Condensed heteroaryls and their application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

 

[001] Phosphoinositide-3-kinase (PI3-kinase or PI3K) are a family of enzymes that may be involved in cellular functions such as growth, proliferation, differentiation, motility, cell survival and intracellular migration, which, in turn, may be involved in the development of cancer.

[002] the PI3K Family may include four different classes, which differ in structural and functional characteristics and called Classes I-IV. The most investigated class is a Class I PI3K. Class I consists of three α-isoform of class I - PI3Kα, PI3Kβ and PI3Kδ. Apparently, PI3Kα plays an important role in cancer and malignant tumors in humans. For cancer in humans may be the overexpression of PI3Kα.

[003] the Target of rapamycin in mammals (mTOR) is located below the cascade kinase PI3K family. Inhibition of mTOR can inhibit the activity of PI3K. Thus, the path of the PI3K/mTOR can also be used to discover new drugs for the treatment of cancer.

[004] According to the present invention proposed at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt of the compound, where

And1represents N or �N;

And4and And5independently represent N or CR2;

And2and And3together with the ring To form a 5-membered heteroaryl or heterocycle containing from 1 to 4 heteroatoms selected from N, O and S, and the specified 5-membered heteroaryl or heterocycle may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

provided that A2and And3together with ring B are;

represents a single bond or double bond;

R1is heteroaryl, possibly substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)n Re, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

R and R2independently selected from H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -OC(O)Ra, -OC(O)NRcRd, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

and each of the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogenoalkane, heteroaryl and heterocycle may be substituted by one or more groups independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle;

each Ra, Rb, Rc, Rd, Re, Rfand Rgindependently selected from H, possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle,

or Raand Rcand/or Rcand Rdand/or Rcand Reand/or Rcand Rfand/or Rdand Reand/or Rgand Rftogether with the atom (atoms) to which they are attached, form a 3-10-membered ring possibly substituted heterocyclic ring; and

in each case, n is independently 0, 1 or 2;

where each maybe substituted by the group listed above can be unsubstituted or independently substituted by one or more, e.g. one, two or three substituents, independently selected from C1-C4of alkyl, cycloalkyl, oxo, aryl, heterocycle, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4halogenated-, -OC1-C4alkyl, OC1-C4alkylphenyl, -C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4alkyl, -OC1-C4halogenoalkane, halogen, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -NH(C1/sub> -C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4alkyl, -C(O)Otsikoilla, -C(O)Aurila, C(O)Heteroaryl, -C(O)Heterocycle, -CON(C1-C4alkyl)(C1-C4alkyl), CONR'R", where R' and R" together with the N atom to which they are attached, form heterocycle, -CON(cycloalkyl)(cycloalkyl), CON(heterocycle)(heterocycle), -CONH(C1-C4alkyl), -CONH(cycloalkyl), CONH(heterocycle), -CONH2, -NHC(O)(C1-C4alkyl), -NHC(O)(cycloalkyl), -NHC(O)(heterocycle), -NHC(O)(aryl) such as-NHC(O)(phenyl), NHC(O)(heteroaryl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(cycloalkyl), N(C1-C4alkyl)C(O)(heterocycle), N(C1-C4alkyl)C(O)(aryl) such as-N(C1-C4alkyl)C(O)(phenyl), N(C1-C4alkyl)C(O)(heteroaryl), -C(O)C1-C4alkyl, -C(O)(cycloalkyl), C(O)(heterocycle), -C(O)(aryl) such as-C(O) phenyl, -C(O)(heteroaryl), -C(O)C1-C4halogenated, -OC(O)C1-C4alkyl, -OS(O)(cycloalkyl), OS(O)(heterocycle), - OS(O)(heteroaryl), OS(O)(aryl) such as-OC(O)phenyl, -SO2(C1-C4alkyl), - SO2(cycloalkyl), -SO2(heterocycle), -SO2(aryl), such as SO2(phenyl), -SO2(heteroaryl), -SO2(C1-C4halogenated), -SO2NH2,-SO 2NR'R", where R' and R" together with the N atom to which they are attached, form heterocycle, -SO2NH(C1-C4alkyl), -SO2NH(cycloalkyl), -SO2NH(heterocycle), -SO2NH(aryl) such as-SO2NH(phenyl), -SO2NH(heteroaryl), NHSO2(C1-C4alkyl), NHSO2(cycloalkyl), NHSO2(heterocycle), NHSO2(aryl) such as-NHSO2(phenyl), NHSO2(heteroaryl), and-NHSO2(C1-C4halogenated), where each alkyl, phenyl, aryl, cycloalkyl, heterocycle and heteroaryl may be substituted by one or more groups independently selected from HE, halogen, cycloalkyl, heterocycle, C1-C4alkyl, C1-C4halogenated-, -OC1-C4alkyl, C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4alkyl, -OC1-C4halogenoalkane, cyano, nitro, -NH2, -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4alkyl) and-N(C1-C4alkyl)C(O)(C1-C4alkyl).

[005] it is Also proposed pharmaceutical composition comprising at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, and at least one pharmaceutically acceptable n�Sitel.

[006] Also proposed a method of inhibiting the activity of PI3K and/or mTOR, comprising bringing the enzyme into contact with an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application.

[007] Also proposed a method of treating cancer responsive to inhibition of PI3K and/or mTOR, comprising administering to a subject in need of treatment of specified cancers, an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application.

[008] Also proposed the use of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, to obtain a medicine for inhibiting the activity of PI3K and/or mTOR.

[009] Also proposed the use of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, to obtain drugs for the treatment of cancer.

[010] it is Assumed that in the present description, the following words, phrases and symbols have the meanings given below, unless � context, in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout the description:

[011] a Dash ( " - " ) that is not between two letters or symbols is used to denote the places of attachment of the Deputy. For example, -CONH2attached via a carbon atom.

[012] the Term "alkyl" in the present description refers to hydrocarbons with straight or branched chain containing 1 to 18, for example, 1-12, for example, 1-6 carbon atoms. Examples of alkyl groups include without limitation, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl and tert-butyl. "Lower alkyl" refers to hydrocarbons with straight or branched chain containing 1-6, for example, 1-4 carbon atoms.

[013] the Term "alkoxy" in the present description refers to an alkyl group with straight or branched chain with the specified number of carbon atoms connected by an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Deut-butoxy, tert-butoxy, pentox, 2-pentyloxy, isopentane, neopentane, hexose, 2-hexose, 3-hexose, 3-methylphenoxy and the like. Alkoxygroup usually contain from 1 to 6 carbon atoms connected by an oxygen bridge. "Lower alkoxy" refers to alkoxy straight or branched chain, in which the alkyl portion contains 1-4 carbon atoms.

[01] the Term "alkenyl" in the present description refers to hydrocarbons with straight or branched chain, containing one or more double C=C bonds and 2-10, for example, from 2 to 6 carbon atoms. Examples of alkenyl groups include, without limitation, vinyl, 2-propenyl and 2-butenyl.

[015] the Term "alkynyl" in the present description refers to hydrocarbons with straight or branched chain containing one or more triple With≡With ties and 2-10, for example, from 2 to 6 carbon atoms. Examples etkinlik groups include, without limitation, ethinyl, 2-PROPYNYL and 2-butynyl.

[016] the Term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups containing 3 to 12, e.g., of 3-8 carbon atoms. Examples cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The ring may be saturated or contain one or more double bonds (i.e. to be partially unsaturated), but not fully conjugated and aromatic, as defined in the present description.

[017] "Aryl" includes:

5 - and 6-membered carbocyclic aromatic rings, e.g., phenyl;

bicyclic system of rings, in which at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and

tricyclic system of rings, in which at least one ring is carbocyclic�m and aromatic, for example, fluorene.

[018] for Example, aryl includes 5-and 6-membered carbocyclic aromatic ring, a condensed 5-to 7-membered cycloalkyl or heterocyclic ring containing 0 or more heteroatoms selected from N, O and S, provided that the point of attachment is on the carbocyclic aromatic ring in the case where the carbocyclic aromatic ring condensed with the heterocyclic ring, and that the point of attachment may be at the carbocyclic aromatic ring or on cycloalkyl, when the carbocyclic aromatic ring condensed with cycloalkyl. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms, give the name as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence, give the name by adding "Eden" to the Name of the corresponding univalent radical, e.g., naftilos group with two seats in joining call naphthylidine. Aryl, however, does not include heteroaryl, separately defined below, and does not interfere with them in any way. Therefore, if one�or more carbocyclic aromatic rings condensed with heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined in the present description.

[019] the Term "halogen" includes fluorine, chlorine, bromine and iodine.

[020] the Term "heteroaryl" applies to

5-7-membered aromatic, monocyclic rings containing one or more, e.g., 1-4 or, in some embodiments, the implementation, 1 to 3 heteroatom selected from N, O and S, with remaining ring atoms are carbon;

8-12-membered bicyclic rings containing one or more, e.g., 1-4 or, in some embodiments, the implementation, 1 to 3 heteroatom selected from N, O and S, with remaining ring atoms are carbon and at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and

11 to 14-membered tricyclic rings containing one or more, e.g., 1-4 or, in some embodiments, the implementation, 1 to 3 heteroatom selected from N, O and S, with remaining ring atoms are carbon and at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[021] for Example, heteroaryl contains 5-7-membered heterocyclic aromatic ring fused with a 5-7 membered cycloalkyl ring. For such a condensed bicyclic, heteroaryl�'s systems of rings, in which only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or on cycloalkenes the ring.

[022] In the case where the total number of atoms S and O in the heteroaryl group exceeds 1, these heteroatoms are not adjacent. In some embodiments, the implementation, the total number of atoms S and O with the heteroaryl group is not more than 2. In some embodiments, the implementation, the total number of atoms S and O in the aromatic heterocycle is not more than 1.

[023] Examples of heteroaryl groups include, without limitation, (according to the numbering from the junction labeled 1), pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, 2,4-pyrimidinyl, 3.5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazyl, furyl, benzofuran, benzimidazole, indole, indoline, pyridazinyl, triazolyl, chinoline, pyrazolyl, pyrrolopyridine (such as 1H-imidazo[2,3-b]pyridin-5-yl), pyrazolopyrimidine (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), benzothiazolyl (such as benzo[d]thiazol-6-yl), indazole (such as 1H-indazol-5-yl and 5,6,7,8-tetrahydroisoquinoline.

[024] the Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by UDA�of moving a single hydrogen atom from the carbon atom with the free valence, give the names by adding "Eden" to the name of the corresponding univalent radical, e.g., meridiabuy group with two seats in accession Tout Perelygina. Heteroaryl does not include aryl as defined above, and does not interfere with them in any way.

[025] Substituted heteroaryl system also includes rings, substituted by one or more oxide (-O -) substituents, such as pyridinyl N-oxides.

[026] by "heterocycle" or "heterocyclic ring" means a 4-12-membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated ring containing at least 2 carbon atoms and 1 to 3 heteroatom independently selected from oxygen, sulfur and nitrogen. "Heterocycle" also refers to a 5-7-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, a condensed 5-, 6 - and/or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring provided that the point of attachment is on the heterocyclic ring when the heterocyclic ring condensed with carbocyclic aromatic or heteroaromatic ring, and that the point of attachment may be at cycloalkene or heterocyclic ring when the heterocyclic ring condensed with cyclol�sludge. "Heterocycle" also refers to aliphatic spirocyclic ring containing one or more heteroatoms selected from N, O or S, provided that the point of attachment is on the heterocyclic ring. Rings can be saturated or have one or more double bonds (i.e. to be partially unsaturated). Heterocycle may be substituted with oxo. The point of attachment may be carbon or heteroatom in the heterocyclic ring. Heterocycl is not heteroaryl specified above.

[027] Suitable heterocycles include, for example (according to the numbering from the junction labeled 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl ureido, 2,3-pyrazolidone, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl and 3-morpholinyl. Substituted heterocycl system also includes rings, substituted by one or more oxo groups, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholine and 1,1-diokso-1-thiomorpholine.

[028] By "possible" or "possible" means that the described event or condition can occur or not occur and that the description includes instances where the event or condition occurs and instances in which it has no place. For example, possibly substituted alkyl" includes "alkyl" and "substituted alkyl", defined�he following. Specialists in the field of technology will be obvious that in the case of any group containing one or more substituents, it is assumed that such a group does not lead to any substitution or substitution, which is the spatial impractical, not feasible from the point of view of synthesis and/or unstable in nature.

[029] In the present description, the term "substituted" means that any one or more of the hydrogen atoms in the target atom or group is replaced with a substituent selected from a specified group, provided that not exceeded the normal valence of the target atom. When a Deputy is oxo (i.e. =O), are replaced by two hydrogen atoms on the atom. Combinations of substituents and/or variables are permissible only if such combinations provide a stable compounds or useful synthetic intermediates. It is assumed that under stable composition or stable structure mean a compound which is sufficiently stable in order to move the isolation from the reaction mixture, and subsequent formulation into an agent having at least practical applicability. Unless otherwise specified, the alternate name Under the main structure. For example, it should be understood that when (cycloalkyl)alkyl mentioned as vozmojnos� Deputy, the point of attachment of the Deputy to the principal structure is alkyl part.

[030] In some embodiments, the implementation of the "substituted one or more groups" refers to two hydrogen atoms in the target atom or a group which is independently substituted with two substituents selected from a specified group of substituents. In some embodiments, the implementation of the "substituted one or more groups" refers to the three hydrogen atoms in the target atom or a group which is independently substituted with three substituents, selected from a specified group of substituents. In some embodiments, the implementation of the "substituted one or more groups" refers to four hydrogen atoms in the target atom or a group which is independently substituted with four substituents selected from a specified group of Vice.

[031] Described in the present application compounds include, without limitation, where possible, their optical isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemate, mixtures of diastereomers, and other mixtures of these isomers, to the extent in which they can be obtained by the average specialist in the field of technology using standard experiments. In such situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric si�thesis or separation of racemates or mixtures of diastereomers. If possible, separation of racemates or mixtures of diastereomers may be accomplished through, for example, standard methods such as crystallization in the presence of the agent for optical splitting or chromatography, e.g., using columns for chiral high performance liquid chromatography (HPLC). In addition, such compounds include Z - and E-forms (or CIS - and TRANS-forms) of compounds with double carbon-carbon bonds. When the compounds described in the present application, exist in different tautomeric forms, it is assumed that the term "connection" includes all tautomeric forms of the compounds in the extent in which they can be obtained without undue experimentation. Such compounds also include crystalline forms, including polymorphs and clathrates, to the extent in which they can be obtained by the average specialist in the field of technology using standard experiments. Similarly, it is assumed that the term "salt" includes all isomers, racemate, other mixtures of Z - and E-forms, tautomeric forms and crystalline forms of salts of Compound in the extent to which they can be obtained by the average Specialist in the field of technology without undue experimentation.

[032] "Pharmaceutically acceptable salts" include, without limitation, inorganic salt sour�, such as hydrochlorate, phosphate, diphosphate, Hydrobromic, sulfate, sulfinate, nitrate and the like; and organic acid salts such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, 2-hydroxyethylsulphonic, benzoate, salicylate, stearate, alkanoate, such as the acetate, and salts with HOOC-(CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, without limitation, sodium, potassium, calcium, aluminum, lithium and ammonium.

[033] in addition, if the connection is described in the present application, receive in the form of salt accession acid, you can obtain the free base by increasing the basicity of the acid salt solution. Conversely, if the product is a free base to obtain the salt of the accession, in particular, pharmaceutically acceptable salt accession, by dissolving the free base in a suitable organic solvent and treatment of the acid solution in accordance with the standard procedures for obtaining salts of accession acid from basic compounds. Specialists in the technique known various methods of synthesis that can be Used without undue experimentation to obtain non-toxic pharmaceutically acceptable salts of accession.

[034] "�Olivet", such as "hydrate", is produced by the reaction between the solvent and compound. It is assumed that the term "connection" includes solvates, including hydrates, of the compounds in the extent to which they can be obtained by the average specialist in the field of technology by conducting standard experiments. Similarly, "salt" includes solvates, such as hydrates, salts in the extent to which they can be obtained by the average specialist in the field of technology by conducting standard experiments. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and palpitate, to the extent in which they can be obtained by the average specialist in the field of technology by conducting standard experiments.

[035] "Chelate" is produced by the coordination compound to a metal ion at two (or more) places. It is assumed that the term "connection" includes chelating compounds. Similarly, "salt" include chelates of salts.

[036] "non-covalent complex" is produced by interaction of the compound and other molecules, and between the compound and the molecule does not form a covalent bond. For example, complexation can occur through van der valauskas interaction, the formation of hydrogen bonds and electrostatic interactive display�Vij (also called ionic bonds). Such non-covalent complexes included in the term "connection".

[037] the Term "hydrogen bond" refers to the form of Association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable donors and hydrogen bond acceptors are widely known in medicinal chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, “Hydrogen Bond Geometry fn Organic Crystals”, Accounts of Chemical Research, 17, pp.320-326 (1984)).

[038] In the present description, the terms "group", "radical" or "fragment" are synonymous; they are supposed to indicate functional groups or fragments of molecules that can be attached to a tie or other fragments of molecules.

[039] the Term "active substance" is used to refer to chemical substances with biological activity. In some embodiments, the implementation of the "active substance" is a chemical substance with pharmaceutical applicability.

[040] "Treating", "treat" or "alleviation" refers to the introduction of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, the subject suffering from cancer, or has�the future of the symptoms of cancer, or having a predisposition to cancer, with the purpose to cure, alleviate, alteration, improvement or affect cancer, the symptoms of cancer or predisposition to cancer.

[041] the Term "effective amount" refers to the amount of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, which is effective for "treatment" as defined above diseases or disorders in a subject. In the case of cancer, the effective amount may cause any of the changes that can be observed or measured in a subject according to the definition of "treatment", "treat" or "facilitate" above. For example, an effective amount may reduce the number of cancer or tumor cells; reduce the tumor size; inhibit or stop the infiltration of tumor cells into peripheral organs including, for example, the spread of the tumor into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; to some extent alleviate one or more symptoms associated with cancer, to reduce morbidity and mortality; improve quality of life; or result in a combination �odobnye effects. An effective amount may be an amount sufficient to reduce symptoms of a disease responsive to the inhibition of the activity of PI3K/mTOR. In the case of cancer therapy efficacy in vivo can be measured, for example, by estimating life expectancy, time to disease progression (TTP), performance indicators (RR), response time and/or quality of life. Effective amounts may vary, as known to experts in the field of technology, depending on ways of introduction, the application of filler and joint use with other agents.

[042] the Term "inhibition" refers to a lower initial level of biological activity or process. "The inhibition of the activity of PI3K and/or mTOR" refers to the reduction in the activity of PI3K and/or mTOR as a direct or indirect response to the presence of at least one compound and/or at least one pharmaceutically acceptable salt described in this application, relative to the activity of PI3K and/or mTOR in the absence of at least one compound and/or at least one pharmaceutically acceptable salt of the compound. The decrease in activity is not bound by any theory, and it may be the result of direct interaction of at least one compound and/or at least one pharmaceutical grade�automatically acceptable salt of the compound, described in the present application, with PI3K and/or mTOR or the result of the interaction of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, one or more factors that in turn affect the activity of PI3K and/or mTOR. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, can reduce the activity of PI3K and/or mTOR by directly binding to PI3K and/or mTOR, through the provision of impact (direct or indirect) on another factor, which in turn causes a decrease in the activity of PI3K and/or mTOR, or by (directly or indirectly) reducing the amount of PI3K and/or mTOR in a cell or organism.

[043] a Detailed description of one or more variants of implementation of the present invention are described below.

[044] According to the present invention proposed at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt of the compound, where

And1represents N or CH;

And4and And5independently represent N or CR2;

And2and And3in conjunction with the ring In performance�control a 5-membered heteroaryl or heterocycle, containing 1 to 4 heteroatoms selected from N, O and S, and the specified 5-membered heteroaryl or heterocycle possibly substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

provided that A2and And3together with the ring are not In;

represents a single bond or double bond;

R1is heteroaryl, possibly substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

R and R2independently selected from H, alkyl, alkenyl, alkynyl, aryl, cyclo�of Lila, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -OC(O)Ra, -OC(O)NRcRd, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

and each of the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogenoalkane, heteroaryl and heterocycle may be substituted by one or more groups independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle;

each Ra, Rb, Rc, Rd, Re, Rfand Rgindependently selected from H, possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkynyl may Deputy�by aryl, possibly substituted cycloalkyl, possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle,

or Raand Rcand/or Rcand Rdand/or Rcand Reand/or Rcand Rfand/or Rdand Reand/or Rgand Rftogether with the atom (atoms) to which they are attached, form a 3-10-membered ring possibly substituted heterocyclic ring; and

in each case, n is independently 0, 1 or 2;

where each maybe substituted by the group listed above can be unsubstituted or independently substituted by one or more, e.g. one, two or three substituents, independently selected from C1-C4of alkyl, cycloalkyl, oxo, aryl, heterocycle, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4halogenated-, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4alkyl, -OC1-C4halogenoalkane, halogen, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4alkyl, -C(O)Otsikoilla, C(O)Aurila, -C(O)Heteroaryl, -C(O)Heterocycle, -CON(C1-C4alkyl)(C1-C4alkyl), -CONR'R", where R' and R" together with the N atom to which they are attached, form heterocycle, -CON(cycloalkyl)(cycloalkyl), -CON(heterocycle)(heterocycle), -CONH(C1-C4alkyl), -CONH(cycloalkyl), -CONH(heterocycle), -CONH2, NHC(O)(C1-C4alkyl), -NHC(O)(cycloalkyl), -NHC(O)(heterocycle), -NHC(O)(aryl) such as-NHC(O)(phenyl), -NHC(O)(heteroaryl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(cycloalkyl), N(C1-C4alkyl)C(O)(heterocycle), -N(C1-C4alkyl)C(O)(aryl) such as-N(C1-C4alkyl)C(O)(phenyl), N(C1-C4alkyl)C(O)(heteroaryl), -C(O)C1-C4alkyl, -C(O)(cycloalkyl), -C(O)(heterocycle), -C(O)(aryl) such as-C(O) phenyl, -C(O)(heteroaryl), -C(O)C1-C4halogenated, -OC(O)C1-C4alkyl, OC(O)(cycloalkyl), -OC(O)(heterocycle), - OS(O)(heteroaryl), OS(O)(aryl) such as-OC(O)phenyl, -SO2(C1-C4alkyl), - SO2(cycloalkyl), -SO2(heterocycle), -SO2(aryl), such as SO2(phenyl), -SO2(heteroaryl), -SO2(C1-C4halogenated), -SO2NH2, -SO2NR'R", where R' and R" together with the N atom to which they are attached, form heterocycle, -SO2NH(C1-C4alkyl), -SO2NH(cycloalkyl), -SO2NH(heterocycle), -SO2NH(ar�l), such as-SO2NH(phenyl), -SO2NH(heteroaryl), -NHSO2(C1-C4alkyl), NHSO2(cycloalkyl), NHSO2(heterocycle), NHSO2(aryl) such as-NHSO2(phenyl), NHSO2(heteroaryl), and-NHSO2(C1-C4halogenated), where each alkyl, phenyl, aryl, cycloalkyl, heterocycle and heteroaryl may be substituted by one or more groups independently selected from HE, halogen, cycloalkyl, heterocycle, C1-C4alkyl, C1-C4halogenated-, -OC1-C4alkyl, C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4alkyl, -OC1-C4halogenoalkane, cyano, nitro, -NH2, -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4alkyl) and-N(C1-C4alkyl)C(O)(C1-C4alkyl).

[045] In some embodiments, the implementation of A2and And3together with the ring To form a 5-membered heteroaryl or heterocycle containing 1 to 3 heteroatoms selected from N, O and S. In some embodiments, the implementation of A2and And3together with the ring To form a 5-membered heteroaryl or heterocycle containing 1 to 3 heteroatoms of nitrogen.

