6,7- dimethoxyquinoxaline (Tech.). The resulting mixture is heated under reflux for approximately one to four hours. The suspension is neutralized to approximately pH 5-8 and distributed between methylene chloride and brine. The residue after concentration of methylene chloride is chromatographed on silica gel, eluting with a mixture of hexane-ethyl acetate or methanol-methylene chloride (095-10095), to obtain the target product. 3. Reductive amination reaction with aminoquinolines and aldehydes or ketones

Appropriately substituted 3-aminoquinoline (Eq.) is mixed with Eq. of the corresponding aldehyde or ketone in 65 V methanol (or other suitable solvent mixture) until TLC shows the completion of imine formation.

An excess of MasmMmVnN» or Mavn or other suitable reducing agent is added and the mixture is stirred until TLC shows consumption of the imine intermediate. The mixture is concentrated and the residue is chromatographed on silica gel with a mixture of hexane-ethyl acetate (0-10095) or chloroform-methanol (0-2095) to give the target product. 4. Interaction of 3-amino substituted quinolines and bromophenyl compounds

In a suitable manner, substituted C3-aminoquinoline (Eq.) is mixed with approximately 1.4 equiv. of a strong base such as sodium tert-butoxide, Eq. of the corresponding bromophenyl compound and catalytic amounts of 2,2-bis(diphenylphosphino)-1,1-binaphthyl (5-VIMAR) and bis(dibenzylideneacetone)palladium (Ra(dra)") in an inert organic solvent such as toluene in an inert medium such as argon, and heated to about 80°C overnight. The mixture was cooled, diluted with a solvent such as ether, filtered, concentrated, and 7/0 chromatographed with a mixture of 5095 E(Ac-hexane) to give the target product. 5. Formation of a simple ether from 3-hydroxy-substituted quinolines by ensuring the conditions of the Mitsunobu (Miivypovy) reaction

A solution of appropriately substituted hydroxyquinoxaline (at approximately 0-257"C) in THF is treated with equivalents of each of the desired alcohol, triphenylphosphine and, at the end, diethylazodicarboxylate (OEAYU) or the corresponding /5 equivalent. The course of the reaction is monitored by TLC and after the end of the reaction (from (about 1 to about 24 hours) the mixture is concentrated, and the residue is chromatographed on silica gel to give the target product 6. Dealkylation of a Lower Alkoxy Substituted Quinoline or Quinoxaline followed by Alkylation

The corresponding lower alkoxy substituted quinoline or quinoxaline (Teq-) in DMF is treated with excess sodium ethanethiolate (usually about 2 or more equiv.) and the reaction mixture is stirred at 2°C for about 1-24 hours. The mixture is partitioned between water and ethyl acetate. Extractive work-up followed by chromatography, if necessary, gives the corresponding target product: a hydroxy-substituted quinoline or quinoxaline.

The hydroxy-substituted quinoline or quinoxaline product can be alkylated using the Mitsunobu reaction conditions detailed above. In accordance with another variant, the target alkylated product yields a simple alkylation by methods well known in the field of chemistry with a reactive alkyl or benzyl halide using Mann or another suitable base in a suitable solvent. (8) 7. Oxidation of nitrogen in quinoline or quinoxaline to the corresponding M-oxide

The imine (-M-) fragment in the quinoline or quinoxaline compound of formula (I) can be transformed into the corresponding compound, in which the imine fragment is oxidized to the M-oxide, preferably by reaction with a peroxyacid, for example, peracetic acid in acetic or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane at a temperature ranging from about room temperature to the reflux temperature, preferably at elevated temperature. co

The compounds of this invention are useful in the free base or free acid form, or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the present invention. ise)

In the case of the compound according to the present invention, substituted by the main fragment, acid-addition salts are formed, which is a more convenient form for use; in practice, the use of a compound in the form of a salt is, strictly speaking, equivalent to the use of a compound in the form of a free base. Among the acids that can be used to obtain acid-addition salts, there are those that, when combined with a free base, create pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the patient in pharmaceutical doses of the salts, thanks to which "

Beneficial inhibitory effects on ROSPE, characteristic of the free base, are not accompanied by harmful side effects, such as those attributed to anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all acid addition salts are useful as sources of the free base form, even if the particular salt as such; required only as an intermediate, such as when a salt is formed only for purification and identification purposes, or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange methods. Pharmaceutically acceptable salts in the scope of the present invention are salts obtained from

Ge» of such acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid, and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid

Me. acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2) p-olpoolsulfonic acid, cyclohexylsulfamic acid, quinic acid, etc. Corresponding 5p Acid additive salts include the following: hydrohalides, for example hydrochloride and hydrobromide, sulfate,

Me. phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate,

He fumarate, maleate, methylene bis-p-hydroxynaphthoates, gentisates, mesylates, isothionates and di-p-toluene tartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

According to another feature of the present invention, acid-addition salts of the compounds according to the present invention are obtained by reacting a free base with a corresponding acid using or adapting iF) known methods. For example, the acid addition salts of the compounds according to the present invention are obtained either by dissolving the free base in an aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, and in this case the salt is released directly or it can be obtained by concentrating the solution.

The compounds of this invention can be regenerated from acid addition salts by applying or adapting known methods. For example, the original (parent) compounds of the present invention can be regenerated from their acid addition salts by treatment with an alkali, for example, an aqueous solution of sodium bicarbonate or an aqueous solution of ammonia.

In the case of the compound according to the present invention, substituted by an acid fragment, base-addition salts can be formed, which is a more convenient form for use; in practice, the use of the compound in the salt form is essentially equivalent to the use of the compound in the free acid form. The bases that can be used to obtain base-additive salts include mainly those that, when combined with a free acid, form pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the animal body in pharmaceutical doses of salts, due to which useful inhibitory effects on ROSBEs characteristic of a free acid are not accompanied by the harmful side effects attributed to cations. Pharmaceutically acceptable salts, which include, for example, salts of alkali and alkaline earth metals, within the scope of the present invention are salts obtained from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide 70, magnesium hydroxide, hydroxide zinc, ammonia, trimethylammonia, triethylammonia, ethylenediamine, n-methylglucamine, lysine, arginine, ornithine, choline, M,M'-dibenzylethylenediamine, chlorprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane , tetramethylammonium hydroxide, etc.

Metal salts of the compounds of this invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with 7/5 bpoluk in the form of a free acid. The aqueous solvent used may be water or a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are usually carried out at ambient temperature, but if necessary, they can be carried out with heating.

Amine salts of the compounds of this invention can be obtained by contacting the amine in an aqueous or organic solvent with the compound in the free acid form. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts can be obtained in a similar way. high school

The compounds of this invention can be regenerated from basic-additive salts by applying or adapting known methods. For example, the original (parent) compounds of this invention can be i) regenerated from their base-addition salts by treatment with an acid, for example, hydrochloric acid.

In addition to their utility as active compounds, the salts of the compounds of the present invention are also useful for the purpose of purifying the compounds, for example by exploiting the differences in solubility between the salts and the parent compounds, with the by-products and/or starting materials by methods well known to those skilled in the art of chemistry. .

The compounds of this invention may contain asymmetric centers. These asymmetric centers can independently have a K or Z configuration. For specialists in this field of chemistry, it is also obvious that some compounds of the formula | c can show geometric isomerism. Geometric isomers include cis and transform compounds of this invention, that is, compounds having alkenyl fragments or substituents in ring systems. In addition, endo- and exoisomers are classified as ise) bicyclic ring systems. This invention covers individual geometric isomers, stereoisomers, enantiomers and mixtures thereof.

Such isomers can be isolated from their mixtures by applying or adapting known methods, for example, chromatography methods and recrystallization methods, or can be obtained separately from the corresponding isomers of their intermediate compounds, for example, by applying or adapting the methods given in this description. starting materials and intermediate compounds are prepared by applying or adapting known methods, such as those described in the examples referred to, or their obvious chemical equivalents, or with methods described in accordance with the invention in this specification.

This invention is further illustrated by examples, but it is not limited to the following illustrative examples, in which the preparation of the compounds of this invention is described. b In addition, the following examples are methods used to synthesize the compounds of this invention.

EXAMPLE 1 3-Cyclohexyloxy-6,7-dimethoxyquinoline) 3-Hydroxy-b,7-dimethoxyquinoline (0.237 g, 1.15 mmol), cyclohexanol 2) (0.347 g, C ,4bmmol), RizR (0.908g, 3.4bmmol). Diethylazodicarboxylate is added in portions until the solution acquires a dark purple color (0.663g, 3.81mmol). After 4 hours, the solution is concentrated and the residue

Me. chromatograph (5095 EBE (OAc in hexanes). The product is recrystallized from a mixture of propanol/hexanes with

Ge by obtaining a hydrogen chloride salt in the form of a white solid (b.p. 229-232"С, decomposition).

EXAMPLE 2 2-anilino-6-isopropoxyquinoxaline hydrochloride

To Mann (0.033g, 0.84mmol) under argon is added 1ml of DMF. Add portions of 2-anilino-b-quinoxalinol (0.1 g, b.42 mmol) in 1.5 ml of DMF. After 30 minutes, 2-bromopropane is added dropwise and the solution is heated to 507 for 1.5 hours. The cooled reaction mixture is quenched with water and distributed between EtOAc and HNO, washed with HNO

F) (Szrazy) brine, dry (Ma95O)4) and concentrate. The obtained residue is chromatographed (3095 E(Ac/hexanes), with the result that 0.05 g of the dialkylated product and 0.00 g of the compound indicated in the title are obtained. An analytical sample of the hydrogen chloride salt is obtained by adding IRA (isopropanol)/HCI to the EG2OL/RA solution of the free base because With the preparation of the hydrogen chloride salt (m.p. 205-210", decomposition). Anal. calculated for C 47H47M3OSNeY: C, 64.65; H, 5.74; M, 13.31. Found: C, 64.51; H, 5.90, M, 13.09.

EXAMPLE 3 2-Anilino-6-methoxyquinoxaline hydrochloride

Aniline (1.3 mL, 14.3 mmol) was added to 2-chloro-b-methoxyquinoxaline (0.93 g, 4.8 mmol) under argon. The reaction mixture is heated at 1207C for 2 hours and then at 15073 for 1.5 hours. The mixture is cooled and SNSI is added to it. The resulting suspension is stirred and the yellow-hot solid is filtered off, washed with CHClClO/EBO and then vigorously stirred in HO for 40 minutes, filtered and washed

ESCO to obtain a light yellow solid.

EXAMPLE 4 2-anilino-6-quinoxalinol

By the Gretsigii method, 0.1: Mihipdiop, K.M. Tei. Gay. 1970, 1327, convert aryl methyl ether into a phenol derivative. Sodium salt of ethanethiol (0.19g, 2mmol) was added to 2-anilino-6-methoxyquinoxaline (0.27g, 1.07mmol) under argon in DMF. The reaction mixture is heated to 1107C overnight. The mixture is concentrated and distributed among

EtOAc and a mixture of NaO/595 tartaric acid so that the pH of the aqueous layer is approximately 4. The organic layer is washed with water (4 times) and then 2.596 Maon (4 times). The basic layers are combined, washed with E(Ac (2 times), acidified again with 590% tartaric acid and repeatedly washed with portions of EtOAc. The organic layers are combined, washed with brine, dried (Ma»5O)) and concentrated. The obtained solid is chromatographed (5095 E(OAc/hexanes). By grinding the product with EG2O, a sample for analysis is obtained in the form of a yellow powder (m.p. 211-2137С). Anal. calculated for С454Н34Ма3О: С, 70.88; Н , 4.67; M, 17.71.

Found: C, 70.64; N, 4.85; M, 17,58.

EXAMPLE 5 Phenyl-|(b-(tetrahydrofuran-3-(K)-yloxy)quinoxalin-2-yl|amine

2-anilino-6-quinoxalinol (0.23g, O0.97mmol) is added to the THF solution at 0"C in argon. (5)-()-3-hydroxytetrahydrofuran (0.08bml, 1.3mmol) and triphenylphosphine are added in portions (0.31g, 1.2mmol) Add in portions

REAO (0.18 ml, 1.2 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours.

The mixture is concentrated and distributed between EFAs and НО. The organic layer is washed with water, brine, dried (M9503) and concentrated. The resulting yellow oil is chromatographed (50956 EOAc/hexanes) and dissolved in EBOLRA. The NSIERO solution is added dropwise and the resulting red-orange powder is dried in a vacuum.

