RU2739489C2 - Novel heterocyclic compounds as cdk8/19 inhibitors - Google Patents

Abstract

FIELD: organic chemistry.SUBSTANCE: present invention relates to a compound of formula I.1:or a stereoisomer thereof, where radicals are defined in the claim. Also disclosed is a method of inhibiting the biological activity of cyclin-dependent protein kinases CDK8/19, a pharmaceutical composition, method of treating a disease or disorder, using the compound for treating a disease or disorder.EFFECT: invention discloses novel organic compounds having CDK8/19 inhibitor properties suitable for treating an oncological or haemato-oncological disease.16 cl, 7 tbl, 135 ex

Description

The present invention relates to novel CDK8 / 19 inhibitors, methods for their preparation, pharmaceutical compositions containing these compounds, and the use of such compounds or such compositions for the treatment of diseases or disorders.

State of the art

CDK8, along with the closely related isoform CDK19 in terms of structural and functional characteristics, 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, R. & 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 CDK1, CDK2, and CDK4 / 6), CDK8 does not play a role in regulating the cell cycle, but knockout of the CDK8 gene in embryonic stem cells results in embryonic growth arrest (Adler, AS, et al. (2012) CDK8 maintains tumor de-differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139) due to its important role in the formation of the pluripotent stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). It should be noted that blocking CDK8 does not suppress the growth of normal cells (Adler, AS, et al. (2012) CDK8 maintains tumor de-differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139, Kapoor, A., et al. . (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109). The role of CDK8 in carcinogenesis is related to its unique function as a regulator of several transcription factors (Xu, W. & L, J. Y. (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38,439-452). High expression of CDK8 has been identified in colon cancer (Firestein, R., 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), melanoma (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109), while in these types of cancer, increased expression of CDK8 is observed in ~ 50% of cases; a similar situation is observed in breast cancer (Broude E., et al. (2015) Expression of CDK8 and CDK8-interacting genes as potential biomarkers in breast cancer, Curr. Cancer Drug Targets, 15 (8), 739-749). Increased CDK8 expression is associated with a poor prognosis in colon cancer (Gyorffy, V., 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).

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), NF-kB 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 maintain the pluripotent phenotype of embryonic stem cells, and that it may be associated with the phenotype of cancer stem cells (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). DNA damage chemotherapy drugs induce 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 the cytokines CXCL1 and CXCL2, which promote the survival and growth of tumor cells. CXCL 1/2 attracts myeloid cells to the tumor by binding to the CXCR2 receptor on the myeloid cell surface. The myeloid cells then secrete small calcium-binding proteins S 100A8 and A9, which are associated with chronic inflammation and tumor growth. S 100A8 / 9 act on tumor cells, promoting both their metastasis and survival during chemotherapy (Huang, et al. (2012) MED 12 Controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling, Cell 151, 937-950).

The search for new compounds that inhibit cyclin-dependent protein kinases CDK8 / 19 is currently topical.

Description of the invention

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

"Alkyl" means a linear or branched aliphatic hydrocarbon group with 1-12 carbon atoms in the chain, more preferably with 1-6 carbon atoms in the chain. "Branched" means that the alkyl chain has one or more "lower alkyl" substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents that may be the same or different.

"Cycloalkyl" means a fully saturated carbocyclic ring containing 3-10 carbon atoms per ring. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, bicyclic groups such as bicycloheptyl or bicyclooctyl. Cycloalkyl may have substituents that may be the same or different.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthranyl, and others. Aryl may have substituents on the ring system that may be the same or different. Aryl can be annelated with a non-aromatic ring system or a heterocycle.

"Alkyloxy" or "Alkoxy" means an alkyl-O— group in which alkyl is defined in this section. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, and n-butoxy.

"Amino" means an R'R "N— group substituted or unsubstituted optionally with the same substituents R" and R "".

"Alkylsulfonyl" (-S (O) ₂ -C ₁ -C ₆ alkyl) means "alkyl", as defined above, attached to the corresponding moiety through the sulfonyl group —SO ₂ -. Examples of alkylsulfonyls include, but are not limited to, methylsulfonyl, ethylsulfonyl, etc.

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

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

"Heterocycle", "heterocyclyl" or "heterocyclic ring" means a monocyclic or polycyclic system containing from 3 to 11 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. The heterocycle can be fused with aryl or heteroaryl. The heterocycle can have one or more substituents, which can be the same or different. Nitrogen and sulfur atoms in the heterocycle can be oxidized to N-oxide, S-oxide or S-dioxide. The heterocycle can be saturated, partially unsaturated, or unsaturated. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro [4.5] decane, piperazine, morpholine, etc.

“Heteroaryl” means an aromatic monocyclic or polycyclic system of 5 to 11 carbon atoms, preferably 5 to 10, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, sulfur or oxygen. The nitrogen atom in the heteroaryl can be oxidized to the N-oxide. Heteroaryl may have one or more substituents, which may be the same or different. Representatives of heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isooxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, ftainoxazolyl -а] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, pyrazolyl, thienopyridyl, quinazolinyl, naphthyridinyl, thienrolopyrimidinyl, iso-pyridinyl, thienrolopyrimidine , 4-triazinyl, thienopyrrolyl, furopyrrolil, etc.

"Partially unsaturated" means a ring system that includes at least one double or triple bond. The term "partially unsaturated" refers to rings having multiple sites for saturation, but does not include aryl and heteroaryl systems as defined above.

The term "oxo" as used herein refers to the radical = O.

"Substituent" means a chemical radical that attaches to a molecular backbone (scaffold, fragment).

"Solvate" means a molecular complex of a compound of the present invention, including pharmaceutically acceptable salts thereof, with one or more solvent molecules. Such solvent molecules are molecules commonly used in pharmaceuticals that are known to be harmless to the recipient, for example water, ethanol, ethylene glycol, and the like. Other solvents can be used as intermediate solvates in making more desirable solvates such as methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S) -propylene glycol, (R) -propylene glycol, 1,4-butanediol, and the like.

The term "hydrate" refers to a complex in which the solvent molecule is water.

The solvates and / or hydrates preferably exist in crystalline form.

The term "bond", "chemical bond" or "single bond" refers to a chemical bond between two atoms or two groups (groups, fragments), if two atoms connected by a bond are considered part of a larger substructure.

The term "chiral" refers to molecules that have the property of being incompatible with their mirror image, while the term "achiral" refers to molecules that have the property of being compatible with their mirror image.

The term "stereoisomers" refers to compounds that have the same chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers can include geometric isomers, enantiomers, diastereomers.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality, and such molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound, which are mirror images of each other that cannot be spatially compatible.

The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers with no optical activity. The enantiomers can be isolated separately from the racemic mixture by chiral separation techniques such as supercritical liquid chromatography (SFC).

The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule relative to its chiral center (s). A particular stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture.

The term "anthropoisomers" refers to compounds with spatial isomerism caused by the lack of rotation around a simple bond, for example, in biphenyls, dinaphthyls and others.

The term "protecting group" refers to groups that are used to block the reactivity of functional groups such as amino, carboxyl, or hydroxy groups. Examples, without limitation, of protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2- (trimethylsilyl) ethoxy) methyl acetal (SEM), trialkylsilyl, alkyl (diaryl) silyl or alkyl.

The term "excipient" is used herein to describe any ingredient other than the compound (s) of this invention.

"Pharmaceutical composition" means a composition comprising a compound of the invention and at least one excipient. The excipient can be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing and receptive agents, delivery agents such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners , sweeteners, flavors, flavorings, antibacterial agents, fungicides, lubricants, delayed delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents that delay the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of grinders and dispensers are starch, alginic acid and its salts, silicates and the like. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

"Pharmaceutically acceptable salt" means relatively non-toxic salts of a compound of the present invention. Salts of the compounds provided for in this document can be obtained from inorganic or organic acids and bases. Examples of the salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like; salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum, salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, ethylenediamine, glucosamine, methylglucamine, theobromine, description of purines, piperapidin, N-piperidine salts are given in Berge SM, et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Amino acids - lysine, ornithine and arginine - can be used as amino acids.

"Medicinal product (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms, intended for the restoration, correction or change of physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Treat", "treatment" and "therapy" refer to a method of alleviating or eliminating a biological disorder and / or at least one of its accompanying symptoms. The term "alleviate" a disease, disease or condition means reducing the severity and / or frequency of the symptoms of a disease, disorder, or condition. In addition, references to “treatment” contained herein include references to curative, palliative and prophylactic therapy.

In one aspect, the subject of treatment or patient is a mammal, preferably a human subject. The aforementioned subject can be male or female of any age.

The term "disorder" means any condition that can be improved by the treatment of the present invention. The definition of this term includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the occurrence of this disorder. Non-limiting examples of treatable diseases include cancers, in particular breast cancer, triple negative breast cancer (TNBC), ovarian cancer, metastatic ovarian cancer, stomach cancer, metastatic stomach cancer, endometrial cancer, salivary gland, lung, kidney, colon, colorectal cancer, melanoma, metastatic melanoma, thyroid, pancreatic, prostate, or bladder cancer; hemato-oncological diseases, leukemia, acute myeloid leukemia and lymphoid malignant neoplasms; neuronal, glial, astrocytal, hypothalamic and other granular, macrophage, epithelial, stromal and blastocoelic disorders; inflammatory, angiogenic and immunological disorders.

A "therapeutically effective amount" is an amount of a therapeutic agent administered during treatment that will relieve to some extent one or more symptoms of the disease being treated.

In the present description and in the following claims, unless the context otherwise requires, the words “have”, “include” and “comprise” or variations thereof such as “has”, “having”, “includes”, “including”, “ contains "or" containing "is to be understood as including the specified whole or group of integers, but not excluding any other whole or group of integers.

Detailed description of the invention

In one embodiment, the present invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof,

where X ₁ represents N, C, CH;

X ₂ X ₃ X ₄ each independently represents C (H) _m , NH, N, CR ₁₃ , CHR ₁₃ ;

L ₁ , L ₂ each independently represents a chemical bond, -C (R _6b ) ₂ -, -O-, -C (O) -, -C (O) -O-, -NH-, -C (= NR ₁₉ ) -;

n, k are each independently selected from 0, 1;

m represents 0, 1, 2;

R ₁ , R ₃ , R _{13 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl, NH ₂ ;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR _7a -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _{6b are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by R ₈ and R ₉ can be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyl; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy;

каждая независимо представляет собой одинарную связь или двойную связь;

each independently represents a single bond or a double bond;

Hal represents chlorine, bromine, iodine, fluorine.

In yet another embodiment, the present invention relates to a compound of Formula I wherein R _{3 is} each independently H, Hal.

In yet another embodiment, the present invention relates to a compound of formula I, wherein L ₁ , L _{2 are} each independently a chemical bond, —C (O) -, —C (O) —O—, —NH—, —C (= NH) -.

In yet another embodiment, the present invention relates to a compound of formula I.1:

where X ₄ represents C (H) _m , N;

m represents 0, 1;

X ₁ represents N, C, CH;

X ₂ , X _{3 are} each independently C (H) _m , NH, N, CR ₁₃ , CHR ₁₃ ;

L ₁ , L ₂ each independently represents a chemical bond, -C (R _6b ) ₂ -, -O-, -C (O) -, -C (O) -O-, -NH-, -C (= NR ₁₉ ) -;

n, k are each independently selected from 0, 1;

R ₁ , R ₃ , R _{13 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl, NH ₂ ;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR _7a -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _{6b are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by R ₈ and R ₉ can be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyl; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy;

R ₁₅ , R ₁₆ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy;

каждая независимо представляет собой одинарную связь или двойную связь;

each independently represents a single bond or a double bond;

Hal represents chlorine, bromine, iodine, fluorine.

In yet another embodiment, the present invention relates to a compound of formula I.1 wherein R _{3 is} each independently H, Hal.

In yet another embodiment, the present invention relates to a compound of formula I.1, wherein L ₁ , L _{2 are} each independently a chemical bond, —C (O) -, —C (O) —O, —NH—, —C ( = NH) -.

In yet another embodiment, the present invention relates to a compound of formula I.2:

where X ₁ represents C, CH, N;

X ₂ X _{3 are} each independently N, CR ₁₃ ;

L ₁ , L ₂ each independently represents a chemical bond, -C (R _6b ) ₂ -, -O-, -C (O) -, -C (O) -O-, -NH-, -C (= NR ₁₉ ) -;

k is 0, 1;

R ₁ , R ₃ , R _{13 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl, NH ₂ ;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR _7a -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _{6b are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by and R ₉ may be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloaclkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₁₉ , R _{20 are} each independently H, C ₁ -C ₆ alkyl.

In yet another embodiment, the present invention relates to a compound of formula I.4:

where L ₁ , L ₂ , R ₁ , R ₂ , R ₃ , R ₄ , k have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.5a:

where L ₁ , L ₂ , R ₂ , R ₃ , R ₄ , R ₁₃ have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.5:

where L ₁ , L ₂ , R ₂ , R ₃ , R ₄ have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.6:

where X ₂ X ₃ each independently represents C (H) _m , NH, N, CR ₁₃ , CHR ₁₃ ;

X ₁ , X _{4 are} each independently C, CH, N;

L ₁ , L ₂ each independently represents a chemical bond, —C (R _6b ) ₂ -, —O—, —C (O) -, —NH—, —C (= NR ₁₉ ) -;

k is 0, 1;

m represents 1, 2;

R ₁ , R ₃ , R _{13 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl, NH ₂ ;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR _7a -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _{6b are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by R ₈ and R ₉ can be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloaclkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R _{24 are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; R ₁₉ , R _{20 are} each independently H, C ₁ -C ₆ alkyl;

каждая независимо представляет собой одинарную связь или двойную связь.

each independently represents a single bond or a double bond.

In yet another embodiment, the present invention relates to a compound of formula I.7:

имеют вышеуказанное значение.where X ₁ , X ₂ , X ₄ , L ₁ , L ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₁₃ , k

have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.8:

where L ₁ , L ₂ , R ₁ , R ₂ , R ₃ , R ₄ have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.9:

where L ₁ , L ₂ , R ₂ , R ₃ , R ₄ have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula I.10:

где X₁, Х₂, Х₃, L₁, L₂, R₁, R₂, R₃, R₄, n, k имеют вышеуказанное значение.

where X ₁ , X ₂ , X ₃ , L ₁ , L ₂ , R ₁ , R ₂ , R ₃ , R ₄ , n, k have the above meaning.

In another embodiment, the present invention relates to a compound of formula I, I.1-I.10, wherein R ₅ is H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, which is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, representing 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, unsubstituted or substituted with one or more substituents selected from the group consisting of from Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ .

In yet another embodiment, the present invention relates to a compound of formula I, I.1-I.10, wherein R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ - C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, representing 4-morpholinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-piperazinyl, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, representing thiophenyl, imidazolyl, pyrazolyl, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl.

Hal represents chlorine, bromine, iodine, fluorine.

In yet another embodiment, the present invention relates to a compound of formula Ia:

or a pharmaceutically acceptable salt or stereoisomer thereof,

where X ₁ represents N, C, CH;

X ₂ , X ₃ , X _{4 are} each independently C (H) _m , NH, N, CR ₁₃ ;

L ₁ , L ₂ each independently represents a chemical bond, —C (R ₆ ) ₂ -, —O—, —C (O) -, —NH—, —C (= NR ₁₉ ) -;

n, k are each independently selected from 0, 1;

m represents 0, 1, 2;

R ₁ , R ₃ , R _{13 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR ₇ -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ each independently represents H, Hal, hydroxy, C ₁ -C ₆ alkyloxy;

R ₇ each independently represents H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by R ₈ and R ₉ can be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl;

R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R _{24 are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₁₉ , R _{20 are} each independently H, C ₁ -C ₆ alkyl;

каждая независимо представляет собой одинарную связь или двойную связь;

each independently represents a single bond or a double bond;

Hal represents chlorine, bromine, iodine, fluorine.

In yet another embodiment, the present invention relates to a compound of formula Ia wherein R ₁ , R _{3 are} each independently H, Hal.

In yet another embodiment, the present invention relates to a compound of formula Ia wherein L ₁ , L _{2 are} each independently a chemical bond, —C (O) -, —NH—, —C (= NH) -.

In yet another embodiment, the present invention relates to a compound of formula Ia.1:

where X ₄ represents C (H) _m , NH, N;

m represents 0, 1;

имеют вышеуказанное значение.X ₁ , X ₂ , X ₃ , L ₁ , L ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₁₃ , n, k,

have the above meaning.

In yet another embodiment, the present invention relates to a compound of formula Ia.1, wherein R ₁ , R _{3 are} each independently H, Hal.

In another embodiment, the present invention relates to a compound of formula Ia.1, wherein L ₁ , L _{2 are} each independently a chemical bond, —C (O) -, —NH—, —C (= NH) -.

The compounds described in the present invention can be obtained in the form and / or can be used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: acid salts formed by reacting a free base compound with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acids and the like; or with an organic acid such as acetic, propionic, nylon, cyclopentanpropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, trifluoroacetic, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic, glucose methylene-bis-3-hydroxy-2-ene-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, etc .; base salts formed by reacting the compound in the free acid form with a pharmaceutically acceptable inorganic base such as a metal or ammonium cation hydroxide, carbonate or bicarbonate, or with an organic base. Pharmaceutically acceptable salt cations include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, iron, zinc, copper, manganese, aluminum; examples of organic bases include, but are not limited to, a primary, secondary, or tertiary amine (e.g. isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine), a substituted amine, including a naturally occurring substituted amine (e.g., lysine, arginine, histidine, caffeine, choline), cyclic amine, dicyclohexylamine, procaine, ethanolamine, 2-diethylaminoethanol, hydrabamine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidi.

The corresponding counterions of pharmaceutically acceptable salts can be investigated and identified using a variety of methods, including but not limited to: ion exchange chromatography, ion chromatography, capillary electrophoresis, plasma induction coupling, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered using at least one of the following methods: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation or, in the case of aqueous solutions, lyophilization. It is to be understood that the reference to a pharmaceutically acceptable salt includes solvent addition salt forms or crystalline forms thereof, in particular solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and can be formed during a crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described in this patent can be readily prepared or formed in the methods described in the present invention. In addition, the compounds provided by the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms when describing the compounds and methods provided by the present invention.

The compounds described in the present invention can be presented in various forms, including listed, but not limited to: structureless forms, milled forms and nanoparticles. In addition, the compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include crystals with different structures and the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, different infrared spectra, melting points, different densities, hardness, crystalline form, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, degree of crystallization and storage temperature can lead to the dominance of one crystalline form.

Screening and characterization of pharmaceutically acceptable salts, polymorphs and / or solvates can be performed by a number of methods including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods are aimed at studying thermochemical decomposition or thermophysical processes, including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationship between polymorphic forms, determine the mass loss, to find the glass transition temperature or to study compatibility with a filler. Such techniques include, without limitation, differential scanning calorimetry (DSC), modulating differential scanning calorimetry (MDSC), thermogravimetric analysis (TGA), thermogravimetric and infrared analysis (TG / IR). Crystallographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to: Raman (Raman), FTIR, UVIS, and NMR (liquid and solid). Various microscopy techniques include, but are not limited to: polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive x-ray analysis (EDX), scanning electron microscopy in vivo with EDX (gas or water vapor), IR microscopy and Raman microscopy.

In yet another embodiment, the present invention relates to a compound selected from the group consisting of:

The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes that demonstrate methods by which the compounds of the present invention can be prepared. The starting products can be obtained from commercial sources or obtained using conventional methods in the art, known to the average specialist. It will also be apparent to those of ordinary skill in the art that the selective deprotection and deprotection steps, as well as the order in which these steps are carried out, can be performed in varying order, depending on the nature of the substituents, to successfully complete the synthesis presented below.

Abbreviations used in the present description, including those given in the illustrative diagrams and the following examples, are well known to the average specialist. Some of the abbreviations are used like the following:

dimethyl sulfoxide - DMSO

(±) -2,2'-bis (diphenylphosphino) -1,1'-dinaphthalene - BINAP

4-methylbenzenesulfonic acid - PTSA

4-Dimethylaminopyridine - DMAP

N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride - EDC⋅HCl

1-hydroxybenzotriazole hydrate - HOBt

diisopropylethylamine - DIPEA

N, N-dimethylformamide - DMF

tetrakis (triphenylphosphine) palladium (0) - Pd (PPh ₃ ) ₄

tetrahydrofuran - THF

2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl - XPhos

methyl tert-butyl ether - MTBE

diphenylphosphoryl azide - DPPA

2- (trimethylsilyl) ethoxymethyl chloride - SEMC1.