[046] In some embodiments, the implementation of A2and And3together with the ring can be� selected from the structures (2)-(6)

where

t represents 1, 2 or 3; and

R3independently selected from H, C1-C6alkyl, C2-C8alkenyl, S2-C8alkenyl, C6-C14aryl, C3-C9cycloalkyl, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -OC(O)Ra, -OC(O)NRcRd, -S(O)nRe, -S(O)nNRcRd, halogen, halogenoalkane, heteroaryl and heterocycle;

and each of the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl and heterocycle may be substituted by one or more groups independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and maybe samisen�th heterocycle, and Ra, Rb, Rc, Rd, Re, Rfand Rgsuch as defined above.

provided that, when A2and And3together with the ring To represent the structure (4), And4is CR2and R2such as defined above.

[047] for Example, R3independently selected from H, HE, CN, NO2of halogen, (C1-C6alkyl, C2-C8alkenyl, C2-C8alkynyl, S6-C14aryl, C3-C9cycloalkyl, heteroaryl and heterocycle, where each of the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl and heterocycle may be substituted by one or more groups independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle;

[048] In some embodiments, the implementation of A2and And3together with co�ICOM selected from the structures (2) to(5), where R3and t are such as defined above.

[049] In some embodiments, the implementation of A2and And3together with the ring selected from the structures (3)-(4), where R3and t are such as defined above.

[050] In some embodiments, the implementation of A4represents N or CH.

[051] In some embodiments, the implementation of A5represents N or CH.

[052] In some embodiments, the implementation of A1, A4and A5represent CH.

[053] In some embodiments, the implementation of A1and A5represent CH, and A4represents N.

[054] In some embodiments, the implementation of R1is heteroaryl, which is selected from the following structures:

for example, R1is heteroaryl selected from

where each of the structures may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogenoalkane, heteroaryl, heterocycle, oxo, --C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -OC(O)Ra, -OC(ONR cRd, -S(O)nRe, -S(O)nNRcRdand halogen, where each of the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogenoalkane, heteroaryl and heterocycle may be substituted by one or more groups independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle;

where each Ra, Rb, Rc, Rd, Re, Rfand Rgindependently selected from H, alkyl, aryl, cycloalkyl, halogenoalkane, heteroaryl and heterocycle, and where each of the above alkyl, aryl, cycloalkyl, heteroaryl and heterocycle in Ra, Rb, Rc, Rd, Re, Rfand Rgmay be substituted by one or more, e.g. one or two, or three, substituents independently selected from halogen and alkyl.

[055] In some embodiments, the implementation of R1/sup> is awhich may be substituted by one or more groups independently selected from:

- alkyl, alkenyl and alkynyl, where each of these groups may bytesmessage groups, independently selected from a possibly substituted alkyl, possibly substituted alkenyl, possibly substituted alkenyl, possibly substituted aryl, possibly substituted cycloalkyl, HE, oxo, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, -NRcRd, -NRcC(O)Ra, -NRcS(O)nRe, -NRcS(O)nNRfRg, -NRcC(O)ORb, -NRcC(O)NRdRe, -NO2, -ORb, -S(O)nRe, -S(O)nNRcRdand halogen , possibly substituted halogenoalkane, possibly substituted heteroaryl and possibly substituted heterocycle;

C(O)NRcRd;

NRcRd;

-ORb;

-halogen;

-cyano;

-NRcS(O)nRe,

where each Ra, Rb, Rc, Rd, Re, Rfand Rgindependently selected from H, alkyl, aryl, cycloalkyl, halogenoalkane, heteroaryl and heterocycle, for example, each Ra, Rb, Rc, Rd, Re, Rfand Rgindependently selected from H, C1-C6of alkyl, phenyl, C3-C6cycloalkyl, C1-C3halogenoalkane, heteroaryl�and heterocycle, where each of the above alkyl, aryl, cycloalkyl, heteroaryl and heterocycle in Ra, Rb, Rc, Rd, Re, Rfand Rgmay be substituted by one or more, e.g. one or two, or three, substituents independently selected from halogen and alkyl.

[056] according to the present invention proposed at least one compound selected from compounds 1-184, and/or at least one pharmaceutically acceptable salt of the compounds described in the present application.

[057] the Compounds described in the present application, and/or pharmaceutically acceptable salts of these compounds can be synthesized from commercially available starting materials using methods well-known in the field of technology, in combination with the description of the present application. The following diagrams illustrate the methods for obtaining compounds described in the present application.

Scheme I

Scheme II

[058] the Compounds thus obtained can be further modified in peripheral positions with obtaining the desired connections. Transformations in synthetic chemistry described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic ynthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[059] Before applying at least one connection and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, can be purified using column chromatography, high performance liquid chromatography, crystallization or other suitable means.

[060] according to the present invention proposed a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, and at least one pharmaceutically acceptable carrier.

[061] the Composition containing at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in this application, you can enter various known methods, for example, orally, parenterally, by means of a spray for inhalation, or implantable reservoir. The term "parenteral" in the present description includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intraarticular, intrasternal, intrathecal, vnutrichasovye and ways of intracranial injection or infusion.

[062] Peroral�I composition may be any dosage form acceptable for oral administration, including, without limitation, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Also in tablets usually add lubricants such as magnesium stearate. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in the oil phase together with emulsifiers or suspendresume agents. If necessary, can be added some sweeteners, flavors or dyes.

[063] a Sterile composition for injection (e.g., aqueous or oily suspension) can be obtained using methods known in the technical field, using suitable dispersing or lubricating agents (such as, for example, tween 80) and suspendida agents. A sterile composition for injection may also be a sterile solution or suspension for injection in a non-toxic diluent or solution that is acceptable for Parenteral administration, for example, in the form of a solution in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be used include man�ital, water, ReSTOR ringer and isotonic sodium chloride solution. In addition, as a solvent or a nutrient mist is usually used sterile fatty oils (e.g., synthetic mono - or diglycerides). Fatty acids such as butyric acid and its glyceride derivatives, and pharmaceutically acceptable oils of natural origin, such as olive oil or castor oil, especially in polyoxyethylated forms, are suitable for obtaining compositions for injection. These oil solutions or suspensions may also contain an alcohol diluent or dispersant with a long chain, or carboxymethyl cellulose or similar dispersing agents.

[064] the Composition for inhalation can be obtained using methods well-known in the field of preparation of pharmaceutical compositions in the form of solutions in saline containing benzyl alcohol or other Suitable preservatives, stimulants absorption to increase bioavailability, fluorocarbons, and/or other solubilizer or Dispersing agents known in the art.

[065] the Composition for local application can be obtained in the form of oil, cream, lotion, ointment, etc. Suitable carriers for the compositions include vegetable or mineral oils, medical petrolatum (white soft paraffin), oils ilemela branched chain, animal fats and alcohols with high molecular weight (above 12). In some embodiments, the implementation of the pharmaceutically acceptable solvent is one in which the soluble active ingredient. Emulsifiers, stabilizers, wetting agents, antioxidants, and ingredients that give color or odor, if necessary, can also be included in the composition. Moreover, in these compositions for topical application can be applied agents that enhance penetration through the skin. Examples of such components may be found in U.S. Patents 3,989,816 and 4,444,762.

[066] Creams can be obtained from a mixture of mineral oils, offering self-emulsifying beeswax and water in which add the active ingredient, dissolved in a small amount of oil, such as almond oil. An example of such a cream is a cream containing about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments can be obtained by mixing the active ingredient in a vegetable oil, such as almond oil with warm soft paraffin and then cooling the mixture. An example of such an ointment is an ointment containing about 30 wt%. almond oil and about 70 wt%. white soft paraffin.

[067] Pharmaceutically acceptable �Sitel relates to the media, which is compatible with the active ingredients of the composition (and in some embodiments, the implementation is able to stabilize the active ingredients and has no harmful effects on the entity to which it is administered. For example, solubilizers agents, such as cyclodextrins (which form specific, more soluble complexes with at least one compound and/or at least one pharmaceutically acceptable role of the compounds described in the present application), can be Used as pharmaceutical excipients for delivery of active ingredients. Examples of other carriers include colloidal silicon hydroxide, magnesium stearate, cellulose, sodium lauryl sulfate and pigments, such as D&C Yellow #10.

[068] For the initial evaluation of the effectiveness of inhibiting the activity of PI3K and/or mTOR at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, can be used suitable in vitro tests. Using in vivo assays can be conducted to further study the effectiveness of said at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, for the treatment of cancer. Eg�measures compounds described in the present application, and/or their pharmaceutically acceptable salts can be administered to an animal (e.g., mouse model), suffering from cancer, and can be evaluated for their therapeutic effects. Positive results in one or more of these tests will be sufficient to replenish the base of scientific knowledge, and thus, it will be enough to demonstrate the practical applicability of the tested compounds and/or salts. On the basis of the results may also be given a suitable range of doses and route of administration to animals, e.g., humans.

[069] Also proposed a method of inhibiting the activity of PI3K and/or mTOR. The method includes bringing the enzyme into contact with at least one compound and/or one pharmaceutically acceptable salt of the compounds described in the present application, in an amount effective for inhibiting the activity of PI3K and/or mTOR.

[070] the Specified at least one connection and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, can be applied to achieve a favorable therapeutic or prophylactic effect, for example, the subjects of breast cancer. In the present description, the term "cancer" apply� to cell violation, characterized by uncontrolled cell proliferation or violation of its regulation, decreased cell differentiation, inappropriate ability to spread into the surrounding tissue and/or the ability to cause new growth in ectopic areas. The term "cancer" includes, without limitation, solid tumors and tumors of the blood. The term "cancer" includes diseases of the skin, tissues, organs, bones, cartilage, and blood vessels. The term "cancer" includes primary and metastatic cancers.

[071] non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colon cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchoalveolar carcinoma (BAC) or adenocarcinoma of the lung; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; cancer of the head and neck organs, including, e.g., squamous cell carcinoma of head and neck organs; skin cancer, including EmOC�emer, malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic, oligodendroglioma, adult glioblastoma multiforme and anaplastic astrocytoma adult; bone cancer; soft tissue sarcoma and carcinoma of the thyroid gland. For example, these solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer and ovarian cancer.

[072] non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including advanced phase CML and blast crisis (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); nahodkinskuju lymphoma (NHL), including follicular lymphoma and b-cell lymphoma, mantle zone; b-cell lymphoma; T cell lymphoma; multiple myeloma (MM); waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA) refractory anemia with ring sideroblasts (RARS), (refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.

[073] In some embodiments, the implementation examples of cancers treated according to the present invention, include, without Og�of anichini, lung cancer, cancer of head and neck organs, cancer of the colon, rectum, pancreas cancer, rectal cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, bone cancer and leukemia.

[074] In some embodiments, the implementation of the specified at least one connection and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, is administered together with another therapeutic agent. In some embodiments, the implementation of the other therapeutic agent is an agent that is commonly administered to patients suffering from a disease or condition treated. The specified at least one connection and/or at least one pharmaceutically acceptable salt of the compounds described in the present application, can be administered with another therapeutic agent in a single dosage form or in separate dosage form. When administered in separate dosage form, the introduction of another therapeutic agent may before, during or after administration of at least one compound and/or at least one pharmaceutically acceptable salt of the compounds described in the present application.

[075] In some embodiments, the implementation of at least one connection �/or at least one pharmaceutically acceptable salt of the compound, described in the present application, is introduced together with an antitumor agent. In the present description, the term "anticancer agent" refers to any agent that is administered to a subject suffering from cancer, to treatment this disease. Non-limiting examples of anticancer agents include: radiation therapy; immunotherapy; chemotherapy agents that damage DNA, and chemotherapeutic agents that violate cell replication.

[076] non-limiting examples of chemotherapeutic agents that Damage DNA, include inhibitors of topoisomerase I (e.g., irinotecan, topotecan, camptothecin and their analogues or metabolites, and doxorubicin); inhibitors of topoisomerase II (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g. melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin and carboplatin); DNA-intercalators and generators of free radicals, such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin and hydroxyurea).

[077] Chemotherapeutic agents that violate the cell replication include:paclitaxel, docetaxel and their analogs; vincristine, vinblastine and their analogs; thalidomide and its analogs (e.g., CC-5013 and CC-4047); inhibitors proteincontaining (e.g., imatinib mesilate and gefitinib); proteasome inhibitors (e.g. bortezomib); inhibitors of transcription factor NF-Kappa B, including the kinase inhibitors of I Kappa B; antibody-bound proteins that sverkhekspressiya cancerous and thereby perform downward regulation of cell reproduction (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes that are activated or sverkhekspressiya for cancer, the inhibition of which leads to down-regulation of cell reproduction.

[078] the following examples are illustrative only and should not be considered in any degree limiting. The authors have endeavoured to ensure the accuracy of the used numerical parameters (e.g., amounts, temperature, etc.), however, one should take into account some errors and deviations in the experiments. Unless otherwise specified, the shares represent the mass fraction, temperature is given in degrees Celsius, and a pressure equal to or approximately equal to the atmospheric pressure. All data is checked for MS PR�forests agilent 6120 and/or agilent 1100. The spectra of1H NMR recorded on a NMR spectrometer Varian 400 MHz using CDCl3or DMSO-d6as the solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) are expressed in ppm (M. D.) in the direction of the weak field from internal TMS, and the values of J are given in Hz. All reagents used in this description, except intermediate compounds are commercially available. All the names of the compounds, with the exception of the names of the reagents generated by the program Chemdraw 10.

[079] In the following examples, abbreviations are used below:

ASonacetic acid
Was helddichloro methane
DMFN,N-dimethylformamide
DMF-DMA1,1-dimethoxy-N,N-dimethylethanamine
DMSOdimethyl sulfoxide
RTIdithiotreitol
EtOActhe ethyl acetate
hhour
ISCO flash chromatography
mlmilliliter (ml)
minminute (min)
Pypyridine
THFtetrahydrofuran
HATU2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate methanamine
DIPEAN,N-diisopropylethylamine
Was helddichloro methane
EAthe ethyl acetate
Dpetroleum ether
Pd(dppf)Cl2The complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
PTCHpreparative thin layer chromatography
HEPES2-[4-(2-hydroxyethyl)piperazine-1-yl]econsultancy acid
EGTAethylene glycol vs acid
CHAPS3-[(3-Cholamidopropyl-dimethylammonio]-1-propanesulfonate
TEAtriethylamine
TLCthin-layer chromatography

Intermediate compound 1

2-(5-aminopyridin-2-yl)-2-methylpropionitrile

[080] To a solution of 2-chloro-5-nitropyridine (10 g, 63 mmol) in THF (150 ml) at room temperature was added K2CO3(Of 17.4 g, 126 mmol) and tert-butyl 2-cyanoacetate (10.7 g, 76 mmol). The reaction mixture was heated to reflux and stirred overnight. Thereafter, the solid is filtered and the filtrate was concentrated to obtain the intermediate compound I-1b (16.6 g), m/z 208 (M+H)+.

[081] the Crude product of tert-butyl 2-cyano-2-(5-nitropyridine-2-yl)acetate (I-1b, 12 g, 47 mmol) was dissolved in 100 ml of HCl/EtOH (about./about. 1:5) and stirred at 80°C for 4 h. then the mixture was concentrated, diluted with H2O and was extracted with EtOAc (4×40 ml). The combined extracts were concentrated, and the residue was purified using chromatography on silica gel (PE:EtOAc = 3:1) to give 2-(5-nitropyridine-2-yl)acetonitrile (I-1C) in the form of a solid (7.7 g, 42,0% output).

[082] To a mixture of 2-(5-nitropyridine-2-yl)acetonitrile (I-1C, 8 g, 46 mmol) and K2CO3(18 g, 110 mmol) in CH3CN (200 ml) was dropwise added itmean (7.5 ml, 120 mmol) at room temperature�ré. The reaction mixture was stirred at 40°With during the night. Thereafter, the mixture was filtered, the filtrate concentrated, and the residue was purified using chromatography on silica gel (PE:EtOAc = 5:1) to give 2-methyl-2-(5-nitropyridine-2-yl)propanenitrile (I-1d) (4.2 g, 48% Yield), m/z 192 (M+H)+.

[083] a Mixture of 2-methyl-2-(5-nitropyridine-2-yl)propanenitrile (I-1d, 2 g, 10.4 mmol) and SnCl2·2H2O (9.3 g, to 41.6 mmol) in EtOAc (10 ml) was stirred under heating to reflux for 4 h. After cooling to Room temperature, to the mixture was added aqueous 2 M NaOH (80 ml) to bring the pH to 8~9, the solid was filtered, and the filtrate was extracted with ethyl acetate (3×40 ml). The combined organic layers were dried over anhydrous Na2SO4and concentrated to give 2-(5-aminopyridin-2-yl)-2-methylpropionitrile (I-1) (1.7 g, 65,3% of output).

Intermediate compound 2

1,1,1-Cryptor-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide

[084] a Mixture of 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (300 mg, 1.1 mmol) and reviewscore Nickel catalyst (Raney-Ni) (10 mg) in MeOH (10 ml) was subjected to the action of H2and stirred for 2 h. After filtration, the filtrate was concentrated to give the compound indicated in the title, in the form of a white solid substances�VA (261 mg). Output: 95,0%.

[085] To a solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (100 mg, 0.4 mmol) and 2,6-di-tert-butyl-4-methylpyridine (115 mg, 0,56 mmol) in dichloromethane (5 ml) was added dropwise to the anhydride triftormetilfullerenov acid (147 mg, 0.52 mmol) at -20°C, after which the mixture was stirred at this temperature for 2 h. the Solvent was removed Under vacuum, and the residue was used for next step without further purification (141 mg). Output: 92,0%.

Intermediate compound 3

6-chloro-3-nitro-1,5-naphthiridine-4-ol

[086] a Mixture of 6-chloropyridin-3-amine (5.0 g, 38,8 mmol) and 5-(methoxymethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.2 g, 38,8 mmol) in i-PrOH (60 ml) was stirred under heating to reflux for 2 h, and the solvent removed to give 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid substance with a yield of 91% (10.0 g), m/z 283 (M+H)+

[087] To the heated fluid Dowtherm A (200 ml) at 200°C was added 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.5 g, 12.4 mmol), after which the mixture was stirred for another 5 min. After cooling to room temperature, to the mixture was added RÉ. The precipitate was collected and dried under vacuum to give 6-chloro-1,5-naphthiridine-4-ol in the form of a dirty-white solid with a yield of 42% (0,94 g), m/z 183 (M+H)+

088] 6-chloro-1,5-naphthiridine-4-ol (1,45 g, 8 mmol) was added to ice-cold conc. H2SO4(15 ml) and then slowly added KNO3(1.62 g, 16 mmol) at 0°C. the Mixture was heated to 100°C for 1 h, then was poured into ice water. The precipitate was collected and dried under vacuum to give 6-chloro-3-nitro-1,5-naphthiridine-4-ol in the form of a solid substance with a yield of 90% (1,97 g).

Intermediate compound 4

2,4-debtor-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzolsulfonat

[089] a Mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.6 g, 25.8 per mmol), PdCl2(dppf)-CH2Cl2(500 mg) and potassium acetate (6.3 g, for 64.5 mmol) in anhydrous 1,4-dioxane (200 ml) was heated to reflux for 2 h. then the solvent was removed. The crude product was purified using chromatography on silica gel using as eluent petroleum ether: EtOAc = 10:1 to obtain 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine with a yield of 81% (5 g), m/z 281 (M+H)+.

[090] To a solution of 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, to 1.79 mmol) in MeOH (50 ml) was added Raney-Ni (50 mg). The reaction mixture was stirred at room temperature in the atmosphere of H2for 2 h. then the precipitate was filtered, and the solvent was removed to give 2-�ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine with a yield of 89% (400 mg). m/z 251 (M+H)+.

[091] To a solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (400 mg, 1.6 mmol) in pyridine (5 ml) was slowly added 2,4-differentialsperre (407 mg, 1.9 mmol), the reaction mixture was stirred at room temperature overnight, the solvent was evaporated under vacuum, and the residue was treated with brine (5 ml) and was extracted with EtOAc (3×10 ml). The combined organic layer was evaporated under vacuum, and the residue was purified using chromatography on silica gel using as eluent petroleum ether: EtOAc = 5:1 with the receipt of the requested product - 2,4-debtor-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzosulfimide in the form of a white solid substance with a yield of 59% (400 mg). m/z 427 (M+H)+.

An intermediate connection 5

8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline

[092] To a solution of quinoxaline-2-ol (1.5 g, 10.3 mmol) in SPLA (15 ml) was added bromine (0,895 ml, 15.5 mmol), the mixture was stirred at room temperature for 6 h, the precipitate was collected and washed with ethyl ether, and dried to obtain 7-bromination-2-ol in the form of a solid substance with a yield of 90% (2 g).

[093] To a suspension of 7-bromination-2-ol (2 g, 8,88 mmol) in pure phosphorus oxychloride (7 ml) was added DMF (2 drops). The mixture was heated to 100°C for 3 h, then cooled to room� temperature. The phosphorus oxychloride was removed under vacuum, and the residue was dissolved in EtOAc and placed in ice-cold water with stirring. Mixture 3 times was extracted with EtOAc, the combined organic layer was washed with saturated solution of NaHCO3. Thereafter, the organic layer was concentrated to give 7-bromo-2-chlorphenoxamine in the form of a solid substance with a yield of 93% (2 g).

[094] To a solution of 7-bromo-2-chlorphenoxamine (2 g, 8.2 mmol) in ethanol (20 ml) was added hydrazine hydrate (85%, 4.5 ml, is 32.8 mmol). The mixture was heated to 78°C for 2 h. After cooling to room temperature the precipitate was collected by filtration to obtain 7-bromo-2-hydrazinecarboxamide in the form of a white solid substance with a yield of 87% (1.7 g).

[095] a Solution of 7-bromo-2-hydrazinecarboxamide (200 mg, 0.83 mmol) in Triethoxysilane (3 ml) was heated to 100°C for 4 h; after cooling to room temperature the mixture was diluted with ethyl ether, and the precipitate was collected by filtration and dried under vacuum to give product indicated in the title, - 8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a solid yellow substance with a yield of 87% (180 mg). m/z 251 (M+H)+.

Intermediate compound 6

8-bromo-1-cyclopropyl-[1,2,4]triazolo[4,3-a]quinoxaline

[096] To a solution of 7-bromo-2-hydrazinecarboxamide (200 mg, 0.83 mmol) in DMF (3 ml) was added HATU (380 mg, 1 mmol), DIPEA (0,205 ml, 1 mmol�) and cyclopropanecarbonyl acid (71 mg, 0,83 mmol). After stirring at room temperature for 5 h the mixture was diluted with EtOAc. The organic layer was three times washed with water, then concentrated to give N'-(7-bromination-2-yl)cyclopropanecarbonitrile in the form of a solid yellow substance, which is used directly in the next step, m/z 309 (M+H)+.

[097] the Crude product N'-(7-bromination-2-yl)cyclopropane carbohydrazide was dissolved in SPLA (5 ml) and then heated to 100°With during the night. The solvent was removed under vacuum, and the residue was washed with water and dried under vacuum, obtaining the connection specified in the title, - 8-bromo-1-cyclopropyl-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a solid yellow substance in a total yield of 42% (100 mg). m/z 291 (M+H)+.

Intermediate compound 7

8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline-1(2H)-he

[098] To a solution of 7-bromo-2-hydrazinecarboxamide (200 mg, 0.83 mmol) in dichloromethane (5 ml) was added triethylamine (0,175 ml, 1.2 mmol), then dropwise added a solution of diphosgene (0.055 ml, 0.46 mmol) in dichloromethane at 0°C with stirring in a nitrogen atmosphere. After stirring at room temperature for 5 h the solvent was removed under vacuum, the residue was washed with water and dried under vacuum, obtaining the connection specified in the title, - 8-bromo-[1,2,4]triazolo[4,3-a]henok�Aline-1(2H)-it is in the form of a solid yellow substance with a yield of 82% (180 mg). m/z 265 (M+H)+.