The powder is made pine-free by mixing in Meon with a washed (Z3KHN 250, 5xMeon) basic ion exchange resin. The mixture is stirred for 30 minutes, filtered, concentrated and recrystallized from the mixture

EtOAc/hexanes to obtain (in two batches) the product (m.p. 173-1757С). Anal. calculated for С 18Н47М3О»9:

C, 70.35; H, 5.57; M, 13.67. Found: C, 70.19; H, 5.60; M, 13.66. with

EXAMPLE 6 2,7-bicyclohexyloxy-b-methoxyquinoxaline

Cyclohexanol (0.7ml, 6b/mmol) was added dropwise to a solution of Man (0.32g, vmmol) in DMF (5ml) under argon. and)

The mixture is stirred at room temperature for 25 minutes, after which 2-chloro-6,7-dimethoxyquinoxaline is added in portions. The reaction mixture is stirred for 15 minutes at room temperature, 2 hours at 907 and 1 hour at 1107C. The mixture is cooled, quenched with HO and partitioned between EtOAc and H2O. The organic layer was washed with water and brine, dried (MazO)) and chromatographed (1095 EAs/hexanes) to obtain a waxy white solid (m.p. 75-787С). Anal. calculated for C 24Nov8M2Oz: C, 70.76; ise)

N, 7.92; M, 7.86. Found: C, 70.81; N, 7.79; M, 7.70. with

EXAMPLE 7 cyclohexyl-(6b,7-dimethoxyquinoxalin-2-ylmethyl)-amine

To a 0.067 M solution of 6,7-dimethoxy-2-quinoxalinecarboxaldehyde in a mixture (2:1) Meon-1,2-dichloroethane (7.5 ml, re)

0.bmmol) add cyclohexylamine (0.1 ml, 0.9 mmol). The reaction mixture was left to stir at room temperature overnight, after which Mavn y (0.038 g, 1 mmol) was added and the reaction mixture was stirred overnight. Then the mixture is concentrated and chromatographed (5095 EtOAc/hexane - about 595 Meon in 5090

EudAc/hexanes). The oil is dissolved in E(Yuds/hexanes and treated with NCI in EYN. The resulting solution is concentrated and the solid particles are triturated with isopropanol to obtain a white solid after drying in vacuum at 60"C (m.p. 185-1907C, decomposition). Anal. . calculated for С 17Н23М302О NS: C, 60.44; H, 7.16; M, 12.44. t) c Found: C, 60.48; H, 6.88; M, 12.07. . EXAMPLE 8 (6,7-dimethoxyquinolin-3-yl)-trans-(3-(K)-methyl-cyclohexyl)amine and i? (6,7-dimethoxyquinolin-3-yl)-cis-(3-(K)-methylcyclohexyl)amine

The reaction is carried out similarly to the preparation described above using a free base

of 3-amino-6,7-dimethoxyquinoline (0.32g, 1.bmmol) and (K)-(7)-3-methylcyclohexanone (0.23ml, 1.9mmol). Received

Ф mixture of products is chromatographed (7095 EAbs/hexanes) and recrystallized from a mixture of EUdAs/hexanes to obtain a white solid (a mixture of cis and trans isomers, 1:1) (m.p. 153-160"). Anal. calculated for

Me. SivNodM2O»: C, 71.97; H, 8.05; M, 9.33. Found: C, 72.12; N, 7.85; M, 9.29. 2) EXAMPLE 9 3-(6,7-dimethoxyquinolin-3-ylamino)-2,2-dimethylpropan-1-ol

The reaction is carried out similarly to the preparation in example 7. To a solution of powdered molecular sieves (4A) (0.35 g) in a meon under argon, add 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.mmol) and

He 2,2-dimethyl-3-hydroxypropionaldehyde (0.19g, 1.9mmol). The mixture of products is chromatographed (390 Meon/snei»z) to obtain 0.10 g of material, which is distributed between CH 25Si» and 1095 Maon. The organic layer is washed with 1090

Mmaon, H»oo and brine, after which it is dried (Ma5O")) and recrystallized from a mixture of EtOAc/hexanes to obtain a light yellow solid (m.p. 170-173, 5"C). Anal. calculated for Cl6Ho» MoOz: C, 66.18; H, 7.64; M, 9.65. Found: C, 66.11; H, 7.49; M, 9.33.

F) EXAMPLE 10 Cyclohexyl-(b-methoxy-7-morpholin-4-yl-quinoxalin-2-yl)amine This preparation is based on the adaptation of the method described by Vispmaia, ei aI., U. At. Spent os, 1996, 118, 7215. To a toluene solution of 2-cyclohexylamino-b-methoxy-7-bromoquinoxaline (0.1 g, 0.3 mmol) in argon, add morpholine (0.1 g, 0.3 mmol), sodium tert-butoxide (0.04g, 0.42mmol), 5-(-)-VIMAR (cat., 0.001g) and bisidibenzylideneacetone)palladium (cat., 0.001g). The reaction mixture is heated to 807°C overnight. The mixture is cooled, diluted with EG2O, filtered, concentrated and chromatographed (5095 EtOAc/hexanes). The product is recrystallized from the EtOAc/hexanes mixture to obtain (in two collections) a yellow solid (m.p. 194-1967C). Anal. calculated for C19NovMa4O: C, 66.64; H, 7.65; M, 16.36. Found: C, 66.60; H, 7.60; M, 16.51. 65 EXAMPLE 11 trans-4-(7-chloro-6-methoxyquinoxalin-2-amino)-cyclohexanol and trans-4-(6-chloro-7-methoxyquinoxalin-2-yl-amino)ucyclohexane

In a reaction flask equipped with a Dean-Stark trap and a reflux condenser, a mixture (6-1, 0.Zog, 1.3 mmol) of 2,7-dichloro-6-methoxyquinoxaline and 2,6-dichloro-7-methoxyquinoxaline is introduced in argon and trans-4-aminocyclohexanol (0.35 g, Zmmol). The reaction mixture is heated to 1707C for about 10 hours,

After that, it is concentrated and chromatographed twice (770 Meon/cHcI from Her then 570 Meon/CHcI3). The product is recrystallized from a mixture of EtOAc/hexanes to give a light yellow solid (m.p. 144-147").

Anal. calculated for Cl19NoveM.02010.4H250: C, 57.20; H, 6.02; M, 13.34. Found: C, 57.21; H, 5.97; M, 13.08. so on

NMR analysis shows that the product is a mixture (2:1) of trans-4-(7-chloro-6-methoxyquinoxaline-2-amino)cyclohexanol and trans-4-(6-chloro-7-methoxy-quinoxaline-2- ilamino)cyclohexanol. 70 EXAMPLE 12 trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol trans-4-aminocyclohexanol (0.11 g, 2 equiv.) and 2-chloro-6,7-dimethoxyquinoxaline (0.1 g, ХТекв.) are combined and heated to 1600-1807 for 4-8 hours. The dark brown suspension is filtered and concentrated. The residue is purified on a flash column, eluting with a mixture of 3906 methanol/methylene chloride to obtain the product in the form of a yellow powder with m.p. 119-123". Anal. calculated for C.6NoiMa3Oz: C, 62.33; H, 7.05; M, 13.63. Found: 75 C, 62.35; H, 7.09; M, 13, 18.

The compound can be recrystallized as follows. From 0.2 g of yellow powder in a mixture of 2.5 ml of water and 1.25 ml of methanol, a transparent solution of yellow-hot color is obtained when heated under reflux.

The hot solution is left to stand and gradually cools. Yellow-hot needle crystals are collected by filtration and dried under high vacuum to give a yellow solid (m.p. 119-120").

According to another variant, the HCI salt of the title compound is obtained in the following way. To a solution of trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol in isopropanol, add a solution of NCI at 07С. The mixture is stirred for 15 minutes, then filtered. The collected solid is dried under high vacuum to give the hydrochloride salt of trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol.

Anal. calculated for С16Но22СИМ3О301.2Н50: С, 53.19; H, 6.80; M, 11.63; SI, 9.81. Found: C, 55.14; N, Ga 56.85; M, 11.24; SI, 10,28.

According to another variant, the sulfate (salt) of the title compound is obtained in the following manner. i9)

By the usual method, trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol is dissolved in acetone or another suitable organic solvent with heating to 45"C, if necessary. To the resulting solution, carefully add an aqueous solution of NaZO) (Teq., 1M solution) with rapid stirring.The resulting solid salt is collected and dried to obtain the sulfate in a yield of 280965.

In a similar way, the following compounds are obtained from the corresponding starting material: o 3-(6,7-dimethoxyquinoxalin-2-ylamino)propan-1-ol (m.p. 154.5-1567"С). Anal. calculated for С.3Н .-7M3O3z: C, "z 59.30; H, 6.51; M, 15.96. Found: C, 59.30; H, 6.46; M, 15.87. 3-(6.7 -dimethoxyquinoxalin-2-ylamino)-2,2-dimethylpropan-1-ol (m.p. 174-176.575C). o

Anal. calculated for С15Н»1М3Оз: С, 61.84; N, 7.27; M, 14.42. Found: C, 61.67; H, 7.22; M, 14, 22. Ge) 4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol (m.p. 168-171"). Anal. calculated for C16H»24M3Oz: C, 70.82; H, 7.80; M, 15 , 48. Found: C, 70.76; H, 7.90; M, 15.20.

EXAMPLE 13 cis-4-(6,7-Dimethoxyquinoxalin-2-amino)cyclohexanol "

A mixture of cis-4-aminocyclohexanol (40mg, 3.48mmol) and 2-chloro-6,7-dimethoxyquinoxaline (450mg, 2mmol) in Bml ethanol is placed in a stoppered test tube and then heated at 1807C for 3 hours. The dark brown mixture is chromatographed on silica gel and eluted with ethyl acetate to give the target product (m.p. 65-677C). Anal. calculated for C 16H21SIM3O30p0.6NhBO: C, 61.17; H, 7.12; M, 13.37. Found: C, 61.22; N, "» 7.19; M, 12.19.

EXAMPLE 14 (x)-bicyclo|2.2.1)hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)amine

Method A: A mixture of 2-chloro-6,7-dimethoxyquinoxaline (5g, 22.mmol) and (xh)-exo-norbornyl-2-amine (10g,

He») 9Omol) is heated at 160-180" overnight. The dark brown residue is dissolved in 200 ml of methylene chloride and washed with sodium hydroxide (5Oml). The organic layer is dried over magnesium sulfate and then filtered. After concentration, the residue is chromatographed on silica gel, eluting with a mixture of o hexane/ethyl acetate (8096) to obtain the target product in the form of a yellow solid, which can be recrystallized from methanol. b Method B: A mixture of 2-chloro-6,7-dimethoxyquinoxaline (9 g, 40 mmol) and exo-norbornyl-2-amine (5.77g,

Kz B52mmol), sodium tert-butoxide (4.22g, 44mmol), 2,2'-bisidiphenylphosphino)-1,1-binaphthyl (VIMAR, 12Omg") and bisidibenzylideneacetone)-palladium Ra(daba)", (20mg) and the mixture is heated at 1007C overnight. Another portion of VIMAR (bOmg) and Ra(aba)" (2Omg) is added and the mixture is heated at 1007C overnight. After dilution with 200 ml of methylene chloride, the reaction mixture is washed with another Masson (100Oml). Organic layer dried over magnesium sulfate and filtered. The residue after concentration was chromatographed on silica gel, eluting with a mixture of hexane/ethyl acetate (8095), to give the target product as a light yellow solid (m.p. 188-18927C). Anal. calculated for C47H241M3Oz: C, 68.20; H, 7.07; M, 14.04 Found: C, 68.18; H, 7.03; M, 14.03.

In a similar way, the following compounds are obtained from the corresponding starting materials (method A): in exo-bicyclo|2.2.1)hept-5-en-2-yl-(6,7-dimethoxyquinoxalin-2-yl)amine (m.p. 175-1777"C). Anal. calculated for C47H19M30200.4H50: C, 60.94; H, 6.56; M, 13.78. Found: C, 66.98; H, 6.62; M, 12 ,73; (2endo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|heptan-2-ol (m.p. 90-93); (2exo,bexo)-5 -(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol (b.p. 97-1007С); (2endo,Zexo,bexo)-5-(6,7-dimethoxyquinoxaline -2-ylamino)bicyclo|2.2.1)heptane-2,3-diol (m.p. 65 220-222"). Anal. calculated for С47Н21М3040п0.2Н50: С, 60.96; H, 6.44; M, 12.54. Found: C, 60.93; H, 6.06; M, 11.60;

cyclohexyl-(6,8-dimethylquinoxalin-2-yl)amine IMS m/2: 255 (Mya)). Anal. calculated for Si6NoiMa: C, 75.26;

H, 8.29; M, 16.46. Found: C, 75.08; H, 8.28; M, 15.86; cis/trans-2-(b-methoxyquinoxalin-2-ylamino)ucyclopentanol (m.p. 137-139"). Anal. calculated for 500 b4NitM2O": C, 64.85; H, 6.61; M, 16 , 20. Found: C, 64.87; H, 6.45; M, 16.22; trans-4-(b-methoxyquinoxalin-2-ylamino)cyclohexanol (m.p. 70-75"C). Anal. calculated for

SiBNioM302500.3H2O: C, 64.64; H, 7.09; M, 15.08. Found: C, 64.68; N, 7.06; M, 14.77;

Izak,45,6K,base|1|-6-(6,7-dimethoxyquinoxalin-2-ylamino)-2,2-dimethyltetrahydrocyclo-penta/|1.3)|dioxol-4-carbo new acid ethylamide (m.pl. 94-977"С). Anal. calculated for C 21Но8МаО5ОП0.3НЙО: С, 59.79; Н, 6.83; М, 70 13.28. Found: С, 59.80; Н, 6.89; М ,12.03; (6,7-dimethoxyquinoxalin-2-yl)-(4-methoxycyclohexyl)amine, (m.p. 58-68"С). Anal. calculated for

С.и7Но2зМ30300.5Н20: С, 62.56; N, 7.41; M, 12.87. Found: C, 62.53; H, 7.22; M, 12,22.

EXAMPLE 15 exo-2-(bicyclo|2.2.1|hept-2-yloxy)-6,7-dimethoxyquinoxaline

A mixture of exo-2-norborneol (223mg, 2mmol) and Mann (6095, 100mg, 2.5mmol) in 10ml of anhydrous THF is heated under reflux for 0.5h, after which 2-chloro-6b,7-dimethoxyquinoxaline (3Zbmg) is added , 1.5 mmol). The resulting mixture continues to be heated under reflux for another two hours. The residue after filtration and concentration is chromatographed on silica gel (5090 ether/hexane) to obtain the target product in the form of a white solid (m.p. 135-1377"C). Anal. calculated for C 47H20M2Oz: C, 67.98; H, 6.71; M, 9.33. Found: C, 67.96; H, 6.762; M, 9.19.

