WO2018151633A1 - Methods for producing 4-(((naphthalen-2-yl)alkyl)amino)quinoxaline-6-carbonitrile derivatives - Google Patents

Abstract

The present invention relates to a method for producing a compound of formula I, where B is, independently, hydrogen or [see appropriate figure], wherein no more than one B is hydrogen; D is NR₁ or O; R₁ is H, R, C₁-C₄ alkyl, unsubstituted or substituted with one or more halogens; R is tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; and n is 0, 1 or 2. The invention also relates to intermediate chemical compounds.

Description

 METHODS FOR PRODUCING 4 - (((NAPHTALIN-2-IL) ALKYL) AMINO) CHINOZALIN-6-CARBONITRILES

Technical field

 The present invention discloses methods for preparing compounds useful for the treatment of cyclin-dependent kinase (CDKI) mediated diseases, such as cancer.

State of the art

CDK8, along with the closely related isoform of CDK19, is an oncogenic kinase that regulates transcription (Xu, W. & L, JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452; Galbraith , MD, et al. (2010) CDK8: a positive regulator of transcription, Transcription. 1, 4-12; Firestein,. & Hahn, WC (2009) Revving the Throttle on an oncogene: CDK8 takes the driver seat, Cancer Res 69, 7899-7901). In contrast to the more well-known members of the CDK family (such as CDKI, CDK2 and CDK4 / 6), CDK8 does not play a role in the development of the cell cycle. CDK8 gene knockout in embryonic stem cells leads to arrest of embryo development (Adler, AS, et al. (2012) CDK8 maintains tumor differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139) due to its important role in the phenotype of pluripotent stem cells (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates betacenin activity, Nature 455, 547-551), but blocking CDK8 does not inhibit normal cell growth (Adler, AS , et al. (2012) CDK8 maintains tumor differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139, Kapoor, A., et al. (2010) The histone variant macro H2A suppresses melanoma progression through regulation of CDK8 , Nature 468, 1105-1109). The role of CDK8 in cancer is associated with its unique function as a regulator of several transcription factors involved in carcinogenesis (Xu, W. & L, JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452). CDK8 has been found to play a role in melanoma (Firestein,., Et al. (2010) CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival, Int. J. Cancer 126, 2863- 2873) and colon cancer (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109), with CDK8 expression increased by -50% in the case of the latter these types of cancer. Increased CDK8 expression in colon cancer is associated with an unfavorable prognosis for colon cancer (Gyorffy, B., et al. (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1, 809 patients, Breast Cancer Res. Treat. 123, 725-731). Expression of CDK8 and its isoforms of CDK19 are negative prognostic markers for breast cancer. CDK8 inhibitors may be useful in the treatment of ER-positive breast cancer (McDermott, M., et. Al. (2017) Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer, Oncotarget).

Known mechanisms associated with CDK8 in cancer include upregulation of the Wnt / [beta] catenin pathway (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109; Alarcon, C, et al. (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways, Cell 139, 757-769), growth factor-induced transcription (DiDonato, JA, et al. (2012) NF-kappaB and the link between inflammation and cancer, Immunol. Rev. 246, 379-400) and the TGF-beta signaling pathway (Acharyya, S., et al. (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis, Cell 150, 165-178). It has also been shown that CDK8 can support the pluripotent phenotype of embryonic stem cells and that it can be associated with the cancer stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). Chemotherapeutic drugs causing DNA damage is induced by TNF-a, an activator of the transcription factor NFKB (Fabian et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol. 23, 329-336), in endothelial cells and in other stromal elements of the tumor microenvironment. Stromal TNF-a acts on tumor cells, where it induces NFkB-mediated production of cytokines CXCL1 and CXCL2, which contribute to the survival and growth of tumor cells. CXCL 1/2 attracts myeloid cells to the tumor by binding to the CXC 2 receptor on the surface of myeloid cells. Myeloid cells then secrete small calcium-binding proteins S 100A8 and A9, which are associated with the processes of chronic inflammation and tumor growth. S 100A8 / 9 acts on tumor cells, promoting both their metastasis and survival against chemotherapy (Huang, et al. (2012) MED 12 Controls the response to multiple cancer drags through regulation of TGF-β receptor signaling, Cell 151, 937-950).

 The publication of international patent application WO / 2013/116786 discloses derivatives of 4 - (((naphthalen-2-yl) alkyl) amino) quinosaline-6-carbonitriles, which are selective inhibitors of the cyclin-dependent kinase CDK8 / CDK19 and may be useful for the prevention and treating cyclin-dependent kinase-mediated diseases such as cancer.

Currently, there is a need for improved methods for the preparation of 4 - ((2- (naphthalen-2-yl) alkyl) amino) quinosaline-6-carbonitrile derivatives and intermediate chemical compounds useful in the synthesis of these derivatives. Improved methods of preparation and intermediate chemical compounds can lead to improved yield and purity of the final product, to reduce the time and / or amount of waste associated with existing methods for the preparation of derivatives of 4- ((2- (naphthalen-2-yl) alkyl) amino) quinosaline- 6-carbonitriles. s Description of the invention

The following are definitions of terms that are used in the description of this invention.

In some embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3% , 2%, 1%, 0.5%, 0.1% or 0.05% of a given value or range.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1 to 12 carbon atoms in a chain, more preferably with 1-6 carbon atoms in a chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Examples of alkyl groups include, but are not limited to, lower (C _\ - C ₄₎ alkyl, or methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ti / eti-butyl? , n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents.

 “Aliphatic alcohol” means an organic compound containing one or more hydroxyl groups directly bonded to a carbon atom in a hydrocarbon radical, wherein the hydrocarbon radical does not contain aromatic bonds. Examples of aliphatic alcohols include, but are not limited to, methanol, ethanol, 2-propanol, 1-propanol.

 "Lower alkyl" means a linear or branched alkyl with 1 to 4 carbon atoms.

"Halo" or "Halogen" (Hal) means fluorine, chlorine, bromine and iodine.

A “halogenating agent” may be any compound or combination of compounds by which a halogen atom can be introduced into the compound. Examples of halogenating agents used in the present invention include, but are not limited to. by them, for example, thionyl halides such as thionyl chloride or thionyl bromide; phosphorus trihalides such as phosphorus trichloride or phosphorus tribromide; oxalyl halides such as oxalyl chloride or oxalyl bromide; phosphorus pentahalides, such as phosphorus pentachloride or phosphorus pentabromide; phosphoryl halides such as phosphoryl chloride or phosphoryl bromide; or tri (phenyl unsubstituted or substituted with C ₁ -C 4 alkyl) phosphine carbon tetrahalides, such as triphenylphosphine tetrachloromethane, tritolylphosphine tetrachloromethane or triphenylphosphine tetrabromomethane; / V-halogenosuccinimides, such as N-iodosuccinimide, / V-bromosuccinimide, / V-chlorosuccinimide.

“Heterocycle” or “heterocyclyl” means an aromatic or non-aromatic monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom, such as nitrogen, oxygen, sulfur . The prefix "aza", "oxa" or "thia" before the heterocycle means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The heterocycle may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocycle can be oxidized to TV-oxide, S-oxide or S-dioxide. Examples of heterocyclic groups include, but are not limited to, piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

 “Substituent" means a chemical radical that binds to a molecular skeleton (scaffold, fragment).

A "planning agent" may be any compound or combination of compounds by which a sinner CN can be introduced into the compound. Examples of cyanating agents used in the present invention may include, but are not limited to, for example, zinc cyanide, copper cyanide, alkali metal cyanides, for example, potassium cyanide and sodium cyanide, alkali metal hexacyanoferrates, for example, potassium hexacyanoferrate (III) and sodium hexacyanoferrate (III).

 The term “protecting group” refers to groups that are used to block the reactivity of functional groups, such as an amino group, a carboxyl group, or a hydroxy group. Examples of, but not limited to, protecting groups are methoxycarbonyl, ethoxycarbonyl, thi? Eti-butoxycarbonyl (Boe), tert-butyl, triphenylmethyl, pivaloyl, benzyloxycarbonyl (Cbz), 2- (trimethylsilyl) ethoxy) methylacetal (SEM), trialkylsilyl, alkyl (diaryl) silyl or alkyl.

 In the present description and in the following claims, unless the context provides otherwise, the words “have”, “include” and “contain” or their variations, such as “has”, “having”, “includes”, “including”, “ contains "or" containing ", it should be understood as including the indicated whole or group of whole, but not the exclusion of any other whole or group of whole.

 DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to improved methods for producing the compounds of formula I:

где В представляет собой независимо водород или

where B is independently hydrogen or

при этом не более, чем один В представляет собой водород; b

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

n represents 0, 1, 2;

and to intermediate chemical compounds useful in the synthesis of the compounds of formula I.

 The novel methods of the present invention for preparing a compound of formula I are summarized in Schemes 1-4.

Scheme 1.

Scheme 2.

· - C], 8r _c i hema 3.

 Scheme 4.

 j - 12 0, 1 Hal ~ C! 8r,!

X ^"

где D имеет вышеуказанные значения.

where D has the above meanings.

When ΝΗ groups are present in the starting reagents, intermediates, they can be protected with alkoxycarbonyl, tert-butyl, triphenylmethyl, pivaloyl, fluorenylmethoxycarbonyl, trifluoroacetyl or acetyl protecting groups. Deprotection can be carried out in the final stages of the synthesis with a strong acid, such as HC1 or trifluoroacetic acid.

 In one embodiment, the present invention relates to a method for producing (step (1)) a compound of formula I:

where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

n represents 0, 1, 2;

comprising the interaction of the compounds of formula II in the form of a free base or in the form of its salt form

 II

where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

 i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, thi? Eti-butyl;

n represents 0, 1, 2;

with a compound of formula III or its salts

 t

 Hal represents chlorine, bromine, iodine;

in the presence of a base.

In one embodiment, the base used in step (1) is an organic base or an inorganic base. In yet another embodiment, the organic base is a tertiary amine or a secondary amine; the inorganic base is sodium, potassium or cesium carbonate or bicarbonate. In yet another embodiment, the organic base may be triethylamine or diisopropylethylamine; the inorganic base may be potassium carbonate or sodium carbonate.

 In accordance with one of the embodiments of the present invention, the interaction in stage (1) is carried out in the presence of a solvent. In yet another embodiment, the solvent is a polar aprotic or protic solvent. In yet another embodiment, the solvent may be acetonitrile, methanol, ethanol, 2-propanol, D'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, D'-dimethylacetamide, tetrahydrofuran or its derivatives or dioxane or its derivatives. A combination of solvents may also be used.

 In one embodiment of the invention, the reaction in step (1) is carried out at a temperature of from about −10 ° C. to about 50 ° C. In yet another embodiment of the invention, the temperature in step (1) is from about 10 ° C to about 30 ° C.

 In one embodiment of the invention, the method for producing a compound of formula I described herein may further include a step for producing (step (4)) of a compound of formula

III or its salts by halogenation of a compound of the formula Sh.Z or its salts

In one embodiment of the invention, the halogenation in step (4) is carried out with a halogenating agent. In one embodiment, the halogenating agents are phosphoryl chloride, phosphoryl bromide, thionyl chloride, thionyl bromide, chloride phosphorus (C), phosphorus chloride (C), phosphorus bromide (C) or phosphorus bromide (C).

 In some embodiments, the halogenation in step (4) is carried out in the presence of an organic base. In some embodiments, the organic base is a tertiary or secondary amine, including an aromatic amine. In some embodiments, the organic base may be triethylamine, diisopropylethylamine, Ν, Ν'-dimethylaniline or N-methylaniline.

 In one embodiment, the halogenation in step (4) is carried out in the presence of a solvent. In yet another embodiment, the solvent is an aromatic hydrocarbon solvent. In yet another embodiment, the solvent may be benzene, toluene, xylene or chlorobenzene. A combination of solvents may also be used.

 In one embodiment, the halogenation in step (4) is carried out at a temperature of from about −15 ° C. to about 100 ° C. In yet another embodiment, the temperature in step (4) is from about 5 ° C to about 80 ° C.

 In one embodiment of the invention, the process for preparing a compound of formula III described herein may further include a step for producing (step (3)) a compound of formula

где Hal представляет собой хлор, бром, иод. В одном варианте осуществления изобретения цианирование на стадии (3) проводят в присутствии планирующего агента. В еще одном варианте осуществления изобретения цианирующие агенты могут представлять собой цианид цинка(П) или цианид меди(1). W.Z or its salts by cyanidation of a compound of the formula ΙΙΙ.2 or its salts

where Hal represents chlorine, bromine, iodine. In one embodiment, cyanidation in step (3) is carried out in the presence of a planning agent. In yet another embodiment, the cyanating agents may be zinc cyanide (P) or copper cyanide (1).

 In one embodiment, cyanidation in step (3) is carried out in the presence of a catalyst. In yet another embodiment of the invention, palladium or copper salts are used as a catalyst. In yet another embodiment, the catalyst may be tetrakis (triphenylphosphine) palladium (0), [1, bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (diphenylphosphino) ferrocene] dichloropalladium (II) adduct with dichloromethane or copper cyanide (one).

 In one embodiment, cyanidation in step (3) is carried out in the presence of a catalyst and an organic ligand. In yet another embodiment, the ligand may be phosphorus or iron compounds. In yet another embodiment, the ligand may be triphenylphosphine, (o-tolyl) phosphine or tricyclohexylphosphine.

 In one embodiment, cyanidation in step (3) is carried out in an aprotic dipolar high boiling solvent. In yet another embodiment, the solvent may be D'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or D'-dimethylacetamide. A combination of solvents may also be used.

 In one embodiment, cyanidation in step (3) is carried out at a temperature of from about 50 ° C to about 130 ° C. In yet another embodiment, the temperature in step (3) is from about 70 ° C to about 110 ° C.

In one embodiment of the invention, a process for the preparation of a compound of formula Sh. H, as described herein, may additionally include a preparation step (step (2)) of the compound of formula III.2 by heterocyclicization of the salt compound

where Hal represents chlorine, bromine, iodine.

 In one embodiment of the invention, the heterocyclization in step (2) is carried out in the presence of formamide or formamidine in the form of a stable salt form. In yet another embodiment, the heterocyclization is carried out with the participation of formamidine acetate or formamidine hydrochloride.

 In one embodiment, the heterocyclization in step (2) is carried out in a solvent. In yet another embodiment, the solvent may be 2-propanol, 1-butanol, glycerol, formamide, trimethyl orthoformate, triethyl orthoformate, or formic acid. A combination of solvents may also be used.

 In one embodiment, the heterocyclization in step (2) is carried out at a temperature of from about 50 ° C to about 150 ° C. In another embodiment, the temperature in step (2) is from about 80 ° C to about 130 ° C.

In one embodiment of the invention, the method for producing a compound of formula I described herein may further include a step for producing (step (12)) a compound of formula II or its salts by reducing a compound of formula II.6

where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents Ri or O;

 Rj represents H, C1-C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

n represents 0, 1, 2.

 In one embodiment of the invention, the reduction in step (12) is carried out using borohydrides or cyanoborides of alkali metal hydrides, or using hydrogen in the presence of a catalyst or activator. In yet another embodiment, the reduction is carried out using hydrogen in the presence of a Raney nickel catalyst or activator, or a palladium-based catalyst.

In one embodiment, the reduction in step (12) is carried out in a solvent. In another embodiment, the solvent may be methanol, ethanol, 2-propanol, 1-butanol, 2-meth-2-proptoya, tetrahydrofuran or its derivatives, toluene, dioxane, L ^ '- dimethylformamide or dimethyl sulfoxide. In one embodiment, mixtures of aliphatic alcohols with water can be used as a solvent. In one embodiment of the invention, the reduction in step (12) is carried out at pH 1-14. In yet another embodiment of the invention, the reduction in step (12) is carried out at pH values of 8-14. In yet another embodiment, the reduction in step (12) can be carried out at pH 8-14 in the presence of ammonia.

 In one embodiment of the invention, the reduction in step (12) is carried out at a temperature of from about 5 ° C to about 60 ° C. In yet another embodiment of the invention, the temperature in step (12) is from about 15 ° C to about 40 ° C.

 In one embodiment of the invention, the method for producing a compound of formula II described herein may further include the step of preparing a compound of formula II.6 from an organic acid of formula P.5-1 or its derivatives

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n represents 0, 1, 2.

In some embodiments, an organic acid derivative of formula P.5-1 is its acid halide of formula P.5-2

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen, where Hal represents chlorine, bromine, iodine,

n represents 0, 1, 2.

In one embodiment, a compound of formula II.6 can be obtained by acylation (step (11)) with an acid halide of formula P.5-2 of an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl.