Intermediate compound 7

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine

[099] an Orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16, 25 60 mmol) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5,90 g, 23,24 mmol), COAs (4.07 g, 41.5 mmol) and PdCl2(dppf).CH2Cl2(0,678 g, 0,830 mmol) in dioxane (60 ml) was heated to 110°C for 10 h in an atmosphere of N2. After concentrating under vacuum to remove the solvent the crude product was purified using a column of silica gel with PE/EtOAc as eluent to obtain pure product as a pale yellow solid (4.5 g, yield 94%). MS (m/z): 289 (M+H)+

Example 1: Synthesis of compounds 1-20

Connection 1

(S)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-hydroxypropan-1-he

[0100] To a suspension of 6-chloro-3-nitro-1,5-naphthiridine-4-ol (5 g, 22,1 mmol) in 15 ml DMF was added a solution of chloroquine phosphorus (2.7 ml, 28.8 mmol) in anhydrous DMF (10 ml) for 3 min. the Mixture was stirred at room temperature overnight, after which it was poured onto crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried under vacuum to yield 2,8-dichloro-7-nitro-1,5-naphthiridine in the form of TV�Gogo yellow substance (4 g, the yield of 74.0%). MS (m/z): 244 (M+H)+.

[0101] a Mixture of 2,8-dichloro-7-nitro-1,5-naphthiridine (4 g, 16.4 mmol), tert-butyl ether 4-amino-piperidine-1-carboxylic acid (4 g, of 19.7 mmol) and triethylamine (3.5 ml) in DMF (15 ml) was stirred at room temperature over night. The reaction mixture was poured into water (250 ml). The precipitate was collected by filtration, washed with H2O, and dried under vacuum to give tert-butyl 4-(6-chloro-3-nitro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate in the form of a solid yellow substance (6,54 g, yield 97.8 percent. The crude product was used for next step without further purification. MS (m/z): 408 (M+H)+.

[0102] To a solution of tert-butyl 4-(6-chloro-3-nitro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate (6,43 g, a 15.7 mmol) in EtOAc (250 ml) was added SnCl2·2H2O (18 g, to 78.8 mmol), and the mixture was stirred at room temperature for 3 h. then to bring the pH to 8 was added saturated NaHCO3. The solid was filtered. The filtrate was concentrated, and the crude product was purified using column chromatography by using EtOAc:PE as eluent to obtain tert-butyl 4-(3-amino-6-chloro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate in the form of a solid yellow substance with a yield of 85.6 per cent (5.1 g). MS (m/z): 378 (M+H)+.

[0103] To a solution of tert-butyl 4-(3-amino-6-chloro-1,5-naphthiridine-4-ylamino)piperidine-carboxylate (2.5 g, The 6.6 mmol) in acetic acid (8 ml) was added NaNO2(460 mg, 6,6 mmol) at 0°C. After stirring the mixture at room temperature for 2 hours was added saturated sodium bicarbonate and ice water. The resulting mixture was extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4and concentrated. The crude product was purified using column chromatography on silica gel using as eluent EtOAc:PE to obtain tert-butyl 4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-carboxylate in the form of a solid yellow substance with a yield of 73.8% (1.9 g). MS (m/z): 388.8 (M+H)+.

[0104] a Solution of tert-butyl 4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-carboxylate (4 g) in CH2Cl2/MeOH was subjected to 3 ml conc. HCl. The resulting solution was then concentrated to give the hydrochloride salt of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine in the form of a solid yellow substance (3,81 g, yield 100%). MS (m/z): 289 (M+H)+.

[0105] To a solution of hydrochloride of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine (1 g, is 3.08 mmol) in 10 ml of CH2Cl2was added (S)-1-chloro-1-oxoprop-2-ylacetic (1.4 g, of 9.23 mmol) and Et3N (2.2 ml); After stirring the mixture at room temperature for 2 h, it was quenched with water (10 ml). The resulting mixture was extracted with CH2 Cl2(2×20 ml). The combined organic layer was dried over anhydrous Na2SO4and then concentrated under vacuum to give (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-1-oxoprop-2-ilaclama (1.2 g). MS (m/z): 403 (M+H)+

[0106] To a solution of (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-1-oxoprop-2-ilaclama (1.2 g, of 2.97 mmol) in a mixture of THF (30 ml) and MeOH (30 ml) was dropwise added LiOH (650 mg, 14.9 mmol). The mixture was stirred at room temperature for 3 h. After concentration under vacuum the residue was diluted with water and the pH was adjusted to 7 using 2N HCl. The mixture was concentrated, and the precipitate was collected by filtration, washed with water and dried under vacuum to give (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-hydroxypropan-1-one in the form of a solid yellow substance. The crude product was used for next step without further purification. (918 mg, yield 85,4%). MS (m/z): 361 (M+H)+.

[0107] To a solution of (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-hydroxypropan-1-one (150 mg, 0,42 mmol) in a mixture of 20 ml of dioxane and 2 ml H2O added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (120 mg, 0,42 mmol), Pd(dppf)Cl2(20 mg, 0.02 mmol) and Na2CO3(100 mg, 0,84 mmol). The resulting mixture ol�duvali N 2and stirred at 100°C overnight, after which the resulting mixture was purified on silica gel with the use of MeOH/H2O as eluent to obtain compound 1 in the form of a solid yellow substance (59,1 mg).1H NMR (400 MHz, DMSO-d6) δ 9,60 (s, 1H), 9,20 (s, 1H), 8,67 (s, 1H), 8,64 (d, J=8,8 Hz, 1H), 8,54 (d, J=8,8 Hz, 1H), to 7.09 (s, 2H), 6,23-of 6.02 (m, 1H), 5,17-5,01 (m, 1H), 4.75 V-4,50 (m, 2H), 4,46-4,27 (m, 1H), 3,00-2,79 (m, 1H), 2,39-1,90 (m, 3H), 1,36-of 1.16 (m, 6H). MS (m/z): 487 (M+H)+.

[0108] the Following compounds 2 to 20 were obtained according to the procedures described for Compound 1, using the corresponding intermediate compounds and Baranovich acids or esters in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
2418 (M+H)+1H NMR (400 MHz, DMSO) δ 9,61 (s, 1H), 9,35 (s, 1H), 8,68 (d, J=8,8 Hz, 1H), 8,53 (d, J=8,8 Hz, 2H), 7,52-7,44 (m, 1H), 6,09-5,90 (m, 1H), 5,19-4,96 (m, 1H), 4.75 V-4,42 (m, 2H), 4,42-4,17 (m, 1H), 3,11 -2,91 (m, 1H), By 2.55 (m, 3H), 2,42 (m, 4H), 1,23 (m, 3H).
3433 (M+H)+1 H NMR (400 MHz, DMSO) δ of 9.52 (s, 1H), of 8.82 (s, 1H), 8,54 (d, J=8,8 Hz, 1H), 8,37 (d, J=8,8 Hz, 1H), 8,17 (s, 1H), system 6.34 (s, 2H), 6,13-5,96 (m, 1H), 5,79-for 5.66 (m, 1H), 5,17-5,01 (m, 1 H), 4.72 in-of 4.25 (m, 3H), 3,14 (m, 5H), 3,04-of 2.93 (m, 1H), 2,16 (m, 7H), 1,23 (m, 4H).
4429 (M+H)+1H NMR (400 MHz, cd3od) δ was 9.53 (s, 1H), 9,18-9,14 (m, 1H), 8,75 (d, J=1,8 Hz, 1H), 8.66 roubles (d, J=8,9 Hz, 1H), 8,43 (d, J=8,9 Hz, 1H), of 6.31-6,03 (m, 1H), 3,58-3,48 (m, 2H), 3,40-3,36 (m, 1H), 3,30-3,26 (m, 1H), To 2.76 (m, 3H), 2,68 (m, 4H).
5434 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,60 (s, 1H), 9,02 (s, 1H), to 8.70 (d, J=8,8 Hz, 1H), 8,35-8,29 (m, 1H), 8,18 (d, J=8,8 Hz, 1H), 7,01-at 6.92 (m, 1H), from 6.22 is 5.98 (m, 1H), 4,89-to 4.68 (m, 1H), 4,68-4,52 (m, 1H), 4,23-4,08 (m, 1H), 4,07 (m, 3H) and 3.59-3,39 (m, 1H), 3,38-3,14 (m, 1H), 2,83-

2,45 (m, 5H), of 1.43 (d, 3H).
6471 (M+H)+1H NMR (400 MHz, cdcl3) δ 9.58 per (s, 1H), 9,06 (s, 1H), 8.66 roubles (d, J=8,8 Hz, 1H), at 8.60 (d, J=2,0 Hz, 1H), 8,17 (d, J=8,8 Hz, 1H), 6,15 (m, 1H), 5,31 (m, 2H), is 4.93 (m, 1H), 4,22 (m, 1H), 3,41 (m, 1H), 2,99 (m, 1H), 2,51 (m, 7H), 1,22 (m, 3H).
7487 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,57 (s, 1H), 9,05 (s, 1H), 8,65 (d, J=8,8 Hz, 1H), 8,59 (s, 1H), 8,16 (d, J=8,8 Hz, 1H), 6,15 (s, 1H), 5,31 (s, 2H), 4,84 (m, 1H), 4,24 (m, 3H), 3,48 (m, 3H), 3,39 (m, 1H), 3,12-2,96 (m, 1H), 2,53 (m, 5H).
8443 (M+H)+1H NMR (400 MHz, DMSO) δ 11,92 (s, 1H), 9,63 (s, 1H), 9,24 (d, J=2,0 Hz, 1H), 8,89 (d, J=1,8 Hz, 1H), to 8.70 (d, J=8,8 Hz, 1H), 8,61 (d, J=8,9 Hz, 1H), 7,60 (s, 1H), 6,65 (s, 1H), 6,08 (m, 1H), 5,10-5,04 (m, 1H)That is 4.57 (m, 2H), 4,34 (m, 1H), 3.46 in (m, 1H), is 3.08 (m, 1H), to 2.29 (m, 3H), of 1.26 (m, 3H).
9483 (M+H)+1H NMR (400 MHz, cdcl3) δ 9.58 per (s, 1H), 9,07 (d, J=2,0 Hz, 1H), 8.66 roubles (d, J=8,8 Hz, 1H), 8,61(d, J=2,3 Hz, 1H), 8,17 (d, J=8,8 Hz, 1H), 6,17 (s, 1H), 5,32 (m, 3H), of 4.88 (m, 1H), 4,57 (m, 1H), 3,50 (m, 1H), 3,06 (m, 1H), 2,52 (m, 5H), 1,32 (m, 2H), of 1.06 (m, 2H), of 0.90 (m, 2H).

10416 (M+H)+1H NMR (400 MHz, cdcl3) δ 9.58 per (s, 1H), remaining 9.08 (s, 1H), 8,65 (d, J=8,9 Hz, 2H), 8,17 (d, J=8,8 Hz, 1H), 6,21-5,97 (m, 1H), is 5.33 (s, 2H), 4,30 (m, 2H), 3,76 (m, 2H), 2,85-2,56 (m, 2H), of 2.38 (m, 2H).
11 433 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,57 (s, 1H), is 8.74 (s, 1H), 8,63 (d, J=8,6 Hz, 1H), 8,13 (d, J=8,9 Hz, 1H), 8,04 (d, J=12,5 Hz, 1H), 6,09 (s, 1H), 5,06-is 4.93 (m, 2H), is 4.85 (m, 1H), of 4.54 (m, 1H), 3,57 (sm, 1H), 3,10 (m, 1H), 2,54 (m, 5H), to 1.86 (m, 1H), of 1.07 (m, 2H), of 0.85 (m, 2H).
12372 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.55 (s, 1H), 8,35 (d, J=2,3, 1H), 8,27 (d, J=1,8, 1H), 8,22 (s, 1H), 8,10 (dd, J=8,7, 2,0, 1H), 7,76-7,71 (m, 2H), value of 7, 37 (t, J=8,9, 1H), 7,10-7,06 (m, 1H), 6,61 (d, J=8,6, 1H), To 6.54 (s, 2H), 6,27 (s, 2H).
13374 (M+H)+1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), to 8.42 (s, 2H), 8,29 (d, J=to 8.7, 1H), to 8.19-8,13. (m, 2H), 7,91 (dd, J=15,2, 8,0, 2H), 7,82 (d, J=8,0, 1H), 7,71 (s, 1H), 6,94 (s, 2H).
14447 (M+H)+1H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 9.63 (s, 1H), 8.37 (s, 1H), 8.31-8.25 (m, 3H), 8.18 (dd, J=8.8, 1.8 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.63 (s, 2H), 6.70 (s, 2H).

15456 (M+H)+1H NMR (400 MHz, DMSO) δ 9,49 (s, 1H), 877 (S, 1H), to 8.57 (s, 1H), 8,28 (d, J=to 8.7, 1H), 8,23-8,16 (m, 2H), 6,70 (s, 2H), 5,80 (t, J=10,7, 1H), 4,50 (d, J=13,3, 1H), was 4.02 (d, J=13,5, 2H), of 3.04 (t, J=11,6, 1H), 2,40 (S, 2H), 2,31-of 2.20 (m, 1H), 2,10-2,02 (m, 4H).
16476 (M+H)+1H NMR (400 MHz, DMSO) δ 9,72 (s, 1H), 9,24 (s, 1H), 8,87 (s, 1H), 8,65 (s, 2H), 8,53 (s, 1H), 8,23 (s, 1H), 7,97 (s, 1H), 6,98 (s, 2H), to 1.86 (s, 6H).
17475 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.71 (s, 1H), 8,90 (d, J=1,9, 1H), 8,65 (d, J=8,9, 1H), 8,52 (d, J=8,9, 1H), 8,49-8,40 (m, 1H), of 8.26 (d, J=1,9, 1H), 8,09 (d, J=8,6, 2H), a 7.85 (d, J=8,6, 2H), 6,99 (s, 2H), Of 1.84 (s, 6H).
18408 (M+H)+1H NMR (400 MHz, DMSO) δ 9,69 (s, 1H), 8,76 (s, 2H), 8,61 (d, J=8,9, 1H), to 8.41 (d, J=8,9, 1H), 8,03 (d, J=8,4, 2H), of 7.88 (d, J=8,4, 2H), 7,14 (s, 2H), of 1.88 (s, 6H).
19443 (M+H)+1H NMR (400 MHz, DMSO) δ 9.58 per (s, 1H), 9,19 (s, 1H), 8,67 (s, 1H), 8,62 (d, J=8,8, 1H), 8,53 (d, J=8,9, 1H), 7,11 (s, 2H), 5,88 is 5.77 (m, 1H), 3,19-3,14 (m, 2H), 2.49 USD is 2.44 (m, 2H), 2,37-to 2.32 (m, 4H), 2,24-of 2.21 (m, 2H), 1,10 (t, J=7,1, 3H).

20469 (M+H)+1H NMR (400 MHz, DMSO) δ 9,59 (s, 1H), 9,19 (d, J=1,8, 1H), 8,68 (d, J=1,9, 1H), 8,62 (d, J=8,9, 1H), 8,53 (d, J=8,9, 1H), 7,10 (s, 2H), 5,87-at 5.76 (m, 1H), or 3.28 (d, J=11,3, 2H), 2,40-of 2.33 (m, 4H), 2,32-2,31 (m, 2H), 2,29-of 2.21 (m, 2H), 0,92-of 0.91 (m, 1H), 0.55 and a 0.47 (m, 2H), 0.18 to 0.09 in (m, 2H).

Example 2: Synthesis of compounds 21-29

Connection 21

(R)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-hydroxypropan-1-he

[0109] To a solution of hydrochloride of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine (600 mg, of 1.85 mmol) in DMF (15 ml) was added (R)-2-hydroxypropanoic acid (540 mg, of 1.85 mmol), HATU (850 mg, or 2.21 mmol) and DIEA (0.8 ml, 3,70 mmol). The mixture was stirred at room temperature over night. Was added 3 EQ. HATU and 2 EQ. DIEA, because according to the testimony of HPLC / MS, the reaction was not completed. The mixture was stirred for another 30 min., then diluted with water. The resulting mixture was twice extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and concentrated to give crude Product, which was then purified using chromatography on silica gel using as eluent EtOAc:PE to obtain (R)-1-(4-(8-chloro-1H-[-1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-hidrocapital-1-one as firmly�of yellow substances (136 mg, the yield of 20.4%). MG, (m/z): 361 (M+H)+

[0110] the Next stage of the synthesis of compound 21 was similar to the corresponding stage of the synthesis of Compound 1.

[0111] Compound 21: solid, 31,0 mg1H NMR (400 MHz, DMSO) δ 9,59 (s, 1H), 9,19 (s, 1H), 8.66 roubles (s, 1H), 8,63 (d, J=8,9 Hz, 1H), 8,53 (d, J=8,9 Hz, 1H), 7,07 (s, 2H), 6,09 (m, 1H), 5,02 (m, 1H), 4,74-4,27 (m, 2H), 2,87 (m, 1H), 2,44-1,90 (m, 3H), 1,27-to 1.21 (m, 4H). MC (m/z): 487 (M+H)+.

[0112] the Following compounds 22-29 were obtained according to the procedures described for Compound 21, using appropriate intermediates and Baranovich acids or esters in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
22433 (M+H)+1H NMR (400 MHz, DMSO) δ was 9.53 (s, 1H), of 8.82 (s, 1H), 8,55 (d, J=8,9 Hz, 1H), 8,37 (d, J=8,9 Hz, 1H), 8,17 (s, 1H), system 6.34 (s, 2H), of 6.02 (m, 1H), 5,06 (m, 1H), 4,55 (m, 2H), 4,32 (m, 1H), 2,99 (s, 1H), to 2.29 (m, 1H), 2,17 (m, 5H), of 1.97 (m, 1H), 1,23 (m, 3H).
23486 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.52 (s, 1H), 8,80(s, 1H), 8,61 (s, 1H), 8,29 (d, J=to 8.7, 1H) 8,22 (d, J=6,4, 2H), 6.75 in (s, 2H), 5,86 (s, 1H), 5,10-4,91 (m, 1H),4,51 (s, 2H), 4,25 (s, 1H), 3,57-of 3.43 (m, 2H), 3,12 (d, J=12,4, 2H), 2,35-to 2.18 (m, 1H), 2,08 (s, 1H), 1,22 (s, 3H).
24486 (M+H)+1H NMR (400 MHz, DMSO) δ 8,16 (s, 1H), 7,80 (d, J=8,2, 1H), 7,40 (s, 3H), 7,27 (t, J=7,6, 2H), made 7.16 interest (d, J=7,4, 1H), to 7.04 (d, J=7,2, 1H), 6,97 (t, J=8,0, 1H), 6.35 mm-6,13 (m, 1H), 5,34-5,10 (m, 1H), 3,80 (s, 3H), of 2.20 (s, 3H), of 1.44 (d, J=6,3, 3H).
25473 (M+H)+1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), 9,22 (d, J=1.6 Hz, 1H), 8,69 (d, J=1.6 Hz, 1H), 8.66 roubles (d, J=8,9 Hz, 1H), of 8.56 (d, J=8,9 Hz, 1H), to 7.09 (s, 2H), 6,13 (s, 1H), of 5.34 (m, 1H), 4,65 (m, 2H), 4,17 (m, 3H), To 2.94 (m, 2H), 2,07 (m, 4H).

26501 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,59 (s, 1H), 9,21 (d, J=2,2 Hz, 1H), 8,67 (d, J=8,8 Hz, 1H), 8,53 (d, J=2.1 Hz, 1H), 8,16 (d, J=8,8 Hz, 1H), 5,98 (s, 1H), and 5.30 (m, 2H), 4,97-of 4.88 (m, 3H), up 3.22 (m, 2H), 2,80 (m, 2H), 2,41 (m, 2H), 1,62 (m, 6H).
27500 (M+H)+1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), 9,21 (s, 1H), 8,73-8,63 (m, 2H), of 8.56 (d, J=8,9 Hz, 1H), 7,11 (s, 2H), 6,19-6,05 (m, 1H), 4,91-4,79 (m, 2H), 3,24-3,11 (m, 2H), 2,47-2,43(mz, 2H), 2,29-2,19 (m, 2H), 1,49 (s, 6H).
28469 (M+H)+1H NMR (400 MHz, DMSO) δ 9.58 per (s, 1H), 9,18 (s, 1H), 8,65 (s, 1H), 8,62 (d, J=8,9 Hz, 1H), 8,52 (d, J=9,0 Hz, 1H), was 7.08 (m, 2H), 6,89 (d, J=6,0 Hz, 1H), from 6.22 5,99 (m, 2H), 5,71 (m, 1H), 4,62 (m, 1H), 4,34 (m, 1H), 3,37 (m, 3H), 2,95 (m, 1H), 2,35-of 1.84 (m, 3H).
29415 (M+H)+1H NMR (400 MHz, DMSO) δ was 9.53 (s, 1H), of 8.82 (d, J=2.1 Hz, 1H), 8,55 (d, J=8,9 Hz, 1H), to 8.38 (d, J=8,9 Hz, 1H), 8,17 (s, 1H), 698-685 (m, 1H), 6.35 mm (s, 2H), 6,23-6,09 (m, 1H), 6,09-596 (m, 1H), 5,75-5,67 (m, 1H), Levels lower than the 5.37-to 5.21 (m, 1H), 4,76-4,62 (m, 1H), 4,46-4,30 (m, 1H), 4,18-was 4.02 (m, 1H), 3,10-2,98 (m, 1H), 2,55-of 2.50 (m, 1H), 2,16 (m, 6H)

Example 3: Synthesis of compounds 30-42

The connection 30

1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-methylpropan-1-he:

[0113] a Mixture of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]martriden (200 mg, 0.69 mmol), isobutyric acid (67 mg, 0,76 mmol), HATU (315 mg, 0.83 mmol) and DIEA (133 mg, 1.04 mmol) in DMF (5 ml) was stirred at room temperature over night. Was then added water (10 ml), the precipitate was collected and dried under vacuum to give 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-methylpropan-1-one in the form of Tverdov� substance (200 mg).

[0114] a Mixture of 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)Piperi-DIN-1-yl)-2-methylpropan-1-one (60 mg, 0.17 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (53 mg, 0.18 mmol), K2CO3(70 mg, 0.51 mmol) and Pd(dppf)Cl2(6 mg) in dioxane/H2O (3:1, 4 ml) was stirred and subjected to microwave irradiation at 160°C for 0.5 h. the Solvent was removed and the residue was purified using flash chromatography (MeOH/H2O=20%-80%) with receipt 1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-2-methylpropan-1-one in the form of a white solid substance (46 mg).1H NMR (400 MHz, DMSO) δ 9,61 (s, 1H), 9,21 (d, J=2,1 H2, 1H), 8.66 roubles (dd, J=12,5, and 5.5 Hz, 2H), 8,55 (d, J=8,9 Hz, 1H), 7,10 (s, 2H), 6,17-6,01 (m, 1H), 4,78-4,59 (m, 1H), 4,35-to 4.26 (m, 1H), 3,40-3,37 (m, 2H), 3,05-of 2.97 (m, 1H), 2,93-2,82 (m, 1H), 2,64-2,52 (m, 1H), 2,39-of 2.21 (m, 1H), 2,16-of 1.96 (m, 1H), of 1.07 (s, 6H). MC (m/z): 485 (M+H)+.