The following compounds are similarly obtained from the corresponding starting material: exo-2-(bicyclo|2.2.1|hept-5-en-2-yloxy)-6,7-dimethoxyquinoxaline (m.p. 108-110"). Anal. calculated for

C.i7NivM2Oz: C, 68.44; H, 6.08; M, 9.39. Found: C, 68.54; H, 6.23; M, 9.27; 2-(bicyclo|2.2.1|hept-5-en-2-yloxy)-6,7-dimethoxyquinoxaline (m.p. 93-95"). Anal. calculated for

C.i7NivM2Oz: C, 68.44; H, 6.08; M, 9.39. Found: C, 68.32; H, 5.98; M, 9.25; ch 2-(1,4-dioxaspiro|4.5)dec-b-yloxy)-6,7-dimethoxyquinoxaline (m.p. 124-125"С). Anal. calculated for

SivNo»MoOrv: C, 62.42; H, 6.40; M, 8.09. Found: C, 62,63; H, 6.46; M, 7.79. and)

EXAMPLE 16 cis/trans-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexanecarboxylic acid

A mixture of cis/trans-4-hydroxycyclohexanecarboxylic acid (144 mg, thymol) and Mann (6095, 160 mg, 4 mmol) in a mixture of anhydrous THF/DMF (1 Oml/2 ml) is heated under reflux for one hour, after which 2-chloro- 6,7-dimethoxyquinoxaline (225mg, 1immol). The resulting mixture continues to be heated under reflux for another four hours. The reaction mixture is neutralized to pH 5 and extracted with ethyl acetate (2x5Oml). ise)

The combined organic solutions are dried over anhydrous magnesium sulfate and filtered. The residue after s concentration is chromatographed on silica gel (ethyl acetate and then methanol) to obtain the target product in the form of a white solid (m.p. 90-93"). Anal. calculated for С47Н20М2О5П10.5НХО: С, 59.89; Н, 6.19; re)

M, 8.22. Found: C, 59.91; H, 6.62; M, 7.90. "at

Similarly, the following compounds are obtained from the corresponding starting material: 4-(6,7-dimethoxyquinoxalin-2-yloxymethyl)cyclohexanol (m.p. 118-121 "C). Anal. calculated for

S.17Но2м20,00,3НїО: С, 63,15; N, 7.03; M, 8.66. Found: C, 63.13; H, 6.65; M, 9.01; 3-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol (m.p. 151-15372). Anal. calculated for С 16Но2оМ»Оу: С, « 63.14; H, 6.62; M, 9.20. Found: C, 62.56; H, 6.58; M, 8.67; with c 4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol (m.p. 162-1647"C). Anal. calculated for C 6NooM"Oud: C, 63.14; H, 6.62; M, 9.20. Found: C, 63.52; H, 6.80; M, 8.88; and? EXAMPLE 17 5-(6,7-Dimethoxyquinoxalin-2-yloxy)bicyclo|2.2.1|heptane-2,3-diol

To a solution of 2-(bicyclo|2.2.1|hept-5-en-2-yloxy)-6,7-dimethoxyquinoxaline (149 mg, 0.5 mmol) and 4-methylmorpholine M-oxide (234 mg, 2 mmol) at room temperature in bml of THF add a solution of 0850, in

F tert-butanol (2.5906 mass, 0.2 ml). The brown solution is intensively stirred for two hours, after which it is quenched with saturated ManNz»O»z (2 ml). The solution is extracted with ether (3X10Oml) and dried over magnesium sulfate. Remainder

Me, filtered and concentrated, then chromatographed on silica gel (5095 ethyl acetate/hexane) to obtain 2) the target product (m.p. 85-887"С). Anal. calculated for С47Н20М2О5ОП0.9НХО: С, 58.73; H, 6.29; M, 8.06.

Found: C, 58.74; H, 5.91; M, 7.53.

Me, It is obtained in a similar way

He (2exo,Zexo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1)heptane-2,3-diol (m.p. 150-153).

EXAMPLE 18 cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)ucyclohexyl ester of acetic acid and cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol.

A mixture of cis-4-acetoxycyclohexanol (632 mg, 4 mmol) and Mann (6095, 220 mg, 5.5 mmol) in 15 ml of anhydrous THF is heated under reflux for 0.5 h, after which 2-chloro-6b,7-dimethoxyquinoxaline is added

F) (674mg, Zmmol). The resulting mixture continues to be heated under reflux for another two hours. The residue after filtration and concentration is chromatographed on silica gel (ether) to obtain cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexyl ester of acetic acid (m.p. 150-152"). in Anal. calculated for C 6NooMaO;: C, 62.42; H, 640; M, 8.09. Found: C, 62.39; H, 6.55; M, 7.82 and cis-4-(6,7-dimethoxyquinoxaline -2-yloxy)ucyclohexanol (m.p. 148-1507"С). Anal. calculated for С 16Н20М2Оу:

C, 63.14; H, 6.62; M, 9.20. Found: C, 62.80; H, 6.76; M, 8.67.

Similarly, cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol MS t/2: (M 7) is obtained.

EXAMPLE 19 4-(6,7-Dimethoxyquinoxalin-2-yloxy)ucyclohexyl ester of dimethylcarbamic acid 65 ACID

A mixture of 4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol (100 mg, 0.3 mmol), dimethylcarbamyl chloride

(9FOmcl, 1.2mmol) Mann (6095, 19.b6mg, 0.49mmol) in bml THF was stirred at room temperature for three days to obtain a white solid (m.p. 152-1557C), isolated by chromatography (50905 ethyl acetate/ hexane).

Anal. calculated for С19Но5МзОрв: С, 60.79; H, 6.71; M, 11,19. Found: C, 60.38; H, 6.54; M, 10.43.

EXAMPLE 20 3-Cyclohexyloxy-6, 7-dimethoxyquinoxaline 1-oxide

A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinoxaline (1100 mg, 0.3 mmol) and metachlorobenzoic peracid (7095, 1133 mg, 0.4 mmol) in 10 ml of methylene chloride was stirred at room temperature during the day. After filtration, the solution is concentrated and the residue is chromatographed on silica gel (2095 ethyl acetate/hexane) to obtain the target product (m.p. 167-169"). 70 Trans-4-(6,7-dimethoxy-4-oxyquinoxaline-2) is obtained in a similar way -ylamino)cyclohexanol (m.p. 220-222"). Anal. calculated for C 16H24M30.00.2NhBO: C, 59.42; H, 6.69; M, 12.99. Found: C, 59.43; H, 6.64; M, 12.95.

EXAMPLE 21 trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexyl ester of acetic acid

A mixture of trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol (303 mg, 1 mmol), acetic anhydride (2 ml) 7/5 | of pyridine (2 ml) in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture was quenched with water (5 ml) and extracted with dichloromethane (2 x 30 ml). After drying over magnesium sulfate and filtering, the solution is concentrated on a rotary evaporator. The residue is chromatographed on silica gel (ethyl acetate) to give the target acetate as a light yellow solid (m.p. 176-1777C). Anal. calculated for

SivNozM3O,y: C, 62.59; H, 6.71; M, 12,17. Found: C, 62.89; H, 6.67; M, 11.95.

EXAMPLE 22 (2exo, Bbexo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol

A mixture of (2exo,bexo)-5-aminobicyclo|2.2.1)heptane-2-acetate (127mg, 0.75mmol) and 2-chloro-6,7-dimethoxyquinoxaline (224mg, mmol) is heated to 180"C for 2 hours Then the mixture is cooled to room temperature, dissolved in methylene chloride and purified on a flash column. The obtained product (2Omg, yield 7.595) is dissolved in methanol (2ml) and a fresh solution of other sodium methoxide (0.06Zml, concentration 0.06Zmmol) is added ). The reaction mixture is heated under reflux for 90 minutes. The crude mixture is purified by preparative thin-layer chromatography to obtain the product in the form of a yellow solid i) substance with a melting point of 97-10070. С.47Н21Мз3О»з (pt/2): 315 .

In a similar way, the following compounds are obtained from the corresponding starting material: (2endo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1)heptan-2-sl in the form of a yellow solid substance, Si17H21MzOz t /2: 315. (2exo, bexo)-5-(6,7-dimethoxyquinoxalin-2-ilimino)bicyclo|2.2.1|1hepan-2-ol in the form of a yellow solid ise) substance (ZOmg, total 2196), С17Н21Мз3зОз t/2: 315. Anal. calculated for С47Н21МзОз: С, 64.74; H, 6.71; M, "9 13.32. Found: C, 58.42; H, 6.26; M, 11.56.

EXAMPLE 23 (2trans, 4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol and o (2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol "at

A mixture of 2-chloro-6,7-dimethoxyquinoxaline (1.08g, 4.81mmol) and (2trans)-4-amino-2-methylcyclohexanol (62Omg, 4.8mmol) is heated to 1807C for 6 hours. The reaction gives two diastereomers.

The main isomer is isolated in the form of a yellow solid, defined as (2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol (240Omg, 0.7bmmol), С47Н2зМ3О3 « (t/2): 317. Anal. calculated for C 47Noz3zMzOzP2NhBO: C, 58.00; N, 7.69; M, 11.94. Found: C, 58.00; H, 6.58; pt) with M, 11.24.

And the minor isomer is also a yellow solid, defined as (2trans,4cis)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol С.и7НозМ3О3 (t/2): 317. Anal. calculated for С47Н2зМ3ОзПН2О С, 60.08; H, 6.94; M, 12.53. Found: C, 61.21; H, 6.94; M, 11.56. (h2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol is further separated by

Ge» of chiral HPLC on its individual enantiomers. The first enantiomer has (u)-rotation (order of elution according to

SpigaseI 0). The second enantiomer has (-)-rotation (elution order according to SpigaseI 0). In the conditions of the analysis of

Me, using the SpPigase column! The OO (y)-enantiomer is eluted second, the (-)-enantiomer shows better activity 2) in the analysis of ROSBE-K by the EI IZA method.

EXAMPLE 24 (2cis,4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol and

Me, (2cis,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol

Ge To a solution of a mixture (2:1) of (2trans,4trans)-4-(6,7-dimethoxyquinoxaline-2-ylamino)-2-methylcyclohexanol and (2trans,4cis)-4-(6,7-dimethoxyquinoxaline-2- ylamino)-2-methylcyclohexanol (120mg, 0.35mmol) in THF (7ml) add triphenyl phosphine (11Omg, 0.42mmol), diethyl azodicarboxylate (0.06bml, 0.42mmol) and benzoic acid dv (46b4mg, 0.38mmol) . The mixture is stirred at room temperature overnight and the residue after processing is separated on silica gel (3095 ethyl acetate/hexane) to obtain a mixture of benzoates.

F) Mn is added to a solution of basic benzoate (5O0mg, O0.12mmol) in methanol (2ml). sodium hydroxide (0.12 ml, ca 0.12 mmol). The pure product (1Zmg, yield 3295) was isolated by preparative thin-layer chromatography as a yellow solid (m.p. 85-8873), identified as (2cis,4cis)-4-(6,7-dimethoxyquinoxalin-2-ylamino) -2-methylcyclohexanol, С.47Но2зМзОз (t/2): 317.

In a similar manner, the secondary benzoate (44mg) was hydrolyzed and the target product was also isolated by preparative thin-layer chromatography as a yellow solid identified as (2cis,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol , P. 47Н»зМ3Оз (t/2): 317.

EXAMPLE 25 (1K,2K,45)-(3)-Bicyclo|2.2.1|)hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)amine 65 (-3-Bicyclo/2.2.1) hept-2-yl-(6,7-dimethoxyquinoxalin-2-ylamine) from example 14 is eluted on a column for chiral HPLC (Spigairas AYU, 25x2 cm, 6095 heptane/4095 ethanol with 10 mM (18)-(-)-camphorsulfonic acid ,

12ml/minute) and obtain the product indicated in the title as the first eluate. The collected fractions are combined and washed with 5 Oml of In. Oil, after which it is dried (MaZO)). The solution after filtration is concentrated on a rotary evaporator and then dried under high vacuum. A yellow solid is obtained: (sh429-19.57 (s-0.20,

СН»оСи»), t. pl. 184-186"C. Anal. calculated for C 47H24M302010.3H2O: C, 66.90; H, 7.15; M, 13.77. Found: C, 66.86; H, 7.01; M, 13 ,86.

EXAMPLE 26 Biotransformative production of (15,2K,45,5K)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|heptan-2-ol

Mushrooms of line EE 2052 (Mogiegeia izarePypa) are purchased from Mogyegp (Myi2ayop Kezeagpy apa Oemeortepi 70. Oimiviop (MKK).

Fungi are stored at -257"C. 2ml of fungal suspension is seeded into conical flasks with a capacity of 25Oml, each of which contains 5bOml of nutrient medium for sowing (medium 216) and incubated on a rotary shaker (200rpm) at 237C for 3 days. In conical flasks with a capacity of 25O0ml, each of which contains 5Oml of the same medium, sow 2ml of the seed culture and incubate it on a rotary shaker (200rpm) 75 at 23"Sb. After 24 hours, (1K,2K,45)-(k)-bicyclo(2.2.1|hept-2-yl-(6,7-dimethoxyquinoxalin-2-ylamine) from example 25 is dissolved in Meon and added to the flasks to the final concentration ZOmg/L. After 24 hours of incubation, cultures are harvested. (Medium 216: glucose 0.495, yeast extract 0.0595, soybean meal 0.0595, Masi 0.0596, KNoRO,; 0.05.) Extraction is carried out using 2 vol. of acetonitrile, 1 volume of tert-butyl methyl ether and 1 volume of n-heptane, which are added to 1 volume of broth. After stirring with a magnetic stirrer at 22"C, the extract is separated into three layers. The intermediate layer is collected and evaporated to dryness and redissolved in ethyl acetate. The ethyl acetate extract was separated on silica gel (0.04-0.06µm) using ethyl acetate as eluent. Fractions containing the biotransformation product were separated on C18 silica using a HO/Meon gradient as eluent. This chromatography gave pure the compound indicated in the title in the form of an amorphous yellow powder, m.p. 190-19276. Ha

EXAMPLE 27 trans-4-(7-Methoxy-6-(2-morpholin-4-ylethoxy)quinoxalin-2-ylamino|1-cyclohexanol and trans-4-1b-methoxy-6-(2-morpholin-4-ylethoxy)quinoxaline -2-ylamino|cyclohexanol and 9)

The title compound is obtained by carrying out the Mitsunobu (Miizipobra) reaction between b-hydroxy-7-methoxy-2-chloroquinoxaline:7-(2-morpholin-4-ylethoxy)-6-methoxy-2-chloroquinoxaline and 2-(morpholine- 4-yl)ethanol using the method of example 1 and the reaction between the resulting He 8-(2-morpholin-4-ylethoxy)-7-methoxy-2-chloroquinoxaline:7-(2-morpholin-4-yl-ethoxy)-6 -methoxy-2-chloroquinoxalin and trans-4-aminocyclohexanol using the method of example 11. o

EXAMPLE 28 2-(2-(trans-4-Hydroxycyclohexylamino)-7-methoxyquinoxaline-b-yloxyl|-1-acetic acid and "Z 2-(2-(trans-4-hydroxycyclohexylamino)-b-methoxyquinoxaline-7- yloxyl|-1-acetic acid

The title compound is prepared by dealkylation of 4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol using the sodium salt of enantiol in DMF as described in Example 4, followed by alkylation with bromoacetic acid in the presence of a base, as described in general operation 6.