 In one embodiment, the acylation in step (11) is carried out in the presence of a base. In yet another embodiment, the base used in step (11) is an organic base or an inorganic base. In yet another embodiment, the organic base is a tertiary, secondary aliphatic amine or aromatic amine; the inorganic base is an alkali metal carbonate, hydrogen carbonate or hydroxide. In yet another embodiment, the organic base may be triethylamine, diisopropylethylamine or 4-U'-dimethylaminopyridine; the inorganic base may be sodium, potassium or cesium carbonate or hydrogen carbonate, or sodium or potassium hydroxide.

In one embodiment, the acylation in step (11) is carried out in organic solvents or in water. In yet another embodiment, the organic solvent may be dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or its derivatives, diethyl ether, methium tert-butyl ether, dioxane, toluene, benzene or xylene. A combination of solvents may also be used.

 In one embodiment, the acylation in step (11) is carried out at a temperature of from about −10 ° C. to about 40 ° C. In yet another embodiment, the temperature of step (11) is from about 5 ° C to about 30 ° C.

 In yet another embodiment, a method for preparing a compound of formula II.6 may further include the step of preparing (step (10)) an acid halide of formula A.5-2 from an organic acid of formula A.5-1 by halogenating agents in the presence of an organic solvent.

 In one embodiment, the halogenating agents are phosphoryl chloride, phosphoryl bromide, thionyl chloride, thionyl bromide, phosphorus chloride (Y), phosphorus chloride (III), phosphorus bromide (Y) or phosphorus bromide (III), oxalyl chloride or oxalyl bromide.

 In one embodiment of the invention, the organic solvent in step (10) may be dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or its derivatives, diethyl ether, methium tert-butyl ether, toluene, benzene, xylene or dioxane or its derivatives. A combination of solvents may also be used.

 In some embodiments of the invention, the preparation of the acid halide P.5-2 in step (10) is carried out in the presence of catalytic amounts of L ^ 'dimethylformamide.

In one embodiment, the preparation of the acid halide P.5-2 in step (10) is carried out at a temperature of from about 0 ° C to about 70 ° C. In another embodiment of the invention, the temperature in step (10) is from about 10 ° C to about 50 ° C.

 In another embodiment, a compound of formula II.6 may be prepared by reacting (step (9)) an organic acid of formula A.5-1

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n represents 0, 1, 2;

или его соли, and aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of cross-linking agents of zero length in an organic solvent.

 In one embodiment, the zero length crosslinking agents are carbodiimides, isoxazolinium compounds, chloroformates, carbonyldiimidazoles, diethyl pyrocarbonates, dihydroquinolines, phosphonium compounds, ammonium compounds, or uronium compounds.

In one embodiment, the reaction in step (9) is carried out using 1, G-carbonyldiimidazole in an organic solvent. In yet another embodiment, the solvent may be acetonitrile, Ν, Ν'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, Ν, Ν'-dimethylacetamide, tetrahydrofuran or its derivatives, or dioxane or its derivatives. A combination of solvents may also be used.

 In one embodiment of the invention, the interaction in step (9) is carried out at a temperature of from about −10 ° C. to about 60 ° C. In another embodiment, the temperature in step (9) is from about 5 ° C to about 40 ° C.

In one embodiment of the invention, the method for producing a compound of formula ΙΙ.6 described herein may further include the step of producing (step (8)) an organic acid of formula P.5-1 or its derivatives by alkaline hydrolysis of an ester of formula ΙΙ.4

where C is independently hydrogen or COO,

R represents methyl or ethyl,

n represents 0, 1, 2.

 In one embodiment, the alkaline hydrolysis in step (8) is carried out in the presence of an alkali metal hydroxide, carbonate or hydrogen carbonate. In yet another embodiment, alkaline hydrolysis is carried out in the presence of lithium, sodium or potassium hydroxide.

In some embodiments, the alkaline hydrolysis of step (8) is carried out in the presence of a solvent, which is an organic solvent, water, or a mixture of an organic solvent and water. In some embodiments, implementation of the invention, alkaline hydrolysis in step (8) is carried out in the presence of aliphatic monohydric alcohols. In some embodiments, alkaline hydrolysis in step (8) is carried out in the presence of a mixture of tetrahydrofuran or its derivatives, or dioxane or its derivatives and water.

 In one embodiment of the invention, the alkaline hydrolysis in step (8) is carried out at a temperature of from about 0 ° C to about 80 ° C. In yet another embodiment, the temperature in step (8) is from about 10 ° C to about 50 ° C.

In one embodiment of the invention, a method for producing a compound of formula P.5-1 described herein may further include a step for producing (step (7)) a nitrile of formula II.4 by cyanidation of a compound of formula P. 3

where C is independently hydrogen or COO,

R represents methyl or ethyl,

Hal has the above meanings,

n represents 0, 1, 2.

 In one embodiment, cyanidation in step (7) is carried out in the presence of a planning agent. In yet another embodiment, the cyanating agents are alkali metal cyanides. In yet another embodiment, the cyanating agent may be potassium or sodium cyanide.

In one embodiment, cyanidation in step (7) is carried out in the presence of a solvent. In yet another embodiment, the solvent is aliphatic monohydric alcohols or aprotic dipolar high-boiling solvents. In yet another embodiment, the solvent may be methanol, ethanol or dimethyl sulfoxide. A combination of solvents may also be used.

 In one embodiment, cyanidation in step (7) is carried out at a temperature of from about 0 ° C to about 90 ° C. In another embodiment, the temperature in step (7) is from about 20 ° C to about 70 ° C.

где С представляет собой независимо водород или COO , In one embodiment of the invention, the method for producing a compound of formula II.4 described herein may further include a step for producing (step (6)) of a compound of formula P. H by halogenating a compound of formula II.2

where C is independently hydrogen or COO,

R represents methyl or ethyl,

n represents 0, 1, 2.

 In one embodiment of the invention, the halogenation in step (6) is carried out in the presence of a halogenating agent. In yet another embodiment, the halogenating agent is N-halosuccinimides. In yet another embodiment, the halogenating agent may be N-bromosuccinimide.

In some embodiments, halogenation in step (6) is carried out in the presence of radical initiators. In some embodiments, the radical initiator in step (6) is dinitrilazobisisobutyric acid or dibenzoyl peroxide. In some embodiments, the initiator of the radical process in step (6) is irradiation with light of a specific wavelength.

 In one embodiment, the halogenation in step (6) is carried out in the presence of a solvent. In yet another embodiment, the solvent may be chloroform, dichloroethane, dichloromethane, carbon tetrachloride, ethyl acetate or acetonitrile. A combination of solvents may also be used.

 In one embodiment of the invention, the halogenation in step (6) is carried out at a temperature of from about 0 ° C to about 100 ° C. In another embodiment, the temperature in step (6) is from about 20 ° C to about 80 ° C.

где А представляет собой независимо водород или СООН, In one embodiment of the invention, the method for producing a compound of formula P.Z. described herein may further include the step of producing (step (5)) an organic acid ester of formula II.2 from an organic acid of formula II.1

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n represents 0, 1, 2.

In one embodiment, the preparation of the organic acid ester in step (5) is carried out by an esterification reaction of the corresponding organic acid in the presence of aliphatic monohydric alcohols. In yet another embodiment, the aliphatic monohydric alcohol may be methanol, ethanol, 2-propanol or 2-methyl-2-propanol. In one embodiment of the invention, the esterification reaction in step (5) is carried out under acid catalysis. In yet another embodiment, the catalyst is an inorganic acid. In yet another embodiment, the inorganic acid may be hydrochloric acid or sulfuric acid. In some embodiments, the esterification reaction in step (5) is carried out in the presence of thionyl chloride or oxalyl chloride.

 In another embodiment, the preparation of the organic acid ester in step (5) is carried out in the presence of an aliphatic monohydric alcohol using zero-length crosslinking agents. In yet another embodiment, the zero-length crosslinking agents are carbodiimides. In yet another embodiment, the zero length crosslinker is Ν, Ν 'dicyclohexylcarbodiimide.

 In one embodiment, the preparation of an organic acid ester by esterification or using zero length cross-linking agents in step (5) is carried out in the presence of a solvent. In yet another embodiment, the solvent may be acetonitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran or its derivatives, diethyl ether, methium tert-butyl ether, toluene, benzene, xylene or dioxane or its derivatives. A combination of solvents may also be used.