[0115] the Following compounds 31-42 were obtained according to the procedures described for Compound 30, with appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
31435 (M+H)+1H NMR (400 MHz, DMSO) δ 9,59 (s, 1H), 8,83 (s, 1H), 8,61 (d, J=8,9 Hz, 1H), 8,45 (d, J=8,9 Hz, 1H), of 8.25 (dd, J=12,7, the 1.8 Hz, 1H), 6,87(s, 2H), 6,15-of 5.91 (m, 1H), 4,68 (d, J=a 12.7 Hz, 1H), 4,29 (d, J=12.0 Hz, 1H), 3,49-to 3.38 (m, 2H), 3,06-2,95 (m, 2H), 2,58-2,52 (m, 1H), 2,36-of 2.24 (m, 1H), 2,17-of 2.05 (m, 1H), of 1.07 (d, J=6,4 Hz, 6H).
32415 (M+H)+1H NMR (400 MHz, DMSO) δ 9,61, (s, 1H), 9,22 (s, 1H), 8,65 (d, J=8,9 Hz, 2H), 8,55 (d, J=8,9 Hz, 1H), of 8.25 (s, 2H), 7,11 (s, 2H), 6,09-5,96 (m, 1H), 3.43 points (d, J=13,4 Hz, 2H), 2,99 (t, J=11,4 Hz, 2H), 2,46-2,31 (m, 4H).
33508 (M+H)+1H NMR (400 MHz, DMSO) δ 9,63 (s, 1H), 9,23 (s, 1H), 8,67 (d, J=9,0 Hz, 2H), of 8.56 (d, J=8,9 Hz, 1H), to 7.09 (s, 2H), 6,21-6,12 (m, 1H), 4,61-4,48 (m, 2H), 3,40-3,52 (m, 2H), 2,61-2,53 (m, 2H), 2,41-of 2.27 (m, 2H), 1,68-of 1.56 (m, 4H).
34500 (M+H)+1H NMR (400 MHz, DMSO) δ 9,61 (s, 1H), 9,21 (s, 1H), is 8.74-8,61 (m, 2H), 8,55 (d, J=8,9 Hz, 1H), 7,10 (s, 2H), 6.18 of-6,07 (m, 1H), 4,65 (d, J=12,6 Hz, 1H), 4,24 (d, J=a 12.7 Hz, 1H), to 3.67 (d, J=14,0 Hz, 1H), only 3.57 (d, J=14,1 Hz, 1H), 3,36 (dd, J=32,3,-20,7 Hz, 2H), 2,95 (t, J=12.3 Hz, 1H), of 2.45 (s, 6H), 2,40-of 2.33 (m, 1H), 2,22-2,07 (m, 2H).
35 485 (M+H)+1H NMR (400 MHz, DMSO) δ 9,51 (s, 1H), 9,11 (s, 1H), 8,58-to 8.45 (m, 3H), 7,03 (s, 2H), 5,98 (s, 1H), a 4.64 (s, 1H), 4,16 (s, 1H), of 2.38 (s, 4H), of 2.05 (s, 2H), 1,54 (s, 2H), 1,17 (s, 2H), to 0.89 (s, 3H).

36540 (M+H)+1H NMR (400 MHz, cdcl3) δ 9.58 per (s, 1H), 9,06 (s, 1H), 8.66 roubles (d, J=9,0, 1H), at 8.60 (s, 1H), 8,17 (d, J=8,8, 1H), 6,20-6,08 (m, 1H), is 5.33 (s, 2H), 4,96-is 4.85 (m, 1H), 4,30-4,19 (m, 1H), 3,49-to 3.38 (m, 1H), 2,95 (m, 3H), by 2.55 (m, 4H), 2,30 (m, 3H), 2,00 (m, 4H), 1,80 (m, 2H).
37499 (M+H)+1H NMR (400 MHz, DMSO) δ was 9.53 (s, 1H), 9,13 (s, 1H), 8,54 (m, 3H), 7,06 (s, 2H), 6,01 (s, 1H), a 4.64 (s, 1H), 4,18 (s, 1H), 2,43-of 1.92 (m, 7H), of 1.50 (s, 2H), 1,25 (m, 3H), of 0.87 (s, 3H).
38497 (M+H)+1H NMR (400 MHz, DMSO) δ 9,39 (s, 1H), of 9.00 (s, 1H), 8,44 (m, 2H), of 8.34 (m, 1H), 6,91 (s, 2H), 5,88 (m, 1H), 4,50 (m, 1H), 3,99 (m, 1H), 2,14 (m, 7H), was 1.04 (m, 1H), 0,84 (m, 1H), of 0.32 (m, 2H), 0,00 (m, 2H).
39 499 (M+H)+1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), 9,21 (s, 1H), 8.66 roubles (d, J=to 8.7 Hz, 2H), of 8.56 (d, J=8,9 Hz, 1H), 7,10 (s, 2H), 6,21-6,09 (m, 1H), 4,61-4,49 (m, 1H), 3,95-3,81 (m, 1H), 3,45-3,36 (m, 1H), 3,17-of 3.07 (m, 1H), To 2.85 (q, J=7,2 Hz, 2H), 2,62-of 2.54 (m, 2H), 2,41-2,31 (m, 1H), 2,25-to 2.18 (m, 1H), of 1.07 (t, J=7,2 Hz, 2H).
40520 (M+H)+1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), 9,22 (d, J=1,9, 1H), 8,69-8,63 (m, 3H), of 8.56 (d, J=8,9, 1H), 7,97 (td, J=7,7, of 1.7, 1H), 7,69 (d, J=7,8, 1H), 7,53 - of 7.50 (m, 1H), 7,11 (s, 2H), 6,21-6.18 of(m, 1H), Of 4.88-of 4.75 (m, 1H), 4,03-4,01 (m, 1H), 2,59-2,51 (m, 3H), 2,46 - of 2.32 (m, 3H).

41519 (M+H)+1H NMR (400 MHz, DMSO) δ 9,61 (s, 1H), 9,21 (d, J=2,1, 1H), 8,65 (t, J=5,5, 2H), 8,54 (d, J=8,9, 1H), 7,55-of 7.46 (m, 5H), 7,10 (s, 2H), 6.18 of-6,07 (m, 1H), 4.95 points-is 4.57 (m, 1H), 4,01-3,74 (m, 1H), 2,57-of 2.54 (m, 1H), 2,48-of 2.45 (m, 1H), 2,38-of 2.28 (m, 3H), 2,08-of 1.91 (m, 1H).
42437 (M+H)+1H NMR (400 MHz, DMSO) δ 9,00 (s, 1H), 8,93 (d, J=1,8, 1H), 8,30-8,20 (m, 3H), 8,08 (d, J=8,9, 1H), 7,98 (d, J=8,4, 1H), of 7.88 (d, J=8,9, 1H), at 6.92 (d, J=25,9, 3H), 3,61 (s, 3H), 1,83 (s, 6H).

Example 4: Synthesis of compounds 43-47

The connection 43

2-(4-(8-(6-amino-5-(trift�rmetal)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-N,N-dimethylacetamide

[0116] a Mixture of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine (100 mg, 0.35 mmol), 2-chloro-N,N-dimethylacetamide (46 mg, 0.38 mmol) and K2CO3(97 mg, 1.04 mmol) in DMF (5 ml) was stirred at room temperature over night. The solvent was removed and the residue was extracted with EtOAc (3×10 ml). The combined organic layers were dried over Na2SO4and concentrated to give crude 2-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)-N,N-dimethylacetamide, which was used for next step without further purification.

[0117] a Mixture of the above product, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (109 mg, 0.38 mmol), K2CO3(145 mg, 1.05 mmol) and Pd(dppf)Cl2(10 mg) in dioxane/H2O (3:1,4 ml) was stirred and subjected to microwave irradiation at 160°C for 0.5 h. the Solvent was removed and the residue was purified using chromatography (MeOH/H2O=20%-80%) to give compound 43 as a pale yellow solid (50 mg).1H NMR (400 MHz, DMSO-d6) δ 9,60 (s, 1H), 9,20 (d, J=2,0 Hz, 1H), 8.66 roubles (dd, J=16.5, and 5.4 Hz, 2H), 8,54 (d, J=8,9 Hz, 1H), 7,12 (s, 2H), 5,97 is 5.77 (m, 1H), 3,40 (s, 2H), 3,29-3,14 (m, 4H), 3,10 (s, 3H), 2,86 (s, 3H), 2,44-of 2.35 (m, 4H). MC (m/z): 500 (M+H)+.

[0118] the Following compounds 44-47 were obtained according to the procedures described for Compound 43, using a suitable�appropriate intermediates and Bronevoy acid or ester in suitable conditions, which will be obvious to a person skilled in the technical field:

ConnectionStructureLC/MSNMR
44499 (M+H)+1H NMR (400 MHz, DMSO) δ 9,60 (s, 1H), 9,21 (d, J=2,0, 1H), of 8.71 (d, J=2,1, 1H), 8,64 (d, J=8,9, 1H), 8,55 (d, J=8,9, 1H), 7,13 (s, 2H), to 4.41 (d, J=5,7, 2H), 4,25 (d, J=5,7, 2H), 2,62 (s, 2H), 2,40-of 2.21 (m, 8H), 1,38 (s, 3H).
45486 (M+H)+1H NMR (400 MHz, DMSO) δ 9,57 (s, 1H), 9,18 (d, J=2,1, 1H), 8,65 (s, 1H), 8,62 (d, J=8,9, 1H), 8,51 (d, J=8,9, 1H), 7,07 (s, 2H), 6,66 (t, J=5,4, 1H), 6,01 (s, 1H), 4,23 (d, J=14,0, 2H), 2,93 (t, J=12,2, 2H), 2,36-2,34 (m, 2H), 2,14-2,12 (m, 2H), 1,98-of 1.96 (m, 2H), 1,02 (t, J=7,1, 3H).
46459 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,73-9,68 (m, 1H), 9,57 (s, 1H), 8,64 (d, J=8,8 Hz, 1H), 8,53 8.48 to (m, 1H), 8,15 (d, J=8,8 Hz, 1H), 5,75-of 5.60 (m, 1H), of 5.40 (s, 2H), 3,78-3,71 (m, 2H), 3,34-3,26 (m, 2H), 3,21-of 3.07 (m, 2H), 2,76-to 2.65 (m, 2H), 2,48-2,34 (m, 2H), 1,31 (m, 4H).
47505 (M+H)+ 1H NMR (400 MHz, DMSO) δ 9,57 (s, 1H), 9,18 (s, 1H), 8,67 (s, 1H), 8,61 (d, J=to 8.7, 1H), 8,51 (d, J=9,2, 2H), 7,79 (s, 1H), 7,53 (d, J=7,4, 1H), 7,27 (s, 1H), to 7.09 (s, 2H), 5,94 of 5.81 (m, 1H), 3,71 (s, 2H), 3,13 (m, 2H), 2,35 (s, 6H).

Example 5: Synthesis of Compound 48

The connection 48

5-(1-(1-((tetrahydro-2H-Piran-4-yl)methyl)piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine-8-yl)-3-(trifluoromethyl)pyridin-2-amine

[0119] In a nitrogen atmosphere the white suspension of 8-chloro-1-(piperidine-4-yl)-1H-[1,2,3]triazolo[4,5-C][1,5]naphthiridine (130 mg, is 0.450 mmol), 4-(methyl bromide) tetrahydro-2H-PYRAN (97 mg, 0,540 mmol) and K2CO3(124 mg, to 0.900 mmol), acetonitrile (15 ml) was heated to reflux for 4 h. After cooling to room temperature the mixture was diluted with 20 ml EtOAc. Then the mixture was filtered through a Buchner funnel, and the organic phase was collected and concentrated. The crude product was used for next step without further purification (35 mg). MS (m/z): 387 (M+H)+.

[0120] In the orange atmosphere of nitrogen a suspension of 8-chloro-1-(1-((tetrahydro-2H-Piran-4-yl)methyl)piperidine-4-yl)-N-[1,2,3]triazolo[4,5-C][1,5]naphthiridine (35 mg, 0,090 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (26,1 mg, 0,090 mmol), Na2CO3(19,18 mg, 0,181 mmol) and PdCl2(dppf).CH2Cl2(3,69 mg, 4,52 mmol) in a mixture of dioxane (20 ml) and N20 (2 ml) was stirred for 10 minutes before heating obtained� mixture to 120°C for 2 hours. After concentration under vacuum, the obtained residue was purified using flash chromatography on 12 g of silica gel (PE/EtOAc) to give product as pale yellow powder (10 mg).1H NMR (400 MHz, DMSO) δ was 9.53 (s, 1H), 9.15, with (d, J=2,1, 1H), 8,65 (s, 1H), 8,61 (d, J=8,9, 1H), 8,51 (d, J=8,9, 1H), 7,07 (s, 2H), 5,99-5,80 (m, 1H), of 3.91 to 3.85 (m, 4H), up 3.22-is 3.08 (m, 4H), 2,41-of 2.15 (m, 10H), 1,73-1,58 (m, 2H). MS (m/z): 513 (M+H)+.

Example 6: Synthesis of Compounds 49-78

The connection 49

2-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,3-a]quinoxaline-1-yl)fenril)-2-methylpropionitrile

[0121] To a solution of 7-bromo-2-hydrazinecarboxamide (1.5 g, 0,063 mol) and 4-(2-cyanoprop-2-yl)benzoic acid (1.1 g, 0,063 mol) in DMF (5 ml) was added HATU (2.4 g, 0,063 mol) and DIEA (1.2 g, 0,095 mol). Thereafter, the reaction mixture was stirred at room temperature over night. The solution was diluted with water (5 ml), and the solid is collected using a filter to obtain N'-(7-bromination-2-yl)-4-(2-cyanoprop-2-yl)benzhydrazide in the form of a solid yellow substance (2.2 g, yield of 85.0%). MS (m/z): 412 (M+H)+.

[0122] a Solution of N'-(7-bromination-2-yl)-4-(2-cyanoprop-2-yl)benzhydrazide (2.2 g, 0,054 mol) in 3 ml of Acoh was stirred at 100°With during the night. After cooling to room temperature the reaction mixture was diluted with water (5 ml). The solid is collected using a filter and washed with saturation. NaHCO3(5 ml) obtained with�eat 2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline-1-yl)phenyl)-2-methylpropionitrile in the form of a solid yellow substance (1.8 g, the yield of 85.0%). MS (m/z): 392 (M+H)+.

[0123] To a mixture of 2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline-1-yl)phenyl)-2-methylpropionitrile (80 mg, 0.21 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (59 mg, 0,21 mmol) and K2CO3(87 mg, 0,63 mmol) in dioxane (3 ml) and H2O (1 ml) was added Pd(dppf)Cl2(3 mg). The reaction mixture was subjected to microwave irradiation at 150°C for 30 min. After cooling to room temperature the reaction mixture was concentrated and was purified using chromatography to obtain compound 49 in the form of a solid yellow substance (52 mg).1H NMR (400 MHz, DMSO) δ at 9.38 (s, 1H), of 8.26 (s, 1H), 8,11 (d, J=8,5, 1H), 7,99-to 7.95 (m, 1H), 7,92 (d, J=8,3, 2H), 7,83 (d, J=8,4, 2H), 7,63 (m, 1H), 7,52 (d, J=1.5 m, 1H), was 6.77 (8, 2H), 1,77 (8, 6H). MC (m/z): 474 (M+H)+.

[0124] the Following compounds 50-78 were obtained according to the procedures described for Compound 49, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
50406 (M+H)+ 1H NMR (400 MHz, DMSO) δ at 9.38 (s, 1H), 8,12 (d, J=8,5, 1H), 7,96-a 7.87 (m, 5H), 7,74 (d, J=1,8, 1H), of 7.64 (s, 2H), 7,55 (d, J=1,8, 1H), 7,27 (d, J=8,4, 1H), 7,10 (dd, J=8,4, 2,0, 1H), is 1.81 (s, 6H).
-51392 (M+H)+1H NMR (400 MHz, DMSO) δ 9,51 (s, 1H), 9,21 (s, 1H), 8,80 (s, 2H), 8,27 (d, J=8,4, 1H), 8,16 (dd, J=8,4, and 1.9, 1H), 7,92 (dd, J=11,7, 2,9, 5H), 7,49 (d, J=1,8, 1H), of 1.84 (s, 6H).
52462 (M+H)+1H NMR (400 MHz, DMSO) δ at 9.38 (s, 1H), 8,12 (d, J=8,5, 1H), 7,96-a 7.87 (m, 5H), 7,74 (d, J=1,8, 1H), of 7.64 (s, 2H), 7,55 (d, J=1,8, 1H), 7,27 (d, J=8,4, 1H), 7,10 (dd, J=8,4, 2,0, 1H), is 1.81 (s, 6H).
53431 (M+H)+1H NMR (400 MHz, DMSO) δ 13,81 (s, 1H), 9,43 (s, 1H), is 8.46 (d, J=2,2 Hz, 1H), 8,21-8,16 (m, 2H), 8,14 (s, 1H), 8,06 (dd, J=8,5, and 1.9 Hz, 1H), 7,92 (q, J=8,5 Hz, 4H), 7,53 (d, J=1,8 Hz, 1H), 1,79 (s, 6H).
54475 (M+H)+1H NMR (400 MHz, DMSO) δ for 9.47 (s, 1H), a 9.09 (dd, J=2,3, 0,8, 1H), and 8.50 (dd, J=8,2, 2,3, 1H), 8,35 (d, J=2,2, 1H), to 8.19 (d, J=8,5, 1H), 8,08-8,02 (m, 1H), 7,96 (dd, J=8,2, 0,8, 1H),7,71 (d, J=2,2, 1H), 7,55 (d, J=1,9, 1H), 6,83 (s, 2H), equal to 1.82 (s, 6H).

55446 (M+H)+1H NMR (400 MHz, DMSO) δ at 9.38 (s, 1H), 8,11 (d, J=8,5, 1H), 7,96 (dd, J=8,5, of 1.7, 1H), 7,90 (q, J=8,5, 4H), 7,55 (s, 2H), of 7.48 (d, J=1,6, 1H), 7,38 (d, J=1,3, 1H), 7,12 (d, J=8,1, 1H), 7,00 (dd, J=8,2, 1,5, 1H), equal to 1.82 (s, 6H).
56463 (M+H)+1H NMR (400 MHz, DMSO) δ 9,43 (s, 1H), a 9.09 (s, 1H), to 8.45 (dd, J=8,2, 2,2, 1H), 8,16 (d, J=8,5, 1H), 8,04-7,96 (m, 2H), 7,76 (d, J=1,9, 1H), 7,66 (s, 2H), 7,53 (d, J=1,8, 1H), 7,30 (d, J=8,4, 1H), made 7.16 interest (dd, J=8,4, 2,0, 1H), 1,83 (s, 6H).
57421 (M+H)+1H NMR (400 MHz, DMSO) δ 9,39 (s, 1H), 9,07 (s, 1H), to 8.45 (dd, J=8,2, 2,3, 1H), 8,11 (d, J=8,5, 1H), 8,00 (d, J=8,2, 1H), 7,94-a 7.87 (m, 2H), 7,44 (d, J=1,8, 1H), 7.23 percent (d, J=1,7, 1H), 6,08 (s, 2H), 2,04 (s, 3H), equal to 1.82 (s, 6H).
58420 (M+H)+1H NMR (400 MHz, DMSO) δ 9,35 (s, 1H), 8,14 (s, 1H), 8,08 (d, J=8,5, 1H), 7,94-7,84 (m, 6H), 7,47 (d, J=1,8, 1H), 7,20 (d, J=1,7, 1H), to 6.05 (s, 2H), 2,03 (s, 3H), of 1.81 (s, 6H),
59426 (M+H)+1NAMR (400 MHz, DMSO) δ 9,51 (s, 1H), 8,99 (d, J=2,8, 1H), 8,58 (d, J=2,1, 1H), of 8.33-8,29 (m, 1H), 8,25-8,21 (m, 2H), 8,15 (d, J=8,5, 1H), with 8.05 (d, J=1,8, 1H), 7,84 (d, J=2,2, 1H), 6,93 (s, 2H).
60414 (M+H)+1H NMR (400 MHz, DMSO) δ 9,50 (s, 1H), 9,13 (d, J=2,8, 1H), 8,32-8,29 (m, 1H), 8,24-to 8.19 (m, 3H), 8,08 (dd, J=8,5, and 1.9, 1H), 7,94 (s, 1H), 7,74 (s, 2H), of 7.46 (d, J=2,4, 2H).

61430 (M+H)+1H NMR (400 MHz, DMSO) δ of 13.18 (s, 1H), 9,41 (s, 1H), 8,16 (d, J=8,5, 1H), 8,09 (s, 1H), 8,01 (dd, J=8,5, and 1.9, 1H), 7,96-7,90 (m, 4H), 7,81 (s, 1H), members, 7.59 (d, J=1,9, 1H), 7,54 (d, J=to 8.7, 1H),7,30 (dd, J=8,7, 1,6, 1H), 1,79 (s, 6H).
62432 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.45 (s, 1H), to 8.42 (s, 1H), to 8.36 (d, J=2,0, 1H), 8,27-8,22 (m, 2H), 8,18 (d, J=8,5, 1H), 8,07 (dd, J=8,5, 1,8, 1H), 7,94 (t, J=7,8, 1H), 7,60 (d, J=2,1, 1H), of 7.42 (d, J=1,8, 1H), To 6.88 (s, 2H).
63420 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.42 (s, 1H), 8,49 (s, 1H), 8,29-8,10 (m, 3H), 7,95 (s, 2H), 7,69 (d, J=8,1, 3H), 7,51 (s, 1H), 7,32 (d, J=7,1, 1H), 7,21 (s, 1H).
64 432 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.45 (s, 1H), 8,44 (d, J=2,2, 1H), 8,21 (d, J=1,8, 1H), to 8.19 (d, J=3,0, 1H), 8,17 (s, 1H), 8,13 (d, J=1,9, 1H), 8,12 (d, J=1,9, 1H), 8,07 (dd, J=8,5, and 1.9, 1H), 7,56 (d, J=2,2, 1H), of 7.46 (d, J=1,9, 1H), 6,87 (s, 2H).
65422 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.40 (s, 1H), 8,88 (s, 1H), to 8.41 (s, 2H), 8,21 (d, J=8,1, 1H), 8,14 (d, J=8,4, 1H), 8,02 (d, J=7,9, 1H), 7,62-7,54 (m, 2H), of 7.48 (s, 1H), 6,83 (s, 2H), 2,63 (s, 3H).
66424 (M+H)+1H NMR (400 MHz, DMSO) δ 9,37 (s, 1H), 8,09 (d, J=8,5, 1H),7,94 (d, J=8,8, 1H), to 7.89 (d, J=1,8, 3H), a 7.87 (s, 1H), 7,83 (s, 1H), value of 7, 37 (s, 1H), 7,21 (d, J=12,5, 1H), to 6.57 (s, 2H), is 1.81 (s, 6H).

67447 (M+H)+1H NMR (400 MHz, DMSO) δ 9,51 (s, 1H), 9,18 (d, J=1,6, 1H), 8,51 (dd, J=8,2, 2,2, 1H), 8,23 (d, J=8,5, 1H), 8,08 (d, J=8,3, 2H), 7,65 (s, 2H), 7,52 (dd, J=19,9, 1,6, 2H), 7.23 percent (d, J=8,1, 1H), 7,12 (dd, J=8,2, 1,6, 1H), 1,92 (s, 6H).
68502 (M+H)+1H NMR (400 M�C, DMSO) δ of 9.42 (s, 1H), 8,18 (d, J=2,1, 2H), 8,15 (d, J=2,8, 1H), 8,13 (s, 1H), 8,03 (s, 1H), 8,01 (d, J=1.5 m, 21-1), 7,99 (d, J=1,9, 1H), 7,97 (d, J=2,0, 1H), 7,81 (s, 1H), 7,79 (s, 1H), 1,94 (s, 6H).
69430 (M+H)+1H NMR (400 MHz, DMSO) δ 11,82 (s, 1H), 9,41 (s, 1H), 8,24-8,13 (m, 2H), 8,04 (d, J=8,2, 1H), 7,93-7,91 (m, 6H), 7,53 (d, J=12,8, 2H), of 6.46 (s, 1H), of 1.80 (s, 6H).
70425 (M+H)+1H NMR (400 MHz, DMSO) δ 9,34 (s, 1H), to 8.36 (d, J=2,2, 1H), 8,11 (d, J=8,5, 1H), 7,99 (dd, J=8,5, and 1.9, 1H), 7,92-7,83 (m, 2H), 7,53 (dd, J=12,2, 5,4, 3H), 7,40 (d, J=1,8, 1H), 6,76 (s, 2H).
71485 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.46 (s, 1H), of 8.26 (dd, J=7,1, 5,0, 3H), 8,23-8,16 (m, 3H), and 8.04 (dd, J=8,5, and 1.9, 1H), 7,78 (y, J=2,2, 1H), EUR 7.57 (d, J=1,8, 1H), 6,83 (s, 2H), 3,35 (s, 3H).
72436 (M+H)+1H NMR (400 MHz, DMSO) δ 9,39 (s, 1H), 8,12 (d, J=8,5, 1H), 7,98-of 7.93 (m, 3H), to 7.89 (d, J=8,5, 2H), 7,53 (d, J=1,8, 1H), of 7.48 (d, J=1,9, 1H), was 7.08 (d, J=1,8, 1H), 6,07 (s, 2H), 3,81 (s, 3H), equal to 1.82 (s, 6H).