EXAMPLE 29 2-|(2-trans-4-Hydroxycyclohexylamino)-7-methoxyquinoxaline-b-yloxyl|-M,M-dimethylacetamide and « 2-(2-(trans-4-hydroxycyclohexylamino)-b-methoxyquinoxaline-b- yloxyl|-M,M-dimethylacetamide

The compound specified in the title is obtained by aminolysis of the compound of example 28 using -c dimethylamine. и EXAMPLE 1 PREPARATION OF THE INTERMEDIATE COMPOUND и" 4-bromo-5-methoxybenzene-1,2-diamine dihydrochloride

595 Ra/s (0.5 g) is added to a solution of EUAs (5 Oml) and 5-bromo-4-methoxy-2-nitrophenylamine (2.5 g, 10 mmol) in argon. The reaction mixture is hydrogenated at 50 psi (3.5 kg/cm?) for 1 hour. The mixture (o) is filtered through Celite into a solution of HCI/E(ЯАs, and the pad of Celite is washed with additional EFAs. The resulting precipitate is filtered to obtain a white solid.

EXAMPLE 2 PREPARATION OF INTERMEDIATE COMPOUND (95) 7-bromo-6b-methoxyquinoxalin-2-ol and b-bromo-7-methoxyquinoxalin-2-ol

To a solution of MeonN (15 ml) in argon, add crushed Maon tablets (0.86 g, 21 mmol) and 4-bromo-5-methoxybenzene-1,2-diamine dihydrochloride (2.7 g, 9.3 mmol). The mixture is stirred for 10 minutes, after which a solution of 4595 ethylene glyoxalate in toluene (2.7 g, 12 mmol) is added in portions. The reaction mixture is heated under reflux for 1 hour, then cooled. Add water and then filter the suspension. The resulting solid is washed successively with HNO, Meon, IRA and EBO to obtain a yellow powder.

EXAMPLE OF PREPARATION OF THE INTERMEDIATE COMPOUND o 7-bromo-2-chloro-6-methoxyquinoxaline and b-bromo-2-chloro-7-methoxyquinoxaline is) To the mixture of 7-bromo-6b-methoxyquinoxalin-2-ol and 6-bromo-7 -Methoxyquinoxalin-2-ol (1g, 3, 9ummol) was added to ROSIZ (bBml). The reaction mixture was heated at reflux for 1 hour, poured into ice water, 60 filtered and then washed with water to give a light reddish brown solid. The ratio of 7-bromo-2-chloro-6-methoxyquinoxaline: 6-bromo-2-chloro-7-methoxyquinoxaline is approximately 7:11 according to the results of analysis by the H NMR method.

EXAMPLE 4 PREPARATION OF THE INTERMEDIATE COMPOUND 5-chloro-4-methoxy-2-nitroaniline 65 To a solution of M-(5-chloro-4-methoxy-2-nitrophenyl)acetamide (2g, 8.2mmol) in 5N. 1,4-dioxane (10ml) is added to NSI (20ml) and the mixture is stirred at 60"C for 1.5 hours. The reaction mixture is concentrated and distributed between

EUAs and 2n. Mahon. The aqueous layers were washed with EtOAc (3 times), brine, dried (M95O)), adsorbed on silica gel and chromatographed (7090 EtOAc/hexane) to obtain a yellow-hot powder.

EXAMPLE 5 PREPARATION OF THE INTERMEDIATE COMPOUND 4-chloro-5-methoxybenzene-1,2-diamine dihydrochloride

595 Ra/s (0.5 g) was added to a solution of EtOAc (25 ml) and 5-chloro-4-methoxy-2-nitrophenylamine (1.6 mg, 7.9 mmol) in argon. The reaction mixture is hydrogenated at 50 psi (3.5 kg/cm) for 1 hour. The mixture is filtered in nitrogen through Celite into a solution of In. HC/BSO in EtOAc, and the celite layer is washed with additional EtOAc.

The resulting precipitate is filtered to obtain a white solid.

EXAMPLE 6 PREPARATION OF THE INTERMEDIATE COMPOUND 7-chloro-6-methoxyquinoxalin-2-ol and b-chloro-7-methoxyquinoxalin-2-ol

TEA (triethanolamine) (2.5 ml, 1 mmol) was added to a solution of 4-chloro-5-methoxybenzene-1,2-diamine dihydrochloride (1.8 g, 7.2 mmol) in EN (15 ml) under argon at 0 °C. The mixture was stirred 20 minutes, after which a solution of ethylene glyoxalate 4595 in toluene (2.1 g, 9.mmol) was added portionwise. The reaction mixture was warmed to room temperature at 75 °C, heated at reflux for 1.5 h, then cooled. Water was added and the suspension was filtered and washed sequentially with HO, IRA, and EBO to obtain a light yellow powder.The product was subjected to azeotropic distillation with toluene several times and dried under vacuum before use.

EXAMPLE 7 PREPARATION OF THE INTERMEDIATE COMPOUND 2,7-dichloro-6-methoxyquinoxaline and 2,6-dichloro-7-methoxyquinoxaline

To a mixture of /7-chloro-b6-methoxyquinoxalin-2-ol and b-chloro-7-methoxyquinoxalin-2-ol (1 g, 4.7 mmol), using a drying tube with calcium chloride (CaSi"), add ROCIz (bml) . The reaction mixture is heated under reflux for 30 minutes, poured into a cold saturated solution of Manso»z, filtered and then washed with water to obtain a solid. The ratio of Ha 2,1-dichloro-b-methoxyquinoxaline:2,6-dichloro-7-methoxyquinoxaline is approximately 6:1 in accordance with the analysis by the IN NAM method. at

EXAMPLE 8 PREPARATION OF THE INTERMEDIATE COMPOUND cis-Aminocyclohexanol cis-4-Aminocyclohexanol is obtained by the method described in the literature with minor changes |). May Spent SM zo 18(6), 634, 1975).

EXAMPLE 9 PREPARATION OF THE INTERMEDIATE COMPOUND and exo-bicyclo|2.2.1)hept-5-en-2-amine and exo-bicyclo|2.2.1)hept-5-en-2-amine are obtained in the same way as in example 15 of the preparation intermediate from 5-norbornene-2-ol through the unstable intermediate exo-2-bicyclo|2.2.1|hept-5-ene-2-ylisoindole-1,3-dione. oh

EXAMPLE 10 PREPARATION OF INTERMEDIATE COMPOUND (Ce) (2exo,bexo)-2-(6-Hydroxybicyclo|2.2.1|hept-2-ylisoindole-1,3-dione and (2exo,bexo)-2-(5-hydroxybicyclo| 2.2.1 |hept-2-ylisoyiindole-1,3-dione

To a mixture of exo-2-bicyclo|2.2.1)hept-5-ene-2-ilyisoindole-1,3-dione (320 mg, 1.344 mmol) in bml THF at 0 °C, add a solution (1 M, 2 ml, 2 mmol) of VNz in THF. The mixture is stirred at room temperature for 2 hours and then water (2 ml) and MavO30p4H5O (900mg) are added. The resulting suspension is stirred overnight. Then it is extracted with ether (3x5Oml) and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (ether) to obtain the target products, which can then be separated. ," EXAMPLE 11 PREPARATION OF THE INTERMEDIATE COMPOUND (2exo,bendo)-2-(5-Hydroxybicyclo|2.2.1)hept-2-yl-isoindole-1,3-dione (a) Mixture of (2exo,bexo)-2-( 6-Hydroxybicyclo|2.2,1)hept-2-ylisoindole-1,3-dione and (o) (2exo,Bexo)-2-(5-hydroxybicyclo-(2.2.1|hept-2-ylisoindole-1,3) -dione (80mg, 3.3mmol) and b pyridinium chlorochromate (2g) in 10ml of methylene chloride are stirred at room temperature for 2 days.

After dilution with ether, the suspension is filtered and the solution is concentrated. The residue is chromatographed on silica gel (95) (ether) to obtain 75mg (95905) of the corresponding ketones. Ketones are then separated by reversed-phase HPLC

FU 50. (SNUSM/НЭО, 10-7095) with the preparation of exo-2-(5-oxybicyclo|2.2.1)hept-2-ylisoindole-1,3-dione. (5) To a solution of exo-2-(5-oxybicyclo|2.2.1|hept-2-ilyisoindole-1,3-dione (25O0mg, 0.98mmol) in 1Oml of methanol that) at 0"C is added Mavna; (3vVmg , immole). The mixture is stirred for another half an hour and quenched with NCI (Iml). After concentration, the residue is extracted with methylene chloride (2x5O0ml). Evaporation of methylene chloride gives the target product, which is used directly without additional purification.

EXAMPLE 12 PREPARATION OF THE INTERMEDIATE COMPOUND (2endo,bexo)-5-Aminobicyclo|2.2.1|)heptan-2-ol, (2exo,bexo)-5-Aminobicyclo|2.2.1)heptan-2-ol, o (2endo, bexo)-6-aminobicyclo|2.2.1|)heptan-2-ol, (2exo,bexo)-6-aminobicyclo|2.2.11-2-ol ime) The compounds indicated in the title are obtained from the corresponding starting material by applying the above-described methods of example 11 for obtaining an intermediate compound. 60 EXAMPLE 13 PREPARATION OF THE INTERMEDIATE COMPOUND 2-methyl-6,7-dimethoxyquinoxaline

The title compound is prepared by adapting the published method of Tatao, et al., Techgapedop, 1982, 38, 3347-3354. 2-Chloro-6,7-dimethoxyquinoxaline (5g, 2bmmol) and MiCl (arrr) (0.14g, 0.2bmmol) were added to the THF solution in argon. The reaction mixture is cooled to 0"C and a solution of MeMoVg in EG2O 65 (1 mL, ZOmmol) is added to it in 3M portions. The reaction mixture is allowed to warm to room temperature, stirred for an hour, and then heated under reflux for 1.5 hours. The mixture is cooled, extinguish 1095 NOI,

stirred for 10 minutes and then alkalized with 595 MaonN. Add СНоСи» and НОО and the resulting mixture is stirred during the night. Then add CH 5Si", NiO and NCI and filter the mixture. The resulting solution is poured into a separatory funnel and the aqueous layers are washed three times with СНоСиИ». The organic layers were combined, washed with Vozsol, dried (M950)), concentrated on silica gel and chromatographed (5095-8095 EtOH/hexanes) to give an orange solid (yield 4990).

EXAMPLE 14 PREPARATION OF THE INTERMEDIATE COMPOUND 6,7-dimethoxy-2-quinoxalinecarboxaldehyde

1,4-dioxane (20ml), 2-methyl-6b,7-dimethoxyquinoxaline (1.09g, 5.3mmol) and 0 are introduced into a reaction flask under argon. 1 zeO" (1.8g, 1bmmol). The mixture is heated to 1007C for 2 hours 45 minutes, cooled and filtered through celite. The celite pad is washed with portions of E(SUac and CHCl). The resulting solution is concentrated, dissolved in a mixture of Meon/ChNhSiCl", loaded onto a column with silica gel and chromatographed (3095 EHUAc/ChNCl) to obtain a not quite white solid (yield 73905).

EXAMPLE 15 PREPARATION OF THE INTERMEDIATE COMPOUND (2exo,bexo)-5-aminobutsiclo!|2.2.1)heptane-2-acetate

Exo-5-acetoxybicyclo|2.2.1|-heptan-2-one and exo-6-acetoxybicyclo|2.2.1|1heptan-2-one are obtained from bicyclo|2.2.1|)heptan-2,5-diene in accordance to the methodology of K. Sadpop (9). Spent boss. Ragkip igapv. 1, 1505 1995), with minor changes.

To a solution of exo-5-acetoxybicyclo|2.2.1)heptan-2-one (ZBOmg, 2.08mmol) in l7Oml of THF at room temperature of 2o, a 1M solution (1.2ml, 1.2mMmol) of borane in THF is added. The mixture is stirred for 0.5 hours, after which it is quenched at 07°C with methanol (3 mL) and 1.5 mL of HCl. The mixture is extracted with ethyl acetate (3 x 30 mL) and dried over magnesium sulfate. The mixture is then filtered and concentrated, and the residue is chromatographed on silica gel with by obtaining (2endo,bexo)-5-acetoxybicyclo-(2.2.1|heptan-2-ol).

To a solution of (2endo,bezo)-5-acetoxybicyclo|2.2.1|heptan-2-ol (350mg, 2.0bmmol) in THF (10ml) add phthalimide (454mg, 3.09mmol), triphenylphosphine (810mg, 3 .09 mmol) and diethyl azodicarboxylate (0.49 ml, 3.09 mmol) at 0"C. The reaction mixture was left to stir overnight and then condensed on a rotary evaporator and i) the residue was purified by column chromatography (2090 ethyl acetate/hexane) to give the target product in in the form of a yellow solid.