 In one embodiment, the preparation of the organic acid ester in step (5) is carried out at a temperature of from about 5 ° C to about 80 ° C. In yet another embodiment, the temperature in step (5) is from about 20 ° C to about 60 ° C.

In another embodiment, a method for producing a compound of formula I described herein may further include a step for producing (step (18)) a compound of formula II or its salts by deprotection of a compound of formula P.4-2

при этом не более, чем один В представляет собой водород; where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

 i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

 X is selected from the group including:

In some embodiments, the deprotection of step (18) is carried out in the presence of an inorganic or organic acid. In some embodiments, the deprotection of step (18) is carried out in the presence of an inorganic or organic acid, wherein the protecting group is thi? Eti-butyl carbonate or di-7i / eti-butyl carbonate. In some embodiments, the inorganic acid may be hydrochloric acid; the organic acid may be trifluoroacetic acid. In some embodiments, the deprotection of step (18) is carried out in the presence of hydrazine hydrate. In some embodiments, the deprotection of step (18) is carried out in the presence of hydrazine hydrate, wherein the protecting group is phthalimide or succinimide.

 In one embodiment, the deprotection of step (18) is carried out in the presence of a solvent. In yet another embodiment, the solvent may be methanol, ethanol, 2-propanol, dichloromethane, dichloroethane, chloroform, dioxane or its derivatives, tetrahydrofuran or its derivatives, water, benzene, xylene or toluene. A combination of solvents may also be used.

 In one embodiment, the deprotection of step (18) is carried out at a temperature of from about 0 ° C to about 100 ° C. In yet another embodiment, the temperature of step (18) is from about 20 ° C to about 80 ° C.

 In another embodiment, the method for producing a compound of formula II described herein may further include a step for producing (step (17)) a compound of formula A.4-2 by reduction of a compound of formula A.3-2

при этом не более, чем один В представляет собой водород; where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O; i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

 X is selected from the group including:

 In one embodiment, the reduction in step (17) is carried out in the presence of a catalyst. In yet another embodiment, the catalyst is a catalyst based on palladium, rhodium, ruthenium. In yet another embodiment, the catalyst may be palladium on carbon. In some embodiments, the reduction in step (17) is carried out in the presence of hydrogen. In some embodiments, the reduction in step (17) is carried out in the presence of ammonium formate.

 In one embodiment, the reduction in step (17) is carried out in the presence of a solvent. In yet another embodiment, the solvent may be methanol, ethanol, 2-propanol, dioxane or its derivatives, tetrahydrofuran or its derivatives, water, formic acid or acetic acid. A combination of solvents may also be used.

In another embodiment, a method for producing a compound of formula A.4-2 described herein may further include a step for producing (step (16)) a compound of formula A.3-2 by metal-catalyzed arylation of compound IV ! V

where j represents 0, 1;

 X is selected from the group including:

the compound of formula A.2-2

при этом не более, чем один В представляет собой водород; ! i - where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, Ci-C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, thi? Eti-butyl;

Hal has the above meanings.

 In some embodiments, the catalyst in step (16) is a salt of palladium, copper, rhodium, ruthenium.

 In some embodiments, the compound of formula IV is vinyl phthalimide.

In some embodiments, the metal-catalyzed arylation of step (16) is carried out in the presence of a salt palladium, copper, rhodium, ruthenium, used as a catalyst, and in the presence of organic phosphorus or iron ligands.

 In some embodiments, the metal-catalyzed arylation of step (16) is carried out in the presence of palladium (II) acetate as a catalyst and three (o-tolyl) phosphine as an organic ligand.

 In one embodiment, the metal-catalyzed arylation of step (16) is carried out in the presence of a base. In yet another embodiment, the base is an organic base or an inorganic base. In yet another embodiment, the organic base is tertiary aliphatic amines; the inorganic base is alkali metal carbonates. In yet another embodiment, the organic base may be triethylamine or diisopropylethylamine; the inorganic base may be sodium carbonate, cesium carbonate or potassium carbonate.

 In one embodiment, the metal-catalyzed arylation of step (16) is carried out in the presence of a solvent. In yet another embodiment, the solvent may be acetonitrile, D'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, D'-dimethylacetamide, tetrahydrofuran or its derivatives, or dioxane or its derivatives. A combination of solvents may also be used.

In one embodiment of the invention, the metal-catalyzed arylation of step (16) is carried out at a temperature of from about 40 ° C to about 150 ° C. In another embodiment, the temperature in step (16) is from about 70 ° C to about 120 ° C. In another embodiment of the invention, the method for producing a compound of formula P. 3 described in the present description may further include a step for producing (step (13)) of compound A.2-2 by reacting an organic acid A.1.1-2

where Hal has the above meanings,

A is independently hydrogen or COOH,

however, no more than one A represents hydrogen,

and aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of cross-linking agents of zero length in an organic solvent.

 In one embodiment, the zero length crosslinking agents are carbodiimides, isoxazolinium compounds, chloroformates, carbonyldiimidazoles, diethyl pyrocarbonates, dihydroquinolines, phosphonium compounds, ammonium compounds, or uronium compounds.

In some embodiments, the reaction in step (13) is carried out using 1, G-carbonyldiimidazole in an organic solvent. In one embodiment of the invention the solvent may be acetonitrile, Ν, Ν'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, Ν, Ν'-dimethylacetamide or tetrahydrofuran or its derivatives. A combination of solvents may also be used.

 In one embodiment, the reaction of step (13) is conducted at a temperature of from about 0 ° C to about 60 ° C. In yet another embodiment of the invention, the temperature in step (13) is from about 10 ° C to about 40 ° C.

где Е представляет собой независимо водород или С(0)На1, In one embodiment of the invention, a method for producing a compound of formula P.3-2 described herein may further include a step for producing (step (15)) of a compound of P.2-2 by acylation of halide -2

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

Hal represents chlorine, bromine, iodine;

aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl. In one embodiment of the invention, the reaction in step (15) is carried out in the presence of a base. In yet another embodiment, the base is an organic base or an inorganic base. In yet another embodiment, the organic base is tertiary aliphatic amines; the inorganic base is alkali metal carbonates. In yet another embodiment, the organic base may be triethylamine or diisopropylethylamine; the inorganic base may be sodium carbonate, cesium carbonate or potassium carbonate.

 In one embodiment of the invention, the reaction in step (15) is carried out in the presence of a solvent. In yet another embodiment, the acylation in step (15) is carried out in organic solvents or in water. In yet another embodiment, the organic solvent may be dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or derivatives thereof, diethyl ether, methium tert-butyl ether, toluene, benzene or xylene. A combination of solvents may also be used.

 In one embodiment of the invention, the reaction in step (15) is carried out at a temperature of from about 0 ° C to about 60 ° C. In yet another embodiment, the temperature in step (15) is from about 10 ° C. to about 40 ° C.

In one embodiment of the invention, a method for producing a compound of formula A.2-2 described herein may further include a step for producing (stage (14)) of a compound A.1.2-2 by reacting an organic acid A.1.1-2

 1 .114 where A represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

Hal has the above meanings;

with halogenating agents in the presence of an organic solvent.

 In one embodiment, the halogenating agents are phosphoryl chloride, phosphoryl bromide, thionyl chloride, thionyl bromide, phosphorus chloride (Y), phosphorus chloride (III), phosphorus bromide (Y) or phosphorus bromide (III), oxalyl chloride or oxalyl bromide.

 In one embodiment, the organic solvent in step (14) is dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or derivatives thereof, diethyl ether, methyl tert-butyl ether, toluene, benzene or xylene. A combination of solvents may also be used.

 In some embodiments, the preparation of halide A.1.2-2 in step (14) is carried out in the presence of catalytic amounts of L ^ '- dimethylformamide.

 In one embodiment of the invention, the preparation of the acid halide A.1.2-2 in step (14) is carried out at a temperature of from about 0 ° C to about 70 ° C. In yet another embodiment of the invention, the temperature in step (14) is from about 10 ° C to about 50 ° C.