Compounds of the present invention can be prepared according to Scheme 1.

Scheme 1.

where X ₂ , X ₃ each independently represents C (H) _m , N, NH;

X ₁ each independently represents C, CH, N;

L ₁ , L ₂ each independently represents a chemical bond, —C (R ₆ ) ₂ -, —O—, —C (O) -, —NH—, —C (= NR ₁₉ ) -;

n is 0, 1;

k is 0, 1;

m represents 1, 2;

R ₁ , R _{3 are} each independently H, Hal, cyano, C ₁ -C ₆ alkyl;

R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR₁₁R₁₂; C₁-С₆ алкил, незамещенный или замещенный одним или несколькими заместителями R₁₄;

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ X ₆ X ₇ each independently represents C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —CH ₂ -, —NH—, —C (O) —NR ₇ -, —C (= NH) -;

p = 0, 1, 2, 3, 4;

R ₅ represents H; Hal; cyano; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ each independently represents H, Hal, hydroxy, C ₁ -C ₆ alkyloxy;

R ₇ each independently represents H, C ₁ -C ₆ alkyl;

R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ , —CN, —C (O) —OR ₂₀ ; or

R ₈ and R ₉ together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring with 1-2 heteroatoms selected from nitrogen and / or oxygen, where the heterocyclic ring formed by R ₈ and R ₉ can be unsubstituted or substituted with 1 or 2 substituents selected from oxo group, C ₁ -C ₆ alkyl;

R _{10 is} each independently selected from the group consisting of H, Hal, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and / or S, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl;

R ₁₁ , R _{12 are} each independently H, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl;

R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R _{24 are} each independently H, C ₁ -C ₆ alkyl;

R ₁₇ , R _{18 are} each independently H, C ₁ -C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy;

R ₁₉ , R _{20 are} each independently H, C ₁ -C ₆ alkyl;

Y each independently represents H, Hal, NH ₂ , OH, —B (OH) ₂ , —CON (Me) —OMe, —C (O) Cl;

A, W represents H, Hal, CN, —C (O) OH, —C (O) Cl.

In the case when OH, NH groups are present in the starting reagents and intermediate compounds, they can be protected with (2- (trimethylsilyl) ethoxy) methyl acetal, trialkylsilyl or alkyl (diaryl) silyl protecting groups.

The reaction between compound 1 and compound B to form compound 2 can be carried out by the reactions: Suzuki between aryl halide 1 and aryl boronic acid B in the presence of a palladium catalyst and a base (A = Hal, Y = -B (OH) ₂ ); Buchwald-Hartwig between aryl halide 1 and amine B in the presence of a palladium catalyst and a base (A = Hal, Y = H); between carboxylic acid 1 and amine B according to the methodology for obtaining an amide bond with the participation of carbodiimide (A = COOH, Y = H); between the carboxylic acid chloride 1 and amine B according to the methodology for obtaining an amide bond in the presence of a base such as trialkylamine (A = C (O) Cl, Y = H). The synthesis of compound 3 from compound 2 and compound C can be carried out using the reactions: Suzuki between aryl halide 2 and aryl boronic acid C in the presence of a palladium catalyst and a base (W = Hal, Y = -B (OH) ₂ ); Buchwald-Hartwig between aryl halide 2 and amine C in the presence of a palladium catalyst and a base (W = Hal, Y = H); between carboxylic acid 2 and amine C according to the methodology for obtaining an amide bond with the participation of carbodiimide (W = COOH, Y = H); between the carboxylic acid chloride 2 and amine C according to the methodology for obtaining an amide bond in the presence of a base such as trialkylamine (W = C (O) Cl, Y = H); between carbonitrile 2 and amine C according to the methodology for the preparation of amidines using organomagnesium reagents (W = CN, Y = H). The synthesis of compound 5 from compound 4 and compound C can be carried out using the reactions: Suzuki between aryl halide 4 and aryl boronic acid C in the presence of a palladium catalyst and a base (W = Hal, Y = -B (OH) ₂ ); Buchwald-Hartwig between aryl halide 4 and amine C in the presence of a palladium catalyst and a base (W = Hal, Y = H); between carboxylic acid 4 and amine C according to the methodology for obtaining an amide bond with the participation of carbodiimide (W = COOH, Y = H); between the carboxylic acid chloride 4 and amine C according to the methodology for obtaining an amide bond in the presence of a base such as trialkylamine (W = C (O) Cl, Y = H); between carbonitrile 4 and amine C according to the methodology for the preparation of amidines using organomagnesium reagents (W = CN, Y = H); between compound 4 and acid chloride C by acylation reaction (W = H, Y = C (O) Cl); between aryl halide 4 and Weinreb amide C according to the Grignard reaction (W = Hal, Y = C (O) N (Me) -OMe). The reaction between compound 5 and compound B to form compound 3 can be carried out according to the reactions: Suzuki between aryl halide 5 and aryl boronic acid B in the presence of a palladium catalyst and a base (A = Hal, Y = -B (OH) ₂ ); Buchwald-Hartwig between aryl halide 5 and amine B in the presence of a palladium catalyst and a base (A = Hal, Y = H); between carboxylic acid 5 and amine B according to the methodology for obtaining an amide bond with the participation of carbodiimide (A = COOH, Y = H); between the carboxylic acid chloride 5 and amine B according to the methodology for obtaining an amide bond in the presence of a base such as trialkylamine (A = C (O) Cl, Y = H).

Compound 2 'is a variant of compound 2, where W is halogen, n = 1, and can be prepared according to Scheme 2.

Scheme 2.

where X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , L ₁ , k, Hal, Y have the above meanings.

The reaction between compound 6 and compound B to form compound 7 can be carried out in a similar manner according to the methods described above and used to obtain compound 2 from compound 1 and compound B. Compound 2 'can be obtained by reacting compound 7 with a phosphorus halide or oxyhalide such as POCl ₃ , PBr ₃ .

Compound 5 'is a variant of compound 5, where A is halogen, and can be prepared from compound 8 according to Scheme 3.

Scheme 3.

where X ₁ , X ₂ , X ₃ , R ₁ , R ₃ , R ₄ , L ₂ , n, k, Hal, Y have the above meanings.

Compound 9 can be prepared by reacting 8 with diphenylphosphoryl azide in tert-butanol with heating. The synthesis of compound 10 from compound 9 and compound C can be carried out using the reactions: Suzuki between aryl halide 9 and aryl boronic acid C in the presence of a palladium catalyst and a base (Y = -B (OH) ₂ ); Buchwald-Hartwig between aryl halide 9 and amine C in the presence of a palladium catalyst and a base (Y = H). Compound 11 can be prepared by reacting compound 10 with a strong acid such as HCl or trifluoroacetic acid. Compound 5 'can be prepared from compound 11 by a diazotization reaction with sodium nitrite and subsequent replacement of the diazonium group with a halogen by reaction with an appropriate metal halide such as potassium iodide.

Compound 3 'is a variant of Compound 3 wherein L ₂ is —C (O) - and Compound 2' can be converted to Compound 3 'according to Scheme 4.

Scheme 4.

where X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , R ₄ , L ₁ , n, k, Hal, Y have the above meanings.

Compound 12 can be prepared from compound 2 'by a cyanidation reaction in the presence of zinc cyanide and a palladium catalyst. Compound 12 can be hydrolyzed to compound 13 by the action of an aqueous alcoholic alkali solution with heating. Compound 3 'can be obtained by the reaction between carboxylic acid 13 and amine C according to the methodology for obtaining an amide bond with the participation of carbodiimide.

Compound 3 ″ is a variation of Compound 3, where L ₂ is —C (N = R ₁₉ ) - and Compound 12 can be converted to Compound 3 ″ according to Scheme 5.

Scheme 5.

where X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , R ₄ , R ₁₉ , L ₁ , n, k, Y have the above meanings.

The formation of amidine 3 '' can occur as a result of the reaction of nitrile 12 and amine C in the presence of organomagnesium reagents.

Compound 3 ″ ″ is a variation of compound 3, where L ₁ is —C (O) - and compound 14 can be converted to compound 3 ″ ″ according to Scheme 6.

Scheme 6.

where X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , R ₄ , L ₂ , n, k, Y, Hal have the above meanings.

Compound 15 can be prepared from compound 14 in a similar manner according to the methods described above and used to obtain compound 10 from compound 9 and compound C. Compound 16 can be synthesized by hydrolysis of compound 15 with an aqueous alcoholic alkali solution. The reaction between Compound 16 and Compound B to form 3 ″ ″ can be carried out in the presence of carbodiimide and a base.

Compounds of the present invention can be prepared according to Scheme 7.

Scheme 7.

where R ₂ , R ₄ , L ₁ , Y, Hal have the above meanings.

Compound 18 can be obtained by reacting compound 17 with malonic acid with heating. Compound 19 can be obtained by Suzuki reactions between aryl halide 18 and aryl boronic acid B in the presence of a palladium catalyst and a base (Y = -B (OH) ₂ ) or Buchwald-Hartwig between aryl halide 18 and amine B in the presence of a palladium catalyst and a base (Y = H). Compound 20 can be prepared by reaction with a dehydrating halogenating agent such as thionyl chloride. Compound 21 can be obtained by reacting compound 20 with amine C.

This production method may further include the step of converting compound 21 to compound 22 in the presence of a trialkylamine, Pd / C, under a hydrogen atmosphere.

where R ₂ , R ₄ , L ₁ , Hal have the above meanings.

Compounds of the present invention can be prepared according to Scheme 8.

Scheme 8.

where R ₁ , R ₂ , R ₃ , R ₄ , L ₁ , L ₂ , Y, Hal have the above meanings.

The reaction of compound 23 with amine C can be carried out in the presence of a base such as potassium t-butoxide or diisopropylethylamine in DMSO to give compound 24. Compound 24 can be converted to compound 25 by reaction with compound B in the presence of a catalyst such as a palladium complex compound with organophosphorus ligands. Compound 26 can be obtained from compound 25 by a hydrogen reduction reaction on Pd / C followed by acid catalyzed cyclization with formic acid trialkyl orthoester. The reaction of substituted nitrobenzoic acid 28 with compound B can be carried out in the presence of a non-nucleophilic base such as trialkylamine and carbodiimide to give compound 29. The reaction of compound 29 and amine C to obtain compound 25 is carried out in a similar manner according to the methods described above and used for obtaining compound 24 from compound 23 and compound C. Conversion of compound 24 to compound 27 can be carried out in an analogous manner according to the methods described above and used to obtain compound 26 from compound 25. Compound 27 can be converted to compound 26 in an analogous manner according to with the methods used to obtain compound 25 from compound 24.

Compounds of the present invention can be prepared according to Scheme 9.

Scheme 9.

Compound 30 can be converted to Compound 31 by reaction with an oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide to form an N-oxide, then reacting the resulting N-oxide with a sulfonic acid halide such as benzenesulfonyl chloride or tosyl chloride, and then reacting with an amine, such as ethanolamine or isopropylamine.

In the case when OH, NH groups are present in the starting reagents and intermediate compounds, they can be protected with (2- (trimethylsilyl) ethoxy) methyl acetal, trialkylsilyl or alkyl (diaryl) silyl protecting groups. Removal of the protective group can be carried out in the final stages of the synthesis with a strong acid such as HCl or trifluoroacetic acid.

In the case when the radicals R ₂ , R ₄ in the final structures contain an ester group -COOC ₁ -C ₆ alkyl, then this ester group can be converted into a group -COOH by interaction with strong bases such as lithium, sodium or potassium hydroxide, followed by treatment with an acid such as hydrochloric or citric. Further, such a —COOH group can be converted into a —C (O) NH ₂ functional group by reaction with ammonium chloride in the presence of carbodiimmide; or can be converted to a -C (O) -NH-S (O) ₂ -C ₁ -C ₆ alkyl functional group by reaction with a C ₁ -C ₆ alkyl-S (O) ₂ -NH ₂ . In the case when in the final structures the radicals R ₂ , R ₄ contain the CN functional group, it can be hydrolyzed to the —C (O) NH ₂ functional group. An NH group in a heterocyclic moiety, eg pyrazole, can be converted to an NC ₁ -C ₆ alkyl group using alkylating reagents such as methyl iodide, ethyl bromide, isopropyl iodide in the presence of a base such as sodium hydride. The —OC ₁ —C ₆ alkyl group can be converted to an OH group by reaction with AlCl ₃ with heating. The azetidine ring can be opened by the action of a hydrohalic acid such as hydrochloric acid to form a hydrogen halide adduct. Intermediates can optionally be prepared and isolated in the form of acid salts, for example, hydrochloride, trifluoroacetate and others, or with bases, for example, sodium, potassium, ammonium trialkylammonium and other salts.

The present invention also relates to a method of inhibiting the biological activity of cyclin-dependent protein kinases CDK8 / 19 in a subject, comprising contacting the cyclin-dependent protein kinases CDK8 / 19 with a compound described herein.

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate thereof, and one or more pharmaceutically acceptable excipients. In yet another embodiment, the pharmaceutical composition of the present invention is intended for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19. In yet another embodiment, the pharmaceutical composition of this invention is for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, wherein the disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological or hemato-oncological disease. In yet another embodiment, the pharmaceutical composition of this invention is intended for the prevention or treatment of colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC), prostate cancer, metastatic ovarian cancer, metastatic stomach cancer, leukemia , acute myeloid leukemia, pancreatic cancer (PCa).

The pharmaceutical composition of the present invention contains, for example, from about 10% to about 100% of the active ingredients, preferably from about 20% to about 60% of the active ingredients. It is understood that the content of the active ingredient or ingredients in an individual dose of each dosage form is not necessarily an effective amount, since the required effective amount can be achieved by administering several unit dosage forms.

A typical composition is prepared by mixing a compound of the present invention and a carrier, diluent, or excipient. Suitable carriers, diluents and excipients are well known to those of skill in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend on the means and purpose for which the compound of the present invention is used. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The compositions can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, glidants, processing aids, colors, sweeteners, fragrances, flavors, and others. known additives to obtain a good appearance of the drug or to assist in the manufacture of a pharmaceutical product (i.e., drug).

The pharmaceutical compositions can also include salts, solvates and hydrates of the compounds of the present invention, or a stabilized form of the compound (eg, a complex with a cyclodextrin derivative or other known complexing agent).

The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral intake of medicines - taking medicine by mouth (Latin per os, oris), by swallowing the medicine. The compounds of the present invention can also be administered buccal, lingual, or sublingual so that the compound enters the bloodstream directly from the oral cavity.

Dosage forms suitable for oral, buccal, lingual or sublingual administration include solid, semi-solid, and liquid systems such as tablets; granules; soft or hard capsules containing multi- or nanoparticles, liquids or powders; lozenges (including liquid-filled); chewable forms; gels; rapidly dissolving dosage forms; films; suppositories; sprays; and buccal / mucoadhesive patches.

Liquid dosage forms include suspensions, solutions, syrups, and elixirs. Such dosage forms can be used as fillers in soft or hard capsules (for example, gelatin or hydroxypropyl methylcellulose) and usually contain a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil and one or more emulsifiers and / or suspending agents. ... Liquid dosage forms can also be prepared by reconstitution of a solid, for example from a sachet.

The compounds of the present invention can also be administered parenterally. As used herein, the term "parenteral administration" of a pharmaceutical composition includes any route of administration that physically disrupts the tissue of the subject and administers the pharmaceutical composition through a tissue disruption, typically resulting in direct entry into the bloodstream, muscle, or an internal organ. Thus, parenteral administration includes, but is not limited to, administering the pharmaceutical composition by injecting the composition, by administering the composition through a surgical incision, by applying the composition via a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intraarticular injection or infusion; and renal dialysis infusion techniques. Intratumoral delivery, such as intratumoral injection, may also be helpful. Regional perfusion is also provided.

Dosage forms of pharmaceutical compositions suitable for parenteral administration usually contain the active ingredient in combination with a pharmaceutically acceptable carrier, for example sterile water or sterile isotonic solution. Such dosage forms can be manufactured, packaged or sold in a form suitable for bolus administration or continuous administration. Injectable dosage forms can be manufactured, packaged, or sold in unit dosage form, such as ampoules, or in multi-dose containers containing a preservative. Dosage forms for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous bases, pastes, and the like.

Dosage forms can be made for immediate and / or modified release. Modified release dosage forms include delayed, sustained, pulsed, controlled, targeted, and programmed release.

In one embodiment, the present invention relates to a method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, which comprises administering in a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention, to a subject in need of such treatment.

In yet another embodiment, the present invention relates to a method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, which is an oncological or hemato-oncological disease, which comprises administering a compound described herein or a pharmaceutical composition of this invention to a subject, in need of such treatment, in a therapeutically effective amount.

In another embodiment, the present invention relates to a method of treatment described above, wherein the cancer or hemato-oncological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC), prostate cancer, metastatic ovarian cancer, metastatic stomach cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa).

It is contemplated that the compounds of this invention can be used in methods of treatment as described above, can be used in treatment as described above and / or can be used in the manufacture of medicaments for treatment as described above.

As used herein, the terms "co-administration," "co-administered," and "in combination with," referring to these compounds with one or more other therapeutic agents, are intended to mean, refer to, or include:

- simultaneous administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form, from which said components are released substantially simultaneously,

- simultaneous administration of such a combination of a compound according to this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated separately in different dosage forms, the administration of which occurs at almost the same time to the specified patient, after which these components are released almost simultaneously,

- sequential administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated separately from each other in separate dosage forms, which are taken sequentially in time by the specified patient with a significant time interval between each administration, after which these components are released at different times; and

- sequential administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form, from which the release of these components occurs in a controlled manner, after which they are simultaneously, sequentially or jointly released into one and the same time and / or different times, where each part can be entered in one or different ways.

It is known to those skilled in the art that therapeutically effective dosages may vary when drugs are used in combination therapy. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of uniform dosage, i.e. the introduction of more frequent and lower doses to minimize toxic side effects has been described in the literature. Combination treatments also include intermittent treatments that start and stop at different times according to the patient's treatment plan. In the combination therapy described in the present patent, the dosages of the co-administered compounds will obviously vary depending on the type of adjuvant used, the specific drug used, the disease or condition being treated, etc.

In addition, the compounds described in the present invention can also be used in combination with procedures that can provide additive or synergistic benefits to the patient. By way of example only, patients are expected to receive therapeutic and / or prophylactic benefits in the methods described in this patent, in which a pharmaceutical composition of a compound of the present invention and / or combination with other therapies is combined with a genetic study to determine whether whether the subject is a carrier of a mutant gene known to be correlated with certain diseases or conditions.

Compounds that are inhibitors of CDK8 / 19 can be used in the methods of treatment described above, as monotherapy or in combination with surgery or radiation therapy or drug therapy.

Such drug therapy may include the administration of one or more anti-cancer agents. Examples of anti-cancer agents include, without limitation, any of the following agents: alkylating agents, alkylated sulfonates, nitrosoureas, or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; antineoplastic antibiotics; topoisomerase inhibitors.

Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, calcium levofolinate) or pyrimidine analogs (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxouridin, gemotabine, azofacidine sapacitabine, elacitarabine, doxifluridine), or purine analogs (eg, mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine), or asparaginase.

Examples of alkylating agents include, but are not limited to, mechloroethamine, cyclophosphamide, chlorambucil, menphalan, bendamustine, hexamethylimelamine, thiotepa, busulfan, carmustine, lomustine, laromustine, semustine, streptozocin, dacarbazdobazine, mitrosulfamide, nimphosphamine treosulfan, carbokhion, apazichion, fotemustine, altretamine, glufosfamide, pipobroman, trophosphamide, uramustine, evophosphamide, VAL-083.

Examples of hormonal agents and hormone antagonists include, but are not limited to, prednisone, prednisolone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, diethylstilbestrol, estradiol, tamoxifen, testosterone propionate, fluoxymesterone, florotidlutamide, leuprolicerone, leuprolicerone , degarelix, dexamethasone, fluocortolone, fulvestrant, goserelin, histrelin, leuprorelin, mitotan, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin-alpha, toremifene, tryptorelin-epithelium, diethrolitholutamide , anastrozole, exemestane, fadrozole, letrozole, testolactone, formestan.