A mixture of the above solid (300 mg, 1 mmol) and hydrazine (0.126 bml, 2.2 mmol) in 5 mL of methanol is heated under reflux for 2 hours. After removal of methanol, the residue is extracted with dichloromethane (300 mL). Concentration of the solvent gave (exo,exo)-5-aminobicyclo|2.2.1|-heptane-2-acetate ise) (127 mg, 7595), which was used in the coupling reaction without further purification. with

(2endo,bexo)-5-aminobicyclo|2.2.1|)heptane acetate, (2endo,bexo)-6-aminobicyclo-(2.2.1|1-heptane-2-acetate and (2exo,bexo) -6-aminobicyclo|2.2.1|heptane-2-acetate from ise) of the corresponding starting material. "at

EXAMPLE 16 PREPARATION OF THE INTERMEDIATE COMPOUND (2trans)-4-Amino-2-methylcyclohexanol

A mixture of 3-methyl-2-cyclohexenone (4g, 36.3bmmol), toluenesulfonic acid (10mg) and ethylene glycol (7ml) in 10000ml toluene is heated under reflux overnight, and the water formed is removed using a Dean-Stark trap . The residue after concentration is chromatographed on silica gel with (1095 ethyl acetate/hexane) to give 3,Zbg (62905) 7-methyl-1,4-dioxaspiro|4.5)|dec-7-ene. . A 1 M solution of borane in THF (22.47 ml, 22.47 mmol) at room temperature. The mixture is stirred for an hour and the reaction is quenched by the addition of H 20 (1 Oml) at 0"C, after which perborate tetrahydrate is added

Sodium (10.0 g, bbmmol). The mixture is left to stir overnight. A water layer also separates the two layers

He" is washed several times with ethyl acetate (4x15O0ml). After flash column chromatography, the target alcohol is obtained as a clear liquid.

Me, The above-mentioned alcohol (1.8g, 10.bmol) is dissolved in methanol (5Oml) and zinc. NSI (1bml). The reaction mixture 2) is left overnight for mixing. The acidic solution is neutralized with 1N. sodium hydroxide (18 ml) followed by the usual water treatment. The crude mixture is purified on a flash column (5095 ethyl acetate) to give

Me, trans-4-hydroxy-3-methylcyclohexanone.

Ge To a solution of trans-4-hydroxy-3-methylcyclohexanone (733Omg, b, mmol) in water (3ml) add hydroxylamine hydrochloride (55Omg, 7.92mmol), followed by the slow addition of a saturated solution of sodium carbonate (32bmg, 3, vmmol) in water (1.02 ml). After stirring for 30 minutes, ether is added to the reaction mixture and the two layers are separated. The organic layer is condensed and dissolved in ethanol (1 Oml). Sodium (1.8 g, 78.3 mmol) is added to the boiling ethanol solution within an hour, and the resulting mixture is heated for another 2.5

F) hours. After removing the ethanol, add n-propanol (1Oml), ether (25ml) and water (3ml). The organic solution is dried over magnesium sulfate and filtered. Concentration of the solvent gave a mixture of (2trans)-4-amino-2-methylcyclohexanol as a white solid. 60 EXAMPLE 17 PREPARATION OF THE INTERMEDIATE COMPOUND 2-methoxy-4,5-diaminophenol dihydrochloride

The compound indicated in the title is obtained by hydrogenation of 2-methoxy-4,5-dinitrophenol in accordance with the method of Epgiysei a/., U. Ogud. Spet., 1947, 12, 522.

EXAMPLE 18 PREPARATION OF INTERMEDIATE COMPOUND 65 7-hydroxy-b-methoxyquinoxalin-2-ol and b-hydroxy-7-methoxyquinoxalin-2-ol

The compounds indicated in the title are obtained from 4-methoxy-5-hydroxybenzene-1,2-diamine dihydrochloride by reaction with Mahon and ethyl glyoxalate according to the method of example 2 for obtaining an intermediate compound.

EXAMPLE 19 PREPARATION OF THE INTERMEDIATE COMPOUND 7-hydroxy-b-methoxy-2-chloroquinoxaline and b-hydroxy-7-methoxy-2-chloroquinoxaline

The compounds indicated in the title are obtained from 7-hydroxy-b-methoxyquinoxalin-2-ol and b-hydroxy-7-methoxyquinoxalin-2-ol by interaction with ROSI according to the method of example C for obtaining an intermediate compound.

Compounds of formula I, as described above, inhibit cell proliferation and/or the production of a cell matrix, and cell movement (chemotaxis) by inhibiting the activity of the tyrosine kinase ROSRB-K. Uncontrolled 7/0 cell proliferation, matrix overproduction, or poorly regulated programmed cell death (apoptosis) cause many disease states. These disease states affect a wide variety of cell types and include diseases such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, fibrosis, atherosclerosis and restenosis that occurs after coronary, femoral or renal angioplasty, or fibroproliferative diseases such as arthritis , fibrosis of lungs, kidneys and liver. In particular, as reported on 7/5, ROOE and ROSE-K are involved in the occurrence of some types of cancer and tumors such as brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma and malignant melanoma. In addition, conditions for cell proliferation with impaired regulation are created after coronary bypass surgery. It appears that inhibition of tyrosine kinase activity would be useful in regulating uncontrolled cell proliferation, matrix overproduction, or poorly regulated 20 programmed cell death (apoptosis).

This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, cell matrix production, cell movement (chemotaxis), regulation of abnormal cell growth, and cell inflammatory response. More specifically, this invention relates to the use of substituted quinolines and quinoxalines that have the ability to selectively inhibit differentiation, proliferation, matrix production, chemotaxis, or mediator release by effectively inhibiting platelet-derived growth factor receptor tyrosine kinase activity (ROSB-K). and)

Initiation of autophosphorylation, i.e., phosphorylation of the growth factor receptor itself, and initiation of host phosphorylation of intracellular substrates are some of the biological events involved in cell signaling, cell proliferation, matrix production, chemotaxis, and mediator release. Due to the effective inhibition of tyrosine kinase I CK activity, the compounds of this invention are also useful in the treatment of transplant resistance and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft-versus-host disease, in with hyperproliferative disorders such as tumors and psoriasis, and in diseases in which cells receive signals about the need for inflammation, such as asthma, inflammatory bowel disease and pancreatitis. For the treatment of transplant resistance, the compounds of this invention can be used either prophylactically or in response to an adverse human reaction to a transplanted organ or transplanted tissue. When used prophylactically, a compound of the present invention is administered to a patient either in the tissue to be transplanted or in the organ to be transplanted during a transplant operation. Prophylactic treatment can also use the administration of the drug after the transplant operation, but before any signs of an adverse reaction to the "transplantation" are detected. When administered in response to an adverse reaction, a compound of the present invention is administered intravenously to the patient to counteract transplant resistance after outward signs of resistance are detected. . According to another feature of the present invention, a method of treating a patient who has (or is prone to) conditions that can be weakened or averted by the introduction of an inhibitor of the tyrosine kinase activity of the ROSB-K receptor and/or the activity of tyrosine kinase I cK (for example, such conditions as described above), which involves administering to the patient an effective amount of a compound of formula | or a composition containing a compound of formula I!, or

Ge" of its pharmaceutically acceptable salt.

The treatment referred to in this specification should be understood to include both prophylactic therapy and

Me, and treatment of conditions that have developed. 2) This invention covers pharmaceutical compositions containing a pharmaceutically acceptable amount of at least 50% of one of the compounds of the formula | together with a pharmaceutically acceptable carrier such as an excipient,

Me. thinner, coating substance and filler.

Ge In practice, the compounds or compositions for treatment in accordance with the present invention may be administered by any of a number of suitable methods, for example, by inhalation, topically, parenterally, rectally, or orally; the oral route of administration is more preferred. More specific methods of administration should include intravenous, intramuscular, subcutaneous, intraocular, intra-articular, colonic, peritoneal, transepithelial, including transdermal, ophthalmic, sublingual, transbuccal,

F) inhaled into the nose by insufflation and aerosol. ka Compounds of the formula | can be presented in forms that allow administration in the most appropriate way, and the invention also relates to pharmaceutical compositions containing at least one compound according to the present invention, for which are suitable for use as medicaments for a patient. These compositions may be prepared by conventional methods using one or more pharmaceutically acceptable excipients or excipients. Excipients include, among other things, diluents, sterile aqueous media and various non-toxic organic solvents. The compositions may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, solutions for injection, elixirs or syrups, and may contain one or more substances selected from the group consisting of sweeteners such as sucrose, lactose , fructose, saccharin or

Nutrasvit (Miigazuleeke), corrigents such as peppermint oil, wintergreen oil or cherry or orange corrigents, colorants and stabilizers such as methyl- or propylaraben, to obtain pharmaceutically acceptable preparations.

The choice of the carrier and the content of the active substance in the carrier are usually determined in accordance with the solubility and

Chemical properties of the product, specific method of administration and safety measures adopted in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrants such as starch, alginic acids, and some complex silica gels, combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc. For the production of 7/0 capsules, it is advantageous to use lactose and a liquid carrier such as high molecular weight polyethylene glycols. Various other materials may be present as a coating or for any change in the physical form of the dosage form. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. When using aqueous suspensions, they may contain emulsifying substances or substances that contribute to the formation of a suspension. Diluents such as sucrose, ethanol, polyols such as 7/5 Polyethylene glycol, propylene glycol and glycerin, and chloroform or mixtures thereof may also be used. In addition, the active compound can be part of long-acting drugs and medicines.

When administered orally, the active compound may be administered, for example, with an inert diluent or with an digestible edible carrier, may be enclosed in hard or soft gelatin capsules, may be compressed into tablets, or may be administered directly with food or combined with an excipient. and used in the form of oral tablets, lozenges, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like.

For parenteral administration, emulsions, suspensions, or solutions of the compounds of this invention in vegetable oil, such as sesame, peanut, or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of pharmaceutically acceptable salts. Injectable forms must be so liquid that they can be easily injected with a syringe, and proper fluidity can be ensured, i) for example, by applying a coating such as lecithin, by ensuring the required particle size in the case of dispersion, and by surface application - active substances. Prolonged absorption of injectable compositions can be ensured by the use of agents that delay absorption, such as aluminum monostearate and gelatin. Salt solutions of the products of this invention are particularly suitable for administration by intramuscular or subcutaneous injection. Solutions of the active compound in the form of a free ise) base or a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. A dispersion in glycerol, liquid polyethylene glycols and their mixtures and in oils can also be prepared. Aqueous solutions, including solutions of salts in pure distilled water, may be used for intravenous administration, provided that their pH is properly adjusted, that they are given adequate buffering properties, and that they are made isotonic with sufficient glucose or chloride. sodium, and that they are sterilized by heat, irradiation, microfiltration, and/or with various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. "

Sterile injectable solutions are prepared by injecting the active compound in the required amount in a suitable solvent with the various other components listed above, if required, followed by sterilization by filtration. Usually, dispersions are prepared by introducing various sterilized active;" components in a sterile carrier containing the main dispersion medium and other necessary components from those specified above. In the case of sterile powders for the manufacture of sterile injection solutions are preferable

Manufacturing methods are vacuum drying and lyophilic drying, which give the powder of the active component plus

He" any other necessary component from the pre-filtered solution for sterilization.

Gels (based on water or alcohol), creams or ointments can be used for local administration

Me. contain the compounds of this invention. The compounds of this invention may also be incorporated into a gel or matrix base for patch application, which would allow for controlled release of the compound.

Through the transdermal barrier.

For administration by inhalation, the compounds of this invention may be dissolved or suspended in

Ge to a suitable carrier for use in a nebulizer or for suspensions or solutions in aerosol form, or may be absorbed or adsorbed on a suitable solid carrier for use in a dry powder inhaler.

For solid compositions for rectal administration, suppositories are provided, manufactured in accordance with known methods and containing at least one compound of formula I. ) by convection and/or diffusion, thereby increasing the residence time of viral particles at the desired site of action. For sustained release, a peri-adventitial depot containing a compound of the present invention may be used. One such depot suitable for administration of a compound of the present invention may be a copolymer matrix such as ethylene vinyl acetate or a polyvinyl alcohol gel, encased in Silastic (Ziazis).In another embodiment, a compound of the present invention may be delivered locally from a silicone polymer implanted in the adventitial sheath.

An alternative method of minimizing washout of a compound of the present invention during transdermal 65 transvascular delivery involves the use of non-diffusible drug-eluting microparticles. Particles can consist of a wide variety of synthetic polymers such as, for example, polylactide,

or natural substances, which include proteins and polysaccharides. Such microparticles provide the possibility of operative manipulation of variables, including the total dose of the drug and the kinetics of its release. The microparticles can be effectively introduced into the arterial or venous wall through a porous balloon catheter or balloon on a stent (dilator) and retained in the vessel wall and periadventitial tissue for at least about two weeks. The composition and methods of local delivery of medicines to a specific place inside the vessel are described in Keiivzzep eyi ai. (9. At. SoiYi. SagaiyuYi. 1994; 23; 1234-1244); the contents of this material are fully incorporated into this description by reference.

The composition of the present invention may also contain a hydrogel prepared from any biocompatible or 7/0 non-cytotoxic (homo or hetero) polymer such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge. Such polymers are already described, for example, in application MU093/08845, the entire content of which is contained in this description by reference. Some of them, such as those derived from ethylene and/or propylene oxide, are commercially available.

When using the compounds of this invention to treat pathologies associated with hyperproliferative 7/5 disorders, these compounds can be administered by various routes. For the treatment of restenosis, the compounds of this invention are administered directly into the blood vessel wall by an angioplasty balloon coated with a hydrophilic film (eg, a hydrogel) that is impregnated with the compound, or by any other catheter containing an infusion chamber for the compound that, thus, can be precisely brought to the site to be treated and allows the compound to be efficiently released precisely at the cellular site where the treatment is needed. This method of administration allows for rapid introduction of the compound into contact with the cells in need of treatment.