 In one embodiment, the present invention relates to a method for producing a compound of formula I:

где В представляет собой независимо водород или

ss

where B is independently hydrogen or

while not more than one represents hydrogen,

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

n represents 0, 1, 2;

including:

(a) heterocyclization (step (2)) of compound III.1 or its salts

where Hal has the above meanings;

with the receipt of the compounds of formula III.2

или его солеи,

or its salts,

where Hal has the above meanings; (b) cyanidation (step (3)) of a compound of formula III.2 or its salts to obtain a compound of formula Sh.Z or its salts

(c) halogenation (step (4)) of a compound of formula III.Z or its salts to obtain a compound of formula III or its salts

 t

where Hal has the above meanings;

 (g) the interaction (stage (1)) of the compounds of formula III in the form of a free base or in the form of its salt form

let

 III

where Hal has the above meanings;

with a compound of formula II or its salts

 It

при этом не более, чем один В представляет собой водород, D представляет собой NRi или О;where B is independently hydrogen or

while not more than one represents hydrogen, D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

n represents 0, 1, 2;

in the presence of a base to obtain a compound of formula I.

 In one embodiment, the present invention relates to a method for producing (step (1)) a compound of formula I:

где В, п имеют вышеуказанные значения;

where B, n have the above meanings;

comprising the interaction of the compounds of formula II in the form of a free base or in the form of its salt form

где В, п имеют вышеуказанные значения;

where B, n have the above meanings;

with a compound of formula III or its salts

Hi

where Hal has the above meanings; in the presence of a base.

In one embodiment, the present invention relates to a method for producing a compound of formula II or its salts

H

where B, n have the above meanings;

including:

где С представляет собой независимо водород или COO , (a) a step for producing (step (5)) an organic acid ester of formula II.2

where C is independently hydrogen or COO,

while not more than one C represents hydrogen,

n represents 0, 1, 2,

 R represents methyl or ethyl;

где А представляет собой независимо водород или СООН, from an organic acid of formula II.1

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n represents 0, 1, 2;

(b) halogenation (step (6)) of a compound of formula ΙΙ.2 to obtain a compound of formula P.Z.

where C is independently hydrogen or COO,

while not more than one C represents hydrogen,

n represents 0, 1, 2,

 R represents methyl or ethyl,

 Hal has the above meanings;

где С представляет собой независимо водород или COOR, (c) cyanidation (step (7)) of the compound of formula P.Z. to give a nitrile of formula II.4

where C is independently hydrogen or COOR,

while not more than one C represents hydrogen,

n represents 0, 1, 2,

R represents methyl or ethyl;

 (d) alkaline hydrolysis (step (8)) of an ester of formula II.4 to obtain an organic acid of formula P.5-1 or its derivative

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n represents 0, 1, 2;

 (e) a step for preparing a compound of formula II.6, comprising

(i) the interaction of an organic acid of formula P.5-1 (stage (9)) and an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of crosslinking agents of zero length in an organic solvent to obtain a compound of formula II.6

where B, n have the above meanings;

 (ii) preparing (step (10)) an acid halide of formula A.5-2 from an organic acid of formula A.5-1 in the presence of an organic solvent

где Е представляет собой независимо водород или С(0)На1,

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

n represents 0, 1, 2,

Hal represents chlorine, bromine, iodine;

или его соли, and acylation (step (11)) with an acid halide of the formula of an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

in the presence of a solvent and a base to obtain a compound of formula P.6;

 (e) reduction (step (12)) of a compound of formula II.6 to thereby give a compound of formula II or its salts.

In another embodiment, the present invention relates to a method for producing a compound of formula II

где В, п имеют вышеуказанные значения;

where B, n have the above meanings;

including:

 (a) interaction

(i) organic acid PL.1-2 (step (13))

 fit 1-2 where A is independently hydrogen or COOH,

however, no more than one A represents hydrogen,

Hal has the above meanings;

and aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of crosslinking agents of zero length in an organic solvent to obtain a compound of formula A.2-2

 h

при этом не более, чем один В представляет собой водород; where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

Ri represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butk

Hal has the above meanings;

(ii) obtaining (step (14)) of an acid halide of formula A.1.2-2 from an organic acid of formula A.1.1-2

 lit 2-2 where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

Hal has the above meanings;

in the presence of an organic solvent

and acylation (step (15)) with a halide A.1.2-2 of an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, thi? Eti-butyl;

in the presence of a solvent and a base, thereby obtaining a compound of formula A.2-2;

(b) metal-catalyzed arylation (step (16)) of compound IV

where] represents 0, 1;

 X is selected from the group including:

a compound of formula A.2-2, with the receipt of the compounds of formula P.3-2

при этом не более, чем один В представляет собой водород; where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

X is selected from the group including:

(c) reduction (step (17)) of a compound of formula A.3-2 to thereby give a compound of formula P. -2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

 X is selected from the group including:

 (g) removing the protective group (step (18)) from the compound of formula A.4-2 to thereby give a compound of formula P.

In one embodiment, the present invention relates to a method for producing a compound of formula II

где В, п имеют вышеуказанные значения;

where B, n have the above meanings;

reduction (step (12)) of the compound of formula II.6.

 In some embodiments, the method of preparing a compound of formula II above may further include the step of preparing a compound of formula II.6:

(i) the interaction of an organic acid of formula P.5-1 (stage (9)) and an aliphatic cyclic amine of the formula

or its salt, where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of cross-linking agents of zero length in an organic solvent, thereby obtaining

compounds of formula II.6;

 (ii) by acylation with an acid halide (step (10)) of the formula A.5-2

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

n represents 0, 1, 2,

 Hal has the above meanings;

или его соли, aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

Ri represents H, R, Ci-C ₄ alkyl, unsubstituted or substituted with one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

in the presence of a solvent and a base to obtain a compound of formula P.6.

где В, п имеют вышеуказанные значения; In one embodiment, the present invention relates to a method for producing a compound of formula II

where B, n have the above meanings;

removal of the protective group (step (18)) from the compound of formula P.4-2

при этом не более, чем один В представляет собой водород; where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

X is selected from the group including:

In some embodiments, the method of producing a compound of formula II above may further include the step of preparing a compound of formula A.4-2 by reduction (step (17)) of a compound of formula A.3-2

where B, X, j have the above meanings.

In one embodiment, the present invention relates to a method for producing a compound of formula II.6

where B, n have the above meanings;

including:

где С, п имеют вышеуказанные значения; (a) cyanidation (step (7)) of a compound of formula P. 3 to produce a nitrile of formula II.4

where C, n have the above meanings;

 (b) alkaline hydrolysis (step (8)) of an ester of formula ΙΙ.4 to obtain an organic acid of formula P.5-1 or its derivatives

where a represents independently hydrogen or COOH,

however, no more than one A represents hydrogen,

n has the above meanings;

(c) stage (i) reacting an organic acid of formula P.5-1 (step (9)) and an aliphatic cyclic amine of the formula

или его соли,

or its salt,

where D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

according to the methodology for the preparation of an amide bond with the participation of crosslinking agents of zero length in an organic solvent to obtain a compound of formula II.6

где Е представляет собой независимо водород или С(0)На1, (ii) preparing (step (10)) an acid halide of formula A.5-2

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

Hal, n have the above meanings;

from an organic acid of the formula P.5-1 in the presence of an organic solvent

или его соли, and acylation (step (11)) with an acid halide of formula A.5-2 of an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O; i represents H, R, C ₁ -C4 alkyl, unsubstituted or substituted with one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

in the presence of a solvent and a base to obtain a compound of formula P.6.

где В, n имеют вышеуказанные значения; In another embodiment, the present invention relates to a method for producing a compound of formula II.6

where B, n have the above meanings;

или его соли, the interaction of an organic acid of formula P.5-1 (stage (9)) and an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;

 R is thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, t-butyl;

according to the methodology for the preparation of an amide bond with the participation of crosslinking agents of zero length in an organic solvent to obtain a compound of formula II.6.

In yet another embodiment, the present invention relates to a method for producing a compound of formula II.6

where B, n have the above meanings;

by acylation (step (11)) with an acid halide P. 5-2 of an aliphatic cyclic amine of the formula

or its salt,

where D represents NRi or O;

i represents H, R, Ci-C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

in the presence of a solvent and a base to obtain a compound of formula P.6.

 In some embodiments, the method of preparing the compound of formula II.6 above may further include the step of preparing (step (10)) an acid halide P.5-2 from an organic acid of formula P.5-1 in the presence of an organic solvent

where E is independently hydrogen or C (0) H1,

however, no more than one E represents hydrogen,

Hal, n have the above meaning.