Examples of platinum compounds include, without limitation, cisplatin, carboplatin, oxaliplatin, eptaplatin, myriplatin hydrate, lobaplatin, nedaplatin, picoplatin, satraplatin.

Examples of antineoplastic antibiotics include, but are not limited to, doxorubicin, daunorubicin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pyrubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plinicamycintocyntocystinitis.

Examples of topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, belotecan, teniposide, etoposide, voreloxin, amonafide.

Examples of anti-cancer agents include, but are not limited to, any of the following agents: microtubule-acting drugs such as taxanes (eg, paclitaxel, docetaxel, cabazitaxel, tesetaxel), vinca alkaloids (eg, vinorelbine, vinblastine, vincristine, vindesine, vinflunine); inhibitors of mitogen-activated protein kinase signaling (eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmanin, or LY294002); mTOR inhibitors (eg sirolimus, temsirolimus, everolimus, ridaforolimus); antibodies (e.g., rituximab, trastuzumab, alemtuzumab, besilesomab, cetuximab, denosumab, ipilimumab, bevacizumab, pertuzumab, nivolumab, ofatumumab, panitumumab, tositumomab, katumaksomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, netsitumumab, nimotuzumab, obinutuzumab, okaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, EDM-525797); kinase inhibitors (fosmatanib, entospletenib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dasatinib, regorafenib, ruxolitinib, sorafenib, sunitinibiate, axolitinibitinit , nintedanib, lenvatinib, linifanib, linsitinib, masitinib, motesanib, neratinib, orantinib, ponatinib, radotinib, tipifarnib, tivantinib, tivosanib, tramethinib, apatinib, ibrutinibnib, calabrutiranibiranibi rigosertib, pimacertib, buparlisib, idealisib, midostaurin, perifosin, XL-647); photosensitizers (eg, thalaporphin, temoporfin, sodium porfimer); cytokines (e.g. aldesleukin, interferon alpha, interferon alpha-2a, interferon alpha-2b, celmoleukin, tasonermin, recombinant interleukin-2, oprelvekin, recombinant interferon beta-1a); vaccines (for example, picibanil, sipuleucel-T, witespen, emepepimut-S, oncoVAX, rindopepimut, troVAX, MGN-1601, MGN-1703); bisantren, decitabine, mitoxantrone, procarbazine, trabectedin, amsacrine, brostallitsin, miltefosine, romidepsin, plitidepsin, eribulin, Ixabepilone, fosbretabulin, denileukin diftitoks, ibritumomab tiuxetan, prednimustine, trastuzumab emtanzin, estramustine, gemtuzumab-ozogamicin, Aflibercept, oportuzumab monatoks, tsintredekin besudoks , edotreotide, inotuzumab-ozogamicin, naptumomab estafenatox, vintafolide, brentuximab vedotin, bortezomib, ixazomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, zoledronic acid, ibandronic acid, tretino pamidinodinodinotin mithamurtide, romurtide, pegaspargase, pentostatin, endostatin, sizofiran, vismodegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide, etanidazole, ganetespib, idronoxil, iniparib, lonidamine, nimostatine, tilophazole, telistostatine trabedersen, ubenimex, valspodar, gendicin, reol isin, retaspimycin, trebananib, virulizin.

In one embodiment, the present invention relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention, for the treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 in a subject in need of such treatment.

In another embodiment, the present invention relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention, in a subject in need of such treatment for the treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 , which is an oncological or hemato-oncological disease.

In yet another embodiment, the present invention relates to the use of a compound described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention, for the treatment of a subject with colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC ), prostate cancer, metastatic ovarian cancer, metastatic stomach cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa). In any of the above treatments, the subject may be human.

The compounds of the present invention will be administered in an amount effective to treat the condition in question, i. E. in doses and for periods of time necessary to achieve the desired result. The therapeutically effective amount may vary depending on factors such as the particular condition being treated, the age, sex, and weight of the patient, and whether the administration of these compounds is self-treatment or in combination with one or more additional treatments.

Dosing regimens can be adjusted to provide the optimal desired response. For example, a single dose may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the severity of the therapeutic situation. It is particularly useful to formulate oral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as dosage units for the patients / subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

In addition, it should be understood that for any particular patient, specific administration regimens should be adjusted over time according to the individual need and at the discretion of the healthcare professional who administers or controls the administration of the compositions, and that the concentration ranges given in this description are given only by way of example and are not intended to limit the scope or practice of the claimed compositions. In addition, the dosage regimen with the compositions of this invention may be based on various factors including the type of disease, age, weight, sex, health status of the patient, severity of the condition, route of administration, and the particular compound of the present invention used. Thus, the dosage regimen can vary widely, but can be determined regularly using standard methods. For example, doses can be adjusted based on pharmacokinetic and pharmacodynamic parameters, which can include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses individual dose escalation as determined by the skilled artisan. Determination of the required dose and regimens are well known in the relevant art and will be understood by the person skilled in the art upon reading the ideas disclosed herein.

Typically, dosages used to treat an adult are typically in the range of 0.02-5000 mg per day, or about 1-1500 mg per day.

When the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which the alleviated disease, disorder, or condition is maintained. Patients may, however, require intermittent treatment over time for any recurrence of symptoms.

The above spectrum is only speculative, as the number of variables in relation to the individual treatment regimen is large, and significant deviations from these recommended values are quite common. These dosages can be varied depending on many variables, not limited to the activity of the compound used, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the attending physician.

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

All publications, patents and patent applications mentioned in this specification are incorporated by reference in this document. Although the aforementioned invention has been described in some detail by way of illustration and example in order to avoid ambiguity, it will be readily apparent to those skilled in the art based on the teachings disclosed in this invention that certain changes and modifications can be made without departing from the spirit and scope of the accompanying variations. implementation of the invention.

Examples of

Example 1. Method for preparing compound BCD-CDK8-1-6e.

Stage 1. Potassium tert-butylate (1.15 g, 10.2 mmol) was added to a solution of 4-bromo-2-fluoronitrobenzene (1.50 g, 6.82 mmol) and methyl 4-aminobenzoate (891 mg, 6.50 mmol) in 100 ml of DMSO. The reaction mixture was stirred at room temperature for 6 h, then poured into 500 ml of water. The suspension was filtered off, the precipitate was washed with water, dissolved in ethyl acetate, and washed with 0.1 M HCl solution. The solvent was distilled off in a vacuum. Product 1-1-3 was isolated by column chromatography on silica gel using hexane-ethyl acetate (8: 2) as an orange powder. Yield 1.33 g (55%).

Stage 2. Obtaining compound 1-1-2.

To a solution of tert-butyl 3- (phenylcarbamoyl) azetidine-1-carboxylate (500 mg, 1.81 mmol) (prepared according to the procedure described in WO 2000/071518) in 5 ml of dichloromethane was added trifluoroacetic acid (0.70 ml, 7.5 mmol). The mixture was stirred for 12 h, after which the solvent was distilled off in vacuo. The residue was dried on a rotary evaporator at 45 ° C and used in the next step without further purification.

Stage 3. A mixture of compounds 1-1-3 (776 mg, 2.22 mmol), 1-1-2 (1.28 g, 4.42 mmol), Cs ₂ CO ₃ (2.52 g, 7.73 mmol), BINAP (138 mg, 0.222 mmol ) and palladium (II) acetate (25 mg, 0.111 mmol) in 15 ml of 1,4-dioxane was stirred under an inert atmosphere for 15 h at 80 ° С. Ethyl acetate was added to the reaction mixture, washed with 0.1 M HCl solution, saturated NaHCO ₃ and NaCl solutions. The organic phase was concentrated in vacuo. Product 1-1-1 was isolated by column chromatography on silica gel using dichloromethane-ethyl acetate-methanol (100: 5: 1) as eluent. Yield 664 mg (67%).

Stage 4. Through a mixture of compound 1-1-1 (200 mg, 0.44 mmol), trimethyl orthoformate (5 ml, 46 mmol), p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol) and 10% wt. Pd / C (40 mg) in 30 ml of methanol was passed hydrogen at atmospheric pressure and 25 ° C for 4 h. Then the suspension was filtered through celite, the filtrate was concentrated in vacuum. The product was isolated by column chromatography on silica gel using hexane-ethyl acetate (1: 1) as eluent. The reaction product BCD-CDK8-l-6e was obtained as a colorless powder. Yield 159 mg (85%).

Example 2. Method for preparing BCD-CDK8-1-6a.

To a solution of BCD-CDK8-1-6e (270 mg, 0.63 mmol) in 20 ml of methanol was added a solution of LiOH⋅H ₂ O (40 mg, 0.95 mmol) in 10 ml of water. The solution was stirred at 100 ° С for 2 h. Methanol was distilled off in a vacuum, the aqueous solution was washed with ethyl acetate, the aqueous phase was brought to neutral medium with 0.1 M HCl solution. The suspension was filtered off. Product BCD-CDK8-1-6a was obtained as a colorless powder. Yield 164 mg (62%).

Example 3. Method for producing BCD-CDK8-1-1.

EDC⋅HCl (42 mg, 0.22 mmol) was added to a suspension of BCD-CDK8-1-6а (70 mg, 0.17 mmol), methanesulfonamide (17 mg, 0.18 mmol), and DMAP (27 mg, 0.22 mmol) in 15 ml of dichloromethane. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane - methanol - formic acid (9: 1: 0.1) as a colorless powder. Yield 55 mg (66%). The compound was further purified using preparative chromatography.

Example 4. Method for preparing compound BCD-CDK8-1-6.

92:8) в виде бесцветного порошка. Выход 60 мг (85%). Соединение было дополнительно очищено с помощью препаративной хроматографии.To a solution of BCD-CDK8-l-6a (71 mg, 0.17 mmol), HOBt (37 mg, 0.24 mmol), NH ₄ Cl (28 mg, 0.53 mmol), DIPEA (45 μL, 0.26 mmol) in 5 mL of DMF was added EDC⋅HCl (71 mg, 0.17 mmol). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol (95: 5

92: 8) as a colorless powder. Yield 60 mg (85%). The compound was further purified using preparative chromatography.

Example 5. Method for preparing compound BCD-CDK8-1-2.

Stage 1. To a solution of 4-nitro-3-fluorobenzoic acid (1.00 g, 5.40 mmol), azetidine hydrochloride (556 mg, 5.94 mmol), HOBt (1.16 g, 7.56 mmol) and DIPEA (3.30 ml, 18.9 mmol) in 50 ml of dichloromethane was added EDC6HCl (1.45 g, 7.56 mmol). The reaction mixture was stirred at room temperature for 12 h, washed with 1 M HCl solution, saturated NaHCO ₃ and NaCl solutions. The organic phase was concentrated in vacuo to give 1-2-4 as a colorless powder. Yield 1.0 g (82%).

Step 2. Compound 1-2-3 was prepared analogously to compound 1-1-3 (example 1, step 1), using compound 1-2-4 instead of 4-bromo-2-fluoronitrobenzene.

Step 3. Compound 1-2-2 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-2-3 instead of compound 1-1-1.

Step 4. Compound 1-2-1 was prepared analogously to compound BCD-CDK8-1-6a (Example 2) using compound 1-2-2 instead of compound BCD-CDK8-1-6e.

Step 5. Obtaining compound BCD-CDK8-1-2.

Compound BCD-CDK8-1-2 was prepared similarly to compound BCD-CDK8-1-1 (Example 3) using 1-2-1 instead of compound BCD-CDK8-1-6a.

Example 6. Method for preparing compound BCD-CDK8-1-3.

Stage 1. 4-Bromonitrobenzene (6.50 g, 32.2 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1 - ((2- (trimethylsilyl) ethoxy ) methyl) -1H-pyrazole (11.5 g, 35.4 mmol) (prepared according to the procedure described in WO 2011/130146), Na ₂ CO ₃ (6.82 g, 64.3 mmol) and Pd (PPh ₃ ) ₄ (743 mg, 0.64 mmol) in a mixture of 100 ml of THF and 50 ml of water was stirred at 70 ° C under an inert atmosphere for 10 h. THF was distilled off in a vacuum, ethyl acetate was added. The layers were separated, the organic layer was washed with saturated solutions of Na ₂ CO ₃ and NaCl, and then concentrated in vacuo. Compound 1-3-5 was isolated by column chromatography on silica gel using hexane-ethyl acetate (8: 2) as a colorless powder. Yield 7.82 g (76%).

Stage 2. A mixture of 1-3-5 (6.32 g, 19.8 mmol) and 10% wt. Pd / C (800 mg) in 100 ml of methanol was stirred at room temperature in a hydrogen atmosphere under a pressure of 5 atm. After 5 h, the reaction mixture was filtered through celite, concentrated in vacuo. Product 1-3-4 was used without further purification. Yield 5.33 g (93%).

Step 3. Compound 1-3-3 was prepared analogously to compound 1-2-4 (example 5, step 1), using piperidine instead of azetidine hydrochloride.

Stage 4. A solution of 1-3-3 (650 mg, 2.58 mmol), 1-3-4 (746 mg, 2.58 mmol) and DIPEA (0.675 ml, 3.87 mmol) in 20 ml DMSO was heated at 90 ° C for 30 am The reaction mixture was poured into 100 ml of water. The suspension was filtered off, the precipitate was washed with water, dissolved in ethyl acetate, and washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. Product 1-3-2 was isolated by column chromatography on silica gel using hexane-ethyl acetate (2: 1) as an orange powder. Yield 712 mg (53%).

Step 5. Compound 1-3-1 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4), using compounds 1-3-2 instead of compound 1-1-1.

Step 6. Obtaining compound BCD-CDK8-1-3.

A solution of 1-3-1 (338 mg, 0.676 mmol) and tetrabutylammonium fluoride (3.38 ml, 3.38 mmol, 1M solution in THF) in 10 ml of THF was stirred at 70 ° С for 14 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate , washed with water and concentrated. The product was isolated by column chromatography on silica gel using dichloromethane-ethyl acetate-methanol (20: 5: 1) as a colorless powder. Yield 132 mg (56%).

Example 7. Method for preparing compound BCD-CDK8-1-16.

Sodium hydride (10 mg, 0.251 mmol) was added to a solution of BCD-CDK8-1-3 (85 mg, 0.228 mmol) in 4 ml of DMF at -20 ° С. The mixture was brought to room temperature. After 15 min at -20 ° C, methyl iodide (17 μL, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 6 h, then concentrated in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol (96: 4) as a colorless powder. Yield 52 mg (61%).

Example 8. Method for preparing compound BCD-CDK8-1-4.

Step 1. Compound 1-4-3 was prepared analogously to compound 1-3-2 (example 6, step 4), using 4-bromo-2-fluoronitrobenzene instead of compound 1-3-3.

Step 2. Compound 1-4-5 was prepared similarly to compound 1-2-4 (example 5, step 1), using 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid instead of 4-nitro-3-fluorobenzoic acid and morpholine instead of azetidine hydrochloride.

Step 3. Compound 1-4-4 was prepared analogously to compound 1-1-2 (example 1, step 2), using compound 1-4-5 instead of tert-butyl 3- (phenylcarbamoyl) azetidine-1-carboxylate.

Step 4. Compound 1-4-2 was obtained similarly to compound 1-1-1 (example 1, step 3), using compound 1-4-3 instead of 1-1-3 and 1-4-4 instead of 1-1- 2.

Step 5. Compound 1-4-1 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-4-2 instead of compound 1-1-1.

Step 6. Compound BCD-CDK8-1-4 was prepared similarly to compound BCD-CDK8-1-3 (Example 6, step 6) using compound 1-4-1 instead of compound 1-3-1.

Example 9. Method for preparing compound BCD-CDK8-1-17.

Compound BCD-CDK8-1-17 was prepared similarly to compound BCD-CDK8-1-16 (Example 7) using BCD-CDK8-1-4 instead of BCD-CDK8-1-3.

Example 10. Method for preparing compound BCD-CDK8-1-5.

Step 1. Compound 1-5-2 was prepared similarly to 1-3-2 (example 6, step 4) using 1-2-4 instead of 1-3-3.

Step 2. Compound 1-5-1 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-5-2 instead of compound 1-1-1.

Step 3. Compound BCD-CDK8-1-5 was prepared analogously to compound BCD-CDK8-1-3 (example 6, step 6) using compound 1-5-1 instead of compound 1-3-1.

Example 11. Method for preparing compound BCD-CDK8-1-18.

Compound BCD-CDK8-1-18 was prepared similarly to compound BCD-CDK8-1-16 (Example 7) using compound BCD-CDK8-1-5 instead of compound BCD-CDK8-1-3.

Example 12. Method for preparing compound BCD-CDK8-1-9.

Stage 1. Compound 1-9-2 was obtained similarly to 1-3-2 (example 6, stage 4), using 4-bromo-2-fluoronitrobenzene instead of 1-3-3 and N, N-dimethyl-n-phenylenediamine instead of 1-3-4.

Step 2. Compound 1-9-1 was prepared similarly to 1-1-1 (example 1, step 3), using 1-9-2 instead of 1-1-3 and 1-4-4 instead of 1-1-2.

Step 3. Compound BCD-CDK8-1-9 was prepared similarly to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-9-1 instead of compound 1-1-1.

Example 13 Method for preparing compound BCD-CDK8-1-10.

Stage 1. Compound 1-10-1 was obtained similarly to 1-3-2 (example 6, stage 4), using 1-2-4 instead of 1-3-3 and N, N-dimethyl-n-phenylenediamine instead of 1- 3-4.

Step 2. Compound BCD-CDK8-1-10 was prepared similarly to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-10-1 instead of compound 1-1-1.

Example 14. Method for preparing compound BCD-CDK8-1-11.

Step 1. Compound 1-11-2 was prepared similarly to 1-2-4 (Example 5. Step 1) using 3-methoxyazetidine instead of azetidine hydrochloride.

Step 2. Compound 1-11-1 was prepared similarly to 1-3-2 (Example 6. Step 4) using 1-11-2 instead of 1-3-3 and 4-methoxyaniline instead of 1-3-4.

Step 3. Compound BCD-CDK8-1-11 was prepared similarly to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-11-1 instead of compound 1-1-1.

Example 15 Method for preparing compound BCD-CDK8-1-12.

Step 1. Compound 1-12-2 was prepared similarly to 1-3-2 (example 6, step 4), using 4-bromo-2-fluoronitrobenzene instead of 1-3-3 and 4-methoxyaniline instead of 1-3-4.

Step 2. Compound 1-12-1 was prepared similarly to 1-1-1 (example 1, step 3), using 1-12-2 instead of 1-1-3 and 1-4-4 instead of 1-1-2.

Step 3. Compound BCD-CDK8-1-12 was prepared similarly to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-12-1 instead of compound 1-1-1.

Example 16. Method for preparing compound BCD-CDK8-l-7e.

Step 1. Compound 1-7-2 was prepared analogously to compound 1-1-3 (example 1, step 1), using 4-bromo-2,6-difluoronitrobenzene instead of 4-bromo-2-fluoronitrobenzene.

Step 2. Compound 1-7-1 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-7-2 instead of compound 1-1-1.

Step 3. Compound BCD-CDK8-1-7e was prepared similarly to 1-1-1 (example 1, step 3) using 1-7-1 instead of 1-1-3.

Example 17 Method for preparing compound BCD-CDK8-1-7a.

Compound BCD-CDK8-1-7a was prepared similarly to compound BCD-CDK8-1-6a (Example 2), using compound BCD-CDK8-1-7e instead of compound BCD-CDK8-1-6e.

Example 18 Method for preparing compound BCD-CDK8-1-7.

Compound BCD-CDK8-1-7 was prepared similarly to compound BCD-CDK8-1-6 (Example 4) using BCD-CDK8-1-7a instead of BCD-CDK8-1-6a.

Example 19. Method for preparing compound BCD-CDK8-1-8.

Step 1. Compound 1-8-3 was prepared analogously to 1-3-2 (example 6, step 4) using 4-bromo-2,6-difluoronitrobenzene instead of 1-3-3.