The method of treatment according to the present invention preferably consists in the administration of the compound according to the present invention to the site to be treated. For example, the composition containing the hydrogel can be applied directly to the surface of the tissue to be treated, for example, during surgery. It is convenient to introduce the hydrogel into the right place inside the vessel by covering it with a catheter, for example, a balloon catheter, and delivering it to the vessel wall, preferably during angioplasty. It is particularly appropriate to inject the saturated hydrogel at the site (8) to be treated using a balloon catheter. When advancing the catheter in the direction of the intended vessel, the balloon can be equipped with a protective sheath to minimize washout of the drug after the introduction of the catheter into the bloodstream. Another embodiment of the present invention provides a compound for administration by means of perfusion balloons. These perfusion balloons, which provide the ability to maintain blood flow and thereby reduce the risk of myocardial ischemia when the balloon is inflated, also provide the ability to deliver the compound to the right place at normal pressure for a relatively long time (more than twenty minutes), which may be necessary for its optimal action. Alternatively, a channelized balloon catheter can be used ("canalized balloon catheter for angioplasty", Mapwiei Meisa!, Voviop Zsiepiyis Sogr., U/agegomp, "o

MA). The latter consists of a traditional balloon covered with a layer of 24 perforated channels that are filled, thanks to an independent lumen, through an additional infusion hole. Various types of balloon catheters such as dual balloon, porous balloon, microporous balloon, channeled balloon, stented balloon, and hydrogel catheter, all of which may be used in the practice of the invention, are described in Keizep et al. (1994); " 70 the entire content of this material is incorporated into this description by reference. in c The use of a perfusion balloon catheter is particularly advantageous, as it provides the ability to keep the balloon inflated for a long period of time while maintaining the properties of easy gliding and ;" specific localization of the hydrogel at the same time.

Another aspect of the present invention relates to a pharmaceutical composition containing a compound of the present invention and a poloxamer, such as Poloxamer (Roiochateg) 407 - a non-toxic biocompatible polyol commercially available

Ge" (VAZE, Ragvirrapu, M).

A poloxamer impregnated with a compound of the present invention can be applied directly to a surface

Me. tissue to be treated, for example, during surgery. Poloxamer gives, in fact, 2) the same advantages as a hydrogel, although it has a lower viscosity.

Application of a channeled balloon catheter with compound-impregnated poloxamer behind it

Me. invention, is particularly advantageous. In this case, it is possible to hold the balloon at the same time

With inflated for a long period of time while maintaining the properties of easy sliding and specific localization of poloxamer.

The percentage content of the active component in the compositions can be changed, and it is necessary that it should be in the proportion that provides the required dosage. It is obvious that several dosage forms can be administered at about the same time. The dose used can be determined by a doctor or qualified medical personnel and

F) depends on the required therapeutic effect, the method of administration, the duration of treatment and the patient's condition. For adults, doses are usually from about 0.001 to about 50, preferably from about 0.001 to about 5, mg/kg of body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to about 70, and more preferably 0.5-10 mg/kg of body weight per day for oral administration and from about 0.001 to 10, preferably 0.01-10, mg/kg of body weight per day for intravenous administration. In each specific case, doses are determined in accordance with the characteristics of the patient to be treated, such as age, weight, general health and other characteristics that may affect the effectiveness of the compound according to the present invention. 65 The compounds and compositions of this invention can be administered as often as necessary to achieve the desired therapeutic effect. Some patients may respond to a higher or lower dose, and much lower maintenance doses may be sufficient for them. For other patients, long-term treatment at the rate of 1-4 doses per day may be necessary, in accordance with the physiological needs of each specific patient. As a rule, the active product can be administered orally 1-4 times a day. But of course

For other patients, no more than one or two doses per day may be necessary.

The compounds of this invention can also be used in combination with other therapeutic agents or in combination with the application of therapeutic methods to address pharmacological conditions that can be alleviated by the use of compounds of formula I! such as the following.

The compounds of this invention can be used to treat restenosis after 7/0 angioplasty using any device such as balloon, cutting or laser procedures. The compounds of the present invention can be used to treat restenosis after the establishment of a stasis in the circulatory system either 1) for the primary treatment of vascular occlusion, or 2) in the event that angioplasty using any device is unable to provide a bypass artery. The compounds of this invention can be used orally, parenterally, by topical application with the introduction of a special device or in /5 View of a properly folded coating on an expander (stent).

The compounds of this invention can be used to treat restenosis in combination with any anticoagulant, antiplatelet, antithrombotic or profibrinolytic agent. Often, patients are treated before, during, and after surgery with agents of these classes to safely perform the surgery or to prevent the adverse effects of thrombosis. Some examples of the classes of agents known as anticoagulant, antiplatelet, antithrombotic, or profibrinolytic agents include any heparin formulation, low molecular weight heparins, pentasaccharides, fibrinogen receptor antagonists, thrombin inhibitors, factor Xa inhibitors, or factor MiIIa inhibitors.

The compounds of this invention can be used in combination with any hypotensive or cholesterol or lipid regulating agent in the treatment of restenosis or atherosclerosis in parallel with the treatment of high blood pressure or atherosclerosis. Some examples of agents suitable for the treatment of high blood pressure include compounds of the following classes: beta-blockers, ACE inhibitors (angiotensin-converting enzyme, ACE), calcium channel antagonists, and alpha-receptor antagonists.

Some examples of agents suitable for the treatment of elevated cholesterol levels or dysregulated lipid levels include compounds known as NMOSCOA reductase inhibitors, compounds of the fibrate class. Compounds of the present invention can be used to treat various forms of cancer alone or in combination with known compounds for the treatment of cancer. X,

It is understood that this invention covers combinations of the compounds of this invention with one or more of the drugs mentioned above.

The compounds in the scope of the present invention show noticeable pharmacological activity in the tests described in the literature, the results of which can be considered to be in line with the pharmacological activity of humans and other mammals. The following results of ip mygo and ip mimo pharmacological tests are typical of the characterization of the compounds of this invention.

Section on obtaining pharmaceutical compositions and pharmacological tests

The compounds of this invention exhibit significant activity as inhibitors of protein tyrosine kinases and have therapeutic value as cellular antiproliferative agents for the treatment of certain conditions, including psoriasis, atherosclerosis, and restenosis. The compounds of this invention provide modulation and/or inhibition. cell signaling, cell proliferation, matrix production, chemotaxis and/or inflammatory response of cells and can be used to prevent or delay the onset or recurrence of such conditions or treat the condition.

Pharmacological methods described below are used to determine the effectiveness of compounds according to the present invention

Ge" tests accepted in this field of medicine and, as is known, correspond to pharmacological activity in mammals. The compounds of the present invention have been subjected to various of these tests and appear to be useful

Me. activity of the mediator of cell differentiation. The results of these tests should be considered to provide sufficient 2) information to specialists in the field of pharmacology and medicinal chemistry to determine the parameters of the use of the investigated compounds in one or more therapeutic measures given in this description.

Me, 1. Analysis of autophosphorylation of tyrosine kinase ROSB-K by the EGISA method

The analysis specified in the title is performed as described in Section a). (U. May. Spec. 1994, 37, 2627) (the material is incorporated into this description by reference), except for the use of cell lysate obtained from human aortic smooth muscle cells (NAM5ZS), as described below. 2. General procedure of mutagenesis analysis a. Cell culture

F) Human aortic smooth muscle cells (passage 4-9) are placed on 96-well plates in a nutrient medium of 6000 cells per well and allowed to grow for 2-3 days. At approximately the 8095th confluence, cell growth is stopped with serum-free nutrient medium (ZEM). in r. Analysis of mitogenesis

After 24 hours of serum deprivation, the medium is removed and replaced with the test compound and carrier in the ZEM (200µL per well). Compounds are dissolved in cell culture OM5O (DMSO) at a concentration of 10 mM and additional dilutions are made in ZEM.

After 30 minutes of pre-incubation with the compound, the cells are stimulated with РОСР at 1 ng/ml. 65 The determination is carried out in duplicate with stimulated and unstimulated wells at each concentration of the compound.

After four hours, ImkkKi zn thymidine/well is added.

Cultivation is completed 24 hours after adding the growth factor. Cells are lifted by trypsin and collected on a filter film (mat) using an automated cell harvester (Umaijas MasP96). The filter film was counted in a scintillation counter (U/aas Veilaria(e)) to determine the label introduced into the DNA.

C. Analysis of chemotaxis

Human aortic smooth muscle cells (NASMS) are obtained from ATSS at early passages. Cells are cultured in Siopeisv ZtoOM 2 Zipdieotzoi (use medium and cells at passages 4-10). At 70 8095th confluence of cells, a fluorescent probe, calcein AM (5mM, Moiiestiag Rhorbe) is added to the medium, and the cells are incubated for 30 minutes. After washing with a saline solution with HERE5 buffer, the cells are digested with trypsin and neutralized with buffer MCOV 131 (Sirso) with 0.195 VZA (bovine serum albumin), 10 mM glutamine and 10956 fetal calf serum. After centrifugation, the cells are washed again and resuspended in the same buffer without fetal calf serum at 30,000 cells per 5 Oml. 75 cells are incubated at different concentrations of the compound of formula I (final concentration in DMSO - 195) for 30 minutes at 37"C. For the study of chemotaxis, modified Boyden chambers with 96 cells (Mepgorgobe, Ips.) and a polycarbonate membrane with a pore size of 8 mm (Rogeiisz) are used , CA). The membrane is coated with collagen (Zidta CZ3657, 0.1 mg/ml). In the lower chamber, ROSE-pp (Zng/ml) is placed in the buffer with and without the compound of formula I. In the upper chamber, cells (30,000) with the inhibitor are placed and without it. Cells are incubated for 4 hours. The filter membrane is removed and the cells on the upper side of the membrane are removed. After drying, the fluorescence on the membrane is determined using Suioiscog Ii (MiProge) at excitation and emission wavelengths of 485 and 5 ZOnm. In each experiment, the average Cell migration is obtained in six replicates.Percent inhibition is determined from control values with DMSO treatment.Based on five evaluations, the concentration-dependent inhibition is calculated , the value of IS so. The results are given as the average Ge value of ZEM (mean square error of measurement) from five such experiments. o 4. Purification of the ESE receptor

Purification of the ЕОСРЕ receptor is based on the procedure of Yarden and Schlessinger (Uagaep apa Zspiezzipdeg). Cells

A431 is cultivated in beakers with an area of 80 cm2 until confluence (2x107 cells per beaker). Cells are washed twice

RVZ (phosphate-saline buffer solution) and collected using RVZ containing 11.0mmol EOTA (1..CCM hour at 372С), and centrifuged at 6009 for 10 minutes. Cells are solubilized in iml per 2x107 cells with cold solubilization buffer (5Hmol Nerez buffer, pH 7.6, 195 Top X-100, 150mmol Mass, 5Bmmol

ESTA, immole PM5BE, 5mg/ml aprotinin, 25mmol benzamidine, bmg/ml leupepsin inhibitor and 1mg/ml soybean trypsin inhibitor) for 20 minutes at 4°C. After centrifugation at 1000009 for 30 minutes, the supernatant is loaded onto UUSA-agarose column (100 ml of packed resin per 2 x 10' cells) and shaken for 2 hours at 47 C. The unabsorbed material is removed and the resin is washed twice with NTM buffer (5 mmol Nerez buffer, pH 7.6, 0.195 Tiop X-100, 150 mmol Mass), two times with NTM buffer containing 1 M Mass, and twice with NTMO buffer (500 mmol Nerevz buffer, pH 7.6, 0.195 Top X-100, 150 mmol Mass and 1096 glycerol). The EsE receptor is eluted periodically with NTMO buffer containing 0.5 M M-acetyl-O-glucosamine " (200 ml per 2 x 10' cells). The eluted material is stored in aliquots at -707C and before use is diluted with TMTMO buffer (50 mmol Ttgiz-Mez buffer, pH 7.6, 0.195 Ttyop X-100, 150 mmol Massey and 10905 glycerol). c 5. Inhibition of autophosphorylation of ESE-K from A431 cell cultures grown to confluence on fibronectin-coated human tissue culture plates.

After washing twice with ice-cooled PB5 solution, cells are lysed by adding 5O0Oml/plate of lysis buffer (5Omol Nerez, pH 7.5, 150mmol Massi, 1.5mmol MoSi", tmol ESTA, 1095 395 glycerol, 1965 Triton X-100, 1mmol PM5BE, mg/ml of aprotinin, Tmg/ml of leupeptin) and incubated for 5 minutes at 4"C.

Ф After stimulation with ESE (500mg/ml, 10 minutes at 37"C), perform immunoprecipitation using anti-ESB-K (o) (Alb 108) and perform the autophosphorylation reaction of the sample (5Oml aliquot, ZmKi (9 2RI|ATP) in the presence 2 or 10 mM of the compounds of this invention for 2 minutes at 4°C. The reaction is stopped by adding hot 50% electrophoresis sample buffer. ZOA-RACE analysis (7.59 Uvsel.) is performed followed by autoradiography and (o) the reaction results are quantified by densitometric scanning of X-ray films.

KZ a. Cell culture

Cells named NEK 14 and K/21A are obtained by transfection of MINZTZ cells (clone 2.2) (from S. Eguipa,

MS, MIN), experiencing a lack of endogenous ESE receptors, with cDNA constructs from the wild-type ESE receptor or a mutant ESE receptor that requires tyrosine kinase activity (in them, Lys 721 in the place of binding to ATP 55 and - and ШЧА is replaced residue Aa, respectively). All cells were cultured in OMEM with 1095 calf serum (Nussiope, I odap, (F)an).