In one embodiment, the present invention relates to a method for producing a compound of formula A.4-2

where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, Ci-C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

X is selected from the group including:

где В, j имеют вышеуказанные значения, reduction (step (17)) of the compound of formula A.3-2

where b, j have the above meanings,

X is selected from the group including:

где ] представляет собой 0, 1 ; In some embodiments, implementation of the present invention, the method of obtaining the compounds of formula P.4-2 above, may additionally include a step for producing a compound of formula P.3-2 by metal-catalyzed arylation (step (16)) of compound IV

where] represents 0, 1;

X is selected from

a compound of formula A.2-2,

 , Ζ-2 where B, Hal have the above meanings.

In one embodiment, the present invention relates to a method for producing a compound of formula A.3-2 metal-catalyzed arylation (step (16))

where] represents 0, 1;

X is selected from the group including:

a compound of formula A.2-2,

where B, Hal have the above meanings.

In one embodiment, the present invention relates to a compound of formula II.6:

where B, n have the above meanings.

 In yet another embodiment, the compound of formula II.6 is

In one embodiment, the present invention relates to a compound of formula P.5-2.1:

where E is independently hydrogen or C (0) C1,

wherein no more than one E is hydrogen;

n represents 1, 2.

 In yet another embodiment, the compound of formula P.5-2.1 is

In one embodiment, the present invention relates to a compound of formula P.5-2.

where E is independently hydrogen or C (0) Br, C (0) 1

wherein no more than one E is hydrogen;

n represents 0, 1, 2.

In yet another embodiment, the compound of formula P.5-2.2 is

 In one embodiment, the present invention relates to a compound of formula A.3-2

B is independently hydrogen

wherein not more than one B is hydrogen;

D represents NRi or O;

 i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

 X is selected from the group including:

В еще одном варианте осуществления изобретения соединение формулы Н.3-2 представляет собой

In yet another embodiment, the compound of formula H.3-2 is

В одном варианте осуществления настоящее изобретение относится к соединению формулы П.4-2:

In one embodiment, the present invention relates to a compound of formula P.4-2:

где В представляет собой независимо водород или

where B is independently hydrogen or

wherein not more than one B is hydrogen;

D represents NRi or O;

i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;

 R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl;

j represents 0, 1;

 X is selected from r pp, including:

когда j=l , X выбирают из группы, включающей:

provided that when j = 0, X is selected from the group including:

when j = l, X is selected from the group including:

 In yet another embodiment, the compound of formula P.4-2 is

For a better understanding of the invention, the following examples are provided. These examples are for illustrative purposes only and are not should be construed as limiting the scope of the invention in any form.

All publications, patents, and patent applications referenced in this specification are incorporated herein by reference. Although the aforementioned invention has been described in some detail by way of illustration and example in order to avoid ambiguous interpretation, it will be readily understood by those skilled in the art that certain changes and modifications may be made without departing from the spirit and scope of the enclosed embodiments. the implementation of the invention.

Examples

Example 1. Obtaining (6- (2-aminoethyl) naphthalen-2-yl) (4-methylpiperisan-1-yl) methanone (2)

6-Methyl-2-naphthoic acid methyl ester (2.2)

 To 850 ml of methanol were loaded 100 g (0.537 mol) of compound 2.1 and 10 ml of thionyl chloride at 25 ° C. The reaction mass was heated to boiling and held for 3 hours, after which it was concentrated to dryness. Yield 103 g (98%).

6- (Bromomethyl) -2-naphthoic acid methyl ester (2.3) To 430 ml of carbon tetrachloride in an argon atmosphere, 100 g (0.499 mol) of compound 2.2, 46 g (0.257 mol) of N-bromosuccinimide (NBS), and 3.7 g (0.023 mol) of azobisisobutyronitrile (AIBN) were added. The reaction mass was heated to boiling and held for 1 h, cooled to 60 ° C and the same amounts of NBS and AIBN were added. The reaction mass was again heated to boiling and held for 2 hours, after which it was cooled and 100 ml of dichloromethane and 100 ml of water were added. The organic layer was separated, dried with anhydrous Na ₂ S0 ₄ , the solvent was distilled off in vacuo. The residue was recrystallized from 300 ml of a mixture of ethyl acetate and hexane. Yield 74 g (53%).

 6- (Cyanomethyl) -2-naphthoic acid methyl ester (2.4)

To 2500 ml of methanol was added 262 g (0.937 mol) of compound 2.3. 73.8 g (1.13 mol) of potassium cyanide were charged at boiling. The reaction mass was kept for 1 h, the solvent was distilled off in vacuo. The residue was dissolved in a mixture of 800 ml of dichloromethane and 500 ml of water. The organic layer was separated, dried with anhydrous Na ₂ S0 ₄ , the solvent was distilled off in vacuo. The residue was recrystallized from 700 ml of ethanol. Yield 168 g (80%).

 6- (Cyanomel) -2-naphthoic acid (2.5-1)

30.6 g (0.72 mol) of LiOH * H ₂ 0 and 1600 ml of tetrahydrofuran (THF) were added to 1500 ml of water. 150 g of compound 2.4 (0.66 mol) were charged. The reaction mass was held for 3 hours and THF was distilled off. To the mixture was added 500 ml of methyl-ti / eti-butyl ether. The layers were separated, the aqueous layer was acidified to pH 2-3 by the action of about 75 ml of hydrochloric acid. The suspension was filtered, the precipitate was washed with 300 ml of water. Yield 138 g (98% yield).

 2- (6- (4-Methylpiperazin-1-carbonyl) naphthalen-2-yl) acetonitrile

(2.6)

Method A. In 60 ml of dry L ^ - dimethylformamide (DMF), 10 g (0.0473 mol) of compound 2.5-1 and 8.5 g (0.052 mol) of carbonyldiimidazole (CDI) were dissolved. The mixture was cooled to 0 ° C and a solution of 5.2 g (0.0052 mol) of TV-methylpiperazine in 5 ml of DMF was added to it. The reaction mass was kept for 10 h, poured into 300 ml of water. The product was extracted with 400 ml of ethyl acetate. The organic extract was washed with 100 ml of a saturated NaCl solution, dried with anhydrous Na ₂ S0 ₄ , the solvent was distilled off to dryness. Yield 10 g (72%).

Method B. To 1800 ml of dry dichloromethane in an argon atmosphere was loaded 180 g (0.852 mol) of acid 2.5-1, 182 ml (1.54 mol) of thionyl chloride, 0.5 ml of DMF was added. The reaction mass was kept at boiling for 3 hours. The solvent was distilled off to dryness and re-concentrated with 100 ml of toluene 3 times. The obtained residue - acid chloride 2.5.1 was dissolved in 1800 ml of dry dichloromethane and 97 ml (0.87 mol) of TV-methylpiperazine and 127 ml (0.907 mol) of triethylamine in 1500 ml of dry dichloromethane in argon atmosphere were added to a solution cooled to 10 ° С for 30 min After 1 h, 500 ml of water was added to the reaction mixture. The layers were separated, the organic layer was dried with anhydrous Na ₂ S0 ₄ , the solvent was distilled off to dryness. Yield 253 g (98%).

 (6- (2-aminoethyl) naphthalen-2-yl) (4-methylpiperazin-1-yl) methanone

(2)

A suspension of Raney nickel, previously prepared from 110 g of NaOH and 63 g of a nickel-aluminum alloy, in about 150 ml of methanol was placed in an autoclave and 500 ml of 25% by weight was added. ammonia solution. A solution of 63 g (0.215 mol) of compound 2.6 in 400 ml of methanol was charged to the suspension and hydrogen (5 atm) was supplied. The reaction mass was held for 3 hours. At the end of the reaction, the catalyst was filtered off, and the filtrate was concentrated. 600 ml of dichloromethane was added to the residue, the layers were separated. The product was further extracted from the aqueous layer with 300 ml of dichloromethane. The combined extract was dried with anhydrous Na ₂ S0 ₄ , the solvent was distilled off to dryness. Yield 60 g (99%).

Example 2. Obtaining (6- (2-aminoethyl) naphthalen-2-yl) (4-methylpiperazin-1-yl) methanone (2)

 (6-Bromonaphthalen-2-yl) (4-methylpiperazin-1-yl) methanone (2.2-2) Method A. In 10 ml of dry DMF, 1 g (0.004 mol) of 6-bromo-2-naphthoic acid 2.1-2 was dissolved and 0.71 g (0.0044 mol) of CDI. The mixture was cooled to 0 ° C and a solution of 0.48 g (0.0048 mol) of N-methylpiperazine in 1 ml of DMF was added to it. The reaction mass was stirred for 18 hours at room temperature, poured into 50 ml of water. The resulting suspension was stirred for 20 minutes and filtered. The precipitate was washed on the filter with 20 ml of water. Yield 1.2 g (90%).