Step 2. Compound 1-8-2 was prepared analogously to compound BCD-CDK8-l-6e (example 1, step 4) using compound 1-8-3 instead of compound 1-1-1.

Step 3. Compound 1-8-1 was prepared similarly to 1-1-1 (Example 1, Step 3), using 1-8-2 instead of 1-1-3 and 1-4-4 instead of 1-1-2.

Step 4. Compound BCD-CDK8-1-8 was prepared similarly to compound BCD-CDK8-1-3 (Example 6, step 6) using compound 1-8-1 instead of compound 1-3-1.

Example 20. Method for preparing compound BCD-CDK8-1-19.

Compound BCD-CDK8-1-19 was prepared similarly to compound BCD-CDK8-1-16 (Example 7) using compound BCD-CDK8-1-8 instead of compound BCD-CDK8-1-3.

Example 21 Method for preparing compound BCD-CDK8-1-13.

Stage 1. Compound 1-13-2 was obtained similarly to 1-3-2 (example 6, stage 4), using 4-bromo-2,6-difluoronitrobenzene instead of 1-3-3 and N, N-dimethyl-n- phenylenediamine instead of 1-3-4.

Step 2. Compound 1-13-1 was prepared analogously to compound BCD-CDK8-l-6e (example 1, step 4) using compound 1-13-2 instead of compound 1-1-1.

Step 3. Compound BCD-CDK8-1-13 was prepared similarly to 1-1-1 (example 1, step 3) using 1-13-1 instead of 1-1-3 and 1-4-4 instead of 1-1- 2.

Example 22 Method for preparing compound BCD-CDK8-1-14.

Step 1. Compound 1-14-3 was prepared analogously to 1-3-2 (example 6, step 4), using 2,3,4-trifluoronitrobenzene instead of 1-3-3.

Stage 2. A solution of 1-14-3 (735 mg, 1.65 mmol), 1-4-4 (1.03 g, 1.81 mmol) and DIPEA (1.01 ml, 5.77 mmol) in 30 ml DMSO was heated at 110 ° С for 5 am The reaction mixture was poured into 100 ml of water. The suspension was filtered off, the precipitate was washed with water, dissolved in ethyl acetate, and washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. The product was isolated by column chromatography on silica gel using hexane-ethyl acetate (1: 1) as an orange powder. Yield 794 mg (81%).

Step 3. Compound 1-14-1 was prepared analogously to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-14-2 instead of compound 1-1-1.

Step 4. Compound BCD-CDK8-1-14 was prepared analogously to compound BCD-CDK8-1-3 (example 6, step 6) using compound 1-14-1 instead of compound 1-3-1.

Example 23 Method for preparing compound BCD-CDK8-1-20.

Compound BCD-CDK8-1-20 was prepared similarly to compound BCD-CDK8-1-16 (Example 7) using compound BCD-CDK8-1-14 instead of compound BCD-CDK8-1-3.

Example 24 Method for preparing compound BCD-CDK8-1-15e.

Step 1. Compound 1-15-2 was prepared similarly to 1-2-4 (Example 5, Step 1), using 4-nitro-2,3-difluorobenzoic acid instead of 4-nitro-3-fluorobenzoic acid.

Step 2. Compound 1-15-1 was prepared analogously to compound 1-1-3 (example 1, step 1), using 1-15-2 instead of 4-bromo-2-fluoronitrobenzene.

Step 3. Compound BCD-CDK8-l-15e was prepared similarly to compound BCD-CDK8-1-6e (example 1, step 4) using compound 1-15-1 instead of compound 1-1-1.

Example 25 Method for preparing compound BCD-CDK8-1-15a.

Compound BCD-CDK8-1-15a was prepared similarly to compound BCD-CDK8-1-6a (Example 2), using compound BCD-CDK8-1-15e instead of compound BCD-CDK8-1-6e.

Example 26 Method for preparing compound BCD-CDK8-1-15.

Compound BCD-CDK8-1-15 was prepared similarly to compound BCD-CDK8-1-6 (Example 4), using BCD-CDK8-1-15a instead of BCD-CDK8-1-6a.

Example 27. Method for preparing compound BCD-CDK8-l-21a.

To a solution of compound BCD-CDK8-1-7a (100 mg, 0.23 mmol) in 10 ml of 1,4-dioxane was added 5 ml of 4M HCl solution in 1,4-dioxane. The mixture was stirred at room temperature for 12 hours, then concentrated in vacuo. The reaction product as a white powder was isolated by silica gel column chromatography using dichloromethane-methanol 94: 6 as eluent. Yield 90 mg (83%).

Example 28 Method for preparing compound BCD-CDK8-1-21.

Compound BCD-CDK8-1-21 was prepared similarly to compound BCD-CDK8-1-6 (Example 4), using BCD-CDK8-l-21a instead of BCD-CDK8-1-6a.

Example 29 Method for preparing compound BCD-CDK8-5-2.

Stage 1. To a solution of 6-iodo-4-hydroxyquinoline (2.00 g, 7.38 mmol) in 25 ml of DMF was added PBr ₃ (0.909 ml, 9.59 mmol) while cooling with an ice bath. Then the reaction mixture was brought to room temperature and stirred for 3 h. Then 300 ml of water was added, and the mixture was extracted with ethyl acetate (3 × 150 ml). The organic layers were separated, washed with saturated solutions of Na ₂ CO ₃ and NaCl, dried with Na ₂ SO ₄ . The reaction product 5-2-4 was obtained as a white powder after concentration of the solution in vacuo. Yield 2.38 g (97%).

Stage 2.5-2-4 (700 mg, 2.10 mmol), 4- (dimethylamino) phenylboronic acid hydrochloride (464 mg, 2.31 mmol) and Cs ₂ CO ₃ (2.39 g, 7.34 mmol) were dissolved in 10 ml 1.4 -dioxane and 5 ml of water. Pd (PPh ₃ ) ₄ (121 mg, 0.105 mmol) was added to the mixture under an inert atmosphere. The reaction mixture was stirred at 80 ° С for 6 hours. Then 250 ml of water was added, and the mixture was extracted with ethyl acetate (3 × 150 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . Product 5-2-3 was isolated by column chromatography on silica gel, eluent hexane-ethyl acetate (9: 1) as a yellow powder. Yield 514 mg (75%).

Stage 3.Pd (PPh ₃ ) ₄ (90 mg, 0.078 mmol) was added to a suspension of 5-2-3 (510 mg, 1.56 mmol) and Zn (CN) ₂ (220 mg, 1.87 mmol) in 5 ml of DMF in an inert atmosphere at room temperature. Then the resulting mixture was stirred at 100 ° C for 1 h. Poured into water, the precipitated crystals were filtered off, washed with water to obtain the product 5-2-2 in the form of a yellow powder. Yield 236 mg (94%).

Stage 4. A solution of KOH (264 mg, 4.71 mmol) in 5 ml of water was added to 5-2-2 (430 mg, 1.57 mmol) dissolved in 10 ml of ethanol. The reaction mixture was boiled for 60 hours. Then a 1M HCl solution was added to pH 4. The brown precipitate of compound 5-2-1 was filtered off. Yield 413 mg (90%).

Stage 5. 5-2-1 (150 mg, 0.513 mmol), (R) -3-hydroxypyrrolidine hydrochloride (70 mg, 5.64 mmol), HOBt (110 mg, 0.718 mmol) and DIPEA (0.357 ml, 2.05 mmol) were dissolved in 3 ml of DMF. EDC⋅HCl (138 mg, 0.564 mmol) was added portionwise to the mixture while cooling with an ice bath, and the mixture was stirred for 16 h at room temperature. Added 100 ml of water, the product was extracted with ethyl acetate (3 × 70 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product BCD-CDK8-5-2 was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (97: 3) as a light brown powder. Yield 89 mg (48%).

Example 30. Method for preparing compound BCD-CDK8-5-2i

Stage 1. To ethylmagnesium bromide (0.914 ml, 2.93 mmol) was added a solution of (R) -3- (tert-butyldimethylsilyloxy) pyrrolidine (766 mg, 3.22 mmol) (prepared according to the procedure described in WO 2003/045315) in 3 ml of dry THF in an inert atmosphere while cooling with an ice bath. The mixture was kept for 1 h at 30 ° C. The resulting solution was added with stirring to a solution of 5-2-2 (200 mg, 0.732 mmol) in 5 ml of dry THF and incubated for 1 h at 30 ° C. The reaction was treated with 50 ml of a saturated solution of NH ₄ Cl and was extracted with ethyl acetate (3 × 30 ml). The organic layers were separated, washed with a saturated NaCl solution, dried with Na ₂ SO _4. Product 5-2i-1 was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (97: 3) as a viscous light yellow liquid. Yield 330 mg (95%).

Stage 2. 5-2i-1 (330 mg, 0.694 mmol) was dissolved in 5 ml of dichloromethane, and while cooling with an ice bath, 3 ml of 4M HCl solution in 1,4-dioxane was added, and the mixture was kept for 16 h at room temperature. After the completion of the reaction, 0.25 ml of 7M NH ₃ solution in methanol was added with stirring, then the solvents were distilled off. The product BCD-CDK8-5-2i was isolated by column chromatography on silica gel, eluent dichloromethane-NH ₃ in methanol (7M) (15: 1) as a yellow powder. Yield 236 mg (94%).

Example 31. Method for preparing compound BCD-CDK8-5-3.

Step 1. Compound 5-3-3 was prepared analogously to compound 5-2-3 (example 29, step 2), using 4-morpholine phenylboronic acid instead of 4- (dimethylamino) phenylboronic acid hydrochloride.

Step 2. Compound 5-3-2 was prepared analogously to compound 5-2-2 (example 29, step 3) using compound 5-3-3 instead of compound 5-2-3.

Step 3. Compound 5-3-1 was prepared analogously to compound 5-2-1 (example 29, step 4) using compound 5-3-2 instead of compound 5-2-2.

Step 4. Compound BCD-CDK8-5-3 was prepared analogously to compound BCD-CDK8-5-2 (example 29, step 5), using compound 5-3-1 instead of compound 5-2-1 and morpholine instead of hydrochloride (R ) -3-hydroxypyrrolidine.

Example 32. Process for preparing compound BCD-CDK8-5-3i

Compound BCD-CDK8-5-3i was prepared analogously to compound 5-2i-1 (example 30, step 1), using compound 5-3-2 instead of compound 5-2-2 and morpholine instead of (R) -3- (tert -butyldimethylsilyloxy) pyrrolidine.

Example 33 Method for preparing compound BCD-CDK8-5-4.

Stage 1. NaH (834 mg, 0.021 mol) was added in portions to 4- (4-bromophenyl) -1H-pyrazole (3.00 g, 0.01 mol) in 10 ml DMF with stirring and cooling with an ice bath. The reaction mixture was brought to room temperature and kept for 15 min. Then 2- (trimethylsilyl) ethoxymethyl chloride (3.36 g, 0.02 mol) was added. After 1 h, it was poured into 300 ml of water, extracted with ethyl acetate (3 × 100 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The reaction product 5-4-5 was obtained as a light yellow powder after concentration of the solution in vacuo. Yield 3.42 g (88%).

Stage 2. To a suspension of 5-4-5 (557 mg, 1.58 mmol), bis (pinacolato) diborane (600 mg, 2.36 mmol), potassium acetate (464 mg, 4.73 mmol), XPhos (150 mg, 0.316 mmol) in 20 ml of 1,4-dioxane was added under an inert atmosphere with stirring, palladium (II) acetate (35 mg, 0.158 mmol). The reaction mixture was kept at 80 ° C for 30 min. Then 5-2-4 (500 mg, 1.50 mmol), Na ₂ CO ₃ (835 mg, 7.88 mmol), Pd (PPh ₃ ) ₄ (182 mg, 0.158 mmol) and 10 ml of water were added. The reaction mixture was stirred at 80 ° C for 3 hours. Then 250 ml of water was added, the product was extracted with ethyl acetate (3 × 150 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . Product 5-4-4 was isolated by column chromatography on silica gel using hexane-ethyl acetate (9: 1) as a yellow powder. Yield 514 mg (75%).

Step 3. Compound 5-4-3 was prepared analogously to compound 5-2-2 (example 29, step 3) using compound 5-4-4 instead of compound 5-2-3.

Step 4. Compound 5-4-2 was prepared analogously to compound 5-2-1 (example 29, step 4) using compound 5-4-3 instead of compound 5-2-2.

Step 5. Compound 5-4-1 was prepared analogously to compound BCD-CDK8-5-2 (example 29, step 5), using compound 5-4-2 instead of compound 5-2-1 and piperidine instead of hydrochloride (R) - 3-hydroxypyrrolidine.

Step 6. 5-4-1 (57 mg, 0.111 mmol) was dissolved in 3 ml of dichloromethane and with cooling with an ice bath, 1 ml of trifluoroacetic acid was added. The solution was stirred for 16 hours at room temperature. Then 50 ml of a saturated solution of Na ₂ CO _{3 was} added, and the mixture was extracted with dichloromethane (3 × 30 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product BCD-CDK8-5-4 was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (97: 3) as a light yellow powder. Yield 30 mg (71%).

Example 34. Method of preparing compound BCD-CDK8-5-4i

Step 1. Compound 5-4i-1 was prepared analogously to compound 5-2i-1 (example 30, step 1), using compound 5-4-3 instead of compound 5-2-2 and piperidine instead of compound (R) -3- (tert-butyldimethylsilyloxy) pyrrolidine.

Step 2. Compound BCD-CDK8-5-4i was prepared similarly to compound BCD-CDK8-5-4 (Example 33, step 6) using compound 5-4i-1 instead of compound 5-4-1.

Example 35 Method for preparing compound BCD-CDK8-5-6.

Stage 1. Compound 5-6-2 was obtained analogously to compound 5-2-3 (example 29, step 2), using 6-iodo-4-hydroxyquinoline instead of compound 5-2-4 and 4-methoxyphenylboronic acid instead of hydrochloride 4- (dimethylamino) phenylboronic acid.

Step 2. Compound 5-6-1 was prepared analogously to compound 5-2-4 (example 29, step 1), using compound 5-6-2 instead of 6-iodo-4-hydroxyquinoline.

Stage 3. To suspension 5-6-1 (100 mg, 0.318 mmol), 2-pyrrolidone (54 mg, 0.637 mmol), BINAP (20 mg, 10% mol.) And Cs ₂ CO ₃ (259 mg, 0.796 mmol) in 5 ml of 1,4-dioxane in an inert atmosphere was added palladium (II) acetate (4 mg, 5% mol.). The reaction mixture was stirred at 80 ° C for 4 hours. Then 50 ml of water was added, and the mixture was extracted with ethyl acetate (3 × 30 ml). The organic layers were separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product BCD-CDK8-5-6 was isolated by column chromatography on silica gel using dichloromethane-methanol (98: 2) as eluent. Yield 76 mg (75%).

Example 36 Method for preparing compound BCD-CDK8-5-7.

Compound BCD-CDK8-5-7 was prepared similarly to compound BCD-CDK8-5-2 (Example 29, step 5) using (S) -3-hydroxypyrrolidine hydrochloride instead of (S) -3-hydroxypyrrolidine hydrochloride.

Example 37 Method for preparing compound BCD-CDK8-5-7i.

Step 1. Compound 5-7i-1 was prepared analogously to compound 5-2i-1 (example 30, step 1) using (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine (prepared according to the procedure described in WO 2014/029983 ) instead of (R) -3- (tert-butyldimethylsilyloxy) pyrrolidine.

Stage 2. 5-7i-1 (150 mg, 0.250 mmol) was dissolved in 2 ml of dichloromethane and, with cooling, 4 ml of 4M HCl solution in 1,4-dioxane was added, kept for 72 h at room temperature. After the completion of the reaction, 0.25 ml of 7M NH ₃ solution in methanol was added with stirring, then the solvents were distilled off. The product BCD-CDK8-5-7i was isolated by column chromatography on silica gel, eluent dichloromethane-NH ₃ in methanol (7M) (15: 1). Yield 70 mg (78%).

Example 38 Method for preparing compound BCD-CDK8-5-8.

Step 1. Compound 5-8-4 was obtained analogously to compound 5-2-3 (example 29, step 2), using compound 1-bromo-4-iodobenzene instead of compound 5-2-4 and 1-methyl-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-pyrazole instead of 4- (dimethylamino) phenylboronic acid hydrochloride.

Step 2. Compound 5-8-3 was prepared analogously to compound 5-4-4 (example 33, step 2) using compound 5-8-4 instead of compound 5-4-5.

Step 3. Compound 5-8-2 was prepared analogously to compound 5-2-2 (example 29, step 3) using compound 5-8-3 instead of compound 5-2-3.

Step 4. Compound 5-8-1 was prepared analogously to compound 5-2-1 (example 29, step 4) using compound 5-8-2 instead of compound 5-2-2.

Step 5. Compound BCD-CDK8-5-8 was prepared analogously to compound BCD-CDK8-5-2 (example 29, step 5), using compound 5-8-1 instead of compound 5-2-1 and piperidine instead of hydrochloride (R ) -3-hydroxypyrrolidine.

Example 39 Method for preparing compound BCD-CDK8-5-8i.

Compound BCD-CDK8-5-8i was prepared analogously to compound 5-2i-1 (example 30, step 1), using compound 5-8-2 instead of compound 5-2-2 and piperidine instead of (R) -3- (tert -butyldimethylsilyloxy) pyrrolidine.

Example 40. Method for preparing compound BCD-CDK8-5-1Cl.

Stage 1. A mixture of 5-iodisatin (2.00 g, 7.32 mmol), malonic acid (838 mg, 8.06 mmol) and sodium acetate (751 mg, 9.16 mmol) was refluxed for 10 h in 15 ml of acetic acid. The suspension was filtered off, the precipitate was washed with ethanol and acetone. The product 5-1Cl-5 was obtained as a dark gray powder. Yield 1.35 g (58%).

Stage 2. Compound 5-1Cl-4 was obtained analogously to compound 5-2-3 (example 29, step 2), using compound 5-1Cl-5 instead of 5-2-4 and 4-methoxycarbonylphenylboronic acid instead of hydrochloride 4- (dimethylamino ) phenylboronic acid.

Step 3. SOCl ₂ (5 ml, 68.9 mmol) was added to 5-1Cl-4 (1.21 g, 3.73 mmol) at 0-5 ° C. The reaction mixture was kept at 100 ° С for 1.5 h. Then, volatile components were removed under reduced pressure. The product 5-1Cl-3 was obtained as a brown powder and was used in the next step without further purification. Yield 1.34 g (100%).

Stage 4. A suspension of 5-1Cl-3 (1.34 g, 3.73 mmol) in 10 ml of dry dichloromethane was added with stirring to a solution of piperidine (1.11 g, 13.1 mmol) and triethylamine (5.21 ml, 37.3 mmol) in 10 ml of dry dichloromethane at 0 -5 ° C. The reaction mixture was kept at room temperature for 6 hours. After concentration, the product 5-1Cl-2 was isolated as a light yellow powder by column chromatography on silica gel, eluent hexane-ethyl acetate (3: 1). Yield 457 mg (30%).

Step 5. Compound 5-1Cl-1 was prepared similarly to compound BCD-CDK8-1-6a (example 2), using compound 5-1Cl-2 instead of compound BCD-CDK8-1-6e.

Step 6. Compound BCD-CDK8-5-1Cl was prepared similarly to compound BCD-CDK8-1-1 (Example 3), using 5-1Cl-1 instead of BCD-CDK8-1-6a.

Example 41 Method for preparing compound BCD-CDK8-5-1.

A mixture of BCD-CDK8-5-1Cl (127 mg, 0.27 mmol), triethylamine (0.075 ml, 0.54 mmol) and Pd / C (20 mg) in 5 ml of methanol was stirred in a hydrogen atmosphere at a pressure of 8 atm for 3 h. After concentration, the product was isolated as a white powder using preparative chromatography. Yield 100 mg (85%).

Example 42. Method for preparing compound BCD-CDK8-5-5Cl.

Step 1. Compound 5-5Cl-2 was prepared analogously to compound 5-1Cl-2 (example 40, step 4) using azetidine hydrochloride instead of piperidine.

Step 2. Compound 5-5Cl-1 was prepared similarly to compound BCD-CDK8-1-6a (example 2), using compound 5-5Cl-2 instead of compound BCD-CDK8-1-6e.

Step 3. Compound BCD-CDK8-5-5Cl was prepared similarly to compound BCD-CDK8-1-1 (Example 3), using 5-5Cl-1 instead of BCD-CDK8-1-6a.

Example 43 Method for preparing compound BCD-CDK8-5-5.

Compound BCD-CDK8-5-5 was prepared similarly to compound BCD-CDK8-5-1 (Example 41) using BCD-CDK8-5-5Cl instead of BCD-CDK8-5-1Cl.

Example 44 Method for preparing compound BCD-CDK8-6-1.

Step 1. Compound 6-1-2 was prepared analogously to compound BCD-CDK8-5-6 (example 35, step 3), using compound 5-2-4 instead of compound 5-6-1 and 4-piperidinecarbonitrile instead of 2-pyrrolidone ...

Step 2. Compound 6-1-1 was obtained similarly to compound 5-2-3 (example 29, step 2), using compound 6-1-2 instead of compound 5-2-4 and 4-morpholine phenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Stage 3. 6-1-1 (101 mg, 0.253 mmol) was dissolved in 2 ml of 80% wt. H ₂ SO ₄ and kept at room temperature for 48 hours. Then the reaction mixture was poured into 50 ml of water, a saturated solution of Na ₂ CO _{3 was} added to pH 8, the product was extracted with ethyl acetate (3 × 50 ml). The combined extract was washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The product BCD-CDK8-6-1 was isolated as a yellow-orange powder by column chromatography on silica gel, eluent dichloromethane-methanol (97: 3). Yield 61 mg (57%).

Example 45 Method for preparing compound BCD-CDK8-6-2.

Step 1. SOCl ₂ (5 ml, 68.5 mmol) was added to 4-bromoquinoline-6-carboxylic acid (530 mg, 2.11 mmol) at 0-5 ° C. The reaction mixture was kept at 100 ° С for 3 h. Then volatiles were removed under reduced pressure. Product 6-2-5 was obtained as a beige powder and was used in the next step without further purification. Yield 476 mg (100%).

Stage 2. A suspension of 6-2-5 (476 mg, 2.11 mmol) in 4 ml of dry dichloromethane was added with stirring to a solution of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine (755 mg, 2.32 mmol) and triethylamine (0.881 ml , 6.33 mmol) in 10 ml of dry dichloromethane at 0-5 ° С. The reaction mixture was kept at room temperature for 6 hours. After concentration, product 6-2-4 was isolated as a white powder by column chromatography on silica gel, eluent hexane-ethyl acetate-dichloromethane (3: 2: 2). Yield 850 mg (72%).

Step 3. Compound 6-2-3 was obtained analogously to compound 5-2-3 (example 29, step 2), using compound 6-2-4 instead of compound 5-2-4 and 4-methoxycarbonylphenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Stage 4. To a solution of 6-2-3 (934 mg, 1.52 mmol) in 12 ml of methanol was added a solution of LiOH⋅H ₂ O (96 mg, 2.28 mmol) in 6 ml of water. The reaction mixture was boiled for 2 h, methanol was distilled off, a 0.1 M HCl solution was added to pH 4. The suspension was filtered, the precipitate was washed with water, and the product 6-2-2 was obtained in the form of a gray powder. Yield 795 mg (87%).

Stage 5. To a solution of 6-2-2 (350 mg, 0.58 mmol), methanesulfonamide (66 mg, 0.70 mmol) and DMAP (11 mg, 0.09 mmol) in 5 ml of dichloromethane with stirring and cooling with a water bath was added portionwise EDC⋅HCl (128 mg, 0.67 mmol). The reaction mixture was kept for 16 h at room temperature. Then the solvent was distilled off, the product 6-2-1 was isolated in the form of a white powder by column chromatography on silica gel, eluent dichloromethane-methanol (94: 6). Yield 90 mg (23%).

Step 6. Compound BCD-CDK8-6-2 was prepared analogously to compound BCD-CDK8-5-7i (Example 37, step 2) using compound 6-2-1 instead of 5-7i-1.

Example 46 Method for preparing compound BCD-CDK8-6-3.

Step 1. SOCl ₂ (1.22 mL, 16.6 mmol) was added to 4-methylpiperidine-4-carboxamide (786 mg, 5.54 mmol) at 0-5 ° C. The reaction mixture was kept at 60 ° C for 10 h. Then the solvent was distilled off, and a 7M solution of NH ₃ in methanol was added to the residue at 0-5 ° C. After concentration, the product 6-3-3 was isolated as a yellow liquid by column chromatography on silica gel, eluent dichloromethane-NH ₃ in methanol (7M) (99: 1). Yield 433 mg (63%).

Step 2. Compound 6-3-2 was prepared similarly to compound BCD-CDK8-5-6 (example 35, step 3), using compound 5-2-4 instead of compound 5-6-1 and 6-3-3 instead of 2 -pyrrolidone.

Step 3. Compound 6-3-1 was obtained analogously to compound 5-4-4 (example 33, step 2), using compound 6-3-2 instead of compound 5-2-4 and 1 - ((4-bromophenyl) methyl ) -4-methylpiperazine instead of compound 5-4-5.

Step 4. Compound BCD-CDK8-6-3 was prepared analogously to compound BCD-CDK8-6-1 (example 44, step 3) using compound 6-3-1 instead of compound 6-1-1.

Example 47 Method for preparing compound BCD-CDK8-6-4.

Step 1. Compound 6-4-2 was prepared similarly to compound BCD-CDK8-5-2 (example 29, step 5), using 4-bromoquinoline-6-carboxylic acid instead of compound 5-2-1 and 3-methoxyazetidine instead of hydrochloride (R) -3-hydroxypyrrolidine.

Step 2. Compound 6-4-1 was prepared analogously to compound 5-4-4 (example 33, step 2) using compound 6-4-2 instead of compound 5-2-4.

Step 3. Compound BCD-CDK8-6-4 was prepared analogously to compound BCD-CDK8-5-4 (Example 33, step 6) using compound 6-4-1 instead of compound 5-4-1.

Example 48 Method for preparing compound BCD-CDK8-6-5.

Step 1. Compound 6-5-3 was prepared similarly to compound BCD-CDK8-5-2 (example 29, step 5), using 4-bromoquinoline-6-carboxylic acid instead of compound 5-2-1 and azetidine hydrochloride instead of hydrochloride ( R) -3-hydroxypyrrolidine.

Step 2. Compound 6-5-2 was obtained analogously to compound 5-2-3 (example 29, step 2), using compound 6-5-3 instead of compound 5-2-4 and 4-methoxycarbonylphenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 3. Compound 6-5-1 was prepared analogously to compound 6-2-2 (example 45, step 4) using compound 6-5-2 instead of compound 6-2-3.

Step 4. Compound BCD-CDK8-6-5 was prepared analogously to compound 6-2-1 (example 45, step 5) using compound 6-5-1 instead of compound 6-2-2.

Example 49. Method for preparing compound BCD-CDK8-6-6.

Step 1. Compound 6-6-3 was prepared similarly to compound BCD-CDK8-5-2 (example 29, step 5), using 4-bromoquinoline-6-carboxylic acid instead of compound 5-2-1 and morpholine instead of hydrochloride (R ) -3-hydroxypyrrolidine.

Step 2. Compound 6-6-2 was obtained similarly to compound 5-2-3 (example 29, step 2), using compound 6-6-3 instead of compound 5-2-4 and 4-methoxycarbonylphenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 3. Compound 6-6-1 was prepared analogously to compound 6-2-2 (example 45, step 4) using compound 6-6-2 instead of compound 6-2-3.

Step 4. Compound BCD-CDK8-6-6 was prepared analogously to compound 6-2-1 (example 45, step 5) using compound 6-6-1 instead of compound 6-2-2.

Example 50 Method for preparing compound BCD-CDK8-6-7.

Step 1. Compound 6-7-1 was obtained analogously to compound 5-4-4 (example 33, step 2), using compound 6-1-2 instead of compound 5-2-4 and 1 - ((4-bromophenyl) methyl ) -4-methylpiperazine instead of 5-4-5.

Step 2. Compound BCD-CDK8-6-7 was prepared analogously to compound BCD-CDK8-6-1 (Example 44, step 3) using compound 6-7-1 instead of compound 6-1-1.

Example 51 Method for preparing compound BCD-CDK8-6-8.

Stage 1. Compound 6-8-1 was obtained similarly to compound 5-2-3 (example 29, step 2), using compound 6-3-2 instead of compound 5-2-4 and 4-morpholine phenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 2. Compound BCD-CDK8-6-8 was prepared analogously to compound BCD-CDK8-6-1 (example 44, step 3) using compound 6-8-1 instead of compound 6-1-1.

Example 52 Method for preparing compound BCD-CDK8-6-9.

Step 1. Compound 6-9-4 was obtained similarly to compound 6-2-4 (example 45, step 2), using (R) -3- (tert-butyldimethylsilyloxy) pyrrolidine instead of (S) -3- (tert-butyldiphenylsilyloxy ) pyrrolidine.

Step 2. Compound 6-9-3 was obtained similarly to compound 5-2-3 (example 29, step 2), using compound 6-9-4 instead of compound 5-2-4 and 4-methoxycarbonylphenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 3. Compound 6-9-2 was prepared analogously to compound 6-2-2 (example 45, step 4) using compound 6-9-3 instead of compound 6-2-3.

Step 4. Compound 6-9-1 was prepared analogously to compound 6-2-1 (example 45, step 5) using compound 6-9-2 instead of compound 6-2-2.

Step 5. Compound BCD-CDK8-6-9 was prepared analogously to compound BCD-CDK8-5-2i (Example 30, step 2) using compound 6-9-1 instead of compound 5-2i-1.

Example 53 Method for preparing compound BCD-CDK8-6-10.

Compound BCD-CDK8-6-10 was prepared similarly to compound 5-4-4 (example 33, step 2), using compound 6-4-2 instead of compound 5-2-4 and 5-8-4 instead of 5-4- 5.

Example 54 Method for preparing compound BCD-CDK8-6-11.

Compound BCD-CDK8-6-11 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 6-5-3 instead of compound 5-2-4 and 5-8-4 instead of 5-4- 5.

Example 55 Method for preparing compound BCD-CDK8-6-12.

Step 1. Compound 6-12-1 was prepared similarly to compound 6-2-4 (example 45, step 2), using pyrrolidine instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine.

Step 2. Compound BCD-CDK8-6-12 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 6-12-1 instead of compound 5-2-4 and 5-8-4 instead of 5 -4-5.

Example 56 Method for preparing compound BCD-CDK8-6-13.

Step 1. Compound 6-13-1 was prepared analogously to compound BCD-CDK8-5-6 (Example 35, step 3) using compound 5-2-4 instead of compound 5-6-1.

Step 2. Compound BCD-CDK8-6-13 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 6-13-1 instead of compound 5-2-4 and 5-8-4 instead of 5 -4-5.

Example 57 Method for preparing compound BCD-CDK8-6-14.

Step 1. Compound 6-14-1 was prepared analogously to compound 6-2-4 (example 45, step 2), using 2-methoxyethylamine instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine.

Step 2. Compound BCD-CDK8-6-14 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 6-14-1 instead of compound 5-2-4 and 5-8-4 instead of 5 -4-5.

Example 58 Method for preparing compound BCD-CDK8-3-1.

Step 1. To 5-bromo-1,7-naphthyridine-3-carboxylic acid (1.00 g, 3.95 mmol) (prepared according to the procedure described in WO 2015/014768) SOCl ₂ (5 ml, 60 mmol) and one drop DMF. The reaction mixture was boiled for 5 h, after which the volatiles were removed under reduced pressure. 5 ml of MTBE was added to the residue, concentrated, the residue was dried in a vacuum on a rotary evaporator. The reaction product 3-1-5, isolated as a yellow-green powder, was used without further purification. Yield 1.04 g (97%).

Stage 2. To a solution of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine (959 mg, 2.94 mmol), triethylamine (1.234 ml, 8.84 mmol) in 20 ml of dichloromethane was added dropwise a solution of freshly prepared 3-1-5 (400 mg , 1.47 mmol), triethylamine (0.411 ml, 2.95 mmol) in 15 ml of dichloromethane in a nitrogen atmosphere at -5 ° С. The resulting mixture was stirred at room temperature for 5 hours. Then the reaction mixture was washed with 1M HCl solution and extracted with dichloromethane. The organic layer was separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ . Product 3-1-4 in the form of a white powder was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (98: 2). Yield 644 mg (78%).

Stage 3. To a solution of 3-1-4 (644 mg, 1.15 mmol), 4-methoxycarbonylphenylboronic acid (248 mg, 1.37 mmol), Cs ₂ CO ₃ (749 mg, 2.23 mmol) in 20 ml of a mixture of 1,4-dioxane -water (1: 1) was added Pd (PPh ₃ ) ₄ (66 mg, 0.057 mmol) in a nitrogen atmosphere at room temperature. The resulting mixture was heated at 70 ° C for 5 h. After that, the reaction mass was concentrated in a vacuum. Product 3-1-3 in the form of a white powder was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (98: 2). Yield 410 mg (58%).

Stage 4. To a solution of 3-1-3 (410 mg, 0.67 mmol) in 10 ml of methanol was added dropwise a solution of LiOH⋅H ₂ O (42 mg, 1.00 mmol) in 5 ml of water. The resulting mixture was stirred for 8 hours. Then a 1M HCl solution was added to pH 4. The suspension was filtered, the precipitate was washed with water (3 × 20 ml), dried in a vacuum to constant weight, yielding product 3-1-2 as a white powder. Yield 360 mg (87%).

Stage 5. To a solution of 3-1-2 (219 mg, 0.364 mmol), methanesulfonamide (42 mg, 0.437 mmol) and DMAP (7 mg, 0.05 mmol) in 15 ml of dichloromethane was added EDC⋅HCl (91 mg, 0.473 mmol) in a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 24 hours. Product 3-1-1 in the form of a white powder was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (9: 1). Yield 101 mg (41%).

Stage 6. To a solution of 3-1-1 (94 mg, 0.138 mmol) in 10 ml of dichloromethane was added dropwise 4 ml of 4M HCl solution in diethyl ether. After two days, the reaction mixture was filtered, washed with diethyl ether (2 × 20 ml). The product BCD-CDK8-3-1 in the form of a white powder was isolated by column chromatography on silica gel using dichloromethane-methanol (9: 1) as eluent. Yield 59 mg (96%).

Example 59 Method for preparing compound BCD-CDK8-3-13.

Stage 1. Compound 3-13-4 was obtained similarly to compound 3-1-4 (example 58, step 2), using (R) -3- (tert-butyldimethylsilyloxy) pyrrolidine instead of (S) -3- (tert-butyldiphenylsilyloxy ) pyrrolidine.

Step 2. Compound 3-13-3 was prepared analogously to compound 3-1-3 (example 58, step 3) using 3-13-4 instead of 3-1-4.

Step 3. Compound 3-13-2 was prepared analogously to compound 3-1-2 (example 58, step 4) using 3-13-3 instead of 3-1-3.

Step 4. Compound 3-13-1 was prepared analogously to compound 3-1-1 (example 58, step 5) using 3-13-2 instead of 3-1-2.

Step 5. Compound BCD-CDK8-3-13 was prepared similarly to compound BCD-CDK8-3-1 (example 58, step 6) using 3-13-1 instead of 3-1-1.

Example 60 Method for preparing compound BCD-CDK8-3-2.

Step 1. Compound 3-2-2 was prepared analogously to compound 3-1-4 (example 58, step 2) using (R) -3-hydroxypyrrolidine hydrochloride instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine.

Step 2. Compound 3-2-1 was prepared analogously to compound 5-4-4 (example 33, step 2) using compound 3-2-2 instead of 5-2-4.

Step 3. Compound BCD-CDK8-3-2 was prepared similarly to compound BCD-CDK8-5-4 (Example 33, step 6) using 3-2-1 instead of 5-4-1.

Example 61 Method for preparing compound BCD-CDK8-3-3.

Compound BCD-CDK8-3-3 was prepared analogously to compound 3-1-3 (example 58, step 3), using 4- (dimethylamino) phenylboronic acid hydrochloride instead of 4-methoxycarbonylphenyl boronic acid.

Example 62 Method for preparing compound BCD-CDK8-3-4.

Compound BCD-CDK8-3-4 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 5-8-4 instead of compound 5-4-5 and compound 3-2-2 instead of compound 5- 2-4.

Example 63 Method for preparing compound BCD-CDK8-3-5.

Compound BCD-CDK8-3-5 was prepared analogously to compound 3-1-3 (Example 58, step 3), using 4-morpholine phenylboronic acid instead of 4-methoxycarbonylphenylboronic acid.

Example 64 Method for preparing compound BCD-CDK8-3-6.

Compound BCD-CDK8-3-6 was prepared analogously to compound 3-1-3 (Example 58, step 3) using 4-methoxyphenylboronic acid instead of 4-methoxycarbonylphenylboronic acid.

Example 65. Method for preparing compound BCD-CDK8-3-8.

Step 1. Compound 3-8-1 was prepared analogously to compound 3-1-4 (example 58, step 2) using N-methylpiperazine instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine.

Step 2. Compound BCD-CDK8-3-8 was prepared analogously to compound 3-1-3 (example 58, step 3), using compound 3-8-1 instead of compound 3-1-4 and 4- (dimethylamino) phenylboronic acid instead of 4-methoxycarbonylphenylboronic acid.

Example 66 Method for preparing compound BCD-CDK8-3-9.

Stage 1.

5-bromo-1,7-naphthyridine-3-carboxylic acid (2.22 g, 8.78 mmol) (prepared according to the procedure described in WO 2015/014768), DPPA (2.27 ml, 10.5 mmol), triethylamine (1.47 ml, 10.5 mmol ) was suspended in anhydrous tert-butanol (50 ml). The mixture was refluxed for 8 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in 50 ml of ethyl acetate, washed with water (2 × 40 ml), saturated NaHCO ₃ solution (50 ml) and saturated NaCl solution (50 ml). The organic layer was dried with Na ₂ SO ₄ . Product 3-9-4 in the form of a light yellow powder was isolated by column chromatography on silica gel using dichloromethane-methanol (96: 4) as eluent. Yield 1.64 g (58%).

Step 2. Compound 3-9-3 was obtained similarly to compound 5-4-4 (example 33, step 2), using compound 3-9-4 instead of compound 5-2-4 and compound 5-8-4 instead of 5- 4-5.

Stage 3. To a solution of compound 3-9-3 (205 mg, 0.51 mmol) in 10 ml of dichloromethane with stirring was added 5 ml of 4M HCl solution in diethyl ether. The reaction mixture was stirred for 1 h, then filtered off, washed with diethyl ether, and dried in vacuum to constant weight. Got 3-9-2. Yield 169 mg (98%).

Stage 4. To a solution of compound 3-9-2 (169 mg, 0.50 mmol) in 1 ml of 6M HCl solution, a solution of NaNO ₂ (52 mg, 0.75 mmol) in 0.5 ml of H ₂ O was added at -5 ° C. After 1 h, a solution of KI (415 mg, 2.50 mmol) in 0.5 ml of H ₂ O was added. After 1 h, the reaction mixture was heated to 80 ° С and stirred for 3 h. The reaction mixture was poured into a saturated solution of Na ₂ SO ₃ , extracted with ethyl acetate (3 × 20 ml). The combined organic layers were washed with NaCl solution, dried with Na ₂ SO ₄ . Product 3-9-1 in the form of a yellow powder was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (98: 2). Yield 132 mg (64%).

Step 5. Compound BCD-CDK8-3-9 was prepared similarly to compound 1-1-1 (example 1, step 3), using compound 3-9-1 instead of compound 1-1-3 and compound 1-4-4, instead of connecting 1-1-2.

Example 67 Method for preparing compound BCD-CDK8-3-11.

Step 1. Compound 3-11-3 was prepared analogously to compound 3-1-4 (Example 58, step 2), using piperidine instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine hydrochloride.

Step 2. Compound 3-11-2 was prepared analogously to compound 3-1-3 (example 58, step 3) using compound 3-11-3 instead of 3-1-4.

Step 3. Compound 3-11-1 was prepared analogously to compound 3-1-2 (example 58, step 4) using compound 3-11-2 instead of 3-1-3.

Step 4. Compound BCD-CDK8-3-11 was prepared analogously to compound 3-1-1 (example 58, step 5) using compound 3-11-1 instead of 3-1-2.

Example 68 Method for preparing compound BCD-CDK8-3-12.

Step 1. Compound 3-12-5 was prepared analogously to compound 3-1-3 (example 58, step 3) using compound 3-7-5 instead of compound 3-1-4.

Step 2. Compound 3-12-4 was prepared analogously to compound 3-9-2 (example 66, step 3) using compound 3-12-5 instead of 3-9-3.

Step 3. Compound 3-12-3 was prepared analogously to compound 3-9-1 (example 66, step 4) using compound 3-12-4 instead of compound 3-9-2.

Step 4. Compound 3-12-2 was obtained analogously to compound 1-1-1 (example 1, step 3), using compound 3-12-3 instead of 1-1-3 and N, N-dimethylazetidine-3-carboxamide trifluoroacetic acid (obtained by the method of the Journal of Medicinal Chemistry, 53 (9), 3645-3674; 2010) instead of compound 1-1-2.

Step 5. Compound 3-12-1 was prepared analogously to compound 3-1-2 (example 58, step 4) using compound 3-12-2 instead of compound 3-1-3.

Step 6. Compound BCD-CDK8-3-12 was prepared analogously to compound 3-1-1 (example 58, step 5) using compound 3-12-1 instead of compound 3-1-2.

Example 69. Process for preparing compound BCD-CDK8-3-14.

Step 1. Compound 3-14-2 was prepared analogously to compound 5-4-4 (example 33, step 2) using 5-bromo-1,7-naphthyridine-3-carboxylic acid ethyl ester (prepared according to the procedure described in WO 2015/014768) instead of 5-2-4 and the compound 5-8-4 instead of 5-4-5.

Step 2. Compound 3-14-1 was prepared analogously to compound 3-1-2 (example 58, step 4) using compound 3-14-2 instead of 3-1-3.

Step 3. Compound BCD-CDK8-3-14 was prepared analogously to compound 1-2-4 (example 5, step 1) using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid.

Example 70 Method for preparing compound BCD-CDK8-3-15.

Compound BCD-CDK8-3-15 was prepared similarly to compound 1-2-4 (example 5, step 1), using 3-methoxyazetidine hydrochloride instead of azetidine hydrochloride and compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid.

Example 71 Method for preparing compound BCD-CDK8-3-16.

Compound BCD-CDK8-3-16 was prepared similarly to compound 1-2-4 (example 5, step 1), using pyrrolidine instead of azetidine hydrochloride and compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid.

Example 72 Method for preparing compound BCD-CDK8-3-17.

Compound BCD-CDK8-3-17 was prepared analogously to compound 1-1-1 (example 1, step 3), using 3-9-1 instead of 1-1-3 and 2-pyrrolidone instead of 1-1-2.

Example 73 Method for preparing compound BCD-CDK8-3-18.

Compound BCD-CDK8-3-18 was prepared similarly to compound 1-2-4 (example 5, step 1), using 2-methoxyethylamine instead of azetidine hydrochloride and compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid.

Example 74 Method for preparing compound BCD-CDK8-4-24.

Step 1. To a solution of 5-bromo-3-iodo-1H-pyrollo [2,3] pyridine (6.78 g, 21 mmol) in 70 ml THF, while cooling in an ice bath, was added NaH (1.51 g, 63 mmol). The suspension was stirred for 15 min, after which SEMC1 (4.1 mL, 23.1 mmol) was added. The reaction mixture was left stirring overnight. Then added 250 ml of water and was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried with MgSO ₄ . Product 4-24-3 was isolated as a light yellow viscous liquid by column chromatography on silica gel with ethyl acetate-hexane (2: 8). Yield 9.01 g (95%).

Stage 2. A solution of compound 4-24-3 (3.00 g, 6.50 mmol) in dry THF was degassed with argon and cooled to -77 ° C. Then, a 2.5 M solution of butyllithium in hexane (3.1 ml, 7.54 mol) was added, and the mixture was stirred at the same temperature for 15 min. To the resulting solution was added N-methoxy-N-methylpyridine-2-carboxamide (990 mg, 5.90 mmol) (prepared according to the procedure described in Bioorganic and Medicinal Chemistry Letters, 19 (16), 4639-4642; 2009). After 20 min, the reaction mixture was diluted with 200 ml of saturated NH ₄ Cl solution, the product was extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . Product 4-24-2 was isolated as a light yellow powder by column chromatography on silica gel with ethyl acetate-hexane (1: 9). Yield 1.90 g (64%).

Stage 3. To a solution of 2-bromo-5-methoxybenzonitrile (250 mg, 1.18 mmol) dissolved in 1.5 ml of 1,4-dioxane was added bis (pinacolato) diborane (449 mg, 1.77 mmol), potassium acetate (139 mg, 1.41 mmol), X-Phos (112 mg, 0.236 mmol) and Pd (OAc) ₂ (26 mg, 0.118 mmol). The reaction mixture was stirred in an inert atmosphere at 85 ° С for 2.5 h. Compound 4-24-2 (510 mg, 1.18 mmol), Cs ₂ CO ₃ (1.15 g, 3.54 mmol), Pd (PPh ₃ ) ₄ (115 mg, 0.117 mol) and 0.5 ml of water. The reaction mixture was stirred in an inert atmosphere for 6 h at 90 ° C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . Product 4-24-1 was isolated as a light yellow powder by column chromatography on silica gel with acetone-hexane (2: 8). Yield 414 mg (91%).

Stage 4. Trifluoroacetic acid (0.75 ml, 9.8 mmol) was added to a suspension of compound 4-24-1 (414 mg, 0.85 mmol) in 1.5 ml of dichloromethane with cooling with an ice bath. The reaction mixture was stirred for 8 h at room temperature. Then it was diluted with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . The reaction product BCD-CDK8-4-24 was isolated as a white powder by column chromatography in acetone-hexane (5: 5). Yield 157 mg (52%).

Example 75 Method for preparing compound BCD-CDK8-4-4.

To a solution of compound BCD-CDK8-4-24 (90 mg, 0.25 mol) in 1 ml of DMSO, K ₂ CO ₃ (38 mg, 0.275 mmol) and 0.25 ml of 30% Н ₂ О ₂ were added. The reaction mixture was stirred at 50 ° C for 5 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . The reaction product was isolated as a white powder by column chromatography on silica gel using acetone-hexane (5: 5). Yield 35 mg (37%).

Example 76 Method for preparing compound BCD-CDK8-4-28.

Step 1. Compound 4-28-2 was prepared analogously to compound 4-24-2 (example 74, step 2) using N-methoxy-N-methylpyridine-3-carboxamide (prepared according to the procedure described in Bioorganic & Medicinal Chemistry Letters , 19 (16), 4639-4642, 2009) instead of N-methoxy-N-methylpyridine-2-carboxamide.

Step 2. Compound 4-28-1 was prepared analogously to compound 4-24-1 (example 74, step 3) using compound 4-28-2 instead of compound 4-24-2.

Step 3. Compound BCD-CDK8-4-28 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-28-1 instead of compound 4-24-1.

Example 77 Method for preparing compound BCD-CDK8-4-8.

Compound BCD-CDK8-4-8 was prepared similarly to compound BCD-CDK8-4-4 (Example 75) using compound BCD-CDK8-4-28 instead of compound BCD-CDK8-4-24.

Example 78 Method for preparing compound BCD-CDK8-4-32.

Step 1. Compound 4-32-2 was prepared analogously to compound 4-24-2 (example 74, step 2) using N-methoxy-N-methylpyridine-4-carboxamide (prepared according to the procedure described in Bioorganic & Medicinal Chemistry Letters , 24 (3), 790-793, 2014) instead of N-methoxy-N-methylpyridine-2-carboxamide.

Step 2. Compound 4-32-1 was prepared analogously to compound 4-24-1 (example 74, step 3) using compound 4-32-2 instead of compound 4-24-2.

Step 3. Compound BCD-CDK8-4-32 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-32-1 instead of compound 4-24-1.

Example 79 Method for preparing compound BCD-CDK8-4-12.

BCD-CDK8-4-12 was prepared similarly to BCD-CDK8-4-4 (Example 75) using BCD-CDK8-4-32 instead of BCD-CDK8-4-24.

Example 80 Method for preparing compound BCD-CDK8-4-21.

Step 1. To a solution of 2-methoxy-N, N-dimethylaniline (3.00 g 19.8 mmol) (prepared according to the procedure described in Angewandte Chemie International Edition, 55 (23), 6776-6779, 2016) in 50 ml of acetonitrile was added N β-bromosuccinimide (3.71 g, 20.8 mmol) with cooling in an ice bath. After 30 min, the mixture was diluted with 250 ml of water, the product was extracted with ethyl acetate, the organic layer was washed with water, NaCl solution and dried with MgSO ₄ . The product was used without further purification. Yield 3.5 g (77%).

Step 2. Compound 4-21-1 was prepared similarly to 4-24-1 (Example 74, Step 3) using compound 4-21-2 instead of 2-bromo-5-methoxybenzonitrile.

Step 3. Compound BCD-CDK8-4-21 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-21-1 instead of compound 4-24-1.

Example 81 Method for preparing compound BCD-CDK8-4-1.

AlCl ₃ (296 mg, 2.22 mmol) was added to a solution of compound BCD-CDK8-4-21 (92 mg, 0.222 mmol) in 20 ml of dichloroethane. The reaction mixture was stirred at 60 ° C for 8 hours. The solvent was removed in vacuo. Saturated NaHCO ₃ solution was added to the residue and extracted with ethyl acetate, the organic layer was dried over MgSO ₄ . The reaction product was isolated as a white powder by column chromatography on silica gel using dichloromethane-methanol (95: 5). Yield 46 mg (52%).

Example 82 Method for preparing compound BCD-CDK8-4-25.

Step 1. Compound 4-25-1 was prepared analogously to compound 4-24-1 (example 74, step 3), using 4-28-2 instead of 4-24-2 and 4-21-2 instead of 2-bromo-5 -methoxybenzonitrile.

Step 2. Compound BCD-CDK8-4-25 was prepared analogously to compound BCD-CDK8-4-24 (Example 74, step 4) using compound 4-25-1 instead of compound 4-24-1.

Example 83 Method for preparing compound BCD-CDK8-4-5.

Compound BCD-CDK8-4-5 was prepared analogously to BCD-CDK8-4-1 (Example 81) using BCD-CDK8-4-25 instead of BCD-CDK8-4-21.

Example 84 Method for preparing compound BCD-CDK8-4-29.

Step 1. Compound 4-29-1 was prepared analogously to compound 4-24-1 (example 74, step 3), using 4-32-2 instead of 4-24-2 and 4-21-2 instead of 2-bromo-5 -methoxybenzonitrile.

Step 2. Compound BCD-CDK8-4-29 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-29-1 instead of compound 4-24-1.

Example 85 Method for preparing compound BCD-CDK8-4-9.

Compound BCD-CDK8-4-9 was prepared similarly to BCD-CDK8-4-1 (Example 81) using BCD-CDK8-4-29 instead of BCD-CDK8-4-21.

Example 86 Method for preparing compound BCD-CDK8-4-22.

Stage 1. To a solution of 2-bromo-5- (dimethylamino) benzoic acid (7.48 g, 30.6 mmol) (obtained according to the method described in WO 2008/079277) in 50 ml of DMF, NH ₄ Cl (4.92 g, 91.8 mmol ), EDC⋅HCl (7.34 g, 38.3 mmol), HOBt (5.18 g, 38.3 mmol) and triethylamine (6.4 mL, 45.9 mmol). The reaction mixture was stirred for 12 h, after which it was diluted with 150 ml of water and extracted with ethyl acetate, the organic layer was dried with MgSO ₄ . The solvent was removed under reduced pressure. The reaction product, obtained as a white powder, was used without further purification. Yield 6.85 g (92%).

Stage 2. To a suspension of compound 4-22-3 (2.97 g, 12 mmol) in 35 ml of chloroform, POCl ₃ (1.71 ml, 18 mmol) was added. The reaction mixture was stirred at reflux. After 2.5 h, the solvent was removed under reduced pressure, the residue was poured into ice water, and NaHCO _{3 was} added. The reaction product was extracted with ethyl acetate, the organic layer was dried with MgSO ₄ . The reaction product was isolated as a white powder by column chromatography on silica gel with ethyl acetate-hexane (1: 9). Yield 1.732 g (63%).

Step 3. Compound 4-22-1 was prepared analogously to compound 4-24-1 (example 74, step 3), using compound 4-22-2 instead of 2-bromo-5-methoxybenzonitrile.

Step 4. Compound BCD-CDK8-4-22 was prepared similarly to BCD-CDK8-4-24 (example 74, step 4) using compound 4-22-1 instead of compound 4-24-1.

Example 87 Method for preparing compound BCD-CDK8-4-2.

BCD-CDK8-4-2 was prepared similarly to BCD-CDK8-4-4 (Example 75) using BCD-CDK8-4-22 instead of BCD-CDK8-4-24.

Example 88 Method for preparing compound BCD-CDK8-4-26.

Step 1. Compound 4-26-1 was prepared analogously to compound 4-24-1 (example 74, step 3), using compound 4-22-2 instead of 2-bromo-5-methoxybenzonitrile and compound 4-28-2 instead of compound 4-24-2.

Step 2. Compound BCD-CDK8-4-26 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-26-1 instead of compound 4-24-1.

Example 89 Method for preparing compound BCD-CDK8-4-6.

Compound BCD-CDK8-4-6 was prepared similarly to BCD-CDK8-4-4 (Example 75), using compound BCD-CDK8-4-26 instead of BCD-CDK8-4-24.

Example 90 Method for preparing compound BCD-CDK8-4-30.

Step 1. Compound 4-30-1 was obtained analogously to compound 4-24-1 (example 74, step 3), using compound 4-22-2 instead of 2-bromo-5-methoxybenzonitrile and compound 4-32-2 instead of compound 4-24-2.

Step 2. Compound BCD-CDK8-4-30 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-30-1 instead of compound 4-24-1.

Example 91 Method for preparing compound BCD-CDK8-4-10.

Compound BCD-CDK8-4-10 was prepared similarly to BCD-CDK8-4-4 (Example 75) using BCD-CDK8-4-30 instead of BCD-CDK8-4-24.

Example 92. Process for preparing compound BCD-CDK8-4-23.

Stage 1. To a solution of o-methoxyaniline (2.50 g, 20 mmol) in 20 ml of DMF, 2,2'-dichlorodiethyl ether (3.00 g, 21 mmol), K ₂ CO ₃ (4.30 g, 40 mol) and KI (3.10 d, 20 mmol). The mixture was stirred at 90 ° С for 5 h. Then 100 ml of water was added, the product was extracted with ethyl acetate. The organic layer was separated, washed with water, dried with Na ₂ SO ₄ . The product was isolated as a gray powder by column chromatography on silica gel, eluent hexane-ethyl acetate (95: 5). Yield 3.35 g (87%).

Stage 2. To a solution of compound 4-23-3 (3.35 g, 17 mmol) in 40 ml of acetonitrile was added N-bromosuccinimide (3.15 g, 18 mmol) at -10 ° C. After 1 h, the solvent was distilled off in vacuo, the residue was dissolved in dichloromethane, washed with water, and dried over Na ₂ SO ₄ . The product was isolated as a dark gray powder by column chromatography on silica gel using hexane-ethyl acetate (95: 5) as eluent. Yield 4.28 g (92%).

Step 3. Compound 4-23-1 was prepared analogously to compound 4-24-1 (example 74, step 3), using compound 4-23-2 instead of 2-bromo-5-methoxybenzonitrile.

Step 4. Compound BCD-CDK8-4-23 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-23-1 instead of compound 4-24-1.

Example 93 Method for preparing compound BCD-CDK8-4-3.

Compound BCD-CDK8-4-3 was prepared similarly to compound BCD-CDK8-4-1 (Example 81) using compound BCD-CDK8-4-23 instead of compound BCD-CDK8-4-21.

Example 94 Method for preparing compound BCD-CDK8-4-27.

Step 1. Compound 4-27-1 was obtained similarly to 4-24-1 (example 74, step 3), using compound 4-23-2 instead of 2-bromo-5-methoxybenzonitrile and compound 4-28-2 instead of compound 4 -24-2.

Step 2. Compound BCD-CDK8-4-27 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-27-1 instead of compound 4-24-1.

Example 95 Method for preparing compound BCD-CDK8-4-7.

Compound BCD-CDK8-4-7 was prepared similarly to compound BCD-CDK8-4-1 (Example 81) using compound BCD-CDK8-4-27 instead of compound BCD-CDK8-4-21.

Example 96 Method for preparing compound BCD-CDK8-4-31.

Stage 1. Compound 4-31-1 was obtained similarly to 4-24-1 (example 74, step 3), using compound 4-23-2 instead of 2-bromo-5-methoxybenzonitrile and compound 4-32-2 instead of compound 4 -24-2.

Step 2. Compound BCD-CDK8-4-31 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-31-1 instead of compound 4-24-1.

Example 97 Method for preparing compound BCD-CDK8-4-11.

Compound BCD-CDK8-4-11 was prepared similarly to compound BCD-CDK8-4-1 (Example 81) using compound BCD-CDK8-4-31 instead of compound BCD-CDK8-4-21.

Example 98 Method for preparing compound BCD-CDK8-4-35.

Stage 1. To a solution of 5-bromo-1H-pyrrolo [2.3] pyridine (1.00 g, 5.07 mmol) in 30 ml of dichloroethane was added AlCl ₃ (2.71 g, 20.3 mmol), the resulting suspension was stirred for 15 minutes, then the acid chloride solution was added; m-methoxybenzoic acid (862 mg, 5.07 mmol) in 10 ml of dichloroethane. The reaction mixture was stirred at the boiling point of the solvent for 1.5 h. The solvent was removed in vacuo. Ice water and saturated NaHCO ₃ solution were added to the residue. The suspension was filtered off, the precipitate was dried in a vacuum oven to obtain the reaction product in the form of a white powder. Yield 928 mg (56%).

Step 2. Compound 4-35-2 was obtained analogously to compound 4-24-3 (example 74, step 1), using compound 4-35-3 instead of 5-bromo-3-iodo-1H-pyrollo [2,3] pyridine.

Step 3. Compound 4-35-1 was prepared analogously to compound 4-24-1 (example 74, step 3) using compound 4-35-2 instead of compound 4-24-2.

Step 4. Compound BCD-CDK8-4-35 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-35-1 instead of compound 4-24-1.

Example 99 Method for preparing compound BCD-CDK8-4-13.

BCD-CDK8-4-13 was prepared similarly to BCD-CDK8-4-4 (Example 75) using BCD-CDK8-4-35 instead of BCD-CDK8-4-24.

Example 100 Method for preparing compound BCD-CDK8-4-33.

Step 1. Compound 4-33-1 was obtained similarly to compound 5-2-3 (example 29, step 2), using compound 4-32-2 instead of compound 5-2-4 and 4-methoxyphenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 2. Compound BCD-CDK8-4-33 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-33-1 instead of compound 4-24-1.

Example 101 Method for preparing compound BCD-CDK8-4-34.

Step 1. Compound 4-34-1 was prepared analogously to compound 5-2-3 (example 29, step 2) using compound 4-35-2 instead of compound 5-2-4.

Step 2. Compound BCD-CDK8-4-34 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-34-1 instead of compound 4-24-1.

Example 102 Method for preparing compound BCD-CDK8-4-36.

Step 1. Compound 4-36-1 was obtained analogously to compound 5-2-3 (example 29, step 2), using compound 4-24-2 instead of compound 5-2-4 and 4-morpholine phenylboronic acid instead of hydrochloride 4- ( dimethylamino) phenylboronic acid.

Step 2. Compound BCD-CDK8-4-36 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-36-1 instead of 4-24-1.

Example 103 Method for preparing compound BCD-CDK8-4-37.

Stage 1. Compound 4-37-1 was obtained similarly to compound 5-2-3 (example 29, step 2), using 4-28-2 instead of 5-2-4 and 4-morpholine phenylboronic acid instead of 4- (dimethylamino) hydrochloride phenylboronic acid.

Step 2. Compound BCD-CDK8-4-37 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-37-1 instead of 4-24-1.

Example 104 Method for preparing compound BCD-CDK8-4-38.

Stage 1. Compound 4-38-1 was obtained similarly to compound 5-2-3 (example 29, step 2), using 4-32-2 instead of 5-2-4 and 4-morpholine phenylboronic acid instead of 4- (dimethylamino) hydrochloride phenylboronic acid.

Step 2. Compound BCD-CDK8-4-38 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-38-1 instead of compound 4-24-1.

Example 105 Method for preparing compound BCD-CDK8-4-39.

Step 1. Compound 4-39-1 was prepared analogously to compound 5-2-3 (example 29, step 2) using compound 4-28-2 instead of compound 5-2-4.

Step 2. Compound BCD-CDK8-4-39 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-39-1 instead of compound 4-24-1.

Example 106 Method for preparing compound BCD-CDK8-4-40.

Step 1. Compound 4-40-1 was prepared analogously to compound 5-2-3 (example 29, step 2) using 4-32-2 instead of 5-2-4.

Step 2. Compound BCD-CDK8-4-40 was prepared analogously to compound BCD-CDK8-4-24 (example 74, step 4) using compound 4-40-1 instead of 4-24-1.

Example 107 Method for preparing compound BCD-CDK8-3-19.

BCD-CDK8-3-4. (35 mg, 0.088 mmol, 1.00 equiv.) Was dissolved in 2 ml of THF and sprinkled with portions of NaH (5 mg, 0.114 mmol, 1.30 equiv., 60% suspension in mineral oil) while cooling with an ice bath. The mixture was stirred for 15 minutes while cooling and then for another 30 minutes at room temperature. Then, with stirring and cooling with a water bath, methyl iodide (9 μL, 0.150 mmol, 1.7 eq.) Was added dropwise; after 5 min, the reaction mixture was brought to room temperature. After 1 h, 10 ml of water was poured in and extracted with ethyl acetate (2 × 15 ml). The organic layers were washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The product was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (96: 4) as a light yellow powder. Yield 18 mg (50%).

Example 108 Method for preparing compound BCD-CDK8-3-20.

Compound BCD-CDK8-3-20 was prepared similarly to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and (S) -3-hydroxypiperidine hydrochloride instead of azetidine hydrochloride.

Example 109. Process for preparing compound BCD-CDK8-3-21.

Compound BCD-CDK8-3-21 was prepared similarly to compound BCD-CDK8-3-19 (Example 107) using BCD-CDK8-3-20 instead of BCD-CDK8-3-4.

Example 110 Method for preparing compound BCD-CDK8-3-22.

Compound BCD-CDK8-3-22 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and dimethylamine hydrochloride instead of azetidine hydrochloride.

Example 111 Method for preparing compound BCD-CDK8-3-23.

Compound BCD-CDK8-3-23 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and diethylamine instead of azetidine hydrochloride.

Example 112 Method for preparing compound BCD-CDK8-3-24.

Stage 1. Compound BCD-CDK8-3-18 (110 mg, 0.283 mmol, 1.00 eq.) Was dissolved in 5 ml of dichloromethane and sprinkled with m-chloroperbenzoic acid (66 mg, 0.326 mmol, 1.15 eq.). After 1 h, 15 ml of water and 5 ml of dichloromethane were poured in, 1M sodium hydroxide solution was added to pH 8. The organic layers were separated, the aqueous layer was additionally extracted with dichloromethane. The combined organic layers were washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The reaction product was isolated as a yellow powder by column chromatography on silica gel using ethyl acetate-dichloromethane-methanol (5: 4.7: 0.3) as eluent. Yield 65 mg (57%).

Step 2. Compound CDK8-3-24-1 (30 mg, 0.074 mmol, 1.00 eq.) Was dissolved in 2 ml of pyridine and n-tosyl chloride (17 mg, 0.089 mmol, 1.20 eq.) Was added. Left under stirring for 1 hour at room temperature. The solvent was distilled off, 3 ml of ethanolamine was added to the reaction mixture, the mixture was stirred at 35 ° С (in a water bath) for 3 h, after which 50 ml of water was added to the reaction mixture. The suspension was filtered off, the precipitate was washed with water, dried in a vacuum, and the product was obtained as a yellow powder. Yield 25 mg (83%).

Example 113 Method for preparing compound BCD-CDK8-3-25.

The compound BCD-CDK8-3-25 was prepared similarly to the compound BCD-CDK8-3-19 (example 107), using the compound BCD-CDK8-3-18 instead of BCD-CDK8-3-4, and also DMF instead of THF as a solvent. ...

Example 114 Method for preparing compound BCD-CDK8-3-26.

Step 1. Compound 3-26-1 was prepared similarly to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-14 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-26 was prepared analogously to compound BCD-CDK8-3-24 (example 112, step 2) using compound 3-26-1 instead of compound 3-24-1.

Example 115 Method for preparing compound BCD-CDK8-3-33.

Compound BCD-CDK8-3-33 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and morpholine instead of azetidine hydrochloride.

Example 116 Method for preparing compound BCD-CDK8-3-27.

Step 1. Compound 3-27-1 was prepared similarly to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-33 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-27 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-27-1 instead of compound 3-24-1.

Example 117 Method for preparing compound BCD-CDK8-3-28.

Compound BCD-CDK8-3-28 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and 2-methoxyethanol instead of azetidine hydrochloride.

Example 118 Method for preparing compound BCD-CDK8-3-29.

Step 1. Compound 3-29-1 was prepared similarly to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-28 instead of BCD-CDK8-3-18.

Stage 2. To a solution of compound 3-29-1 (132 mg, 0.323 mmol) in 5 ml of pyridine was added n-tosyl chloride (80 mg, 0.42 mmol), the reaction mixture was stirred for 1 hour at room temperature. Ethanolamine (20 mg 0.323 mmol) was added to the resulting solution. After one hour of stirring, additional ethanolamine (30 mg, 0.484 mmol) was added. After 1.5 hours of stirring, the reaction mass was poured into water, the product was extracted with ethyl acetate, dried over Na ₂ SO ₄ . The reaction product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol 95: 5. Yield 48 mg (37%).

Example 119 Method for preparing compound BCD-CDK8-3-30.

Compound BCD-CDK8-3-30 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and N-methylpiperazine instead of azetidine hydrochloride.

Example 120 Method for preparing compound BCD-CDK8-3-31.

Step 1. Compound 3-31-3 was prepared analogously to compound 3-24-1 (Example 112, step 1) using compound 3-14-2 instead of compound BCD-CDK8-3-18.

Step 2. Compound 3-31-2 was prepared analogously to compound BCD-CDK8-3-29 (Example 118, step 2) using compound 3-31-3 instead of compound 3-29-1.

Step 3. Compound 3-31-1 was prepared analogously to compound BCD-CDK8-1-6a (Example 2), using compound 3-31-2 instead of compound BCD-CDK8-1-6e.

Step 4. Compound BCD-CDK8-3-31 was prepared similarly to compound BCD-CDK8-5-2 (example 29, step 5) using compound 3-31-1 instead of compound 5-2-1 and N-methylpiperazine instead of hydrochloride (R) -3-hydroxypyrrolidine.

Example 121 Method for preparing compound BCD-CDK8-3-32

Step 1. Compound 3-32-1 was prepared analogously to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-25 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-32 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-32-1 instead of compound 3-24-1.

Example 122 Method for preparing compound BCD-CDK8-3-34.

Step 1. Compound 3-34-1 was prepared analogously to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-15 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-34 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-34-1 instead of compound 3-24-1.

Example 123 Method for preparing compound BCD-CDK8-3-35.

Compound BCD-CDK8-3-35 was prepared similarly to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and N, N, N'-trimethylethylenediamine instead of azetidine hydrochloride.

Example 124 Method for preparing compound BCD-CDK8-3-37.

Compound BCD-CDK8-3-37 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and cyclopropylamine instead of azetidine hydrochloride.

Example 125 Method for preparing compound BCD-CDK8-3-38.

Step 1. Compound 3-38-1 was prepared analogously to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-37 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-38 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-38-1 instead of compound 3-24-1.

Example 126 Method for preparing compound BCD-CDK8-3-39.

Compound BCD-CDK8-3-39 was prepared analogously to compound 1-2-4 (example 5, step 1), using compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid and cyclopropylmethanamine instead of azetidine hydrochloride.

Example 127 Method for preparing compound BCD-CDK8-3-40.

Step 1. Compound 3-40-1 was prepared similarly to compound 3-24-1 (Example 112, step 1) using BCD-CDK8-3-39 instead of BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-40 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-40-1 instead of compound 3-24-1.

Example 128 Method for preparing compound BCD-CDK8-3-42.

Compound BCD-CDK8-3-42 was prepared analogously to compound BCD-CDK8-3-24 (Example 112, step 2) using compound 3-29-1 instead of compound 3-24-1.

Example 129 Method for preparing compound BCD-CDK8-3-41.

Stage 1. Nitrogen was passed through a suspension of benzotriazole (84 mg, 0.7 mmol, 0.2 eq) and copper (I) iodide (135 mg, 0.7 mmol, 0.2 eq) in 20 mL of DMSO for 30 min. Then 1-bromo-4-iodobenzene (1.00 g, 3.5 mmol, 1 eq.), Imidazole (265 mg, 3.8 mmol, 1.1 eq.) And potassium tert-butylate (595 mg, 5.3 mmol, 1.5 eq.) Were added. The reaction mixture was stirred in a closed flask for 3 hours at 140 ° C, then at room temperature overnight. The mixture was filtered through celite, the precipitate was washed 3 times with ethyl acetate, the mother liquor was washed with water and NaCl solution (2 × 50 ml). The organic layer was separated, washed with water, dried with Na ₂ SO ₄ . The product was isolated as a gray powder by column chromatography on silica gel using hexane-ethyl acetate (7: 3) as eluent. Yield 430 mg (55%).

Step 2. Compound 3-41-2 was prepared analogously to compound 3-1-4 (example 58, step 2), using 2-methoxyethylamine instead of (S) -3- (tert-butyldiphenylsilyloxy) pyrrolidine.

Step 3. Compound BCD-CDK8-3-41 was prepared analogously to compound 5-4-4 (example 33, step 2), using compound 3-41-2 instead of compound 5-2-4 and compound 3-41-1 instead of connections 5-4-5.

Example 130. Analysis of the obtained compounds.

The purity and structure of the obtained compounds were confirmed by LC / MS chromatography-mass spectrometry and 1H NMR spectroscopy (Table 1).

Equipment data:

Chromato-mass spectrometry

NMR spectrometer

Example 131. Determination of chemical stability.

The chemical stability of the compounds described herein was determined in artificial intestinal juice and human blood plasma.

An enzyme-free SGF concentrate, pH = 1.4 (Sigma Ireland, cat # 01651) was used as artificial intestinal juice. The candidate stock solution (10 mM in DMSO) was diluted with SGF working solution to a concentration of 10 μM (test solution). The test solution was kept in a solid-state thermostat for 2 hours at a temperature of 37 ° C. By HPLC using an Agilent 1200 chromatograph (Agilent, USA), the peak areas of compounds in the test samples corresponding to the initial test time (before exposure) and the final test time (after incubation in a solid-state thermostat for 2 hours at 37 ° C) were determined. Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. The amount of substance in the sample was determined in% after thermostating.

Determination of stability in human blood plasma was carried out using pooled human blood plasma taken from ten healthy donors. The candidate stock solution (10 mM in DMSO) was diluted with the pooled blood plasma to a concentration of 10 μM (test solution). The test solution was kept in a solid-state thermostat for 4 hours at a temperature of 37 ° C. The HPLC method using an Agilent 1200 chromatograph (Agilent, USA) was used to determine the peak areas of the compounds in the test samples corresponding to the initial test time (before exposure) and the final test time (after holding in a solid-state thermostat for 4 hours at 37 ° C) with preliminary precipitation of proteins acetonitrile. Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. The amount of substance in the sample was determined in% after thermostating.

The stability of the compounds was evaluated. The compounds described herein have chemical stability values greater than 75%, i. E. are chemically stable in the acidic environment of artificial gastric juice and in human blood plasma (table 2).

Example 132. Determination of enzymatic stability in human liver microsomes.

Determination of the enzymatic stability of the candidates made it possible to evaluate the resistance of the compounds of the present invention to the action of liver microsomal enzymes.

и скорость разложения CL_int:The rate of enzymatic degradation of the compound was determined by keeping in a solid-state thermostat at 37 ° C a reaction mixture containing 0.5 mg / ml of pooled human liver microsomes (XenoTech, USA, cat # H2620), 10 μm compound, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth , UK, cat # NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer pH = 7.4. The reaction was stopped with acetonitrile at the rate of 100 μL of acetonitrile per 100 μL of the reaction mixture. After stopping the reaction, the samples were centrifuged for 10 minutes at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent 1200 chromatograph (Agilent, United States). Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. A plot of the logarithm of the area of the peak of the substance versus time was built. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the half-life of the drug was calculated

and the decomposition rate CL _int :

Based on the data obtained, a conclusion was drawn about the enzymatic stability of candidates in human liver microsomes. The compounds of the present invention showed sufficient resistance to the action of human liver microsome enzymes and had a Cl _int enzymatic degradation rate of less than 47 μl / min / mg. The results are shown in Table 3.

Example 133. Determination of enzymatic stability in s9 fractions of human liver.

Determination of the enzymatic stability of the candidates made it possible to evaluate the resistance of the compounds of the present invention to the action of the S9 enzymes of human liver fractions.

и скорость разложения CL_int:The rate of enzymatic degradation of the compound was determined by keeping in a solid-state thermostat at 37 ° C a reaction mixture containing 0.5 mg / ml of pooled S9 human liver fractions (XenoTech, USA, cat # H0610), 10 μm of the compound, 2 mM β-nicotinamide adenine dinucleotide ( Carbosynth, UK, cat # NN 10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer pH = 7.4. The reaction was stopped with acetonitrile at the rate of 100 μL of acetonitrile per 100 μL of the reaction mixture. After stopping the reaction, the samples were centrifuged for 10 minutes at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent 1200 chromatograph (Agilent, United States). Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. A plot of the logarithm of the area of the peak of the substance versus time was built. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the half-life of the drug was calculated

and the decomposition rate CL _int :

Based on the data obtained, a conclusion was made about the enzymatic stability of candidates in S9 fractions of human liver. The compounds of the present invention showed sufficient resistance to the action of the S9 enzymes of the liver fractions and had a Cl _int enzymatic degradation rate of less than 13 μl / min / mg. The results are shown in Table 4.

Example 134. Determination of permeability through a monolayer of Caco-2 cells.

Determination of permeability through a monolayer of Caco-2 cells makes it possible to assess the ability of substances to penetrate biological membranes by both active and passive transport.

Cells of intestinal epithelium Saco-2 were cultured in inserts with filters (with pores of 0.4 μm, BD Falcon with High Density) for 21 days, after which the integrity of the monolayer was checked using Lucifer Yellow dye (Sigma-Aldrich, USA) according to the standard protocol ... When setting the transfer A-> B (transfer "intestinal lumen" - "blood flow"), solutions of the test substances were introduced in a pH 6.5 buffer (HBSS, 10 mM HEPES, 15 mM Glucose solution) at a concentration of 10 μM into the upper chamber; the lower chamber was filled with a buffer with pH 7.4 (HBSS, 10 mM HEPES, 15 mM glucose solution, 1% BSA). When setting the transfer B-> A (transfer "blood flow" - "intestinal lumen"), the upper chamber was filled with a pH 6.5 buffer, and solutions of the studied substances were introduced in a pH 7.4 buffer at a concentration of 10 μM into the lower chamber. Propranolol was used as a control as a highly permeable substance.

After incubation for 2 hours at 37 ° C in an atmosphere with 5% CO _2, test substances were determined amount in the upper and lower chambers by HPLC using Agilent 1200 chromatograph (Agilent, USA) with a preliminary precipitation of proteins with acetonitrile. Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. The areas of the peaks corresponding to the compounds were determined on the chromatograms. Based on the values of the peak areas of the compounds in the calibration standards, the concentration of the compound in the initial solution and in samples from the wells of the upper and lower chambers was determined.

Permeability through the Papp cell layer was calculated by the formula:

P _app = (С _(t) * V) / (С ₍₀₎ * t * Area), where

P _appr - effective permeability constant, m / s

V is the volume of solution (in test A-> B - 0.8 ml, in test B-> A - 0.2 ml), ml

Area - membrane surface area (0.33 cm ² ), cm ²

t - holding time (7200 sec), sec

С ₍₀₎ - concentration of the initial solution, μM

С _(t) - concentration of the solution after 2 hours (in test A-> B - concentration in the sample from the well of the lower chamber; in test B-> A - concentration in the sample from the well of the upper chamber), μM

The efflux coefficient showed the ability of cells to eliminate a substance from the bloodstream. The value was calculated using the formula:

efflux = P _appB-A / P _appA-B , where

P _appA-B - direct analysis permeability value А->В;

P _appB-A is the value of the inverse analysis permeability B-> A.

The compounds of the present invention showed a high rate of direct transport "intestinal lumen" - "blood flow", while the efflux coefficient did not exceed 2, which indicates that the Pgp transporter does not impose restrictions on the bioavailability of the substance. The results are shown in Table 5.

Example 135. Antiproliferative activity against CDK8-sensitive cell lines in vitro.

The antiproliferative activity of the CDK8 inhibitors of the present invention was measured in a transplantable cell test MV4-11 (biphenotypic myelomonocytic leukemia, ATCC® CRL-9591 ™), KG-1 (acute myelogenous leukemia, ATCC® CCL-246 ™), HL-60 (acute promyelocytic leukemia, ATCC® CCL-240 ™) with AlamarBlue (ThermoFisher, # DAL1100). The cells were grown in RPMI-1640 medium (PanEko, # C330p) supplemented with 10% FBS (Gibco, # 16140-071), washed and re-seeded on 10% FBS medium (Gibco, # 16140-071) in 96-well culture plates (Corning, # 3599) at ≈10 × 10 ³ cells in 100 μl of medium per well. Test compounds were dissolved in DMSO and diluted with 10% medium) FBS (Gibco, # 16140-071) to a final concentration ranging from 0 to 100 μM. Diluted compounds in a volume of 50 μl were then added to each well (the final concentration of DMSO was no more than 1%) and incubated at 37 ° C in an incubator with 5% CO ₂ for 120 h. After the end of incubation, 15 μl of AlamarBlue reagent was added to the wells (ThermoFisher, # DAL1100), the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), then they were additionally incubated for 3 to 5 h at 37 C in an incubator with 5% CO ₂ . The number of living cells was detected on a microplate spectrophotometer (Tecan Infinite M200Pro, Switzerland) by measuring the fluorescent signal at an excitation wavelength (λEx) of 540 nm and an emission wavelength (λEm) of 590 nm.

The IC ₅₀ value was determined using the Magellan 7.2 program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with optimization according to Levenberg-Markart (table 7, table 7).

The CC ₅₀ value was determined in the cytotoxicity test. The studies were performed on HepG2 cells (hepatocellular carcinoma, ATCC® HB-8065 ™). The cells were plated into 96-well plates (Corning, # 3599) at a concentration of ≈20 × 10 ³ cells in 100 μL of medium per well and incubated for 72 h with added compounds in the concentration range from 200 to 0.78 μM. Cell viability was assessed by the method described above. The results are shown in Table 6.

Claims (244)

1. Compound of formula I.1:

or its stereoisomer, where (i) when n is 1, X ₄ represents C (H) _m , N; m represents 0, 1; X ₁ represents N, C, CH; X ₂ , X _{3 are} each independently C (H) _m , NH, N, CR ₁₃ , CHR ₁₃ ; L ₁ represents a chemical bond, —O—, —C (O) -, —C (O) —O—, —NH—, —C (= NR ₁₉ ) -; L ₂ represents a chemical bond, —C (O) -, —C (O) —O—, —NH—, —C (= NR ₁₉ ) -; k is selected from 0, 1; R ₁ , R ₃ , R _{13 are} each independently H, Hal, NH ₂ ; R ₂ , R _{4 are} each independently selected from the group consisting of:

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl substituted with one or more R ₁₄ substituents; X ₅ X ₆ X ₇ each independently represents C, CH, N; L ₃ , L ₄ each independently represents a chemical bond, —C (O) -, —O—, —C (O) —NR _7a -; p = 0, 1, 2; R ₅ represents H; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; phenyl; 6-membered heterocyclyl with 2 heteroatoms selected from N and / or O; R ₆ , R _6a each independently represents H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl; R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ ; R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl; R ₁₁ is C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₂ represents H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; R ₁₇ , R _{18 are} each independently H, phenyl;

each independently represents a single bond or a double bond; Hal is chlorine, bromine, iodine, fluorine; (ii) when n is 0, X ₄ represents C (H) _m , N; m represents 0, 1; X ₁ represents N, C, CH; X ₂ , X _{3 are} each independently C (H) _m , NH, N, CR ₁₃ , CHR ₁₃ ; L ₁ , L ₂ each independently represents a chemical bond, —O—, —C (O) -, —C (O) —O, —NH—, —C (= NR ₁₉ ) -; k is independently selected from 0, 1; R ₁ , R ₃ , R _{13 are} each independently H, Hal; R _{2 is} selected from the group consisting of:

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl substituted with one or more R ₁₄ substituents, and where X ₅ represents C, CH, N, X ₆ , X _{7 are} each independently C, CH; and wherein (ii.1) when p = 1, L ₃ represents a chemical bond, —C (O) -, —O—, —C (O) —NR _7a -; and R ₅ represents H; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; phenyl; 6-membered heterocyclyl with 2 heteroatoms selected from N and / or O; R ₆ , R _{6a are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; R ₇ is H, C ₁ -C ₆ alkyl; R _7a represents C ₁ -C ₆ alkyl; R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ ; L ₄ represents —C (O) -, —O—, —C (O) —NR _7a -; R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl; R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; R ₂₃ is C ₁ -C ₆ alkyl; L ₄ represents a chemical bond; R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₂ -C ₆ alkyl; R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; R ₂₃ is C ₁ -C ₆ alkyl; (ii.2) when p = 2, then L ₃ represents a chemical bond, —C (O) -, —O—, —C (O) —NR _7a -; and R ₅ represents H; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; phenyl; 6-membered heterocyclyl with 2 heteroatoms selected from N and / or O; R ₆ , R _{6a are} each independently H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl; R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ ; L ₄ represents a chemical bond, —C (O) -, —O—, —C (O) —NR _7a -; R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl; R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₄ , R ₂₃ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; R _{4 is} selected from the group consisting of:

-NR ₁₁ R ₁₂ ; C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₄ substituents, and where X ₅ X ₆ X ₇ each independently represents C, CH, N; L ₃ represents a chemical bond, —C (O) -, —O—, —C (O) —NR _7a -; and wherein p = 0, 1, 2; R ₅ represents H; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; phenyl; 6-membered heterocyclyl with 2 heteroatoms selected from N and / or O; R ₆ , R _6a each independently represents H, Hal, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; R ₇ , R _{7a are} each independently H, C ₁ -C ₆ alkyl; R ₈ , R _{9 are} each independently H, C ₁ -C ₆ alkyl, —C (O) —NR ₂₁ R ₂₂ ; L ₄ represents —C (O) -, —O—, —C (O) —NR _7a -; wherein R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₁ -C ₆ alkyl; R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; L ₄ represents a chemical bond; wherein R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, —NR ₂₃ R ₂₄ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and / or O, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; -S (O) ₂ -C ₂ -C ₆ alkyl; R ₁₁ , R _{12 are} each independently H; C ₁ -C ₆ alkyl unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, —NR _23a R _24a ; C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ each independently represents Hal, —C (O) NR ₁₇ R ₁₈ , C ₁ -C ₆ alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R ₂₁ , R ₂₂ , R ₂₄ , R _23a , R _{24a are} each independently H, C ₁ -C ₆ alkyl; R ₂₃ is C ₁ -C ₆ alkyl; R ₁₇ , R _{18 are} each independently H; phenyl;

each independently represents a single bond or a double bond; Hal represents chlorine, bromine, iodine, fluorine. 2. A compound according to claim 1, wherein L ₁ , L ₂ each independently represents a chemical bond, —C (O) -, —C (O) —O—, —NH—, —C (= NH) -. 3. A compound according to claim 1, wherein R ₅ is H; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; phenyl; 6-membered heterocyclyl with 2 heteroatoms selected from N and / or O, which is a 6-membered heterocyclyl with 1 O and 1 N atom, selected from 4-morpholinyl; R ₁₅ , R _{16 are} each independently H, C ₁ -C ₆ alkyl. 4. A compound according to claim 1, wherein R _{10 is} each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, hydroxy, cyano, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and / or O, representing 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls; 5-6-membered heteroaryl with 1-2 heteroatoms selected from N and / or O, which is imidazolyl, pyrazolyl, unsubstituted or substituted with one or more C ₁ -C ₆ alkyls. 5. Connection according to PP. 1-4, where R ₃ each independently represents H, Hal. 6. The connection according to claim 1, which is: 1- (1- (4 - ((methylsulfonyl) carbamoyl) phenyl) -1H-benzo [d] imidazol-6-yl) -N-phenylazetidine-3-carboxamide (BCD-CDK8-1-1), 4- (6-azetidine-1-carbonyl) -1H-benzo [d] imidazol-1-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-1-2), (1- (4- (1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) (piperidin-1-yl) methanone (BCD-CDK8-1-3), (1- (1- (4- (1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1- 4), (1- (4- (1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) (azetidin-1-yl) methanone (BCD-CDK8-1-5), methyl 4- (6- (3- (phenylcarbamoyl) azetidin-1-yl) -1H-benzo [d] imidazol-1-yl) benzoate (BCD-CDK8-1-6E), 4- (6- (3- (phenylcarbamoyl) azetidin-1-yl) -1H-benzo [d] imidazol-1-yl) benzoic acid (BCD-CDK8-1-6A), 1- (1- (4-carbamoylphenyl) -1H-benzo [d] imidazol-6-yl) -N-phenylazetidine-3-carboxamide (BCD-CDK8-1-6), methyl 4- (6- (3- (phenylcarbamoyl) azetidin-1-yl) -4-fluoro-1H-benzo [d] imidazol-1-yl) benzoate (BCD-CDK8-1-7E), 4 - (- 6- (3- (phenylcarbamoyl) azetidin-1-yl) -4-fluoro-1H-benzo [d] imidazol-1-yl) benzoic acid (BCD-CDK8-1-7A), 1- (1- (4-carbamoylphenyl) -4-fluoro-1H-benzo [d] imidazol-6-yl) -N-phenylazetidine-3-carboxamide (BCD-CDK8-1-7), (1- (1- (4- (1H-pyrazol-4-yl) phenyl) -4-fluoro-1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD- CDK8-1-8), (1- (1- (4- (dimethylamino) phenyl) -1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1-9), azetidin-1-yl- (1- (4- (dimethylamino) phenyl) -1H-benzo [d] imidazol-6-yl) methanone (BCD-CDK8-1-10), (3-methoxyazetidin-1-yl) (1- (4-methoxyphenyl) -1H-benzo [d] imidazol-6-yl) methanone (BCD-CDK8-1-11), (1- (1- (4-methoxyphenyl) -1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1-12), (1- (1- (4- (dimethylamino) phenyl) -4-fluoro-1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1-13) , (1- (1- (4- (1H-pyrazol-4-yl) phenyl) -7-fluoro-1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD- CDK8-1-14), methyl 4- (6- (azetidine-1-carbonyl) -7-fluoro-1H-benzo [d] imidazol-1-yl) benzoate (BCD-CDK8-1-15E), 4- (6- (azetidine-1-carbonyl) -7-fluoro-1H-benzo [d] imidazol-1-yl) benzoic acid (BCD-CDK8-1-15A), 4- (6- (azetidine-1-carbonyl) -7-fluoro-1H-benzo [d] imidazol-1-yl) benzamide (BCD-CDK8-1-15), (1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) (piperidin-1-yl) methanone (BCD-CDK8-1-16 ), (1- (1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD- CDK8-1-17), azetidin-1-yl (1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanone (BCD-CDK8-1-18), (1- (1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4-fluoro-1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1-19), (1- (1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-fluoro-1H-benzo [d] imidazol-6-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8-1-20), 4- (6 - ((2- (chloromethyl) -3-oxo-3- (phenylamino) propyl) amino) -4-fluoro-1H-benzo [d] imidazol-1-yl) benzamide (BCD-CDK8-1 -21A), 4- (6 - ((2- (chloromethyl) -3-oxo-3- (phenylamino) propyl) amino) -4-fluoro-1H-benzo [d] imidazol-1-yl) benzoic acid (BCD-CDK8- 1-21), (S) -4- (3- (3-hydroxypyrrolidine-1-carbonyl) -1,7-naphthyridin-5-yl) -N- (methanesulfonyl) benzamide (BCD-CDK8-3-1), (R) - (5- (4- (1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (3-hydroxypyrrolidin-1-yl) methanone (BCD-CDK8-3-2 ), (R) - (5- (4- (dimethylamino) phenyl) -1,7-naphthyridin-3-yl) (3-hydroxypyrrolidin-1-yl) methanone (BCD-CDK8-3-3), (R) - (3-hydroxypyrrolidin-1-yl) (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8 -3-4), (R) - (3-hydroxypyrrolidin-1-yl) (5- (4-morpholinophenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8-3-5), (R) - (3-hydroxypyrrolidin-1-yl) (5- (4-methoxyphenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8-3-6), (5- (4- (dimethylamino) phenyl) -1,7-naphthyridin-3-yl) (4-methylpiperazin-1-yl) methanone (BCD-CDK8-3-8), (1- (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) azetidin-3-yl) (morpholino) methanone (BCD-CDK8- 3-9), N- (methylsulfonyl) -4- (3- (piperidine-1-carbonyl) -1,7-naphthyridin-5-yl) benzamide (BCD-CDK8-3-11), N, N-dimethyl-1- (5- (4 - ((methylsulfonyl) carbamoyl) phenyl) -1,7-naphthyridin-3-yl) azetidine-3-carboxamide (BCD-CDK8-3-12), (R) -4- (3- (3-hydroxypyrrolidine-1-carbonyl) -1,7-naphthyridin-5-yl) -N- (methanesulfonyl) benzamide (BCD-CDK8-3-13), azetidin-1-yl- (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8-3-14), (3-methoxyazetidin-1-yl (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8-3-15) , (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (pyrrolidin-1yl) methanone (BCD-CDK8-3-16), (1- (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) pyrrolidin-2-one (BCD-CDK8-3-17), N- (2-methoxyethyl) -5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-18), (R) -3- (methoxypyrrolidin-1-yl) (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8 -3-19), (R) -3-hydroxypiperidin-1-yl) (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridyl-3-yl) methanone (BCD-CDK8- 3-20), (R) -3- (methoxypiperidin-1-yl) (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8 -3-21), N, N-dimethyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-22), N, N-diethyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-23), 8-amino-N- (2-methoxyethyl) -5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-24 ), N- (2-methoxyethyl) -N-methyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-25 ), (8-amino-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (azetidin-1-yl) methanone (BCD-CDK8-3 -26), (8-amino-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (morpholino) methanone (BCD-CDK8-3-27), 2-methoxyethyl-5- [4- (methyl-1-H-pyrazol-4-yl) phenyl] -1,7-naphthyridine-3-carboxylate (BCD-CDK8-3-28), 2-methoxyethyl-8-amino-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxylate (BCD-CDK8-3-29), (4-methylpiperazin-1-yl) (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) methanone (BCD-CDK8-3-30 ), (8-amino-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (4-methylpiperazin-1-yl) methanone (BCD-CDK8 -3-31), 8-amino-N- (2-methoxyethyl) -N-methyl- (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD- CDK8-3-32), (5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (morpholino) methanone (BCD-CDK8-3-33), (8-amino-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3-yl) (3-methoxyazetidine) methanone (BCD-CDK8-3-34 ), N- (2- (dimethylamino) ethyl) -N-methyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8- 3-35), N-cyclopropyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-37), 8-amino-N-cyclopropyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-38), N- (cyclopropylmethyl) -5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-39), 8-amino-N- (cyclopropylmethyl) -5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-40), 5- (4 (1H-imidazol-1-yl) phenyl) -N- (2-methoxyethyl) -1,7-naphthyridin-3-yl) carboxamide (BCD-CDK8-3-41), 8-amino-N- (2-hydroxyethyl) -5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,7-naphthyridine-3-carbamide (BCD-CDK8-3-42 ), (5- (4- (dimethylamino) -3-hydroxyphenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-2-yl) methanone (BCD-CDK8-4-1), 5- (dimethylamino) -2- (3-picolinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-2), (5- (3-hydroxy-4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-2-yl) methanone (BCD-CDK8-4-3), 5-methoxy-2- (3-picolinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-4), 5- (4- (dimethylamino) -3-hydroxyphenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-5), 5- (dimethylamino) -2- (3-nicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-6), (5- (3-hydroxy-4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-7), 5-methoxy-2- (3-nicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-8), (5- (4- (dimethylamino) -3-hydroxyphenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-9), 5- (dimethylamino) -2- (3-isonicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-10), (5- (3-hydroxy-4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-11), 2- (3-isonicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -5-methoxybenzamide (BCD-CDK8-4-12), 5-methoxy-2- (3- (3-methoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide (BCD-CDK8-4-13), (5- (4- (dimethylamino) -3-methoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-2-yl) methanone (BCD-CDK8-4-21), 5- (dimethylamino) -2- (3-picolinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-22), (5- (3-methoxy-4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-2-yl) methanone (BCD-CDK8-4-23), 5-methoxy-2- (3-picolinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-24), (5- (4- (dimethylamino) -3-methoxyphenyl) -1H-pyrrolo [2,3-6] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-25), 5- (dimethylamino) -2- (3-nicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-26), (5- (3-methoxy-4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-27), 5-methoxy-2- (3-nicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-28), (5- (4- (dimethylamino) -3-methoxyphenyl) -1H-pyrrolo [2,3-6] pyridin-3-yl) (pyridin-2-yl) methanone (BCB-CDK8-4-29), 5- (dimethylamino) -2- (3-isonicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-30), (5- (3-methoxy-4-morpholinophenyl) -1H-pyrrolo [2,3-6] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-31), 2- (3-isonicotinoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -5-methoxybenzonitrile (BCD-CDK8-4-32), (5- (4-methoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-33), (5- (4- (dimethylamino) phenyl) -1H-pyrrolo [2,3-6] pyridin-3-yl) (3-methoxyphenyl) methanone (BCD-CDK8-4-34), 5-methoxy-2- (3- (3-methoxybenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) benzonitrile (BCD-CDK8-4-35), (5- (4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-2-yl) methanone (BCD-CDK8-4-36), (5- (4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-37), (5- (4-morpholinophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-38), (5- (4- (dimethylamino) phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-3-yl) methanone (BCD-CDK8-4-39), (5- (4- (dimethylamino) phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone (BCD-CDK8-4-40), N- (methylsulfonyl) -4- (4- (piperidine-1-carbonyl) quinolin-6-yl) benzamide (BCD-CDK8-5-1), 4- (4- (piperidine-1-carbonyl) -2-chloroquinolin-6-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-5-1C1), (R) -1 - ((6- (4- (dimethylamino) phenyl) quinolin-4-yl) (imino) methyl) pyrrolidin-3-ol (BCD-CDK8-5-2i), (R) - (6- (4- (dimethylamino) phenyl) quinolin-4-yl) (3-hydroxypyrrolidin-1-yl) methanone (BCD-CDK8-5-2), morpholino (6- (4-morpholinophenyl) quinolin-4-yl) methanimine (BCD-CDK8-5-3i), morpholino (6- (4-morpholinophenyl) quinolin-4-yl) methanone (BCD-CDK8-5-3), (6- (4- (1H-pyrazol-4-yl) phenyl) quinolin-4-yl) (piperidin-1-yl) methanimine (BCD-CDK8-5-4i), (6- (4- (1H-pyrazol-4-yl) phenyl) quinolin-4-yl) (piperidin-1-yl) methanone (BCD-CDK8-5-4), 4- (4- (azetidine-1-carbonyl) quinolin-6-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-5-5), 4- (4- (azetidine-1-carbonyl) -2-chloroquinolin-6-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-5-5C1), 1- (6- (4-methoxyphenyl) quinolin-4-yl) pyrrolidin-2-one (BCD-CDK8-5-6), (S) -1 - ((6- (4- (dimethylamino) phenyl) quinolin-4-yl) (imino) methyl) pyrrolidin-3-ol (BCD-CDK8-5-7i), (S) - (6- (4- (dimethylamino) phenyl) quinolin-4-yl) (3-hydroxypyrrolidin-1-yl) methanone (BCD-CDK8-5-7), (6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-4-yl) (piperidin-1-yl) methanimine (BCD-CDK8-5-8i), (6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-4-yl) (piperidin-1-yl) methanone (BCD-CDK8-5-8), 1- (4- (4-morpholinophenyl) quinolin-6-yl) piperidine-4-carboxamide (BCD-CDK8-6-1), (S) -4- (6- (3-hydroxypyrrolidine-1-carbonyl) quinolin-4-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-6-2), 4-methyl-1- (4- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) quinolin-6-yl) piperidine-4-carboxamide (BCD-CDK8-6-3), (4- (4- (1H-pyrazol-4-yl) phenyl) quinolin-6-yl) (3-methoxyazetidin-1-yl) methanone (BCD-CDK8-6-4), 4- (6- (azetidine-1-carbonyl) quinolin-4-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-6-5), N- (methylsulfonyl) -4- (6- (morpholine-4-carbonyl) quinolin-4-yl) benzamide (BCD-CDK8-6-6), 1- (4- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) quinolin-6-yl) piperidine-4-carboxamide (BCD-CDK8-6-7), 4-methyl-1- (4- (4-morpholinophenyl) quinolin-6-yl) piperidine-4-carboxamide (BCD-CDK8-6-8), (R) -4- (6- (3-hydroxypyrrolidine-1-carbonyl) quinolin-4-yl) -N- (methylsulfonyl) benzamide (BCD-CDK8-6-9), (3-methoxyazetidin-1-yl) (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-6-yl) methanone (BCD-CDK8-6-10), azetidin-1-yl (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-6-yl) methanone (BCD-CDK8-6-11), (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-6-yl) (pyrrolidin-1-yl) methanone (BCD-CDK8-6-12), 1- (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinolin-6-yl) pyrrolidin-2-one (BCD-CDK8-6-13), N- (2-methoxyethyl) -4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) quinoline-6-carboxamide (BCD-CDK8-6-14). 7. A method of inhibiting the biological activity of cyclin-dependent protein kinases CDK8 / 19 in a subject, which consists in contacting cyclin-dependent protein kinases CDK8 / 19 with a compound according to any one of claims. 1-6. 8. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims. 1-6 and one or more pharmaceutically acceptable excipients, for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19. 9. A pharmaceutical composition according to claim 8 for the prevention or treatment of a disease or disorder mediated by activation of cyclin-dependent protein kinase CDK8 / 19, wherein the disease or disorder mediated by activation of cyclin-dependent protein kinase CDK8 / 19 is an oncological or hemato-oncological disease. 10. The pharmaceutical composition according to claim 9, wherein the cancer or hemato-oncological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC), prostate cancer, metastatic ovarian cancer, metastatic cancer stomach, leukemia, acute myeloid leukemia, pancreatic cancer (PCa). 11. A method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, comprising administering in a therapeutically effective amount of a compound according to any one of claims. 1-6 or a pharmaceutical composition according to claim 8 for a subject in need of such treatment. 12. The method of treating a disease or disorder according to claim 11, wherein the disease or disorder mediated by activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological or hemato-oncological disease. 13. A method for treating a disease or disorder according to claim 12, wherein the oncological or hemato-oncological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC), prostate cancer, metastatic ovarian cancer , metastatic gastric cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa). 14. The use of a compound according to any one of claims. 1-6 or a pharmaceutical composition according to claim 11 for treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 in a subject in need of such treatment. 15. Use according to claim 14, wherein the disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological or hemato-oncological disease. 16. Use according to claim 15, wherein the cancer or hemato-oncological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, triple negative breast cancer (TNBC), prostate cancer, metastatic ovarian cancer, metastatic stomach cancer , leukemia, acute myeloid leukemia, pancreatic cancer (PCa).