Ge 6. Selectivity depending on RKA and RKS is determined using commercial sets of devices: a. Riegse colorimetric kit for PCA analysis, format Zriphute vo Short protocol: test tube 10 with PCA enzyme (bovine heart) peptide (dye-labeled) substrate Kemptide minutes at 307"C

Spectral absorptivity at 57 Ohm in 5 years. Riegse colorimetric kit for RKS analysis, Zriphute format

Brief protocol:

tube 0.025) with the enzyme PKC (rat brain) peptide (labeled with a dye) substrate Neurogranin

30 minutes at 307C

Spectral absorbance at 57 Ohm 7. Measurement of the activity of inhibition of tyrosine kinase p5bek

The tyrosine kinase inhibitory activity of p5BEC is determined according to the method disclosed in the US patent

Mo5714493, given in this description by reference.

In accordance with another option, the activity of tyrosine kinase inhibition is determined by this method. Substrate 70 (substrate containing tyrosine, Viok(rATa)z-I uv-MaI-sish-I uv-Pe-s1u-s10-s1u-Tng- Tug-sIy-MaI-MaI-Tug-Huz-(MH 2 ), recognized with the help of rB5bsK ЯМмМкМ) are first phosphorylated in the presence or absence of a given concentration of the test compound by a given amount of enzyme (the enzyme is made by expressing the robisk gene in a yeast construct), purified from cloned yeast (enzyme purification is carried out by the following classical methods), in the presence of ATP (1ΩmM), Mosi" (2.5mM), Mysii (2.5mM), Mas! (25mM), OT (0.4mM) in 79 Nerez BOMM, pH 7.5, for 10 minutes at ambient temperature. The total volume of the reaction mixture is B5Oml, and the reactions are performed in a black 96-well fluroplate. The reaction is stopped by adding 150 μl of stopping buffer (100 mM Nerez, pH 7.5, KE 400 mM, EOTA 133 mM, VZA 1 g/l), containing an antibody to tyrosine labeled with europium cryptate (RU20-K), at 0O.8 μg/ml, and allophycocyanin-labeled streptavidin (XI 665) at 4 μg/ml. Labeling of streptavidin and antibodies to tyrosine was carried out

Siv-Vio Ipiegpayopa! (France). The mixture was counted using a Raska Oivsomegh counter capable of measuring the transfer of uniform fluorescence with time resolution (excitation at 337 nm, reading at 620 nm and bbb5 nm). The ratio of the bbbnm signal to the b20nm signal is a measure of the concentration of phosphorylated tyrosine. A blank experiment is obtained by replacing the enzyme with a buffer. The characteristic signal is the difference between the ratio obtained without inhibitor and the ratio in the blank experiment. Calculate the characteristic signal in c 29 percent. Calculate the ISvo with 10 concentrations of the inhibitor in duplicate, using software d) provision of HIN. The reference compound is staurosporine (Zydta), which shows ISvko-ZO0zh6NM (n-20).

The results obtained by the experimental methods described above prove that the compounds of this invention have a useful ability to inhibit the protein tyrosine kinase of the ROS receptor and the ability to inhibit the tyrosine kinase rBbK and therefore have therapeutic value. The results of the pharmacological tests described above can be used to determine the dose and method of administration for the intended specific Ge) therapeutic measure.

This invention can be implemented in other specific ways within its essence or essential features. about (Se)

Claims (1)

Formula of the invention (Se) 1. Quinoline or quinoxaline compounds of formula I: Ac « 2 Chi 2. Uh ne c | - z» in -- and (is) where X represents I OH or 1 525; F II represents (SEK zaKz)g or (SKzaKz)t-23-(SKzakKz)n; 9) Y" represents (SK zaKz)p-24-(SKzakKz)d or ethenyl; 714 represents CH or M; b 72" is hydroxy(C3-C10)cycloalkyl, optionally substituted with 1-3 substituents selected from the group consisting of C1-C4 alkyl, hydroxy, acyloxy, C1-Syralkoxy, halogen, KeKeM , acylBM, carboxy and KeKeMSO; hydroxy(C3-C:o)cycloalkenyl, optionally substituted with 1-3 substituents selected from the group consisting of C.-Suralkyl, hydroxy, acyloxy, C.i-Syralkoxy, halogen, KoBKeM, acylUBM, carboxy and kKeKBMSOo; hydroxyheterocyclyl, wherein heterocyclyl is a 4-10-membered, monocyclic or polycyclic system in which one or more ring atoms are other than carbon and selected from nitrogen, oxygen or sulfur, optionally F, substituted with 1-3 substituents selected from from the group including C.-C.iralkyl, hydroxy, acyloxy, C.-C.-ralkoxy, co halogen, K5KeM, acylkM, carboxy and K5KeMSO; or hydroxyheterocyclenyl, where heterocyclenyl is heterocyclyl as defined above, containing at least one carbon-carbon or carbon-nitrogen double bond, optionally substituted with 1-3 substituents selected from the group consisting of C.4- C.alkyl, hydroxy, acyloxy, C4-C-ralkoxy, halogen, K5KeM, acylKM, carboxy and K5KeMSO; and when cycloalkyl is substituted with at least two hydroxy substituents, then at least two hydroxy substituents can be ketalized or acetalized with an aldehyde or ketone with 1-6 carbon atoms to form the corresponding ketal or acetal; 65 73 is O, MK, 5, ZO or 505; 74 represents O, MK, 5, ZO, 50" or connection; t is equal to 0 or 1; n equals 2 or 3, and n '- t - 2 or 3; r and 4 are equal, independently, to 0,1,2, Zabo4, rust, 1,2, Z or 4, when 7; is a bond, irna-0,1,2, or 3, when 77 is other than a bond; r is equal to 2, C or 4; Ka and Ki represent, independently, C 1-C-dalkyl with a straight or branched chain, optionally substituted by a C.i-C-ralkoxy group, halogen, carboxy, hydroxy or K5KeM group; Se-Sirdaryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, halogen, 70. C1-Syralalkyl, C1-Syralkoxy, carboxy, C4-Syralkoxycarbonyl and U M2MSO, where U and y, independently, are hydrogen or C-Sialkyl; heteroaryl, which is a 5-10-membered aromatic monocyclic or polycyclic hydrocarbon ring system in which one or more ring atoms are other than carbon and selected from nitrogen, oxygen or sulfur, optionally substituted with one or more substituents selected from groups that include hydrogen, hydroxy, halogen, C.-C.sub.3-alkyl, C.--C.sub.zoalkoxy, carboxy, C.--Siraloxycarbonyl and U'M2MSO, where U! and U, 75 independently, represent hydrogen or C.4-C.dalkyl; hydroxy; acyloxy; C4-Ci-Alkoxy, optionally substituted with one or more substituents selected from the group consisting of amino, C1-C-ralkoxy, carboxy, C.1-Croxycarbonyl, carboxy(C1-C10)aryl, carbamoyl or heterocyclyl, where heterocyclyl has the above meaning; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted with groups as described above for cycloalkyl; heterocyclyl-O-, wherein heterocyclyl is as defined above, optionally substituted with groups as described above for cycloalkyl; heterocyclyl-C(O)O-, where heterocyclyl is as defined above, optionally substituted with groups as indicated above for cycloalkyl; C is -Siraryloxy, optionally substituted with groups as indicated above for aryl; heteroaryl-O-, wherein the heteroaryl is as defined above, optionally substituted with groups as indicated above for aryl; cyano; K 5K6M or acyl-K5M, or one of Ka and K/l is hydrogen or halogen, and the other is C 4-C ialkyl, optionally substituted as indicated for it above; Gee! Se-Siraryl, optionally substituted as indicated for it above; heteroaryl as defined above is optionally substituted as above for aryl; hydroxy; acyloxy; Co 3-Siralkoxy, optionally substituted as indicated for it above; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted as indicated above; heterocyclyl-O-, where heterocyclyl is defined above, optionally substituted as above for cycloalkyl; heterocyclyl-C(F)O-, where heterocyclyl has the above-mentioned values, He is optionally substituted with groups, as indicated above for cycloalkyl; C 5-C-raryloxy, optionally substituted with groups as indicated above for aryl; heteroaryl-O-, where heteroaryl is as defined above, optionally substituted with groups as above for aryl; cyano, K5KeM or acyl-KeM; co Ks represents hydrogen, C 4-C/ralalkyl with a straight or branched chain, optionally substituted as indicated for it above; C 1 -Sioaryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, halogen, C 1 -Syralalkyl, C 1 -Syralkoxy, carboxy, C 4 -C syloxycarbonyl and (Ce) mUgMSO , where those U, independently, are hydrogen or C 4-C-alkyl; heteroaryl, which is a 5-10-membered aromatic monocyclic or polycyclic hydrocarbon ring system in which one or more ring atoms are other than carbon and selected from nitrogen, oxygen or sulfur, optionally substituted with one or more substituents selected from from the group including hydrogen, hydroxy, halogen, C-C-alkyl, C-C-alkyl, C-70 carboxy, C1-C-alkyloxycarbonyl and U1MX2MCO, where U! and 2, independently, represent hydrogen or C 1-Cyralalkyl; with hydroxy; acyloxy; C1-C1-Cialkyl, optionally substituted with one or more substituents selected from the group consisting of amino, C1-C1-Cialkyl, carboxy, C1-C1-alkyloxycarbonyl, carboxy(Ce-C/od)aryl , carbamoyl or heterocyclyl, wherein heterocyclyl is as defined above; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted with groups as above for cycloalkyl; heterocyclyl-O-, wherein heterocyclyl 79 is as defined above, optionally substituted groups as indicated above for cycloalkyl; F heterocyclyl-C(O)O-, wherein the heterocyclyl is as defined above, optionally substituted with groups as indicated above for cycloalkyl; C 6-Sidaryloxy, optionally substituted with groups, as above for aryl; heteroaryl-O-, wherein heteroaryl is as above, optionally substituted with groups as above for aryl; halogen; cyano; K5KeM or acyl-KeMm; He) 50 Kza, Kz, Kza and Kuz , independently, are hydrogen or C 4-C alkyl with a straight or branched chain; iz Ku is hydrogen, C.4-Siralalkyl with a straight or branched chain, H-CO- or C.-Siralalkyl-CO-; and KB and Kv, independently, represent hydrogen or C 4-C-ralalkyl with a straight or branched chain, or KB and Kb, taken together with the nitrogen atom to which K 5 and Kv are connected, form azaheterocyclyl, where heterocyclyl 99 defined above, GF) or their M-oxide, hydrate, solvate, prodrug, or pharmaceutically acceptable salt. t 2. The compound of formula 1 according to claim 1, in which: Y represents (СЕ заКз)т- 23 (SKzakKzv)n; in Y" is (SR zaKZzv)r-2y(SVzakz); and | And 72" is hydroxy(C3-C10)cycloalkyl, optionally substituted with 1-3 substituents selected from the group that includes C.-Sialkyl, hydroxy, acyloxy, C--Siraloxy, halogen, K5KeM, acyl5M, carboxy and K5KeMSO, or hydroxyheterocyclyl, where heterocyclyl is a 4- to 10-membered, monocyclic, or polycyclic system in which one or more ring atoms are other than carbon and selected from nitrogen, oxygen, or sulfur, optionally substituted with 1- 3 substituents selected from the group consisting of C.-C.alkyl, hydroxy, acyloxy, C.-C.-ralkoxy, halogen, K5ReM, acyl5M, carboxy and K5KeMSO; 74 represents O and ME; t is equal to 0; n equals 2 or 3; rta-0 or 1; Echa and Ki, independently, represent C 1-C-dalkyl with a straight or branched chain, optionally substituted by a C.--Sirdalkoxy group, halogen, carboxy, hydroxy or KeKeM group; C--C-ralkoxy, optionally substituted with one or more substituents selected from the group consisting of amino, C4-C-dralkoxy, carboxy, C--Syralkoxycarbonyl, carboxy(Ce-Sio)aryl, carbamoyl and heterocyclyl , where heterocyclyl has the aforementioned meaning; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted with groups as described above for cycloalkyl; heterocyclyl-O-, wherein heterocyclyl is as defined above, optionally substituted with groups as described above for cycloalkyl; or K KM; or one of Ca and Cl is hydrogen or halogen, and the other of Ca and Cl is straight or branched C 1 -C 4 -alkyl optionally substituted with C 4 -C 4 -alkyl, halogen, carboxy, hydroxy or CoKeM - a group; C.1-Syralkoxy, optionally substituted with one or more substituents selected from the group consisting of amino, C-Ci-Siralkyl, carboxy, C-Ci-Siralkyloxycarbonyl, carboxy(Ce-Co)aryl, carbamoyl and heterocyclyl, where heterocyclyl has the above-mentioned meaning; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted with groups as described above for cycloalkyl; heterocyclyl-O-, wherein heterocyclyl is as defined above, optionally substituted with groups as described above for cycloalkyl, or KeReM; Ks is hydrogen, C 4-C-alkyl with a straight or branched chain, optionally substituted C.-Syralkoxy group, halogen, carboxy, hydroxy or CoBReM group; or C 1 -C ralcoxy, optionally substituted with one or more substituents selected from the group consisting of amino, C 1 -C 4 ralcoxy, carboxy, C.1-Croxycarbonyl, carboxy(C1-C10)aryl, carbamoyl or heterocyclyl, where heterocyclyl has the above meaning; from Eza; Kz, KZ'vi Ku, independently, represent hydrogen or S.-Svalkil; Ge) Ku is hydrogen; and Kb and Bb, taken together with the nitrogen atom to which Kb and Co are bound, form azaheterocyclyl, or its M-oxide, its hydrate, its solvate, its prodrug, or its pharmaceutically acceptable salt. 3. The compound of formula 1 according to claim 1, in which: c X represents 1,522; "so Y" is (SE zaKz)r-74-(SKzaKzv)d; 72" is hydroxy(C3-C10)cycloalkyl, optionally substituted with 1-3 substituents selected from the group consisting of C-C-alkyl, hydroxy, acyloxy, C-C-ralkoxy, halogen, K5KeM , acyl5M, carboxy and K5KeMSO; "o 74 represents O and ME; p is equal to 0; |se) a is equal to 0 or 1; Echa and Ki, independently, represent C 1-C-dalkyl with a straight or branched chain, optionally substituted by a C.--Sirdalkoxy group, halogen, carboxy, hydroxy or KeKeM group; C--C-ralkoxy, "optionally substituted with one or more substituents selected from the group consisting of amino, C4-C-dralkoxy, carboxy, C1-C4-alkyloxycarbonyl, carboxy(Ce-Cd)aryl, carbamoyl or heterocyclyl, where heterocyclyl has the above meaning; cycloalkyl-O-, wherein cycloalkyl is as defined above, optionally substituted with "" groups as specified above for cycloalkyl, or heterocyclyl-O-, wherein heterocyclyl is as defined above, " optionally substituted with groups as specified above for cycloalkyl; or one of K 44 and K/j is hydrogen or halogen, and the other of K and K/j is straight- or branched-chain C.-C.alkyl, optionally substituted by C.-C-ralkoxy group, halogen, carboxy, hydroxy or KeKeM group; C.-Syralkoxy, (2) optionally substituted with one or more substituents selected from the group consisting of amino, C4-C-dralkoxy, F-carboxy, C.i-Syralkoxycarbonyl, carboxy(Ce-C-o)aryl, carbamoyl or heterocyclyl, where heterocyclyl is as defined above, or cycloalkyl-O-, where cycloalkyl is as defined above, optionally substituted with groups as above for cycloalkyl; heterocyclyl-O-, where heterocyclyl has the above-mentioned values, FO 20 is optionally substituted by groups, as indicated above for cycloalkyl; Ks is hydrogen; IR) Ka and Kz, independently, represent hydrogen; and Ku is hydrogen, or an M-oxide thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 22 4. The compound according to claim 1, in which 74 is CH. o 5. The compound according to claim 1, in which 74 is M. b. The compound according to claim 1, in which 75 is hydroxy(C 3-Ci0)cycloalkyl, optionally substituted with 1-3 substituents selected from the group consisting of C.1-C.-alkyl, hydroxy, acyloxy, C- -C-ralkoxy, halogen, KeReM, acylBM, carboxy and K5KeMSO. because 7. Compound according to claim 1, in which row and d are 0. 8. Compound zap. 1, in which Sun is 1. 9. The compound according to claim 1, in which 74 is 0. 10. The compound according to claim 1, in which 74 represents O, and r and d represent 0. 11. The compound according to claim 1, in which 74 is O, and a - 1. bo 12. The compound according to claim 1, in which 74 is MK. 13. The compound according to claim 1, in which 74 represents MK, and p and 4 represent 0. 14. The compound according to claim 1, in which 74 is MKU, and ir a is 1. 15. The compound according to claim 1, in which 74 is 5. 16. The compound of claim 1, wherein 74 is 5, and p and 4 are 0. 17. The compound according to claim 1, in which 74 represents 5, and r. na - 1. 18. The compound according to claim 1, in which Ka and K/j, independently, represent an optionally substituted hydroxy group C.-Cylalkyl, hydroxy, C-Cyloxy, cycloalkyl-O-, where cycloalkyl has the values specified in claim 1, optionally substituted by groups as specified in claim 17 for cycloalkyl, heterocyclyl-O-, where heterocyclyl has the values specified in claim 1 value, optionally substituted by groups as specified in claim 1 for cycloalkyl; or one of Ka and Kl represents 7/0 Hydrogen or halogen, and the other of Ka and K/i represents an optionally substituted hydroxy group C/-Salkyl, hydroxy, C-Salkyloxy, cycloalkyl-O-, where cycloalkyl has the specified in claim 1 values optionally substituted by groups as specified in claim 1 for cycloalkyl, heterocyclyl-O-, where heterocyclyl has the values specified in claim 1, optionally substituted by groups as specified in claim 1 for cycloalkyl. 19. A compound according to claim 1, in which Ka and Kir, independently, are heterocyclyl-C(O)0O-, where heterocyclyl has the values specified in claim 1, optionally substituted by groups as specified in claim 1 for cycloalkyl, or C 5-Svalcoxy, optionally substituted by groups as indicated for it in claim 1. 20. The compound according to claim 19, in which C--Svalcoxy is methoxy or ethoxy. 21. The compound according to claim 1, in which Ka and Cl, independently, are S.-Svalkil. 22. The compound according to claim 21, in which C--Svalkyl is methyl or ethyl. 23. The compound according to claim 1, in which one of Ka and Cl is S.-Svalcoxy, and the other of Ka and Cl is a halogen. 24. The compound according to claim 23, in which C--Svaloxy is methoxy or ethoxy, and halogen is chlorine or bromine. 25. The compound according to claim 1, in which one of Ka and Kl is S.-Svalkyl, and the other of Ka and Kl is C4-Svalcoxy. 26. The compound according to claim 25, in which C./-Svaloxy is methoxy or ethoxy, and C.sub.-Svalky is methyl or ethyl. with 27. The compound according to claim 1, in which one of Ka and K/l is C 4-Caloxy, and the other of Ka and Ki is cycloalkyl-O-, where cycloalkyl has the values specified in claim 1. (8) 28. The compound according to claim 27, in which C--Chaloxy is methoxy or ethoxy, and cycloalkyl-O- is cyclopentyloxy or cyclohexyloxy. 29. The compound according to claim 1, in which one of Ka and K/j represents hydrogen, and the other of K 44 and Kir represents c zo C.-Svalkoxy, cycloalkyl-O- or heterocyclyl-O-, where the specified radicals have values specified in claim 1. 30. The compound according to claim 29, in which C4--Chaloxy is methoxy or ethoxy, and cycloalkyl-O- is cyclopentyloxy ise) or cyclohexyloxy, and heterocyclyl-O- is furanyloxy. with 31. The compound according to claim 1, in which Ks is hydrogen, C1-Svalkyl or Si-Svalcoxy. 32. The compound according to claim 31, in which C-Svalky is methyl or ethyl and C--Svaloxy is methoxy or ethoxy. ise) 33. The compound according to claim 1, in which 22 is hydroxy(C3-C10)cycloalkyl, optionally substituted with hydroxy or with C1-Sralalkyl. 34. The compound according to claim 33, in which 75 is a hydroxy(C 3-C 10 )cycloalkyl, optionally substituted with C-C alkyl. 35. The compound according to claim 19, in which C4-C-Croxy is optionally substituted by a C.-C-ralkoxy group, heterocyclyl, where "Heterocyclyl has the values specified in claim 1, a carboxy group, C1-C-ralkoxycarbonyl or carbamoyl. from p. 36. The compound according to clause C5, in which one of Ka and Kl is unsubstituted C.--Svalcoxy, and the other from Ka and Kl1 is heterocyclyl-C(0)O-, where heterocyclyl has the properties specified in claim 1 values, optionally replaced by groups like ;" is indicated in claim 1 for cycloalkyl, or C--Salkoxy, substituted by C--Syralkoxy group, heterocyclyl, where heterocyclyl has the values indicated in claim 1, carboxy group, C4-Syralkoxycarbonyl or carbamoyl. 37. The compound according to item Zb, in which one of K and K is a methoxy, and the other of K 44 and K is a He»P1,4Lbipiperidin-1'-ylcarbonyloxy, 2-(ethoxy)ethoxy, 2- (4-morpholinyl)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy, me)M-methylaminocarbonylmethoxy or M,M-dimethylaminocarbonylmethoxy. 2) 38. The compound according to claim 1, which is: trans-4-(7-chloro-6-methoxyquinoxalin-2-ylamino)cyclohexanol; Me, trans-4-(6-chloro-7-methoxyquinoxalin-2-ylamino)cyclohexanol; He trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol; cis-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol; (2endo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol; (2exo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol; (2-endo,Zexo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1)heptane-2,3-diol; F) cis-2-(b-methoxyquinoxalin-2-ylamino)cyclopentanol; ka trans-2-(6-methoxyquinoxalin-2-ylamino)ucyclopentanol; trans-4-(6-methoxyquinoxalin-2-ylamino)cyclohexanol; in Izak,45,6K,base|1|-6-(6,7-dimethoxyquinoxalin-2-ylamino)-2,2-dimethyltetrahydrocyclopenta!|1.3|dioxole-4-carboxylic acid ethylamide; 2-(1,4-dioxaspiro|(4.5|dec-8-yloxy)-6,7-dimethoxyquinoxaline; 4-(6,7-dimethoxyquinoxalin-2-yloxymethyl)cyclohexanol; 3-(6,7-dimethoxyquinoxaline-2 -yloxy)cyclohexanol; 65 4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol; 5-(6,7-dimethoxyquinoxalin-2-yloxy)bicyclo|2.2.1|heptane-2,3-diol; (2exo,Zexo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1)heptane-2,3-diol; cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexyl ester of acetic acid; cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol; 4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexyl ether of dimethylcarbamic acid; trans-4-(6,7-dimethoxy-4-oxyquinoxalin-2-ylamino)cyclohexanol; trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexyl ester of acetic acid; (2exo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo|2.2.1|)heptan-2-ol; (2-endo,bexo)-5-(6,7-dimethoxyquinolin-2-ylamino)bicyclo|2.2.1)heptan-2-ol; 70 (2exo,bexo)-6-(6,7-dimethoxyquinolin-2-ylamino)bicyclo-(2.2.1|)heptan-2-ol; 4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (h2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (3-(2trans,А4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (-)-(2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino) -2-methylcyclohexanol; (2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol; (2cis,4cis)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2 -methylcyclohexanol; (2cis,A4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol, and 4-(6,7-dimethylquinoxalin-2-ylamino)cyclohexanol, or its M-oxide, hydrate , solvate, prodrug, or pharmaceutically acceptable salt. 39. The compound according to claim 1, which is trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol, or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 40. The compound according to claim 1, which is cis-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol, or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 41. The compound according to claim 1, which is 4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol, or its M-oxide, hydrate, solvate, prodrug, or pharmaceutically acceptable salt. 42. The compound according to claim 1, which is (8) (2exo,bexo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo-(2.2.1)heptan-2-ol, or its M-oxide , hydrate, solvate, prodrug, or pharmaceutically acceptable salt. 43. The compound according to claim 1, which is trans-4-(7-chloro-6-methoxyquinoxalin-2-ylamino)cyclohexanol, or its C Zo M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 44. The compound according to claim 1, which is 4-(6,7-dimethoxyquinolin-2-ylamino)cyclohexanol, or its M-oxide, co-hydrate, solvate, prodrug or pharmaceutically acceptable salt. with 45. The compound according to claim 1, which is (-)-(2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methylcyclohexanol, or its //M-oxide, hydrate, ise) With CsOolvate, prodrug or a pharmaceutically acceptable salt. "at 46. The compound according to claim 1, which is (15, 2, 45, 5K)-5-(6,7-dimethoxyquinoxalin-2-ylamino)bicyclo(|2.2.1|heptan-2-ol, or its M- oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 47. The compound according to claim 1, which is trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol sulfate. " 48. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable carrier. from p. 49. The method of inhibiting the tyrosine kinase activity of the ROSBE growth factor, which differs in that the compound . claim 1 is subjected to contact with the composition containing the tyrosine kinase ROSPE. and?" 50. A method of inhibiting the activity of tyrosine kinase I sk, which differs in that the compound according to claim 1 is brought into contact with a composition containing tyrosine kinase I sk. 51. A method of inhibiting cell proliferation, differentiation or release of a mediator in a patient suffering from a disorder characterized by such proliferation and/or differentiation and/or release of a mediator, which is characterized by the fact that the patient is administered a pharmaceutically effective amount of Me, the amount of the compound according to claim 1. 2) 52. The method according to claim 51, in which the disorder is leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, arthritis, lung fibrosis, kidney fibrosis, liver fibrosis, Me atherosclerosis, or restenosis after coronary artery, femoral artery, or renal artery angioplasty. Ge 53. A method of treating a pathology associated with a hyperproliferative disorder, which differs in that the patient is administered a pharmaceutically effective amount of the compound according to claim 1. 54. The method according to claim 53, in which the indicated pathology is restenosis. 55. The method according to claim 53, in which the pathology associated with the hyperproliferative disorder is a cancer susceptible to treatment by inhibition of the ROSBE growth factor tyrosine kinase. F) 56. The method according to claim 55, in which the cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma, or malignant melanoma. 57. A method of treating restenosis, which differs in that the patient in need of such treatment is administered a pharmaceutically effective amount of the compound according to claim 1, capable of inhibiting the proliferation of smooth muscle cells of blood vessels and migration in a given place. 58. The method according to claim 57, in which the specified place is the place of mechanical damage to the arterial wall, obtained as a result of the treatment of an atherosclerotic lesion by angioplasty. 59. The method according to claim 57, in which the compound according to claim 1 is administered using an angioplasty balloon covered with a hydrophilic film impregnated with the compound according to claim 1. 60. The method according to claim 57, in which the compound according to claim 1 is administered using a catheter equipped with an infusion chamber containing the compound according to claim 1. 61. The method according to claim 57, in which the compound according to claim 1 is administered using a coating on an expanding device (stent) containing the compound according to claim 1. 62. A method of treating inflammation in a patient suffering from such a disorder, wherein said patient is administered a pharmaceutically effective amount of the compound of claim 1. 63. A method of treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, asthma, inflammatory bowel disease or pancreatitis, which is characterized by the fact that the patient in need of such treatment is administered an inhibitory tyrosine kinase I sk amount of the compound according to claim 1 . 0. и и и 0. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 5, 15.05.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c schi 6) c (Se) (ze) (Se) (Se) - with . and? (o) (o) (95) (o) Ko) ime) 60 b5