Method B. In an argon atmosphere, 5 g (0.019 mol) of 6-bromo-2-naphthoic acid 2.1-2 were suspended in 30 ml of dry dichloromethane, 7.1 g (0.059 mol) of thionyl chloride and 2-3 drops of DMF were added. The mixture was stirred at the boil until the precipitate dissolved and then another 1 h, the solvent was distilled off, the residue was re-evaporated with 20 ml of toluene. The obtained residue, acid chloride 2.1.2-2, was dissolved in 30 ml of dry dichloromethane, and 2.1 g (0.02 mol) of N-methylpiperazine and 2 g (0.019 mol) of triethylamine in 30 ml of dry dichloromethane in argon atmosphere were added to a solution cooled to 0 ° С. At the end of the dosage, the reaction was mixed. a mixture of 2 hours. Then the reaction mass was washed with water, a solution of NH ₄ C1, the solvent was distilled off. Yield 5 g (76%).

 (£) -2- (2- (6- (4-Methylpiperazin-1-carbonyl) naphthalen-2-yl) vinyl) - isoindolin-1,3-dion (2.3-2)

 In 20 ml of dry acetonitrile, 3.5 g (0.010 mol) of compound 2.2-2, 1.9 g (0.011 mol) of vinyl phthalimide, 0.32 g (0.001 mol) of tri (o-tolyl) phosphine, 0.07 g (0.0003 mol) of palladium acetate and 2 g were mixed (0.015 mol) of diisopropylethylamine in an argon atmosphere. The reaction mass was boiled for 12 hours, cooled, and the suspension was filtered. The precipitate was washed with 10 ml of acetonitrile and 20 ml of water. Yield 3.5 g (80%).

 2 (2- (6- (4-Methylpiperazin-1-arbonyl) naphthalen-2-yl) ethyl) - isoindolin-1,3-dione (2.4-2)

To a suspension of 1 g (0.006 mol) of compound 2.3-2 in 10 ml of methanol was added 1 ml of formic acid, 2 ml of water, and 0.124 mg of 10% by weight. Pd / C. The reaction mass was heated to boiling and 3 g of NH ₄ OAc was added. The reaction mass was filtered through a pad of celite. To the mother liquor at room temperature was added 50 ml of water and made basic with 5% wt. Na ₂ C03 solution to pH 8. The suspension was filtered. The precipitate was washed with 20 ml of water. Yield 0.8 g (80%).

 (6- (2-aminoethyl) naphthalen-2-yl) (4-methylpiperazin-1-yl) methanone

(2)

 To a suspension of 2.5 g (0.006 mol) of compound 2.4-2 in 30 ml of a mixture of methanol-dichloromethane (1: 1) was added 1.16 g (0.012 mol) of 50% by weight. hydrazine hydrate solution. The resulting mixture was kept for 3 hours at 40 ° C. The suspension was filtered, the filtrate was concentrated to dryness. Yield 1.7 g (99%).

 Example 3. Obtaining 4-chloroquinosaline-6-carbonitrile (3)

6-Иодхинозалин-4(3/ )-он (3.2)

6-Iodhinosaline-4 (3 /) -one (3.2)

 200 g (0.76 mol) of 2-amino-5-iodobenzoic acid 3.1 and 76.8 g (0.74 mol) of formamidine acetate were charged to 500 ml of 1-butanol. At boiling with a frequency of 30 min, formamidine acetate was charged 5 times in an amount of 23.8 g (0.228 mol). After the last portion was added, formamidine acetate kept the reaction mass for another 1 h. At the end of the reaction, the reaction mass was cooled to 0 ° C, and the suspension was filtered. The precipitate was washed with 100 ml of water. The precipitate was suspended in 100 ml of water and 10 ml of 25% by weight was added. ammonia solution to pH 8-9. The suspension was filtered. The precipitate was washed with 300 ml of water. Yield 198 g (96%).

 4-O-3,4-dihydroquinosaline-6-arbonitrile (3.3)

 To 850 ml of DMF were added 178 g (0.65 mol) of compound 3.2, 53.6 g (0.46 mol) of zinc cyanide and 9 g (0.0078 mol) of tetrakis (triphenylphosphine) palladium (0) in an argon atmosphere. The reaction mass was kept at 110 ° C for 2 hours. At the end of the reaction, the reaction mass was cooled to 20-25 ° C. The suspension was filtered. The precipitate was washed with 300 ml of acetonitrile and 300 ml of water. Yield 84 g (75%).

 4-chlorochinosaline-6-arbonitrile (3)

 To 200 ml of dry toluene in an argon atmosphere, 80 g (0.467 mol) of compound 3.3 were charged, 118 ml (0.678 mol) of diisopropylethylamine were added.

The reaction mass was kept for 10 min at 20-25 ° C. At 10 ° С, a solution of phosphorus oxychloride 60.8 ml (0.647 mol) in 50 ml of dry toluene was added, kept at 20 ° С for 1 h and at 85-90 ° С for 3 hours. The reaction mass was cooled to 5 ° С, and the suspension was filtered. The precipitate was washed with 80 ml of chilled toluene, 150 ml of a mixture of acetone-water (1: 1), 150 ml of acetone. Yield 78 g (74%).

Example 3. Obtaining 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) - naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile (1)

To a solution of 276 g (0.866 mol) of compound 2 in 4720 ml of acetonitrile was added 366 ml (2.60 mol) of triethylamine in an argon atmosphere. At 10-15 ° C, 164.5 g (0.831 mol) of compound 3 was added. The mixture was kept at 30 ° C for 5 hours. The suspension was filtered, the precipitate was washed with acetonitrile 2 times 500 ml, water 2 times 500 ml, 500 ml acetonitrile. Yield 300 g (77%).

 Example 4. Obtaining 4 - ((2- (6- (piperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile (4)

 7 o ^ / m-butyl-4- (6- (cyanomethyl) -2-naphthoyl) piperazin-1-arbo silate (4.1)

 Compound 4.1 was prepared analogously to compound 2.6, using tert-butium piperazine-1-carboxylate instead of TV-methylpiperazine.

 7 o ^ / m-butyl-4- (6- (2-aminomethyl) -2-naphthoyl) piperazin-1-arbo silate (4.2)

 Compound 4.2 was prepared analogously to compound 2, using compound 4.1 instead of compound 2.6

7 o ^ / m-butyl-4- (6- (2 - ((6-cyanoquinazolin-4-yl) amine) ethyl) -2- naphthoyl) piperazin-1-arbo silate (4.3) Compound 4.3 was prepared analogously to compound 1, using compound 4.2 instead of compound 2.

 4 - ((2- (6- (piperazin-1-arbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-arbonitrile (4)

 To a solution of compound 4.3 (71 mg, 0.132 mmol) in 3 ml of dichloromethane, 1 .5 ml of a 4M solution of hydrochloric acid in dioxane was added dropwise while cooling with a water bath. After 15 hours, the precipitate was filtered off and washed with dichloromethane (2 x3 ml). Compound 4 hydrochloride was dissolved in water and made basic with 10% wt. NaHCC solution to pH 9. The resulting precipitate was filtered off, washed with water (2x3 ml). Yield 47 mg (81%).

Example 5. Analysis of the obtained compounds.

 The purity and structure of the obtained compounds were confirmed by LC / MS chromatography-mass spectrometry and * H NMR spectroscopy (Table.

one)·

 Equipment data:

 Chromatography mass spectrometry

Спектрометр ЯМР

NMR spectrometer

Table 1. Analytical data for example compounds

Industrial applicability

 The invention can be used in medicine and veterinary medicine.