73 421 (M+H)+1H NMR (400 MHz, DMSO) δ 9,49 (d, J=7,3, 2H), of 8.71 (dd, J=8,2, 2,1, 1H), to 8.42 (dd, J=4,8, 3.2 m, 2H), to 8.19 (d, J=8,5, 1H), 8,06 (dd, J=8,5, of 1.7, 1H), 7,94 (s, 1H), of 7.70 (s, 2H), 7,47-7,44 (m, 3H).
74436 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.42 (s, 1H), 8,16 (d, J=8,4, 1H), 7,95-7,90 (m, 4H), 7,81 (dd, J=8,5, and 1.9, 1H), 7,40 (d, J=1,9, 1H), 7,21 (d, J=2,3, 1H), of 6.96 (d, J=2,3, 1H), a 3.87 (S, 3H), of 1.85 (s, 6H).
75450 (M+H)+1H NMR (400 MHz, DMSO) δ 9,35 (s, 1H), 8,09 (d, J=8,5, 1H), 7,92-of 7.88 (m, 3H), 7.87 ft-7,83 (m, 2H), 7,45 (dd, J=14,5, 1,9, 2H), 7,03 (d, J=2,0, 1H), 5,96 (s, 2H), 4,01 (q, J=6,5, 2H), 1,79 (s, 6H), of 1.35 (t, J=6,9, 3H).
76451 (M+H)+1H NMR (400 MHz, DMSO) δ 9.41 (d, J=1.5 M, 1H), 8,15 (d, J=8,5, 1H), 8,00 (dd, J=8,5, 1,8, 1H), of 7.88 (q, J=8,4, 4H), 7,45 (dd, J=15,9, 1,9, 2H), of 7.36 (d, J=2,0, 1H), 3,84 (s, 3H), of 3.80 (s, 3H), of 1.80 (s, 6H).
77440 (M+H)+1H NMR (400 MHz, DMSO) δ 9,37 (s, 1H), 8,09 (d, J=8,5, 1H), 7,97-7,86 (m, 6H), 7,50 (d, J=2,2, 1H), 7,45 (d, J=1,8, 1H), 6,62 (s, 2H), is 1.81 (s, 6H).
78462 (M+H)+1H NMR (400 MHz, DMSO) δ 9,43. (s, 1H), 8,89-is 8.84 (m, 1H), 8,22-8,17 (m, 3H), 8,11 (s, 1H), 7,97 (d, J=8,4, 1H), 7,61-7,54 (m, 3H), 3,94 (s, 3H), 3,02 (s, 3H), 2,65 (s, 3H).

Example 7: Synthesis of compounds 79-87

Compound 79

(S)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,3-a]quinoxaline-1-yl)piperidine-1-yl)-2-hydroxypropan-1-he

[0125] a Mixture of 1-tert-butyl 4-demerol-1,4-dicarboxylate (4.84 g, 20 mmol) and LiOH (2,52 g, 60 mmol) in THF (90 ml)/MeOH (90 ml)/H2O (30 ml) was stirred at room temperature over night. Then the solvent was removed, and the pH of the precipitate was adjusted to 2 using 2N HCl. The resulting mixture was extracted with EtOAc (3×20 ml). The combined organic layers were dried over Na2SO4and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100,0%)

[0126] a Mixture of 7-bromo-2-hydrazine (3 g, of 12.55 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3,16 g, 13,81 mmol), EDCI (2,89 g, with 15.06 mmol), HOBt (2,03 g, with 15.06 mmol) and TEA (1.9 g, 18,83 mmol) in DMF (100 ml) was stirred at room temperature over night. The mixture was diluted with water (10 ml) and was extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na2SO4and concentrated under vacuum with p�torch tert-butyl 4-(2-(7-bromination-2-yl)geringerer)piperidine-1-carboxylate in the form of a pale yellow solid (3.5 g, yield 62%).

[0127] a Mixture of tert-butyl 4-(2-(7-bromination-2-yl)geringerer)piperidine-1-carboxylate (900 mg, 2.0 mmol) in Acoh (10 ml) was heated to reflux over night. Then the solvent was removed, and the residue was purified using flash chromatography (MeOH/H2O=20%-90%) to give 8-bromo-1-(piperidine-4-yl)-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a pale yellow solid (550 mg, yield 83.0 per cent). MS (m/z): 332 (M+H)+

[0128] a Mixture of 8-bromo-1-(piperidine-4-yl)-[1,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol), HATU (346. mg, of 0.90 mmol) and DIEA (116 mg, of 0.90 mmol) in DMF (5 ml) was stirred at room temperature for 6 h. then the solvent was removed, and the residue was purified using flash chromatography (MeOH/H2O=20%-90%) to give (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline-1-yl)piperidine-1-yl)-2-hydroxypropan-1-one as pale yellow solid (200 mg, yield of 66.0%). MS (m/z): 404 (M+H)+

[0129] a Mixture of (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline-1-yl)piperidine-1-file)-2-hydroxypropan-1-one (65 mg, 0,16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (51 mg, 0.18 mmol), K2CO3(67 mg, 0.48 mmol) and Pd(dppf)Cl2(5 mg) in dioxane/H2About (3:1,4 ml) was subjected to microwave irradiation at 150°C for 0.5 h. T thereafter, the solvent was removed, and the residue was purified� using flash chromatography (MeOH/H 2O=20%-80%) to give compound 72 in the form of a solid yellow substance (30 mg).1H NMR (400 MHz, DMSO) δ 9,28 (s, 1H), 8,72 (d, J=2,0 Hz, 1H), 8,32 (s, 1H), 8,16-8,12 (m, 2H), with 8.05 (dd, J=8,5, 1.5 Hz, 1H), about 6,82 (s, 2H), 4,91 (dd, J=7,2, 6,5 Hz, 1H), 4,47 (dd, J=17,8, to 11.8 Hz, 2H), 4,29 (t, J=a 10.6 Hz, 1H), 4,15 (t, J=11.2 Hz, 1H), 3,09-of 2.97 (m, 1H), 2,27 (dd, J=15,6, 14,5 Hz, 2H), of 1.97 (dd, J=12,0, and 4.5 Hz, 1H), 1,78 (dd, J=7,1, 5,0 Hz, 1H), 1,25-of 1.15 (m, 3H). MS (m/z): 486 (M+H)+.

[0130] the Following compounds were 80-87 obtained according to the procedures described for Compound 79, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the technical field:

ConnectionStructureLC/MSNMR
80474 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.27 (s, 1H), of 8.33 (s, 1H), to 8.19-8,08 (m, 2H), 8,02 (d, J=8,5 Hz, 1H), 7,72-members, 7.59 (m, 3H), of 7.48 (d, J=8,3 Hz, 1H), of 4.88 (dd, J=18,5, of 12.3 Hz, 1H), 4,42 (dd, J=24,2, of 18.1 Hz, 2H), 4,17 (dd, J=26,5, of 14.0 Hz, 2H), 3,06 (d, J=7,2 Hz, 1H), 2,34-2,22 (m, 2H), 2,00 (d, J=14.6 Hz, 1H), 1,90-of 1.75 (m, 1H), 1,29-of 1.15 (m, 3H).
81474 (M+H)+1H NMR (400 �Hz, DMSO) δ to 9.27 (s, 1H), of 8.33 (s, 1H), 8,20-8,12 (m, 2H), 8,02 (d, J=8,6 Hz, 1H), 7,71-7,61 (m, 3H), of 7.48 (d, J=8.4 Hz, 1H), 4,98-to 4.76 (m, 1H), 4,51-4,37 (m, 2H), 4,25-4,11 (m, 2H), 3,12-3,01 (m, 1H), 2,35-of 2.21 (m, 2H), 2,04-to 1.94 (dd, J=33,4, 10,8 Hz, 1H), 1,90-to 1.77 (m, 1H), 1,20 (d, J=6,5 Hz, 3H).
82470 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 8,72 (d, J=2,0 Hz, 1H), 8,27 (s, 1H), 8,13 (d, J=8.4 Hz, 2H), 8,03 (dd, J=8,4, 1.5 Hz, 1H), about 6,82 (s, 2H), 4,33 (d, J=12,5 Hz, 1H), 3,78 (d, J=13,3 Hz, 1H), only 3.57 (d, J=4.4 Hz, 2H), 3,04-2,96 (m, 1H), 2,60-2,48 (m, 1H), 2,38-to 2.29 (m, 1H), of 1.97 (s, 3H) 1,78 (d, J=12,6 Hz, 2H), 1,43-of 1.31 (m, 1H), 1,28-of 1.18 (m, 1H).
83458 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 8,30 (s, 1H), 8,14 (dd, J=7,5, 5.1 Hz, 2H), 7,99 (dd, J=8,5, 1.5 Hz, 1H), 7,72-to 7.60 (m, 3H), of 7.46 (d, J=8.4 Hz, 1H), of 4.38 (d, J=12,6 Hz, 1H), 3,81 (d, J=14,0 Hz, 1H), 3,54 (d, J=6,5 Hz, 2H), 3,03 (t, J=11,8 Hz, 1H), 2,60-2,51 (m, 1H), 2,42-of 2.28 (m, 1H), of 1.97 (s, 3H), 1,83 (d, J=12,8 Hz, 2H), 1,40 (dt, J=10,5, 6,7 Hz, 1H),

1,29-1,20 (m, 1H).
84444 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 8,32 (s, 1H), to 8.19-8,10 (m, 2H), 805-8,78 (m, 1H), 7,72-of 7.58 m, 3H), 7,41 (d, J=8,1 Hz, 1H), 4.38 gigabytes-to 4.23 (m, 1H), 4,17-was 4.02 (m, 1H), 3,98-of 3.91 (m, 1H), 3,88-of 3.80 (m, 1H), 2,89-2,78 (m, 1H), 2,36-of 2.23 (m, 2H), of 2.15 (s, 3H), of 1.84 (d, J=21.4 Hz, 1H), 1,79-1,62 (m, 1H).
85429 (M+H)+1H NMR (400 MHz, DMSO) δ 9,22 (d, J=2.1 Hz, 1H), 8,68 (s, 1H), 8,23 (d, J=3.7 Hz, 1H), 8,12 (d, J=8.4 Hz, 2H), 8,01 (d, J=8,5 Hz, 1H), was 6.77 (d, J=6,2 Hz, 2H), 4,67-4,55 (m, 1H), 3,39-3,35 (m, 1H), 2,22-2,10 (m, 2H), 2,03-of 2.93 (m, 2H), 1,87-to 1.77 (m, 2H), 1,77-of 1.66 (m, 2H).
86428 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.45 (s, 1H), 8,67 (s, 1H), 8,52 (s, 1H), 8,18 (d, J=8,4 Hz, 1H), 8,14 (dd, J=8.4 Hz, 2.0 Hz, 1H), 8,11 -8,08 (m, 1H), 6,90 (s, 2H), 3,76-3,61 (m, 4H), 1,99 (m, 2H), 1,92 (m, 2H).
87414 (M+H)+1H NMR (400 MHz, cd3od) δ of 9.23 (s, 1H), 8,99 (d, J=1.9 Hz, 1H), 8,61 (d, J=2.1 Hz, 1H), 8,23 (d, J=8,5 Hz, 1H), 8,14 (d, J=1.9 Hz, 1H), 7,97 (dd, J=8,5, and 1.9 Hz, 1H), 4,47 (m, 2H), of 4.38 (m, 2H), 2,73 (m, 4H), Of 1.88 (m, 4H).

Example 8: Synthesis of Compounds 88-118

The connection 88

(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanon

[0131] a Mixture of 8-dichloro-7-nitro-1,5-naphthiridine (3,55 g, 14,55 mmol) and K2WITH3 (6,02 g, 43,65 mmol) in DMF (8 ml) was stirred at room temperature overnight, and then poured into ice water (~20 ml). The precipitate was collected, washed three times with water and dried under vacuum to give tert-butyl 4-(6-chloro-3-nitro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate in the form of a solid yellow substance (5,22 g, yield 88%), which was used for next step without further purification. MS (m/z): 409 (M+H)+.

[0132] a Mixture of tert-butyl 4-(6-chloro-3-nitro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate (600 mg, about 1.47 mmol) and SnCl2.H2O (996 mg, to 4.41 mmol) in ethyl acetate (20 ml) was stirred at room temperature for 2 h, and then was podslushivaet 5% NaOH. The mixture was filtered through celiby filter. The filtrate was extracted with ethyl acetate (3×15 ml). The organic layers were combined and washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl 4-(3-amino-6-chloro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate in the form of a solid yellow substance (499 mg, yield 90%) which was used for next step without further purification. MS (m/z): 378 (M+H)+.

[0133] a Mixture of tert-butyl 4-(3-amino-6-chloro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate (200 mg, 0.53 mmol), triethoxysilane (94 mg, 0.64 mmol) and PyHCl (6 mg, 0,053 mmol) in toluene (5 ml) was heated with reverse� fridge for 3.5 h. The solvent was removed under vacuum, and the residue was added to a solution of HCl in MeOH (6N, 3 ml). The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (20 ml). The resulting mixture was washed with saturated NaHCO3(10 ml) and brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated to give 8-chloro-1-(piperidine-4-yl)-1H-imidazo[4,5-C][1,5]naphthiridine in the form of a solid yellow substance (110 mg, yield 72%), which was used for next step without further purification.

[0134] To a solution of 8-chloro-1-(piperidine-4-yl)-1H-imidazo[4,5-C][1,5]naphthiridine (110 mg, of 0.382 mmol) and Et3N (106 μl 0,764 mmol) in THF (15 ml) was added cyclopropanecarbonyl (38 µl, 0,420 mmol) under cooling in a water bath with ice. The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum. The residue was dissolved in ethyl acetate (20 ml). The resulting solution was washed with NaHCO3(10 ml) and brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated to give (4-(8-chloro-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanone in the form of a solid yellow substance (100 mg, yield 73%) which was used for next step without further purification. MS (m/z): 356 (M+H)+

[0135] a Mixture of (4-(8-chloro-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanone (100 mg, 0,281 mmol), PdCl2(dppf)2(12 mg, of 0.014 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (97 mg, 0,337 mmol) and 2N solution of K2CO3(1 ml) in dioxane (4 ml) was subjected to microwave irradiation at 150°C for 30 min. the Solvent was removed and the residue was purified using flash chromatography (MeOH/H2O 0% ~100%) to give compound 88 in the form of a yellowish solid compound (70 mg).1H NMR (400 MHz, DMSO) δ 9,20 (s, 1H), 9,13 (d, J=1,9, 1H), of 8.71 (s, 1H), 8,59 (d, J=2,0, 1H), 8,49 (d, J=8,9, 1H), 8,32 (d, J=8,9, 1H), 6,99 (s, 2H), 5,98 is 5.92 (m, 1H), of 4.66 (s, 1H), 4,58 (s, 1H), 3,25 (s, 2H), 2,35 (s, 2H), 2,09 is 2.01 (m, 2H), 2,01-1,90 (m, 1H), 0,80-0,71 (m, 4H). MS (m/z): 482 (M+H)+.

[0136] the Following compounds 89-118 were obtained according1the procedures described for Compound 88, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
89475 (M+H)+1H �Mr (400 MHz, DMSO) δ at 9.38 (s, 1H), remaining 9.08 (d, J=2,6 Hz, 1H), 8,79 (s, 1H), to 8.70 (d, J=2 Hz, 1H), 8,55 (d, J=8,9 Hz, 1H), of 8.47 (dd, J=8,4, 2.5 Hz, 1H), of 8.34 (d, J=8,9 Hz, 1H), 8,16 (d, J=2.1 Hz, 1H), of 7.88 (d, J=8.4 Hz, 1H), 6,90 (s, 2H), of 1.85 (s, 6H).
90421 (M+H)+1H NMR (400 MHz, DMSO) δ 9,32 (d, J=1.2 Hz, 1H), 9,11 (s, 1H), 8,77 (d, J=1.2 Hz, 1H), 8,49-8,43 (m, 2H), 8,37 (s, 1H), 8,22 (d, J=9,0 Hz, 1H), 7,95 (d, J=8.4 Hz, 1H), 7,72 (s, 1H), of 6.20 (s, 2H), 2,10 (s, 3H), To 1.87 (s, 6H).
91406 (M+H)+1H NMR (400 MHz, DMSO) δ 9,41 (s, 1H), 9,11 (d, J=2,0 Hz, 1H), 8,87 (s, 1H), of 8.82 (s, 1H), at 8.60 (d, J=8,8 Hz, 1H), of 8.39 (t, J=7.5 Hz, 1H), with 8.05 (d, J=6,2 Hz, 1H), 7,94 (d, J=8.4 Hz, 1H), 7,28 (d, J=8,2 Hz, 1H), 2.49 USD (s, 3H), 1,89 (s, 6H).
92452 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.40 (s, 1H), 9,12 (d, J=2.5 Hz, 1H), 8,81 (s, 1H), at 8.60 (d, J=8,8 Hz, 1H), 8,40-8,35 (m, 2H), 7,97-a 7.92 (m, 2H), 7,80 (d, J=2,0 Hz, 1H), of 3.91 (s, 3H), a 3.87 (s, 3H), 1,90 (s, 6H).

93442 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.45 (s, 1H), 9,16 (s, 1H), 9,10 (s, 1H), 8,96 (s, 1H), 8,86 (s, 1H), 8,69 (d, J=8.8 G�, 1H), 8,55 (d, J=8,8 Hz, 1H), 8.48 to (d, J=8,3 Hz, 1H), 8,08-7,98 (m, 3H), of 7.82 (t, J=7.5 Hz, 1H), 7,66 (t, J=7,4 Hz, 1H), 1.93 and (s, 6H).
94408 (M+H)+1H NMR (400 MHz, DMSO) δ 9,36 (s, 1H), 9,10 (s, 1H), 8,80 (s, 1H), 8,64 (s, 2H), 8,52 (d, J=8,8 Hz, 1H), of 8.39 (d, J=8,5 Hz, 1H), of 8.25 (d, J=8,9 Hz, 1H), 7,93 (d, J=8.4 Hz, 1H), 7,07 (s, 2H), 1.91 a (s, 6H).
95437 (M+H)+1H NMR (400 MHz, DMSO) δ 9,34 (s, 1H), 9,13 (d, J=2.4 Hz, 1H), 8,76 (s, 1H), and 8.50 (d, J=8,8 Hz, 1H), 8,44 is 8.38 (m, 1H), of 8.26 (d, J=9,0 Hz, 1H), 8,16 (s, 1H), 8,02 (s, 1H), 7,91 (d, J=8.4 Hz, 1H), 6.18 of (s, 2H), 3,83 (s, 3H), of 1.86 (s, 6H).
96470 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,37 (s, 1H), 9,04 (d, J=1.3 Hz, 1H), 8,61 (d, J=8,8 Hz, 1H), to 8.57(d, J=the 1.7 Hz, 1H), 8,22(s, 1H), 8,06 (d, J=8,8 Hz, 1H), 6,17 is 5.98 (m, 1H), 5,32 (m, 2H), 5,00 (m, 1H), 4,13 (s, 1H), 3,35 (m, 1H), 2,83 (s, 1H), of 2.57 (m, 2H), 2,46 (m, 2H), 2,03 (m, 4H), 1,32-1,31 (m, 3H).

97541 (M+H)+1H NMR (400 MHz, DMSO) δ 9,31 (s, 1H), 9,22 (s, 1H), of 8.85 (s, 1H), 8,72 (S, 1H), 8,59 (d, J=8,9, 1H), 8,44 (d, J=8,9, 1H), 7,11 (s, 2H), 3,69 (m, 4H), 3,63 m, 3H), 3,51 (m, 3H), and 3.31 (m, 2H), 3,16 (m, 2H), 2,39-of 2.25 (m, 5H).
98499 (M+H)+1H NMR (400 MHz, DMSO) δ 9,31 (s, 1H), 9,22 (s, 1H), is 8.84 (s, 1H), 8,72 (s, 1H), at 8.60 (d, J=8,9, 1H), 8,43 (d, J=8,9, 1H), 7,11 (s, 2H), 3,27 (s, 2H), 3,18 (m, 2H), 3,14 (s, 3H), 2,89 (s, 3H), 2,40-to 2.18 (m, 7H).
99476 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,36 (s, 1H), at 8.60 (d, J=8,8 Hz, 1H), and 8.50 (m, 1H), 8,31 (s, 1H), 8,03 (d, J=8,8 Hz, 1H), 7,83 (m, 1H), 6,06 is 5.77 (m, 1H), 4,10 (d, 6H), 3,25 (m, 2H), 3,09 (s, 3H), 2,98 (s, 3H), 2,74-2,60 (m, 2H), of 2.45 (m, 2H), 2,31-of 2.20 (m, 4H).
100430 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,35 (s, 1H), 9,29 (d, J=2,0 Hz, 1H), 8,59 (d, J=8,8 Hz, 1H), of 8.33 (m, 1H), 8,27 (s, 1H), 8,07 (d, J=8,8 Hz, 1H), of 7.36 (d, J=8,1 Hz, 1H), 5,91-5,71 (m, 1H), 3,34 (m, 2H), 3,23 (m, 2H), 3,10 (s, 3H), 2,98 (s, 3H), 2,67 (s, 3H), of 2.54 (m, 2H), of 2.45 (m, 2H), and 2.26 (m, 2H).

101485 (M+H)+1H NMR (400 MHz, DMSO) δ 9,21 (s, 1H), 9.15, with (s, 1H), 8,73 (s, 1H), 8,61 (s, 1H), and 8.50 (d, J=8,8, 1H), of 8.34 (d, J=8,8, 1H), 7,01 (s, 2H), 6,63 (s, 1H), 5,87 (s, 1H), to 4.26 (m, 2H), of 3.07 (m, 2H), 2,84 (m, 2H), And 2.26 (m, 2H), 1,99 (m, 2H),1,02 (m, 3H).
102456 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.25 (s, 1H), 9,17 (s, 1H), 8,73 (s, 1H), 8,64 (s, 1H), 8,54 (d, J=to 8.7, 1H), 8,37 (d, J=8,9, 1H), to 7.04 (s, 2H), 5,98 (s, 1H), 4.72 in (m, 1H), 4,15 (m, 1H), 3,24 (m, 1H), 2,73 (m, 1H), 2,34 (m, 2H), 2,11 (s, 3H), 2,00 (m, 2H).
103492 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 9,14 (d, J=1,9, 1H), 8,79 (s, 1H), 8,63 (d, J=2,1, 1H), 8,55 (d, J=8,9, 1H), 8,37 (d, J=8,9, 1H), to 7.04 (s, 2H), 5,84 (m, 1H), 3,90 (m, 2H), 2,98 (s, 3H), 2,46 (m, 2H), 2,29-2,19 (m, 2H), 2,08-of 1.88 (m, 2H).
104474 (M+H)+1H NMR (400 MHz, DMSO) δ 9,44-9,29 (m, 1H), of 8.71 (dd, J=7,7, 5,4, 2H), 8,59-of 8.50 (m, 1H), 8,32 (d, J=8,9, 1H), 8,18 (s, 1H), 7,90 (d, J=5,9, 2H), 7,84-7,74 (m, 2H), 6,89 (s, 2H), 1,83 (s, 6H).

105498 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.25 (d, J=5,7, 1H), 9,16 (s, 1H), 8,78-8,76 (m, 1H), 8,70-8,67 (m, 1H), 8,53 (d, J=8,8, 1H), 8,37 (d, J=8,9, 1H), 7,06 (s, 2H), 5,77-5,73 (m, 1H), 4,40 (d, J=5,4, 2H), 4,24 (d, J=5,6, 2H), 2,86-2,83 (m, 2H), 2,61 (s, 2H), 2,29-to 2.13 (m, 6H), of 1.37 (s, 3H).
106 415 (M+H)+1H NMR (400 MHz, DMSO) δ to 9.27 (d, J=12,4, 1H), 9,20 (d, J=10,7, 1H), 8,79 (d, J=12,4, 1H), 8.66 roubles (d, J=10,7, 1H), 8,60-of 8.50 (m, 1H), of 8.39 (t, J=10,6, 1H), 7,06 (d, J=11,0, 2H), 5,97-5,93 (m, 1H), 4,17-4,12 (m, 2H), 3,61-3,55 (m, 2H), 2,31-of 2.23 (m, 4H).
107486 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.25 (d, J=4,2, 1H),9,18 (s, 1H), is 8.74 (s, 1H), 8,64 (s, 1H), 8,54 (dd, J=8,5, 3,5, 1H), to 8.42-of 8.34 (m, 1H), 7,05 (s, 2H), 6,00-5,95 (m, 1H), 4,74-4,71 (m, 1H), 4,56-of 4.54 (m, 1H), 4,39-is 4.36 (m, 1H), 3,22-3,18 (m, 1H), 2,82-to 2.79 (m, 1H), 2,41-of 2.38 (m, 2H), 2,17-of 1.98 (m, 2H), 1,27-1,25 (m, 3H).
108451 (M+H)+1H NMR (400 MHz, dmsr) δ 9,30 (d, J=1.4 Hz, 1H), remaining 9.08 (d, J=2.5 Hz, 1H), 8,73 (d, J=1.3 Hz, 1H), is 8.46 (d, J=8,9 Hz, 1H), to 8.36 (dd, J=8,4, 2,6 Hz, 1H), 8,20 (d, J=9,0 Hz, 1H), 7,94 (d, J=1,8 Hz

1H), 7,86 (d, J=8.4 Hz, 1H), of 7.42 (S, 1H), 6,07 (s, 2H), of 4.05 (q, J=6,9 Hz, 2H), is 1.81 (s, 6H), of 1.35 (t, J=6,9 Hz, 3H).
109444 (M+H)+1H NMR (400 MHz, DMSO) δ 9,19 (s, 1H), 9,14 (s, 1H), ,57 (s, 1H), 8,49 (d, J=7,7, 3H), 8,31 (d, J=7,7, 1H), 6,95 (s, 2H), 5,01 (d, J=6,2, 2H), 3,41 (t, J=7,0, 4H), 2,88 (t, J=7,0, 2H), 2,39 (m, 4H).
110486 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 9,18 (s, 1H), is 8.74 (s, 1H), 8,64 (s, 1H), 8,55 (d, J=8,9, 1H), to 8.38 (d, J=8,9, 1H), to 7.04 (s, 2H), 6,05-of 5.92 (m, 1H), 4,73-4,70 (m, 1H), 4,55-4,52 (m, 1H), 4.38 gigabytes is 4.35 (m, 1H), 3,24-3,21 (m, 1H), 2,83-2,77 (m, 1H), 2,40-is 2.37 (m, 2H), 2,15-of 1.97 (m, 2H), 1,28-1,22 (m, 3H).
111428 (M+H)+1H NMR (400 MHz, DMSO) δ 9,24 (s, 1H), 9,18 (d, J=2,0, 1H), 8,64 (d, J=2,1, 1H), of 8.56-8,51 (m, 2H), 8,37 (d, J=8,9, 1H), 7,01 (s, 2H), 5,04 (t, J=6,3, 2H), of 3.07 (t, J=6,3, 3H), 2,51 (d, J=1,7, 4H), Of 1.65 (s, 4H).
112438 (M+H)+1H NMR (400 MHz, DMSO) δ 9,32 (s, 1H), 8,77 (s, 1H), to 8.57 (d, J=to 8.7 Hz, 1H), 8,16 (d, J=to 8.7 Hz, 1H), 8,07 (dd, J=4,9, and 1.9 Hz, 1H), 7,78 (dd, J=7,5, and 1.9 Hz, 1H), only 6.64 (dd, J=7,5, and 4.9 Hz, 1H), to 6.57 (s, 2H),

5,85 is 5.77 (m, 1H), 4.75 in-the 4.67 (m, 1H), 4,62-of 4.54 (m, 1H), 2,93-to 2.76 (m, 1H), 2,42-of 2.28 (m, 2H), 2,18-of 1.96 (m, 4H), 0,81-0,72 (m, 4H).
113 417 (M+H)+1H NMR (400 MHz, DMSO) δ at 9.38 (d, J=1,9, 1H), 9,32 (s, 1H), 8,75 (s, 1H), 8,64 (d, J=8,8, 1H), 8,54 (dd, J=8,1, 2,3, 1H), to 8.42 (d, J=8,8, 1H), 7,52 (d, J=7,9, 1H), of 5.89-5,84 (m, 1H), 4,78-a 4.64 (m, 1H), 4,61-4,47 (m, 1H), 4,42-to 4.26 (m, 1H), 3,31-3,27 (m, 1H), 2,94-2,82 (m, 1H), 2,58 (s, 3H), 2,45-2,34 (m, 2H), 2,22-2,03 (m, 2H), 1,28-1,24 (m, 3H).
114458 (M+H)+1H NMR (400 MHz, DMSO) δ 9,18 (s, 1H), 9,11 (s, 1H), 8,58 (s, 1H), 8,51-of 8.39 (m, 2H), 8,29 (d, J=8,9 Hz, 1H), 6,97 (s, 2H), of 4.88 (t, J=6,7 Hz, 2H), 3,39 (d, J=4,2 Hz, 4H), 2,20 (tt, J=13,7, 6,9 Hz, 8H).
115472 (M+H)+1H NMR (400 MHz, DMSO) δ 9,22 (s, 1H), 9,13 (s, 1H), is 8.74 (s, 1H), 8,63 (s, 1H), 8,51 (d, J=8,9 Hz, 1H), of 8.34 (d, J=8,9 Hz, 1H), 7,00 (s, 2H), 5,71 (m, 1H), 3,47 (m, 3H), 3,10(m, 2H), 2,41 (m, 2H), 2,24(m, 2H), 2,13 (m, 5H), 1,67-of 1.57 (m, 2H).

116458 (M+H)+1H NMR (400 MHz, DMSO) δ 9,22 (s, 1H), 9.15, with (d, J=2,0 Hz, 1H), 8,73 (s, 1H), 8,64 (d, J=2,0 Hz, 1H), 8,51 (d, J=8,9 Hz, 1H), 8,35 (d, J=8,9 Hz, 1H), 7,00 (s, 2H), 5,69 (s, 1H), 4,61-4,34 (m, 1H), 3,54 (s, 2H), 3,12 (d, J=14,3 Hz, 4H), 2,20 (d, J=7.9 Hz, 6H).
117 468 (M+H)+1H NMR (400 MHz, DMSO) δ 9,30-9,09 (m, 2H), is 8.84-8,44 (m, 4H), 8,37 (s, 1H), 7,01 (s, 2H), 6,93-about 6,82 (m, 1H), 6,27-6,09 (m, 1H), 6,07-5,90 (m, 1H), of 5.81-to 5.62 (m, 1H), 4,81-the 4.67 (m, 1H), 4,49-4,32 (m, 1H), 2,86-of 2.75 (m, 1H), 2,42-of 2.24 (m, 3H), 2,15-of 1.97 (m, 2H).
118480 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (d, J=2,7, 1H), 9,18 (d, J=2,1, 1H), is 8.74 (d, J=5,9, 1H), 8,64 (d, J=2,1, 1H), 8,55 (d, J=8,9, 1H), to 8.38 (d, J=8,9, 1H), to 7.04 (s, 2H), 6,08-5,96 (m, 1H), 4,67-4,58 (m, 2H), 2,92-2,83 (m, 1H), 2,47-2,34 (m, 3H), of 2.21-2,11 (m, 1H), of 2.06 (s, 3H), 2,03-of 1.97 (m, 1H).

Example 9: Synthesis of Compounds 119-146

The connection 119

(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-methyl-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanon

[0137] a Mixture of tert-butyl 4-(3-amino-6-chloro-1,5-naphthiridine-4-ylamino)piperidine-1-carboxylate (200 mg, 0.53 mmol) in acetic acid (3 ml) was stirred at 100°With during the night. The solvent was removed under vacuum, and the residue was added to a solution of HCl in MeOH (6N, 3 ml). The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (20 ml). The resulting solution was washed with saturated NaHCO3(10 ml) and brine (10 ml), dried over anhydrous Na2SO4, filtered and �have koncentrirebuli with obtaining the crude 8-chloro-2-methyl-1-(piperidine-4-yl)-1H-imidazo[4,5-C][1,5]naphthiridine in the form of a solid yellow substance (110 mg, yield 68%) which was used for next step without further purification.

[0138] To a solution of 8-chloro-2-methyl-1-(piperidine-4-yl)-1H-imidazo[4,5-C][1,5]naphthiridine (110 mg, 0,364 mmol) and Et3N (101 μl, 0,728 mmol) in THF (15 ml) was added cyclopropanecarbonyl (36 µl, 0,401 mmol) while cooling in a water bath with ice. The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum. The precipitate was dissolved in a mixture of CH2Cl (10 ml) and H2O (10 ml). The resulting solution then was extracted with EA (2×10 ml). The combined organic layers were concentrated to give crude (4-(8-chloro-2-methyl-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanone in the form of a solid yellow substance (105 mg, yield 80%) which was used for next step without further purification. MS (m/z): 370 (M+H)+.

[0139] a Mixture of crude (4-(8-chloro-2-methyl-1H-imidazo[4,5-C][1,5]naphthiridine-1-yl)piperidine-1-yl)(cyclopropyl)methanone (105 mg, 0,284 mmol), PdCl2(dppf)2(12 mg, of 0.014 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (98 mg, 0,340 mmol) and 2N solution of K2CO3(1 ml) in dioxane (4 ml) was subjected to microwave irradiation at 150°C for 30 min. the Solvent was removed and the residue was purified using flash chromatography (MeOH/H2O 0% ~100%) %) to give compound 19 as yellowish solid compound (57 mg). 1H NMR (400 MHz, DMSO) δ of 9.11 (d, J=6,8, 2H), 8,58 (s, 1H), 8.48 to (d, J=8,8, 1H), 8,29 (d, J=8,3, 1H), 6,97 (s, 2H), 4,67-4,58 (m, 2H), 4,06 (s, 1H), 2,75 (m, 5H), 2,11-2,04 (m, 4H), 0,81 (s, 1H), of 0.71 (m, 4H). MS (m/z): 496 (M+H)+

[0140] the Following compounds 120-146 were obtained according to the procedures Described for Compound 119, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
120484 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,24 (s, 1H), 9,03 (s, 1H), to 8.57 (d, J=to 8.7 Hz, 1H), 8,51 (d, J=8,7 H4, 1H), 7,98 (s, 1H), 5.25 in (s, 3H), 5,11-to 4.92 (m, 1H), 4,16 (m, 1H), or 3.28 (m, 2H), 2,78 (m, 5H), of 2.45 (m, 3H), 2,20 (m, 3H), 1,24 (m, 4H).
121512 (M+H)+1H NMR (400 MHz, DMSO) δ 9,39-9,11 (m, 2H), 8,62 (s, 1H), 8,51 (t, J=8,5, 1H), 8,31 (d, J=8,3, 1H), 7,02 (s, 2H), about 6,82-6,36 (m, 1H), 4,39-4,37 (m, 2H), 4,26-to 4.23 (m, 2H), 2,84-2,79 (m, 5H), 2,64-2,61 (m, 2H), 2,27-2,19 (m, 3H), 2,09-of 1.98 (m, 3H), of 1.35 (s, 3H).
122 500 (M+H)+1H NMR (400 MHz, DMSO) δ 9,14 (d, J=3,9, 1H), 8.66 roubles is 8.62 (m, 1H),8,52 (dd, J=8,8, 3,3, 1H), 8,37-of 8.33 (m, 1H), 8,21-8,18 (m, 1H), 7,01 (s, 2H), and 5.36-is 4.93 (m, 1H), 4.75 in-4.72 in (m, 1H), 4,58-4,55 (m, 1H), 4,47-4,32 (m, 1H), 3,19-3,16 (m, 2H), 2,79 (s, 3H), of 2.21-1,91 (m, 4H), 1,28-1,24 (m, 3H).
123513 (M+H)+1H NMR (400 MHz, DMSO) δ 9,19 (s, 1H), 9,13 (s, 1H), 8,62 (s, 1H), 8,51 (d, J=8,9, 1H), 8,32 (d, J=8,8, 1H), 7,01 (s, 2H), 3,24 (s, 2H), 3,12 (m, 3H), 2,83 (m, 6H), 2,32 (m, 2H), 2,01 (s,

3H), 1,23 (s, 3H).
124555 (M+H)+1H NMR (400 MHz, DMSO) δ 9.15, with (d, J=22,8, 2H), 8,61 (s, 1H), 8,49 (d, J=8,0, 1H), 8,31 (d, J=8,3, 1H), to 7.04 (s, 2H), 4,12 (s, 1H), 3,65-3,44 (m, 8H), 3,26-3,03 (m, 7H), of 2.81 (s, 3H), 2,30 (m, 2H), 2,02 (m, 2H).
125539 (M+H)+1H NMR (400 MHz, DMSO) δ 9,19 (s, 1H), 9,13 (s, 1H), 8,63 (s, 1H), 8,51 (d, J=8,9, 1H), 8,32 (d, J=8,9, 1H), 7,01 (s, 2H), 3,51 (m, 2H), 3,23-3,09 (m, 8H), 2,82 (s, 3H), 2,34 (m, 2H), 2,05-1,72 (m, 7H).
126 500 (M+H)+1H NMR (400 MHz, DMSO) δ 9,18-9,14 (m, 1H), 8,64-8,59 (m, 1H), 8,52 (d, J=8,8, 1H), of 8.34 (d, J=7,8, 1H), of 8.26-8,23 (m, 1H), 7,00 (s, 2H), 5,44-with 4.86 (m, 1H), 4,74-4,70 (m, 1H), 4,58-4,55 (m, 1H), 4,50-to 4.28 (m, 1H), 3,21-3,16 (m, 2H), 2,79 (s, 3H), of 2.21-2,06 (m, 3H), 2,04-of 1.92 (m, 1H), 1,28-1,23 (m, 3H).
127431 (M+H)+1H NMR (400 MHz, DMSO) δ 9,32 (s, 1H), 9,21 (s, 1H), at 8.60 (d, J=8,8, 1H), 8,55-8,49 (m, 1H), to 8.38 (d, J=6,9, 1H), 7,52 (d, J=7,7, 1H), 4,73-to 4.68 (m, 2H), 4,52-of 4.33 (m, 2H), 2,96-2,80 (m, 5H), 2,59-2,53

(m, 5H), 2,06-of 1.88 (m, 2H), 1,29-to 1.21 (m, 3H).
128519 (M+H)+1H NMR (400 MHz, DMSO) δ 9,10 (s, 1H), 8,59 (S, 1H), of 8.47 (d, J=8,8 Hz, 2H), 8,27 (d, J=8,8 Hz, 1H), 7,86-7,63 (m, 1H), 7,53 (d, J=7,7 Hz, 1H), 7,25 (s, 1H), 6,99 (m, 2H), 3,69 (m, 2H), 3,12 (m, 4H), 2,80 (s, 3H), 2,13 (m, 5H).
129472 (M+H)+1H NMR (400 MHz, DMSO) δ 9,13 (s, 1H), 8,63 (s, 1H), 8,51 (d, J=8,9 Hz, 1H), to 8.42 (s, 1H), of 8.34 (d, J=8,9 Hz, 1H), 4,33-4,13 (m, 1H), 3,62 (s, 6H), 3,14 (s, 3H), of 2.81 (s, 4H), of 2.27 (s, 3H), 2,00 (m, 3H).
130486 (M+H)+1H NMR (400 MHz, DMSO) δ 9,09 (3, 1H), to 8.57 (s, 1H), 8,45 (d, J=8,8 Hz, 1H), 8,32 (s, 1H), of 8.26 (d, J=8,9 Hz, 1H), 6,97 (s, 2H), of 3.75 (s, 6H), 3,52 (s, 3H), 3,26 (s, 3H), 3,11 (d, J=10.1 Hz, 3H), 2,78 (s, 3H), Of 2.57 (t, J=5,9 Hz, 2H), 2,24 (d, J=10.0 Hz, 3H).
131443 (M+H)+1H NMR (400 MHz, cdcl 3) δ 9,32 (d, J=1,4, 1H), 8,64 8.48 to (m, 2H), 8,01 (dd, J=8,8, 1.5 m, 1H), 7,27 (d, J=0,9, 1H), and 5.7 (s, 2H), 4,31 (d, J=8,3, 2H), 3,71 (t, J=11,6, 2H), 3,17 (d, J=7,3, 2H), 1,65 (m, 4H), To 1.58 (t, J=7,4, 3H).

132533 (M+H)+1H NMR (400 MHz, DMSO) δ 9,11 (m, 2H), 8,59 (m, 2H), 8.48 to (d, J=8,9 Hz, 1H), 8,36-8,22 (m, 1H), 8,01-a 7.87 (m, 1H), 7,72-7,63 (m, 1H), 7,54-7,41 (m, 1H), 7,01 (s, 2H), 4,92-to 4.76 (m, 1H), 4,05-3,92 (m, 1H), 3,26-3,19 (m, 1H), 3,11-is 2.88 (m, 2H), 2,78 (S, 3H), 2,43-1.83 (m, 4H).
133429 (M+H)+1H NMR (400 MHz, cd 3 od) δ 9,24 (s, 1H) 9,09 (s, 1H), 8,67 (s, 1H), 8,53 (d, J=9,2 Hz, 1H), 8,22 (d, J=9,2 Hz, 1H), 4,26-4,17 (m, 2H), of 3.77-3,70 (m, 2H), 2,87 (s, 3H), 2,17-of 1.73 (m, 4H)
134 386 (M+H)+1H NMR (400 MHz, DMSO-d6) δ a 9.64 (s, 1H), of 9.42 (s, 1H), 8,21 (s, 1H), 8,63 (d, J=8,8 Hz, 1H), 8,51 (d, J=8,8 Hz, 1H), of 8.26 (s, 1H), 4,25-to 4.14 (m, 2H), 3,78-to 3.67 (m, 2H), 2,85 (s, 3H), 2,02-of 1.76 (m, 4H)
135585 (M+H)+1H NMR (400 MHz, DMSO-d6) δ 11,81 (s, 1H), 9,27 (s, 1H), 9,13 (s, 1H), 8,53 (d, J=8,8 Hz, 1H), to 8.42 (d, J=8,8 Hz, 1H), 7,53 (d, J=3.2 Hz, 1H), a 6.53 (d, J=3.2 Hz, 1H), 4,18-4,10 (m, 2H), 3,70-3,62 (m, 2H), To 2.79 (s, 3H), a 2.01-1,70 (m, 4H)

136458 (M+H)+1H NMR (400 MHz, cdcl 3) δ 9,20 (s, 1H), 8,81 (d, J=2,1, 1H), and 8.50 (d, J=8,8, 1H), 8,15 (S, 1H), 7,98 (d, J=8,8, 1H), 7,10-of 6.96 (m, 1H), 4,71 (s, 2H), 3,81 (m, 4H), 2,95 (s, 3H), 2,52 (m, 6H), is 2.40 (s, 1H), 2,30 (m, 2H), 2,28 (s, 3H), of 1.92 (m, 2H), 1,70 (m, 2H)
137512 (M+H)+1H NMR (400 MHz, cdcl 3) δ of 9.23 (s, 1H), 9,02 (d, J=1,7, 1H), 8.66 roubles (d, J=1,9, 1H), of 8.56 (d, J=8,8, 1H), 8,01 (d, J=8,8, 1H), 7,00-6,86 (m, 1H), 5.25 in (s, 2H), 3,80 (m, 4H), 3,49 (m, 1H), 2,97 (s, 3H), 2,56 (m, 3H), 2,48 (m, 2H), is 2.40 (s, 1H), 2,28 (m, 2H), 1,90 (m, 2H), 1,68 (m, 2H).
138 506 (M+H)+1H NMR (400 MHz, DMSO) δ 9,19 (s, 1H), 9.15, with (s, 1H), 8,65 8.48 to (m, 2H), 8,32 (d, J=8,8, 1H), 7,00 (s, 2H), 3,92-3,89 (m, 2H), 3,06 (s, 3H), 2,94 (d, J=11,2, 2H), 2,82 (s, 3H), of 2.50 (s, 3H), 2,18 (s, 2H).
139454 (M+H)+1H NMR (400 MHz, DMSO) δ 9,54 (s, 2H), 9,21 (s, 1H), 8,62 (d, J=8,8, 1H), to 8.38 (d, J=8,8, 1H), 4,92-4,56 (m, 1H), was 4.02 (s, 3H), 3,85 (d, J=11,5, 2H), 3,17 (s, 3H), 3,03 (d, J=11,6, 2H), 2,82 (s, 3H), 2,53-2,51 (m, 2H), 2,29-of 1.81 (m, 2H).

140482 (M+H)+1H NMR (400 MHz, DMSO) δ 9,23 remaining 9.08 (m, 2H), 8,52 (d, J=8,8, 1H), of 8.33 (d, J=to 8.7, 1H), 7,03-6,86 (m, 3H), 6,16 (d, J=16,7, 1H), 5.78% was established-of 5.68 (m, 1H), 4,78-of 4.75 (m, 1H), 4,42-is 4.36 (m, 1H), 3,32-3,19 (m, 4H), 2,86-2,79 (m, 1H), 2,78 (S, 3H), 2,22-of 2.06 (m, 3H).
141428 (M+H)+1H NMR (400 MHz, DMSO) δ 9,06 (s, 1H), 8,73 (s, 1H), to 8.41 (d, J=8,9, 1H), 8,28-of 8.25 (m, 2H), 8.17-a 7,97 (m, 2H), 6,95-6,80 (m, 1H), 6,25-of 6.06 (m, 2H), 5,73-for 5.66 (m, 1H),4,83-4,68 (m, 1H), 4,61-4,45 (m, 1H), 4,42-to 4.28 (m, 1H), 3,53 (s, 3H), or 3.28-3,19 (m, 2H), 2,95-2,86 (m, 1H), 2,74 (s, 3H), 2,13-2,07 (m, 3H).
142472 (M+H)+ 1H NMR (400 MHz, DMSO) δ 9,18 (s, 1H), 9,11 (s, 1H), 8,58 (s, 1H), 8,51-of 8.39 (m, 2H), 8,29 (d, J=8,9 Hz, 1H), 6,97 (s, 2H), of 4.88 (t, J=6,7 Hz, 2H), 3,39 (d, J=4,2 Hz, 4H), 2,20 (m, 8H).
143511 (M+H)+1H NMR (400 MHz, DMSO) δ of 9.25 (s, 1H), 9.15, with (s, 1H), of 8.82 (s, 1H), of 8.56 (d, J=8,8, 1H), to 8.38 (s, 1H), 4,57 (d, J=39,0, 2H), 4,06 (s, 4H), to 2.76 (s, 5H), a 2.01 (s, 4H), 0.79 in (d, J=6,9, 1H), of 0.68 (s, 4H).

144494 (M+H)+1H NMR (400 MHz, DMSO) δ 9,14 (s, 2H), 8,61 (s, 1H), 8,52 (d, J=8,8, 1H), of 8.33 (d, J=8,8, 1H), 7,01 (s, 2H), 4,69-4,56 (m, 2H), 3,35-3,26 (m, 3H), 2,88-2,83 (m, 1H), 2,79 (s, 3H), 2,28-to 2.13 (m, 3H), of 2.06 (s, 3H).
145496 (M+H)+1H NMR (400 MHz, DMSO) δ 9,13 (s, 2H), at 8.60 (s, 1H), 8,51 (d, J=8,8, 1H), 8,32 (d, J=to 8.7, 1H), 7,00 (s, 2H), 6.75 in (td, J=13,4, 6,6, 1H), 6,61 (d, J=15,2, 1H), 4,81-to 4.68 (m, 1H), 4,46-4,22 (m, 1H), 3,81-and 3.72 (m, 1H), or 3.28-3,18 (m, 2H), 2,80-2,78 (m, 1H), 2,77 (s, 3H), 2,22-2,02 (m, 3H), of 1.87 (d, J=6,7, 3H).
146498 (M+H)+1H NMR (400 MHz, cdcl3) δ 9,48 (s, 1H), 9,30 (s, 1H), 8,67-8,44 (m, 2H), 8,01 (s, 1H), 5,64 (s, 2H), 4,30-be 4.29 (d, 2H), ,11 (s, 2H), 3,71-3,65 (m, 3H), 2,63 (m, 4H), of 1.81 (m, 4H), 1,68 (m, 4H).

Example 10: Synthesis of Compounds 147-178

Compound 147

2,4-debtor-N-(2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-yl)pyridin-3-yl)benzolsulfonat

[0141] a Mixture of 7-bromo-2-hydrazinecarboxamide (200 mg, 0,84 mmol) and Acoh (5 ml) was heated to reflux over night. After cooling to room temperature the mixture was treated with water (10 ml); the solid substance was collected using a filter, and dried under vacuum to give 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a solid gray matter (200 mg, yield: 91,0%).

[0142] a Mixture of 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (60 mg, 0,23 mmol), 2,4-debtor-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzolsulfonat (107 mg, 0.25 mmol), K2CO3(95 mg, 0.69 mmol) and Pd(dppf)Cl2(6 mg) in dioxane/H2O (3: 1,4 ml) was subjected to microwave irradiation at 160°C for 0.5 h. Then the solvent was removed, and the residue was purified using flash chromatography (MeOH/N2About=20% -80%) to give compound 147 in the form of a white solid substance (60 mg).1H NMR (400 MHz, DMSO) δ 10,44 (s, 1H), 9,26 (s, 1H), of 8.47 (d, J=the 1.7 Hz, 1H), of 8.34 (d, J=1.5 Hz, 1H), 8,13 (t, J=10.3 Hz, 1H), 8,02 (d, J=2.1 Hz, 1H), 7,92 (dd, J=8,4, 1.5 Hz, 1H), 7,76 (dd, J=14,9, 8,5 Hz, 1H), 7,51 (dd, J=14,2, 5.4 Hz, 1H), 7,18 (t, J=7.5 Hz, 1H), 3,68 (s, 3H), 3,17 (s, 3H). MC (m/z): 483 (M+H)+.

[0143] with the Following�connection 148-178 were obtained according to the procedures described for Compound 147, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
148499 (M+H)+1H NMR (400 MHz, DMSO) δ 10,39 (s, 1H), of 8.82 (s, 2H), 8,30 (s, 1H), 7,92 (d, J=8,4, 1H), 7,86 (d, J=2,2, 1H), 7,82 (d, J=6,4, 1H), 7,78 (dd, J=8,4, and 1.9, 1H), 7,51 (t, J=8,8, 1H), 7,21 (t, J=8,6, 1H), 3,69 (s, 3H), 3,62 (s, 3H).
149513 (M+H)+1H NMR (400 MHz, DMSO) δ to 10.38 (s, 1H), 8,83-8,77 (m, 2H), 8,32 (d, J=2,2, 1H), 7,90 (d, J=8,4, 1H), 7,86 (d, J=2,3, 1H), 7,84-7,79 (m, 1H), 7,78-7,74 (m, 1H), 7,56-7,49 (m, 1H), 7.23 percent-to 7.18 (m, 2.2 m, 1H), 3,99 (q, J=7,2, 2H), 3,69 (s, 3H), of 1.34 (t, J=7,2, 3H).
150385 (M+H)+1H NMR (400 MHz, DMSO) δ 9,30 (s, 1H), 8,52 (d, J=2,3, 1H), 8,43 (d, J=1,7, 1H), to 8.19 (d, J=8,4, 1H), 8,07 (d, J=2,3, 1H), 8,00 (dd, J=8,4, 1,8, 1H), 4,00 (s, 3H), up 3.22 (s, 3H), 3,10 (s, 3H).
151 497 (M+H)+1H NMR (400 MHz, DMSO) δ 9.15, with (s, 1H), of 8.82 (s, 1H), 8,54 (d, J=3,5, 1H), 8,52 (s, 1H), 8,28 (d, J=8,9, 1H), 8,14 (s, 1H), 7,84-7,76 (m, 1H), 7,53 (t, J=to 8.7, 1H), 7,20 (td, J=8,6,

2,2, 1H), of 4.45 (s, 3H), of 3.78 (s, 3H), 2,69 (s, 3H).
152465 (M+H)+1H (400 MHz, DMSO) δ to 9.45 (s, 1H), 8,21 (d, J=8,4, 1H), 8,03 (d, J=2,3, 1H), 7,99-7,90 (m, 3H), 7,66 (d, J=2,3, 1H), 7.62 mm (d, J=1,9, 1H), members, 7.59-7,53 (m, 2H), 3,96 (s, 3H), 3,02 (s, 3H).
153483 (M+H)+1H NMR (400 MHz, DMSO) δ 10,41 (s, 1H), 9,27 (s, 1H), 8,92 (d, J=2,0, 1H), 8,60-of 8.56 (m, 2H), 8,51 (s, 1H), 8,35 (d, J=8,9, 1H), 7,79 (td, J=8,6, 6,4, 1H), 7,61-7,52 (m, 1H), 7,21 (td, J=8,4, 2,1, 1H), 4,47 (s, 3H), of 3.77 (s, 3H).
154484 (M+H)+1H NMR (400 MHz, DMSO) δ 9,51 (s, 1H), 8,54 (d, J=8,1, 1H), 8,28-8,21 (m, 4H), 7,79 (d, J=7,0, 1H), 7,21,-7,18 (m, 1H), 7,03-of 6.99 (m, 1H), 4,73 (s, 3H), 3,83 (s, 3H).
155 439 (M+H)+1H NMR (400 MHz, DMSO) δ 9,31 (s, 1H), 8,64 (d, J=2,0, 1H), 8,44 (d, J=1,7, 1H), 8,18 (dd, J=11,1, 5,4, 2H), 8,01 (dd, J=8,4, 1,8, 1H), 4,00 (s, 3H), 3,23 (s, 3H).

156467 (M+H)+1H NMR (400 MHz, DMSO) δ 9,31 (s, 1H), 8,62 (s, 1H), 8,35 (d, J=1,6, 1H), to 8.19 (d, J=8,4, 1H), 8,14 (s, 1H), 7,95-7,76 (m, 3H), 7,51-7,47 (m, 1H), 7,22-of 7.19 (m, 1H), 3,16 (s, 3H), a 2.36 (s, 3H).
157499 (M+H)+H1NMR (400 MHz, DMSO) δ 9,12 (s, 1H), 8,45 (d, J=1,9, 1H), of 8.34 (d, J=2,1, 1H), 8,15 (s, 1H), 8,08 (d, J=8,4, 1H), 7,94 (d, J=2,3, 1H), of 7.88 (dd, J=8,4, 2,0, 1H), 7,82-to 7.77 (m, 1H), 7,56-of 7.48 (m, 1H), 7,21 (td, J=8,2, 2,2, 1H), 4,42 (s, 3H), and 3.72 (s, 3H).
158526 (M+H)4H1NMR (400 MHz, DMSO) δ 9,36 (s, 1H), 8,81 (d, J=1,8, 1H), and 8.50 (d, J=2,3, 1H), 8,18 (d, J=8,4, 1H), 8,15 (s, 1H), 8,08 (d, J=2,3, 1H), 8,01-7,97 (m, 1H), to 7.77 (td, J=8,6, 6,4, 1H), 7,58-7,53 (m, 1H), 7,20 (td, J=8,4, and 2.3, 1H), 4,29 (m, 2H), 3,69 (s, 3H), 2,31 (s, 6H).
159439 (M+H)+1H NMR (400 MHz, DMSO) δ 9,3 (s, 1H), 8,99 (d, J=2,0, 1H), 8,67-8,55 (m, 3H), to 8.42 (d, J=8,9, 1H), 4,50 (s, 3H), was 4.02 (s, 3H).

160512 (M+H)+1H NMR (400 MHz, DMSO) δ to 10.38-10,29 (m, 1H), 8,87 (s, 1H), 8,51 (d, J=2,1, 1H), to 8.41 (d, J=1,6, 1H), 8,10 (d, J=8,8, 1H), 8,02 (d, J=2,2, 1H), 7,86 (dd, J=8,9, 1,8, 1H), 7,76 (dd, J=14,9, 8,5, 1H), 7,56 (dd, J=14,3, 5,5, 1H), 7,20 (t, J=7,3, 1H), 3,89 (s, 3H), 3,66 (m, 3H), 3,52 (s, 3H).
161469 (M+H)+1H NMR (400 MHz, DMSO) δ 10,46-10,31 (m, 1H), 10,22 (s, 1H), at 9.38 (s, 1H), of 8.82 (d, J=1,9,1 H), 8,59 (d, J=2,3, 1H), 8,16 (dd, J=5,4, 3,1, 2H), 8,00 (dd, J=8,5, and 1.9, 1H), to 7.77-7,69 (m, 1H), members, 7.59-7,51 (m, 1H), 7.23 percent-7,14 (m, 1H), 3,63 (s, 3H).
162509 (M+H)+1H NMR (400 MHz, DMSO) δ 13,11 (s, 1H), 10,60-10,24 (m, 1H), 8,83 (d, J=2,0, 1H), 8,80 (s, 1H), to 8.36 (d, J=2,1, 1H), 7,92 (d, J=8,4, 1H), a 7.87 (d, J=2,3, 1H), 7,82-7,76 (m, 2H), 7,53 (dd, J=14,3, 5,4, 1H), 7,20 (td, J=8,3, 2,0, 1H), 3,68 (s, 3H).

163485 (M+H)+1H NMR (400 MHz, DMSO) δ 10,50-10,35 (m, 1H), 9,26 (d, J=4,8, 1H), 8,87 (d, J=1,8, 1H), 8,51 (d, J=2,3, 1H) 8,16 (d, J=8,4, 1H), 8,07 (d, J=2,4, 1H), 8,01-7,99 (m, 1H), 7,74 (dt, J=4,1, of 1.9, 1H), 7,53 (dd, J=14,4, 5,3, 1H); 7,22-7,17 (m, 1H), 3,68 (s, 3H), of 1.30 (dt, J=8,0, 2,9, 2H), 1,20 (dt, J=11,4, 5,6, 3H).
164399 (M+H)+1H NMR (400 MHz, DMSO) δ in 9.44 (s, 1H), 9,27 (s, 1H), 8,53 (d, J=2,2, 1H), 8,40 (s, 1H), 8,16 (d, J=8,4, 1H), 8,06 (d, J=2,2, 1H), 7,97 (dd, J=8,5, and 1.5, 1H), 4,00 (s, 3H), 3,18-3,13 (m, 2H), 1.27 mm (t, J=7,3, 3H), of 1.20 (s, 3H).
165482 (M+H)+1H NMR (400 MHZ, DMSO) δ 9,39 (s, 1H), 8,21 (d, J=8,5, 3H), 7,95 (d, J=6,7, 3H), 3,89 (s, 3H), 3,17 (s, 2H), 2,50 (s, 6H).
166453 (M+H)+1H NMR (400 MHz, DMSO) δ 9,26 (s, 1H), 8,80 (d, J=2,1, 1H), at 8.60 (d, J=2,2, 1H), of 8.56 (d, J=8,9, 1H),

8,35 (d, J=8,9, 1H), 4,48 (s, 3H), 3,97 (s, 3H), 2,70 (s, 3H).
167494 (M+H)+1H NMR (400 MHz, DMSO) δ 9,49 (d, J=9,7, 1H), to 8.57 (d, J=1,8, 1H), 8,45 (d, J=2,3, 1H), 8,23 (d, J=8,5, 1H), 8,10 (dd, J=8,5, and 1.9, 1H), ,00 (d, J=2,3, 1H), 4,01 (s, 3H), 3,71 (dt, J=18,0, 6,8, 4H), 2,89-2,77 (m, 1H), 2,03-to 1.79 (m, 5H), of 1.03 is 0.92 (m, 4H).
168468 (M+H)+1H NMR (400 MHz, DMSO) δ 9,48 (d, J=2,7, 1H), to 8.42 (d, J=2,3, 1H), 8,27 (d, J=1, 8,1 H), of 8.25 (d, J=8,5, 1H), 8,09 (dd, J=8,5, and 1.9, 1H), 7,98 (d, J=2,3, 1H), 4,01 (s, 3H), 3,26 (s, 3H), 3,13 (s, 3H), 2,80 (s, 1H), was 1.04 with 0.93 (m, 4H).
169(M+H)+1H NMR (400 MHz, DMSO) δ 10,13 (s, 1H), 9,49 (s, 1H), 8,37 (d, J=2,2, 1H), 8,28-8,21 (m, 2H), 8,04 (dd, J=8,5, 1,8, 1H), 7,95 (d, J=2,2, 1H), to 7.89-7,81 (m, 2H), 7,63 (t, J=7,3, 1H), 7,56 (t, J=7,4, 2H), And 3.72 (s, 3H), 3,30 (s, 3H), 3,17 (s,

3H).
170441 (M+H)+1H NMR (400 MHz, DMSO) δ 9,51 (s, 1H), 9,41 (s, 1H), 8,52 (t, J=2,3, 2H), 8,23 (d, J=8,4, 1H), 8,10 (d, J=2,3, 1H), 8,06 (dd, J=8,4, and 1.9, 1H), is 5.33 (s, 2H), was 4.02 (s, 3H), 3.43 points (s, 3H), 2,80 (m, 1H), 1,06-of 0.91 (m, 4H).
171484 (M+H)+1H NMR (400 MHz, DMSO) δ 9,29 (s, 1H) 8,53 (d, J=2,3, 1H), of 8.39 (d, J=1,6, 1H), 8,17 (d, J=8,4, 1H), 8,06 (d, J=2,3, 1H), 8,00 (dd, J=8,4, of 1.7, 1H), 3,98 (s, 3H), 3,79-3,74 (m, 2H), 3,57-of 3.53 (m, 4H), is 3.08 (s, 3H), 2,96-of 2.91 (m, 2H), 2,48 (m, 4H).
172470 (M+H)+1H NMR (400 MHz, DMSO) δ 9,33 (s, 1H), is 8.84 (d, J=1,8, 1H), 8,51 (d, J=2,3, 1H), 8,17 (d, J=8,4, 1H), 8,03 (dd, J=6,9, 2.1 m, 2H), 4,34 (s, 2H), 3,98 (s, 3H), 3,50 (s, 4H), 3,06 (s, 3H), 2,52 (m, 4H).
173468 (M+H)+1H NMR (400 MHz, DMSO) δ 10,44 (s, 1H), 9,18 (s, 1H), 9,06 (s,

1H), 8,81 (s, 1H), 8.66 roubles (s, 1H), 8,32-8,17 (m, 2H), 8,06-7,91 (m, 2H), 7,83 (s, 1H), of 7.64 (s, 1H), 7,27 (s, 1H), and 3.72 (s, 3H).
174454 (M+H)+1H NMR (400 MHz, cd3od) δ of 9.23 (s, 1H), of 9.00 (s, 1H), 8,37 (d, J=2.1 Hz, 1H), 8,23-8,18 (m, 1H), 8,14 (d, J=1.9 Hz, 1H), 7,96 (d, J=8,5 Hz, 1H), 4,46 (s, 2H), 4,11 (s, 3H), 3,05 (s, 3H), 2,74 (m, 4H), of 1.88 (m, 4H).
175516 (M+H)+1H NMR (400 MHz, cd3od) δ 9,20 (s, 1H) 8,88 (s, 1H), 8,15 (d, J=8,5 Hz, 1H), 7,98 (s, 1H), of 7.88 (d, J=6,5 Hz, 3H), 7,78 (d, J=9,3 Hz, 1H), 7,49-7,39 (m, 3H), of 4.45 (m, 2H), 3,88 (s, 3H), 2,70 (m, 4H), 1.83 (m, 4H).
176424 (M+H)+1H NMR (400 MHz, DMSO) δ 9,13 (s, 1H), of 9.00 (s, 1H), 8,75 (d, J=1,8, 1H), 8,61 (s, 1H), 8,17-to 8.14 (m, 2H), 7,97-7,94(m, 1H), 7,92-7,90 (m, 1H), 3,98 (s, 3H).
177484 (M+H)+1H NMR (400 MHz, DMSO) δ 9,22 (s, 1H), 8,89 (d, J=2,2, 1H), 8,54 (dd, J=5,5, 3,3, 2H), and 8.50 (S, 1H), 8,32 (d, J=8,9, 1H), 5,04 (t, J

=5,9, 2H), 4,00 (s, 3H), 3.45 points-of 3.42 (m, 4H), 3,09 (s, 3H), 2,90 (t, J=6,0, 2H), of 2.38 (m, 4H).
178496 (M+H)+1H NMR (400 MHz, DMSO) δ 9,22 (s, 1H), 8,52 (d, J=8,9, 1H), of 8.47 (dd, J=4,8, 1,6, 3H), 8,24 (d, J=8,9, 2H), 5,11-to 5.05 (m, 2H), a 3.87 (s, 3H), 2,94-2,90 (m, 2H), 2,14 (s, 6H).

Example 11: Synthesis of Compounds 179-182

Compound 179

N-(2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-yl)pyridin-3-yl)-4-methylbenzenesulfonamide

[0144] a Mixture of 7-bromo-2-hydrazinolysis�Lina (1 g, 4,18 mmol) in acetic acid (10 ml) was heated to reflux for 18 h. half of the acetic acid was removed under vacuum and the residue was poured into ice water. The precipitate was collected using a filter, washed with water and dried under vacuum to give crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline in the form of a dark red solid (1 g, yield 90%) which was used for next step without further purification. MS (m/z): 263 (M+H)+.

[0145] a Mixture of crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (809 mg, of 3.07 mmol), PdCl2(dppf)2(132,6 mg, 0,153 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (1 g, 4.3 mmol) and K2CO3(1.7 g, to 12.28 mmol) in DMF (40 ml) and water (15 ml) was stirred at 100°With during the night. Half of the solvent was removed. After cooling to room Temperature the mixture was poured into ice water. The precipitate was collected, washed three times with water and dried under vacuum to give 2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-yl)pyridin-3-amine in the form of a solid gray matter (730 mg, yield 77%), which was used for next step without further purification. MS (m/z):307 (M+H)+.

[0146] To a mixture of crude 2-methoxy-5-(1-methyl-[1,2,4]triazo lo[4,3-a]quinoxaline-8-yl)pyridin-3-amine (50 mg, 0,163 mmol) in pyridine (2 ml) was added 4-methylbenzol-1-sulfonyl�orig (31,3 mg, 0,164 mmol). The mixture was stirred at room temperature overnight, and then heated at 50°C for 5 h. the Solvent was removed, and the residue was purified using PTCH to produce a compound 179 in the form of a solid gray matter (22 mg).1H NMR (400 MHz, DMSO) δ 10,00 (s, 1H), 9,27 (s, 1H), 8,44 (d, J=2,3, 1H), 8,32 (d, J=1,8, 1H), 8,15 (d, J=8,4, 1H), 7,98 (d, J=2,3, 1H), to 7.89 (dd, J=8,4, 1,8, 1H), 7,68 (dd, J=,8,4, 1.8 m, 2H), 7,35 (d, J=8,0, 2H), 3,71 (s, 3H), 3,17 (s, 3H), 2,33 (s, 3H). MS (m/z):461 (M+H)+

[0147] the Following compounds 180-182 were obtained according to the procedures described for Compound 179, using appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

ConnectionStructureLC/MSNMR
180465 (M+H)+1H NMR (400 MHz, DMSO) δ 10,31 (s, 1H), 9,28 (s, 1H), 8,51 (d, J=2,0, 1H), to 8.36 (s, 1H), 8,16 (d, J=8,4, 1H), 8,04 (d, J=2,2, 1H), 7,93 (d, J=8,5, 1H), 7,72 (t, J=7,5, 2H), of 7.48-7,39 (m, 1H), 7,31 (t, J=7,6, 1H), 3,66 (s, 3H), 3,18 (s, 3H).
181447 (M+H)+ 1H NMR (400 MHz, DMSO) δ of 10.09 (s, 1H), 9,28 (s, 1H), of 8.47 (d, J=2,3, 1H), of 8.34 (d, J=1,8, 1H), 8,16 (d, J=8,4, 1H), 8,00 (d, J=2,3, 1H), 7,91 (dd, J=8,4, 1,8, 1H), 7,79-to 7.77 (m, 2H), 7,65-7,61 (m, 1H), EUR 7.57-7,54 (m, 2H), 3,68 (s, 3H), 3,18 (s, 3H).
182465 (M+H)+1H NMR (400 MHz, DMSO) δ 10,14 (s, 1H), 9,28 (s, 1H), 8,49 (d, J=2,0, 1H), of 8.34 (s, 1H), 8,16 (d, J=8,4, 1H), 8,02 (d, J=2,0, 1H), 7,92 (d, J=8,5, 1H), 7,83 (dd, J=8,6, 5.1 m, 2H), 7,40 (t, J=8,8, 2H), 3,69 (s, 3H), 3,18 (s, 3H).

Example 12: Synthesis of Compounds 183 and 184

Compound 183

2-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-C]cinnolin-1-yl)phenyl)-2-methylpropionitrile

[0148] To a white suspension of 1-(2-Dapsone base)ethanone (25 g, 185 mmol) and Et3N (33,4 ml, 240 mmol) was held at 0°C was added dropwise AcCl (15,70 ml, 222 mmol) in 25 ml of was held. Then the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction according to LC-MS the reaction mixture was cooled to 0°C and then quenched with H2O (100 ml). Isolated organic phase; the aqueous layer was extracted with was held. The organic phase was combined and washed with H2O and brine. The resulting organic phase was dried over anhydrous MgSO4, was filtered and given concerts to dryness to obtain crude N-(2-acetylphenyl)acetamide, which was used in next stud�and without further purification (30 g, yield 92%). MS (m/z): 136 (M+H)+.

[0149] In the atmosphere of N2a pale yellow suspension of crude N-(2-acetylphenyl)acetamide (28 g, 158 mmol) in Acoh (300 ml) was stirred for 5 min, and after 1 h at room temperature was added Br2(12,95 ml, 253 mmol). Then, the resulting mixture was stirred at room temperature for 75 min. After completion of the reaction according to LC-MS the reaction was quenched with H2O (200 ml). The mixture was filtered through a Buchner funnel and the collected solid substance in the form of N-(2-acetyl-4-bromophenyl)acetamide (35 g, yield 86%). MS (m/z): 216 (M+H)+.

[0150] In the atmosphere of N2a mixture of N-(2-acetyl-4-bromophenyl)acetamide (35 g, 137 mmol) and HCl (100 ml, 600 mmol) in THF (400 ml) was heated to reflux for 1 h. After concentration under vacuum to remove the solvent, the mixture was treated with EtOAc (100 ml). The aqueous layer was concentrated to remove THF, and at room temperature was added 6N HCl (100 ml, 600 mmol). After cooling to 0°C to this mixture was dropwise added NaNO2(9,43 g, 137 mmol) in 20 ml of N2O. the Reaction mixture was then stirred at room temperature for 15 h. then the reaction mixture was heated to reflux for another 6 h. the Mixture was cooled to room temperature. Collected solid, which was dried under vacuum to give the desired n�of keep this product in the form of a solid white substance. The crude product is directly used for next/step without further purification. (Of 19.5 g, yield of 63.4%) MS (m/z): 227 (M+H)+.

[0151] In the atmosphere of N2the orange solution of 6-bracingly-4-ol (18.5 g, 82 mmol) in HNO3(90 ml, 82 mmol) was cooled to 0°C and added H2SO4(30 ml). The resulting mixture was then heated to 60°C for 3 h. After completion of the reaction according to LC-MS the reaction mixture was cooled to 0°C and then quenched with H2O (20 ml). The mixture was diluted with EtOAc (25 ml). According to the General methods of treatment, the crude residue was submitted to silica gel and was suirable PE/EtOAc to obtain 6-bromo-3-nitroindole-4-ol in the form of a pale yellow solid (13 g, yield 58.6 per cent).

[0152] In the atmosphere of N2the brown solution of 6-bromo-3-nitroindole-4-ol (2 g, 7.41 mmol) in DMF (10 ml) was cooled to 0°C and added dropwise POCl3(0,897 ml, 9,63 mmol). The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction according to LC-MS the reaction mixture was cooled to 0°C and then quenched with H2O (50 ml). The mixture was filtered through a Buchner funnel and the precipitate was collected. The crude 6-bromo-4-chloro-3-nitrocinnamic used inherits stage without further purification (1.75 g, yield 82%). MS (m/z): 290 (M+H)+.

[0153] a Yellow suspension of 6-bromo-4-chloro-3-nitroindoline (1,75 g, 6,07 mmol), 2-(4-Dapsone base)-2-methylpropionitrile (1,069 g, to 6.67 mmol) and K 2CO3(1,677 g, 12,13 mmol) in MeCN (2 ml) was heated to reflux for 5 min. Processing was carried out according to standard processing procedures, and the crude substance was purified on silica gel using as eluent PE/EtOAc to obtain 2-(4-(6-bromo-3-nitroindole-4-ylamino) phenyl)-2-methylpropionitrile in the form of a solid yellow substance (2.5 g, yield 100%). MS (m/z): 414 (M+H)+.

[0154] In the atmosphere of N2the orange solution of 2-(4-(6-bromo-3-Nitryl-4-ylamino)phenyl)-2-methylpropionitrile (2.5 g, of 6.06 mmol) and SnCl2.2H2O (5,21 g, 24,26 mmol) in EtOAc (50 ml) was heated at 45°C for 3 h. After cooling to room temperature, the pH value of the mixture was adjusted to 8 using saturated Na2CO3. The mixture was filtered through a Buchner funnel, and the filtrate was collected and concentrated to give 2-(4-(3-amino-6-bracingly-4-ylamino)phenyl)-2-methylpropionitrile (1.6 g, yield 69%). MS (m/z): 384 (M+H)+

[0155] In the atmosphere of N2a brown solution of 2-(4-(3-amino-6-bracingly-4-ylamino)phenyl)-2-methyl-propanenitrile (250 mg, of 0.654 mmol) in HCO2H (3 ml) was heated to reflux for 4 h. the Reaction mixture was quenched with H2O and then concentrated to remove the solvent. The crude product is directly used for next step without further purification (250 mg, yield 97%). MS (m/z): 394 (M+H)+.

[0156] In the atmosphere of N2an orange suspension of 2-(4-(8-bromo-1H-imidazo[4,5-C]cinnolin-1-yl)phenyl)-2-methylpropionitrile (100 mg, 0,255 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (95 mg, 0,331 mmol), Na2CO3(54,0 mg, 0,510 mmol) and PdCl2(dppf).CH2Cl2(10,41 mg, 0,013 mmol) in dioxane (20 ml) and H2O (2 ml) was stirred for 10 minutes at room temperature. The resulting mixture was then heated at 120°C for 2 h. the Mixture was concentrated under vacuum, and the residue was purified using chromatography to produce a compound 183 in the form of a pale yellow powder (50 mg).1H NMR (400 MHz, DMSO) δ 8,87 (s, 1H), 8,63 (d, J=8,9, 1H), 8.48 to (d, J=2,0, 1H), 8,22 (dd, J=9,0, of 1.9, 1H), 7,95 (d, J=8,6, 2H), of 7.88 (d, J=8,6, 2H), 7,76 (d, J=2,1, 1H), 7,52 (d, J=1,8, 1H), at 6.84 (s, 2H), 1,78 (s, 6H). MS (m/z): 474 (M+H)+.

[0157] the Following compound 184 was obtained according to the procedures described for Compound 183, by using the appropriate intermediates and Bronevoy acid or ester in suitable conditions that will be obvious to a person skilled in the art.

1H NMR (400 MHz, DMSO) δ of 8.56 (d, J=8,9, 1H), of 8.33 (d, J=2,1, 1H), 8,13 (dd, J=9,0, 2,0, 1H), of 7.88 (d, J=9,3, 4H), 7,69 (d, J=1,9, 1H), 7,10 (d, J=1,7, 1H), 6,80 (s, 2H), 2,51 (s, 3H), 1,79 (s, 6H).
ConnectionStructureLC/MSNMR
184488 (M+H)+

Example 13

Analysis of ADP PI3Ka using the Transcreener

[0158] In this analysis was performed by fluorescence polarization. The final conditions for the analysis of kinase were as follows: 10 μm ATP, and 0.2 ng/µl PI3Kα kinase, 30 µmol/l of lipid substrate and the buffer for analysis (50 mmol/l HEPES (pH 7.5), 100 mmol/l NaCl, 1 mmol/l EGTA, 3 mmol/l MgCl2, 1 mmol/l RTI and 0.03% CHAPS and 2% DMSO).

[0159] 5 μl of the test compounds in 10% DMSO and 10 ál 0.5 ng/ál kinase 13α-kinase (Invitrogen, PV4788) in buffer for analysis were placed in a 96-well plate (Greiner, Cat. 675076), and then started the reaction by adding 10 ál of 75 µmol/l PIP2 (PS Lipid Substrate Invitorgen, PV5100) and 25 μmol/l of a mixture of ATP. After incubation of the mixture for 60 minutes at room temperature was added 25 μl of the reagent from the kit for the determination of kinase method transcreener - "ADP Detection Mix" - (Bellbrook Labs), after which the reaction was continued for another 1.5 h. At the end of the reaction plates were analyzed using reader Tecan Infinite F500 at excitation and 610 nm and emission at 670 nm.

[0160] the Standard curve for ADP has been parallel by replacing the connection and PI3Kα-kinase DMSO and buffer for analysis, respectively. When this standard curve analysis instead of a fixed concentration of ATP used�Ute various concentrations of ATP, 0-10 μm, and ATP, 10-0 μm (ATP+ADP equal to 10 microns). Other conditions are the same as described above. A standard curve was made using the software Origin 8.0. Inhibition of the tested compounds in the formulation of ADP was calculated based on the concentrations of ATP standard curve. The value S was calculated using the software XLfit 2.0.

[0161] Results

The above connection 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 90, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 142, 143, 144, 145, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 inhibited receptor kinase PI3Kα with a value of IC50<100 nm.

Example 14

Analysis of P-Akt using the platform Acumen

[0162] Compounds were tested using analysis of p-Akt on the basis of the cells on the platform Acumen. Line of prostate cancer cells human RS ATSS) culturebully in the medium F-12 with 10% fetal bovine serum. For analysis of p-Akt on the platform Acumen, cells RS were seeded at a cell density of 5000 cells/90 µl in Poly-D-lysine 96-well plate (BD, 356692). After incubation for 24 hours d�balali different concentrations of the tested compounds (10 µl), and the cells were incubated for another 2 hours. Added 100 ál of 4% pre-warmed paraformaldehyde, and the cells were fixed for 45 minutes at room temperature. After removal of the paraformaldehyde was added 100 μl of 0.1% Triton X-100, and the cells were incubated for another 30 minutes at room temperature. Cells were washed twice with 160 μl of PBS, after which was added 100 μl blocking buffer (1% BSF in PBS), and cells further incubated For another 2-3 hours. Cells were again washed with 160 μl of PBS, and treated with 30 ál of Ser473-p-Akt (Cell signaling, CAT: 4060), diluted in 0.1% % BSA at a concentration of 1:250 and incubated at 4°C over night. Then the cells were washed twice with 160 μl of PBS. Added 35 µl of immunoglobulin goat against rabbit Alexa Fluor 488 (Invitrogen, A11034) in buffer with a dilution of 1:1000 or 0.1% BSA in PBS), and the reaction mixture incubated in the dark for 1.5 hours. The mixture was twice washed with 160 μl of PBS, and then to each well was added 35 μl of 1.5 μm, propidium iodide (Sigma, P4170), and the reaction plate was incubated at 37°C, 5% CO2within 30 minutes. Finally, the tablet was placed in the Acumen platform eh (TTP LabTech) and scanned with the proper settings.

[0163] the Inhibition of the tested compounds was calculated based on the ratio in cells treated and not treated with compound. The value of IC50calculated using the software XLfit 2.0.

Each connection according to the present invention, is illustrated by the following example, inhibited receptor PI3Kα with a value of IC50<1.0 micron.

Example 15

Analysis of mTOR TR-FRET

[0164] Compounds were tested using analysis of LanthaScreen TR-FRET. Kinase reaction was performed in 384-well black tablet (Corning, Cat. 3676). The final conditions for kinase analysis were as follows: 10 mmol/l ATP, and 0.2 ng/ál kinase mTOR, 0.4 µmol/l of the substrate GFP-4EBP1 and buffer for analysis (50 mmol/l HEPES, pH 7.5, and 0.01% Tween 20, 1 mmol/l EGTA, 10 mmol/l MnCl2, 2 mmol/l DTT and 1% DMSO).

[0165] To each well was added to 2.5 μl of the test compounds in 4% DMSO and 2.5 μl of 0.8 ng/ál kinase mTOR (Invitrogen, PV4753), diluted in buffer for analysis. The start of the reaction was initiated by adding 5 μl of a mixture of 0.8 mmol/l substrate GFP-4EBP1 (Invitorgen, PV4759) and 20 µmol/l of mixtures of ATP. The mixture was incubated at room temperature for 60 minutes. Added 10 µl of 20 mmol/l EDTA and 4 nmol/l antibody Tb-anti-p4EBP1 [pThr46] (Invitrogen, PV4755), diluted in the dilution buffer, TR-FRET, and incubated for another 1 hour. Then the tablet was analyzed using reader BioTek, Synergy2 at excitation 340 nm and emission of 490 nm and 528 nm.

[0166] the Inhibition of the tested compounds were calculated on the basis of the ratio of 528 nm/490 nm. The value of IC50test compounds were calculated using the software XLfit 2.0.

[017] the Results: the Above-mentioned compounds 1, 6, 7, 9, 10, 12, 14, 16, 17, 21, 25, 26, 30, 33, 35, 42, 43, 44, 45, 46, 49, 50, 52, 53, 55, 56, 58, 63, 66, 72, 75, 88, 96, 98, 102, 103, 105, 106, 107, 119, 120, 121, 122, 123, 129, 131, 147, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165, 166, 178, 180, 181 inhibited mTOR with a value of IC50<100 nm.

Example 16

Analysis of P-S6 using the platform Acumen

[0168] Compounds were tested using analysis of P-S6 of cell-based platform Acumen. Line of prostate cancer cells human RS ATSS) culturebully in the medium F-12 with 10% fetal bovine serum. For analysis of p-S6 on the platform Acumen, cells RS were seeded at a cell density of 5000 cells/90 µl in Poly-lysine 96-well plate (BD, 356692). After incubation for 24 hours was added 10 μl of various concentrations of test compounds and cells were incubated for 2 hours, after which was added 100 µl of 4% pre-warmed paraformaldehyde. Cells were fixed for 45 minutes at room temperature. After removal of the paraformaldehyde solution was added 100 μl of 0.1% Triton X-100, and the cells were incubated at room temperature for 30 minutes. Then the cells were washed twice with 160 μl of PBS, after which was added 100 μl blocking buffer (1% BSF in PBS), and then cells were incubated for another 2-3 hours. Cells were again washed with 160 μl of PBS, and treated with 30 μl of antibody p-S6 (Cell signaling, CAT: 4858), diluted in 0.1% BSA at a concentration of 1:250 and incubated p�and 4°C over night. Then the cells were washed twice with 160 μl of PBS. Added 35 µl of immunoglobulin goat against rabbit Alexa Fluor 488 (Invitrogen, A) in buffer with a dilution of 1:1000 or 0.1% BSA in PBS), and the reaction mixture incubated in the dark for 1.5 hours. The mixture was twice washed with 160 μl of PBS, and then to each well was added 35 μl of 1.5 μm, propidium iodide (Sigma, P4170), and the reaction plate was incubated at 37°C, 5% CO2within 30 minutes. Finally, the tablet was placed in the Acumen platform eh (TTP LabTech) and bikanervala with appropriate settings.

[0169] Inhibition of the tested compounds was calculated based on the ratio in cells treated and not treated with compound. The value of IC50calculated using the software XLfit 2.0. Each connection according to the present invention, illustrated in the examples, inhibited mTOR with a value of IC50<10,0 µm.

1. The compound of formula 1:

and/or at least one pharmaceutically acceptable salt of the compound, where
And1represents CH;
And4and And5independently represent CR2or N;
And2and And3together with the ring To form a 5-membered heteroaryl or heterocycle, and the specified 5-membered heteroaryl or heterocycle selected from

where
t represents 1 �whether 2; and
R3independently selected from H, C1-C6alkyl, C6-aryl, S3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl that represents a pyridine, and heterocycle, which represents a piperidine and tetrahydropyran;
and each of the above alkyl, aryl, cycloalkyl, heteroaryl and heterocycle may be substituted by one group independently selected from C1-C6of alkyl, possibly substituted by one Deputy, selected from-CONMe2With3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen; substituted by one group-Soma heterocycle, represent a piperidine;
provided that when A4is a CR2And2and And3together with the ring selected from the structure (3), (5) or (6);
represents a single bond or double bond;
R1is heteroaryl, which represents a 6-membered or 9-10-membered aromatic mono or bicyclic ring containing 1-3 heteroatom selected from nitrogen, oxygen and sulphur, possibly substituted with one or two groups independently selected from C1alkyl, C2 alkynyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenoalkane;
R2independently selected from N;
each Ra, Rb, Rc, Rdand Reindependently selected from N;
With1-C4of alkyl, possibly substituted by one Deputy, selected from-OH, -OMe, -CN, -NH2, -NMe2With3-cycloalkyl;
With2-C3alkenyl;
With3alkinyl;
With6aryl, possibly substituted by one or two substituents selected from fluorine or a methyl group;
With3-membered cycloalkyl, possibly substituted by one Deputy, selected from-HE-CN;
halogenoalkane;
heteroaryl representing a pyridine; and
substituted by one methyl group of the heterocycle that constitutes piperidine,
or Rcand Rdtogether with the atom (atoms) to which they are attached, form a 5-6-membered heterocyclic ring representing pyrrolidine or morpholine; and
in each case, n is independently equal to 2.

2. The compound according to claim 1, characterized in that the specified R3independently selected from H, C1-C6alkyl, C6-aryl, S3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl that represents a pyridine, and heterocycle, which represents a piperidine and tetrahydropyran;
and each of hig�the above alkyl, aryl, cycloalkyl, heteroaryl and heterocycle may be substituted by one group independently selected from C1-C6of alkyl, possibly substituted by one Deputy, selected from-CONMe2With3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen; substituted by one group-Soma of a heterocycle, which represents a piperidine.

3. The compound according to any one of claims.1-2, characterized in that A5represents N or CH.

4. The compound according to any one of claims.1-2, characterized in that A5represents CH.

5. The compound according to any one of claims.1-2, characterized in that A4represents CH.

6. The compound according to any one of claims.1-2, characterized in that A2and And3together with the ring To represent

7. The compound according to any one of claims.1-2, characterized in that A2and And3together with the ring selected from

8. The compound according to any one of claims.1-2, characterized in that A4represents N.

9. The compound according to claim 8, characterized in that A2and And3together with the ring To represent.

10. The compound according to claim 8, differs�seese, that And2and And3together with the ring selected from

11. The compound according to any one of claims.1-2, 9-10, characterized in that R1is heteroaryl, which represents a 6-membered or 9-10-membered aromatic mono or bicyclic ring containing 1-3 heteroatom selected from nitrogen, oxygen and sulphur, possibly substituted with one or two groups independently selected from C1alkyl, C2alkynyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenoalkane.

12. Compound selected from the group comprising





























13. Pharmaceutical composition for inhibiting the activity of PI3K and/or mTOR containing at least one compound according to any one of claims.1-12 and/or at least one pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable carrier.

14. Method for inhibiting the activity of PI3K and/or mTOR, comprising bringing the enzyme into contact with an effective amount of at least one compound according to any one of claims.1-12 and/or at least one pharmaceutically acceptable salt of the compound.

15. The use of at least one compound according to any one of claims.1-12 and/or at least one pharmaceutically acceptable salt of the compound to obtain a medicine for inhibiting the activity of PI3K and/or mTOR.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .

EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.

13 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chemical compounds of general formula I wherein LA, LB, LC, cycle A, cycle B, RA, RB, RC, RD, RE and RF have the values specified in the patent claim. The compounds of formula (I) are protein kinase inhibitors.

EFFECT: invention refers to pharmaceutical compositions containing the above compounds, as well as to using the above compounds for treating and/or preventing the diseases related to aberrant protein kinase activity, particularly oncological diseases.

10 cl, 14 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formulas R1 represents substituted phenyl, substituted or unsubstituted heterocyclyl, which represents an aromatic cycloalkyl containing 6 to 10 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N, wherein the above substitutes are specified in C1-8alkyl, triazolyl, halogen, aminocarbonyl, cyano or hydroxyalkyl; R2 represents H, substituted or unsubstituted C1-8alkyl, substituted C3-6cycloalkyl, unsubstituted heterocyclyl, which represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N or O; unsubstituted heteroyclylalkyl, wherein heterocyclyl represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N and O; substituted or unsubstituted phenylalkyl or substituted or unsubstituted C3-6cycloalkylalkyl, wherein the above substitutes are specified in C1-4alkyl, CF3, OR and NR2, wherein R represents H or C1-4alkyl; each R3 and R4 independently represents H, unsubstituted C1-8 alkyl, or R3 and R4 together with the atom to which they are attached form C3-6cycloalkyl; or R2 and one of R3 and R4 together with the atom to which they are attached form substituted or unsubstituted heterocyclyl containing 5 to 6 atoms in the cycle and which can contain additional heteroatom specified in O; wherein the substitutes are specified in -C(O)CH2OCH3, -CH2CH2OCH3, OCH3 or CH3.

EFFECT: invention refers to compounds of formula

and ,

a based pharmaceutical composition and to a method of treating or preventing cancer, immunological conditions, diabetes, obesity, neurological disturbances and age-related diseases, a method for mTOR kinase inhibition in a cell, a method of treating or preventing the condition, which can be treated or prevented by mTOR kinase metabolic path inhibition.

53 cl, 1 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein A and V independently represents H or a halogen; Q is absent; R4 independently represents H, a C1-C6 alkyl or C3-C6 cycloalkyl; R7 represents H; and R8 represents a C1-C10 alkyl substituted by OH or C1-C6 alkoxy; or C1-4 alkyl substituted by a 5-6-merous aromatic heterocyclic ring containing 1-2 heteroatoms specified in N and S, wherein the above aromatic heterocyclic ring is optionally substituted by a C1-C10 alkyl; or in -NR7R8, R7 and R8 together with N can form an optionally substituted azacyclic ring containing where applicable an additional heteroatom specified in H, O and S, as a cycle member, optionally substituted by a C1-C10 alkyl, which is substituted by a C1-C6 alkoxy; m is equal to 0; n is equal to 0. The invention also refers to a compound of formula (wherein the substitutes are those as specified in the patient claim), to a pharmaceutical composition containing a therapeutically effective amount of the compounds of formula (VIII), and to a method of treating or relieving a cell-proliferative disorder.

EFFECT: compound of formula (VIII) inhibiting cell proliferation or cell apoptosis.

12 cl, 1 dwg, 14 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula and to its pharmaceutically acceptable salts, stereoisomers and isomers, wherein T: N, U: N, X: CR3 and Y: N; or T: CR6, U: CR4, X: CR3 and Y: N; or T: CR6, U: N, X: NR3 and Y: C; or T: O, U: N, X: CR3 and Y: C; or T: NR6, U: N, X: CR3 and Y: C; and R1, R2 and R5: H, heteroaryl substituted by 1-2 substitutes; or T: CR6, U: N, X: CR3 and Y: N; or T: N, U: CR4, X: CR3 and Y: N; and R1 and R2: H, heteroaryl substituted by 1-2 substitutes; R5: heteroaryl substituted by 1-2 substitutes; R3: H, bridging (C7-C10)cycloalkyl; (C1-C8)alkyl optionally substituted by 1 substitute; (C3-C10)cycloalkyl optionally substituted by 1 substitute; (C6-C8)cycloalkenyl substituted by two (C1-C6)alkyl; (C6)aryl optionally substituted by 1-2 substitutes; heteroaryl optionally substituted by (C1-C6)alkyl; heterocyclyl optionally substituted by (C1-C6)alkyl or heteroaryl; or R3: -A-D-E-G, wherein: A: a bond or (C1-C6)alkylene; D : (C1-C2)alkylene optionally substituted by (C1-C6)alkyl, bridging (C6-C10)cycloalkylene optionally substituted by (C1-C6)alkyl, (C3-C10)cycloalkylene optionally substituted by 1-2 substitutes, (C4-C6)cycloalkenylene optionally substituted by (C1-C6)alkyl, (C6)arylene, heteroarylene or heterocyclylene optionally substituted by one (C1-C6)alkyl; E: a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)O-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)C(O)ORe- or -Re-N(Ra)S(O)2-Re-; wherein in each case, E is bound to either a carbon atom, or a nitrogen atom in D; G: H, -N(Ra)(Rb), halogen, -ORa, S(O)2Ra, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -C(O)Ra, -CF3, N(Ra)S(O)2Rb, -(C1-C6)alkyl optionally substituted by 1-3 substitutes; -(C3-C6)cycloalkyl optionally substituted by CN; -heteroaryl optionally substituted by 1-2 halogens, CN, -C(O)NH2 or -CF3; -heterocyclyl optionally substituted by 1-5 substitutes, -(C6-C10)aryl optionally substituted by 1-3 substitutes; wherein in a fragment containing -N(Ra)(Rb), nitrogen, Ra and Rb can form a ring so that -N(Ra)(Rb) represents (C3-C6)heterocyclyl optionally substituted by 1 substitute, wherein said (C3-C6)heterocyclyl is bound through nitrogen; R4 and R6: H, (C1-C4)alkyl optionally substituted by -OH, -COOH; (C3-C8)cycloalkyl, phenyl, optionally substituted by -SO2CH3 or -NHSO2CH3, halogen or -J-L-M-Q; wherein: J: (C2-C6)alkenylene; L: a bond; M: a bond; Q: -C(O)ORa; Ra and Rb: H, (C1-C4)alkyl optionally substituted by cyano, -CF3 or cyclopropane; (C6)aryl optionally substituted by halogen or -O(C1-C4)alkyl; and Re: a bond, (C1-C4)alkylene or (C3)cycloalkylene. Besides, the invention refers to specific compounds, a pharmaceutical composition based on the compound of formula I, using the compound of formula I for treating and using the compounds of formulas 2-6

for preparing the compound of formula I.

EFFECT: prepared are the new compounds effective in treating a condition mediated by Jak1, Jak3 or Syk protein kinase activity.

51 cl, 34 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 1.7-diazacarbazole compounds of formula (I) or to its solvates, hydrates or salts , where X, Y, Z, R3, R5 and R6 are such as given in i.1 of the invention formula. In addition, invention relates to pharmaceutical composition, containing formula (I) compounds, which possesses inhibiting activity with respect to kinase of control point 1 (chk1).

EFFECT: novel compounds, which can be useful as kinase inhibitors and therefore are useful as anticancer therapeutic medications, are obtained and described.

26 cl, 403 ex, 16 tbl

FIELD: chemistry.

SUBSTANCE: described are novel polycyclic nitrogen-containing heteroaromatic compounds - tetracyano-substituted 1,4,9b-triazaphenalenes of general formula 1

, where R denotes phehyl, substituted with NO2, halogen, C1-4 alky or -OR1 group, where R1 denotes methyl, naphthyl or heteroaryl of the composition C4H3S, and a method for production thereof from corresponding R-substituted 1,1,2,2-tetracyanocyclopropanes while boiling in 1,2-dichlorobenzene.

EFFECT: described compounds can be used as fluorescent indicators for new-generation opto-chemosensors or as material for light-emitting diodes.

2 cl, 12 ex, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, in which: one of A, B, C and D denotes N, and the rest independently denote CH and C(R1); m equals a whole number from 1 to 4; n equals a whole number from 0 to 4; R1 denotes halogen; R2 and R3 denote hydrogen; R4 is selected from H, C1-6alkyl; Ar denotes aryl, optionally substituted with one or more halogen atoms; X denotes -C(Ra)(Rb)-, where Ra and Rb denote H; Y denotes -S(O)2-. The invention also relates to a pharmaceutical composition having CRTH2 receptor antagonist properties and containing a compound of formula I, to use of a compound of formula I when producing a drug for treating or preventing CRTH2 mediated diseases and a method for antagonistic action on CRTH2 receptor in mammals.

EFFECT: novel compound, which can be useful as a CRTH2 receptor antagonist, is obtained and described.

16 cl, 6 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

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