Claims

Claim A method of obtaining a compound of formula I,

where independently represents hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; n represents 0, 1, 2; comprising the interaction of the compounds of formula II in the form of a free base or in the form of its salt form

where independently represents hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O;  i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; n represents 0, 1, 2; with a compound of formula III or in the form of its salt form

 t where Hal represents chlorine, bromine, iodine; in the presence of a base.  2. The method of claim 1, wherein the base is an organic base or an inorganic base.  3. The method according to p. 2, in which the organic base can be selected from a tertiary or secondary amine; the inorganic base may be selected from carbonates or hydrogen carbonates of sodium, potassium, cesium.  4. The method of claim 3, wherein the organic base is triethylamine or diisopropylethylamine; the inorganic base is potassium carbonate or sodium carbonate.  5. The method according to p. 1, in which the reaction is carried out in a polar aprotic or protic solvent. 6. The method according to claim 5, in which the solvent is selected from acetonitrile, methanol, ethanol, 2-propanol, D'-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, D'-dimethylacetamide, tetrahydrofuran or its derivatives, or dioxane or its derivatives, or mixtures thereof. 7. The method according to p. 1, further comprising the step of obtaining a compound of formula III or its salt by halogenation of a compound of formula Sh.Z or its salt

8. The method according to p. 7, in which the halogenation is carried out by a halogenating agent selected from the group consisting of phosphoryl chloride, phosphoryl bromide, thionyl chloride, thionyl bromide, phosphorus chloride (U), phosphorus chloride (III), phosphorus bromide (Y) or phosphorus bromide (III) )  9. The method of claim 7, wherein the halogenation is carried out in the presence of an organic base.  10. The method according to p. 7, further comprising the step of obtaining a compound of formula Sh.Z or its salts by cyanidation of a compound of formula III.2 or its salts

where Hal represents chlorine, bromine, iodine.  11. The method according to p. 10, in which cyanidation is carried out in the presence of a cyanating agent selected from the group comprising zinc cyanide (P), copper cyanide (1).  12. The method according to p. 10, in which cyanidation is carried out in the presence of a catalyst. 13. The method according to p. 10, further comprising the step of obtaining a compound of formula III.2 by heterocyclicization of compound III.1 or its salts

where Hal represents chlorine, bromine, iodine.  14. The method according to p. 13, in which the heterocyclization is carried out in the presence of formamide or formamidine in the form of a salt stable form.  15. The method of claim 1, further comprising the step of preparing a compound of formula II or a salt thereof by reducing a compound of formula II.6

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; n represents 0, 1, 2.  16. The method of claim 15, wherein the reduction is carried out in the presence of an alkali metal borohydride or cyanoborohydride, or using hydrogen in the presence of a catalyst or activator. 17. The method according to p. 1, further comprising the step of obtaining a compound of formula II or its salt by removing a protective group from a compound of formula A.4-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, Ci-C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1;  X is selected from the group including:

 18. The method according to p. 17, in which the removal of the protective group is carried out in the presence of an inorganic or organic acid, or in the presence of hydrazine hydrate.  19. A method of obtaining a compound of formula II or a salt thereof by reducing a compound of formula II.6

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; n represents 0, 1, 2.  20. The method of claim 19, wherein the reduction is carried out in the presence of an alkali metal borohydride or cyanobohydride, or in the presence of hydrogen and a catalyst or activator.  21. The method of claim 19, further comprising the step of preparing a compound of formula II.6, including: (i) the interaction of an organic acid of formula P.5-1

where a represents independently hydrogen or COOH, however, no more than one A represents hydrogen, n represents 0, 1, 2; and aliphatic cyclic amine of the formula

or its salt, where D represents NRi or O; Ri represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens; represents thi? eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; according to the methodology for the preparation of an amide bond with the participation of crosslinking agents of zero length in an organic solvent to obtain a compound of formula II.6; (ii) obtaining an acid halide of the formula A.5-2

where E is independently hydrogen or C (0) H1, however, no more than one E represents hydrogen, n represents 0, 1, 2, Hal represents chlorine, bromine, iodine; from an organic acid of the formula P.5-1 in the presence of an organic solvent and acylation with an acid halide of formula A.5-2 of an aliphatic cyclic amine of the formula

or its salt, where D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butm in the presence of a solvent and a base to obtain a compound of formula P.6. 22. The method of obtaining the compounds of formula II or its salts, including the removal of the protective group from the compounds of formula P.4-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, Ci-C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X represents any protecting group, including one selected from

23. The method according to p. 22, in which the removal of the protective group is carried out in the presence of hydrazine hydrate or acid.  24. The method according to p. 22, further comprising obtaining a compound of formula P.4-2 recovery of the compounds of formula P.3-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O;  i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X represents any protecting group, including one selected from

25. The method according to p. 24, in which the reaction proceeds in the presence of ammonium formate or in the presence of hydrogen.  26. The method according to p. 24, in which the recovery is carried out in the presence of a catalyst.  27. The method according to p. 26, in which the catalysts are catalysts based on palladium, rhodium, ruthenium.  28. The method according to p. 27, in which palladium on carbon is used as a catalyst. 29. A method of obtaining a compound of formula II.6 by acylation with an acid halide of formula P.5-2 of an aliphatic cyclic amine of the formula

or its salt, where D represents NRi or O; i represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; in the presence of a solvent.  30. The method according to p. 29, in which the acylation is carried out in the presence of a base.  31. The method according to p. 29, further comprising the step of obtaining a halide of formula -2

where E is independently hydrogen or C (0) H1, however, no more than one E represents hydrogen, n represents 0, 1, 2, Hal represents chlorine, bromine, iodine; from an organic acid of formula P.5-1 in the presence of an organic solvent.  32. The method of claim 31, wherein the step of producing the halide is carried out in the presence of halogenating agents selected from the group consisting of phosphoryl chloride, phosphoryl bromide, thionyl chloride, thionyl bromide, phosphorus chloride (U), phosphorus chloride (W), phosphorus bromide (U) or phosphorus bromide (III), oxalyl chloride, oxalyl bromide.  33. A method of obtaining a compound of formula II.6, comprising reacting an organic acid of formula P.5-1

where a represents independently hydrogen or COOH, however, no more than one A represents hydrogen, n represents 0, 1, 2; and aliphatic cyclic amine of the formula

or its salt, where D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; according to the methodology for the preparation of an amide bond with the participation of cross-linking agents of zero length in an organic solvent.  34. The method of claim 33, wherein the zero-length crosslinking agents are selected from the group consisting of carbodiimides, isoxazolinium compounds, chloroformates, carbonyldiimidazoles, diethyl pyrocarbonates, dihydroquinolines, phosphonium-containing compounds, ammonium-containing compounds, uronium-containing compounds.  35. The method of obtaining the compounds of formula P.4-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₁ -C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X is selected from the group including:

the recovery of the compounds of formula P.3-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X is selected from the group including:

36. The method according to p. 35, in which the reaction proceeds in the presence of ammonium formate or hydrogen.  37. The method according to p. 35, in which the reaction proceeds in the presence of a catalyst.  38. The method according to p. 37, in which the catalyst is selected from a catalyst based on palladium, rhodium, ruthenium.  39. The method according to p. 38, in which palladium-carbon is used as a catalyst. 40. A method of obtaining a compound of formula P.3-2, including metal-catalyzed arylation of IV

where] represents 0, 1; X is selected from r pp including:

the compound of formula A.2-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens; represents thi? eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; Hal has the above meanings.  41. The method according to p. 40, in which the compound of formula IV is vinylphthalimide.  42. The method according to p. 40, in which the catalyst is a salt of palladium, copper, rhodium, ruthenium.  43. The method according to p. 40, in which the metal-catalyzed arylation is carried out in the presence of a base.  44. The method of claim 43, wherein the base is an organic base selected from tertiary aliphatic amines, or an inorganic base selected from alkali metal carbonates. 45. The compound of formula II.6

where B is independently hydrogen or

more than one B being hydrogen; D represents NRi or O;  i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; and n represents 0, 1, 2. 46. The compound of claim 45, which is:

47. The compound of formula P.5-2.1

where E is independently hydrogen or C (0) C1, with no more than one E being hydrogen; n represents 1, 2.  48. The compound of claim 47, which is:

 2.5-2 49. The compound of formula P.5-2.2

where E is independently hydrogen or C (0) Br, C (0) 1, with no more than one E being hydrogen; n represents 0, 1, 2.  50. The compound of claim 49, which is:

 51. The compound of formula P.3-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O; i represents H, R, C ₄ alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X is selected from the group including:

The compound of claim 51, which is

53. The compound of formula Π.4-2

where B is independently hydrogen or

wherein not more than one B is hydrogen; D represents NRi or O;  i represents H, R, C1-C4 alkyl unsubstituted or substituted by one or more halogens;  R represents thi? Eti-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, triphenylmethyl, pivaloyl, tert-butyl; j represents 0, 1; X is selected from the group including:

provided that when j = 0, X is selected from the group including:

when j = l, X is selected from the group including:

54. The compound of claim 53, which is: