EA041908B1 - 1,7-NAPHTHIRIDINE DERIVATIVES AND THEIR USE AS CDK8/19 INHIBITORS - Google Patents

Description

Technical field

The present invention relates to new 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 its structurally and functionally closely related isoform CDK19, is an oncogenic transcription-regulating kinase (Xu, W. & L, J. Y. (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452; Galbraith, M. D., et al. (2010) CDK8: a positive regulator of transcription, Transcription. 1, 4-12; Firestein, R. & Hahn, W. C. (2009) Revving the Throttle on an oncogene: CDK8 takes the driver seat, Cancer Res 69, 7899-7901). In contrast to better known members of the CDK family (such as CDK1, CDK2, and CDK4/6), CDK8 has no role in cell cycle regulation, but knockout of the CDK8 gene in embryonic stem cells results in embryonic development arrest (Adler, A. S., 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 phenotype of pluripotent stem cells (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, A. S., 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 CDK8 expression 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 Drag Targets, 15(8), 739-749). Increased CDK8 expression is associated with poor prognosis in colon cancer (Gyorffy, B., et al. (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients, Breast Cancer Res Treat 123, 725731).

Known mechanisms associated with CDK8 in cancer include positive regulation 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, J. A., et al. (2012) NF-kappaB and the link between inflammation and cancer, Immunol. Rev. 246, 379-400) and 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 can be associated with the cancer stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). DNA-damaging chemotherapy drugs induce TNF-α, a transcription factor activator 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-α acts on tumor cells, where it induces NFyB-mediated production of the cytokines CXCL1 and CXCL2, which promote tumor cell survival and growth. CXCL 1/2 attract myeloid cells to the tumor by binding to the CXCR2 receptor on the surface of myeloid cells. Myeloid cells then secrete small calcium-binding proteins S100A8 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) MED12 Controls the response to multiple cancer drags through regulation of TGF-P receptor signaling, Cell 151, 937 -950).

Currently, the search for new compounds that inhibit cyclin-dependent protein kinases CDK8/19 seems to be relevant.

Description of the invention

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

Alkyl means an aliphatic hydrocarbon linear or branched 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, t-butyl, n-pentyl, 2-pentyl, 3- pentyl, neopentyl, n-hexyl. The alkyl may have substituents which 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 which 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 ring system substituents which 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, isopropoxy, and n-butoxy.

An amino group means an R'RN- group substituted or unsubstituted with optionally the same substituents R' and R.

Alkylsulfonyl (-S(O) ₂ -C ₁ -C ₆ alkyl) means alkyl as defined above attached to the corresponding molecular moiety via a sulfonyl group -SO2-. 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 may be fused to an aryl or heteroaryl. The heterocycle may have one or more substituents, which may be the same or different. Nitrogen and sulfur atoms located in the heterocycle can be oxidized to N-oxide, S-oxide or S-dioxide. The heterocycle may 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, and others.

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 found in heteroaryl can be oxidized to an N-oxide. The heteroaryl may have one or more substituents, which may be the same or different. Representative heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isooxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, quinoxalinyl, phthalazinyl, imudαzo[1,2 -a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, pyrazolyl, thienopyridyl, quinazolinyl, naphthyridinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridyl, isoquinolinyl, benzoazindolyl ,4triazinyl, thienopyrrolyl, furopyrrolyl, 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 =O radical.

The substituent means a chemical radical that is attached to the 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, such as water, ethanol, ethylene glycol and the like. Other solvents can be used as intermediate solvates in the preparation of 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 the two atoms connected by the bond are considered as part of a larger substructure.

The term chiral refers to molecules that have the property of being incompatible with

- 2 041908 by its 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 identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, diastereomers.

A diastereomer refers to a stereoisomer with two or more centers of chirality, and such molecules are not mirror images of each other. 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 that are mirror images of each other that cannot be matched in space.

The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomers with no optical activity. The enantiomers can be isolated individually from the racemic mixture by a chiral separation method such as, for example, supercritical fluid 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 about its chiral center(s). A particular stereoisomer can also be defined as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture.

The term anthropoisomers refers to compounds that exhibit steric isomerism due to the lack of rotation around a single bond, such as in diphenyls, dinaphthyls, and others.

The term protecting group refers to groups that are used to block the reactivity of functional groups such as amino groups, carboxyl groups or hydroxy groups. Non-limiting examples of protecting groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methylacetal (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 may be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and receptive agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners , sweeteners, flavors, flavors, 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, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with 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 with agents that slow down 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 and 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 spreaders 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, topical or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in standard form of administration as a mixture with conventional pharmaceutical carriers. Suitable unit administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols,

- 3 041908 implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

A pharmaceutically acceptable salt means relatively non-toxic salts of a compound of the present invention. Salts of the compounds provided herein may be derived from inorganic or organic acids and bases. Examples of salts thus obtained 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; sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts, salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine (Detailed description of the properties of such salts is given in Berge S. M., et al., Pharmaceutical Salts J. Pharm. Sci. 1977, 66: 1-19). As amino acids, the amino acids lysine, ornithine and arginine can be used.

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 finished forms, intended to restore, correct or change physiological functions in humans and animals, as well as for the treatment and disease prevention, diagnostics, anesthesia, contraception, cosmetology and other.

Treat, cure 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 to reduce the severity and/or frequency of the symptoms of the 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 above subject may be male or female of any age.

The term disorder means any condition that can be improved as a result of 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 diseases to be treated include oncological diseases, in particular breast cancer, triple negative breast cancer (TNBC), ovarian cancer, metastatic ovarian cancer, gastric cancer, metastatic gastric cancer, endometrial, salivary gland, lung, kidney, colon, colorectal, melanoma, metastatic melanoma, thyroid, pancreatic, prostate, or bladder cancer; hemato-oncological diseases, leukemias, acute myeloid leukemia and lymphoid malignancies; neuronal, glial, astrocytic, hypothalamus and other granular, macrophage, epithelial, stromal and blastocele disorders; inflammatory, angiogenic and immunological disorders.

A therapeutically effective amount is the amount of a therapeutic agent administered during treatment that relieves to some extent one or more of the 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 contain, or variations thereof, such as has, having, includes, including, contains, or containing, should be understood to mean the inclusion of the specified whole or group of integers, but not the exclusion of any other integer 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 thereof, or a stereoisomer thereof, wherein X1 is N, C, CH;

X ₂ , X ₃ , X4 are each independently C(H) _m , NH, N, CR ₁₃ , CHR ₁₃ ;

Li, L ₂ each independently represents a chemical bond, -C(R _6b ) ₂ -, -O-, -C(O)-, -C(O)-O-, -NH-, -C(=NRi ₉ )-;

- 4 041908 n, k each independently selected from 0, 1;

m is 0, 1, 2;

R1, R ₃ , R ₁₃ are each independently H, Hal, cyano, C1-C6 alkyl, NH ₂ ;

R ₂ , R ₄ are each independently selected from the group consisting of

C1-C6 alkyl, unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ , X6, X ₇ are each independently C, CH, N;

L ₃ , L ₄ each independently represents a chemical bond, -C(O)-, -O-, -CH ₂ -, -NH-, -C(O)NR7a-, -C(=NH)-;

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

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, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1-C6 alkyloxy, NR15R16; 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, C1-C6 alkyl, C1-C6 alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _6b are each independently H, Hal, hydroxy, C1-C6 alkyl, C1-C6 alkyloxy;

R ₇ , R _7a are each independently H, C1-C6 alkyl;

R ₈ , R ₉ are each independently H, C1-C6 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 may be unsubstituted or substituted with 1 or 2 substituents selected from oxo, C1-C6 alkyl;

R ₁₀ is each independently selected from the group consisting of H, Hal, C1-C6 alkyl, hydroxy, cyano, C1-C6 alkyloxy, C1-C6 alkyloxy C1-C6 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 _r C ₆ alkyl; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and/or S, unsubstituted or substituted with one or more C1-C6 alkyls; -S(O) ₂ -C1-C ₆ alkyl;

R11, R ₁₂ are each independently H; C1-C6 alkyl, unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, -NR _23a R _24a ; C _r C ₆ alkoxy C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ is each independently Hal, -C(O)NR ₁₇ R ₁₈ , C _r C ₆ alkoxy;

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

R ₁₇ , R ₁₈ each independently represents H, C _r C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C _r C ₆ alkyl, C1C ₆ alkoxy;

each independently represents a single bond or a double bond;

Hal is chlorine, bromine, iodine, fluorine.

In another embodiment, the present invention relates to a compound of formula I, where R ₃ each independently represents H, Hal.

In yet another embodiment, the present invention relates to a compound of formula I, where L1, L ₂ each independently represents 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 is 0, 1;

X1 is N, C, CH;

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

L1, L ₂ each independently represents a chemical bond, -C(R _6b ) ₂ -, -O-, -C(O)-, -C(O)-O-,

-NH-, -C(=NR19)-;

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

- 5 041908

R1, _R3 , _R13 are each independently H, Hal, cyano, C1-C6 alkyl, NH2;

R ₂ , R4 are each independently selected from the group consisting of

C1-C6 alkyl, unsubstituted or substituted with one or more R ₁₄ substituents;

X ₅ , X6, X ₇ are each independently C, CH, N;

L ₃ , L4 each independently represents a chemical bond, -C(O)-, -O-, -CH ₂ -, -NH-, -C(O)NR7a-, -C(=NH)-;

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

R ₅ is H; Hal; cyano; C ₁ -C 6 alkyl; C ₁ -C 6 alkyloxy; C1-C6 alkyloxy C1-C6 alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _6b each independently represents H, Hal, hydroxy, C1-C6 alkyl, C ₁ -C ₆ alkyloxy;

R ₇ , R _7a are each independently H, C1-C6 alkyl;

R8, R ₉ are each independently H, C1-C6 alkyl, -C(O)-NR ₂₁ R ₂₂ , -CN, -C(O)-OR ₂₀ or

R8 and _R9 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 _R8 and _R9 may be unsubstituted or substituted with 1 or 2 substituents selected from oxo, C1-C6 alkyl;

R ₁₀ is each independently selected from the group consisting of H, Hal, Q-C6 alkyl, hydroxy, cyano, C _r C ₆ alkyloxy, C _r C ₆ alkyloxy C1-C6 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 C1-C6 alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and/or S, unsubstituted or substituted with one or more C1-C6 alkyls; -S(O) ₂ -C ₁ -C ₆ alkyl;

R _1b R ₁₂ each independently represents H; C1-C6 alkyl, unsubstituted or substituted by hydroxy, C3-C6 cycloalkyl, -NR _23a R _24a ; C1-C6 alkoxy C ₁ -C ₆ alkyl; C3-C6 cycloalkyl;

R ₁₄ is each independently Hal, -C(O)NR ₁₇ R ₁₈ , C1-C6 alkoxy; R ₁₅ , R ₁₆ , R ₁₉ , R 20 , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , _{R 24a each} independently represents H, C1-C6 alkyl;

R ₁₇ , R ₁₈ each independently represents H, C1-C6 alkyl; aryl unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1C6 alkoxy;

each independently represents a single bond or a double bond;

Hal is chlorine, bromine, iodine, fluorine.

In another embodiment, the present invention relates to a compound of formula I.1, where R ₃ each independently represents H, Hal.

In another embodiment, the present invention relates to a compound of formula I.1, where L1, L ₂ each independently represents 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 X1 represents C, CH, N;

X1, X ₃ are each independently N, CR ₁₃ ;

L1, L ₂ each independently represents a chemical bond, -C(R _6b ) ₂ -, -O-, -C(O)-, -C(O)-O-, -NH-, -C(=NR19) -;

k is 0, 1;

R1, R ₃ , R ₁₃ are each independently H, Hal, cyano, C1-C6 alkyl, NH ₂ ;

R ₂ , R ₄ are each independently selected from the group consisting of

- 6 041908

C _r C ₆ alkyl, unsubstituted or substituted with one or more R ₁₄ substituents,

X ₅ , X ₆ , X7 are each independently C, CH, N;

L ₃ , L4 each independently represents a chemical bond, -C(O)-, -O-, -CH ₂ -, -NH-, -C(O)NR7 _a -, -C(=NH)-;

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

R5 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, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C _r C ₆ alkyl, C _r 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 _r C ₆ alkyl, C _r C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _6b each independently represents H, Hal, hydroxy, C _r C ₆ alkyl, C _r C ₆ alkyloxy;

R7, R7 _a are each independently H, C _r C ₆ alkyl;

R ₈ , R ₉ are each independently H, C _r 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 may be unsubstituted or substituted with 1 or 2 substituents selected from oxo, C _r C ₆ alkyl;

R ₁₀ is each independently selected from the group consisting of H, Hal, C _r C ₆ alkyl, hydroxy, cyano, C 1 -C 6 alkyloxy, C _r C ₆ alkyloxy, C _r 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 alkyl; 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 -C1-C ₆ alkyl;

R11, R ₁₂ are each independently H; C ₁ -C ₆ alkyl, unsubstituted or substituted by hydroxy, C ₃ -C ₆ cycloalkyl, -NR _23a R _24a ; C _r C ₆ alkoxy C _g C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ is each independently Hal, -C(O)NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R _23a , R _24a each independently represents H, C _r C ₆ alkyl;

R ₁₇ , R ₁₈ each independently represents H, C _r C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C _r C ₆ alkyl, C1C ₆ alkyloxy;

R ₁₉ , R ₂₀ are each independently H, C _r C ₆ alkyl.

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

where L1, L ₂ , R1, R ₂ , R ₃ , R4, k are as defined above.

In yet another embodiment, the present invention relates to a compound of formula G5a:

where L1, L ₂ , R ₂ , R ₃ , R4, R ₁₃ have the above meaning.

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

where L1 _? L ₂ , R ₂ , R3, R4 have the above meaning.

- 7 041908

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

where X ₂ , X3 each independently represents C(H)m, NH, N, CR ₁₃ , CHR ₁₃ ;

x1 _? X ₄ each independently represents C, CH, N;

L1, L2 each independently represents a chemical bond, -C(R _6b ) ₂ -, -O-, -C(O)-, -NH-, -C(=NR19)-;

k is 0, 1;

m is 1, 2;

R1, R ₃ , R ₁₃ are each independently H, Hal, cyano, C ₁ -C ₆ alkyl, NH2;

R ₂ , R ₄ are each independently selected from the group consisting of

C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₄ substituents,

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

L ₃ , L4 each independently represents a chemical bond, -C(O)-, -O-, -CH2-, -NH-, -C(O)NR _7a -, -C(=NH)-;

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

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, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C _r C ₆ alkyl, C _r 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 _r C ₆ alkyl, C _r C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ , R _6a , R _6b each independently represents H, Hal, hydroxy, C _r C ₆ alkyl, C _r C ₆ alkyloxy;

R ₇ , R _7a each independently represents H, C _r C ₆ alkyl;

R8, R9 are each independently H, C _r 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 may be unsubstituted or substituted with 1 or 2 substituents selected from the oxo group, C _r C ₆ alkyl;

R ₁₀ is each independently selected from the group consisting of H, Hal, C _r C ₆ alkyl, hydroxy, cyano, C 1 -C 6 alkyloxy, C _r C ₆ alkyloxy, C _r 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 _r 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;

R11, R ₁₂ are each independently H; C _r C ₆ alkyl, unsubstituted or substituted by hydroxy, C ₃ -C ₆ cycloalkyl, -NR _23a R _24a ; C _r C ₆ alkoxy C _g C ₆ alkyl; C ₃ -C ₆ cycloalkyl;

R ₁₄ is each independently Hal, -C(O)NR ₁₇ R ₁₈ , C _r C ₆ alkoxy;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ each independently represents H, C1-C ₆ alkyl;

R ₁₇ , R ₁₈ each independently represents H, C _r C ₆ alkyl; aryl unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C _r C ₆ alkyl, _Cr C 6 alkyloxy;

R ₁₉ , R ₂₀ each independently represents H, C _r C ₆ alkyl;

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

where X1, X2, X4, Li, L2, Ri, R2, R3, R4, R13, k are as defined above.

- 8 041908

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

where L1, L2, R1, R2, R3, R4 are as defined above.

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

Η 1.9, where L1, L2, R2, R3, R ₄ have the above meaning.

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

I.10

where X1, X ₂ , X ₃ , L1, L ₂ , R1, R ₂ , R ₃ , R4, n, k have the above meaning.

In another embodiment, the present invention relates to a compound of formula I, I.1-I.10, where R ₅ represents H; Hal; cyano; C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 alkyloxy C1-C6 alkyl; NR ₁₅ R ₁₆ ; aryl, which is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1-C6 alkyloxy, NR ₁₅ R ₁₆ ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, which is 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, unsubstituted or substituted with one or more substituents selected from the group consisting of from Hal, C1-C6 alkyl, C1-C6 alkyloxy, NR ₁₅ R ₁₆ .

In yet another embodiment, the present invention relates to a compound of formula I, I.1-I.10, where R ₁₀ is each independently selected from the group consisting of H, Hal, C1-C6 alkyl, hydroxy, cyano, C1-C6 alkyloxy, C1-C6 alkyloxy C1-C6 alkyl, -NR23R24; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O and/or S, which is 4-morpholinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-piperazinyl, unsubstituted or substituted with one or more C1-C6 alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and/or S, which is thiophenyl, imidazolyl, pyrazolyl, unsubstituted or substituted with one or more C1-C6 alkyl; -S(O) ₂ -C1-C ₆ alkyl.

Hal is chlorine, bromine, iodine, fluorine.

In yet another embodiment, the present invention relates to a compound of formula Ia r ₂ r ₃

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein X1 is N, C, CH;

X ₂ , X ₃ , X ₄ are each independently C(H)m, NH, N, CR ₁₃ ;

L1, L2 each independently represents a chemical bond, -C(R ₆ ) ₂ -, -O-, -C(O)-, -NH-, -C(=NR19)-;

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

m is 0, 1.2;

R1, R ₃ , R ₁₃ are each independently H, Hal, cyano, Ci-C ₆ alkyl;

R ₂ , R ₄ are each independently selected from the group consisting of

- 9 041908

C1-C6 alkyl, unsubstituted or substituted with one or more R ₁₄ substituents,

X ₅ , X ₆ , X7 are each independently C, CH, N;

L ₃ , L4 each independently represents a chemical bond, -C(O)-, -O-, -CH2-, -NH-, -C(O)NR7-, -C(=NH)-;

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

R5 is H; Hal; cyano; C1- _C6 alkyl; C1- _C6 alkyloxy; C1- _C6 alkyloxy C1- _C6 alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C ₆ alkyl, C1-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 _r C ₆ alkyl, C _r C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

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

R7 is each independently H, C _r C ₆ alkyl;

R ₈ , R ₉ each independently represents H, C _r 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 may be unsubstituted or substituted with 1 or 2 substituents selected from the oxo group, C _r C ₆ alkyl;

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

Rii, R ₁₂ are each independently H, C _r C ₆ alkyl, C _r C ₆ alkoxy, C _r C ₆ alkyloxy C1C6 alkyl;

R ₁₄ is each independently Hal, -C(O)NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ each independently represents H, C1-C ₆ alkyl;

R ₁₇ , R ₁₈ each independently represents H, C1-C6 alkyl; aryl unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1- _C6 alkyl, _C1C6 alkyloxy; R ₁₉ , R ₂₀ are each independently H, C1-C6 alkyl;

------each independently represents a single bond or a double bond;

Hal is chlorine, bromine, iodine, fluorine.

In another embodiment, the present invention relates to a compound of formula Ia, where R1, R ₃ each independently represents H, Hal.

In another embodiment, the present invention relates to a compound of formula Ia, where L1, L2 each independently represents a chemical bond, -C(O)-, -NH-, -C(=NH)-.

In yet another embodiment, the present invention relates to a compound of formula Ia.1 r ₄

R ₂ R3 l ₂

where X ₄ represents C(H)m, NH, N;

m is 0, 1;

X1, X2, X3, L1, L2, R1, R2, R3, R4, R13,n, k,

------have the above meaning.

In another embodiment, the present invention relates to a compound of formula Ia.1, where R1, R ₃ each independently represents H, Hal.

In another embodiment, the present invention relates to a compound of formula Ia.1, where L1, L2 each independently represents a chemical bond, -C(O)-, -NH-, -C(=NH)-.

The compounds described in the present invention can be obtained in the form and/or they 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 compound in free base form 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, caproic, cyclopentanepropionic, glycolic,

- 10 041908 pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, trifluoroacetic, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic acids, 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-en-1carboxylic, glucoheptonic, 4,4'-methylene-bis-3-hydroxy-2-en-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, and the like; base salts formed by reacting a free acid compound 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-ethylpiperidine.

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

The salts are recovered using at least one of the following techniques: filtration, precipitation with a precipitant followed by filtration, solvent evaporation or, in the case of aqueous solutions, lyophilization. It is to be understood that 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 may be formed during the 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 easily obtained or formed in the methods described in the present invention. In addition, the compounds provided by the present invention may 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 of the present invention.

The compounds described in the present invention can be presented in various forms, including listed, but not limited to: structureless forms, ground 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 of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, different infrared spectra, melting points, different densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, degree of crystallization, and storage temperature can cause one crystal form to dominate.

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 directed to the study of thermochemical degradation or thermophysical processes, including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationship between polymorphs, determine the loss in mass, to find the glass transition temperature, or study compatibility with the filler. Such methods 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 methods used include, but are not limited to, Raman spectrum (Raman), FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to: polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) analysis, scanning electron microscopy in natural mode with EDX (in a gas or water vapor atmosphere), IR microscopy and Raman microscopy.

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

Formula Name Cipher O. H 1 -(1 -(4-((Methylsulfonyl) / ν° carbamoyl)phenyl)-1R- BCD-CDK8- ίί /GL ⁰ benzo [d \ imidpazol-6 -yl) -I- 1-1 ΥΎ/> phenylazetidine-3 - N carboxamide Ο. n Ύχ 4-(6-Azetidine-1-carbonyl)- οΟ BCD-CDK8- 1 I- benzo [d \ imidazol-1 -yl) - 1-2 ζ^^ζ Ρ 0 A-(methylsulfonyl)benzamide ο- (1-(4-(1I-Pyrazole-4- cj yl)phenyl)-1R- BCD-CDK8- oW benzo[<Dimidazol-6yl)(piperidin-1-yl)methanone 1-3 /Ϊ ^Η (1 - (1 - (4- (1H-pyrazole-4- At yl)phenyl)-1R- BCD-CDK8- benzo[<Dimidazole-6- 1-4 ΟJ Τχ > yl)azetidine-3- silt)(morpholino)methanone Ο (1-(4-(1I-Pyrazole-4- G/ yl)phenyl)-1R- BCD-CDK8- Λ benzo[<Dimidazole-6- 1-5 oVx> ΧχΧ^Ν yl) (azetidin-1 -yl) methanone 0. U'X Methyl-4 - (6 - (3 - (phenyl Η X Ο carbamoyl)azetidine-1 -yl)- BCD-CDK8- u_Jy 1 I-benzo [d \ imi dazol-1 - 1-6E XX? yl) benzoate Woo-OH 4-(6-(3- Q ϊ O (phenylcarbamoyl)azetidine-1 - BCD-CDK8- ^H Vn^. X yl)-1H-benzo[<Dimidazole-1- 1-6A ΎΎ /> XX N yl) benzoic acid 0. γ-ΝΗ ₂ 1 - (1 - (4-Carbamoylphenyl) - 1R- Q1 O benzo[</]imidazol-6-yl)-I- BCD-CDK8- -uYr phenylazetidine-3 - 1-6 γχ> carboxamide fl Methyl-4-(6-(3- ίΆ (phenylcarbamoyl)azetidine-1 - BCD-CDK8- G ( / yl)-4-fluoro-1R- 1-7E Ύ T/> Xj^-N benzo[J]imidazole-1 - F yl) benzoate

- 12 041908

Oy-OH L, P 0¼ F nh ₂ A. 0 ό Ν F α l ρ F \ _ Ν r·^ Ρ oj Vn^ _n 'τχ> \ίΡ^Ν \ Ν - χΡ OQP θ' A Co ο \ίΤ ^Ν rv Ρ W 4-(-6-(3- (Phenylcarbamoyl)azetidine1-yl)-4-fluoro-1Ηbenzo[<D imidazol-1yl)benzoic acid 1-(1-(4-Carbamoylphenyl)-4fluoro-1 R-benzo[<D imidazole-6 and l)-A-phenyl azetidine-3 carboxamide (1-(1-(4-(1H-Pyrazol-4-yl)phenyl)-4-fluoro-1H-benzo[d]imidazol-6-yl)azetidin-3yl)(morpholino)methanone (1-(1-(4-(Dimethylamino)phenyl)-1H-benzo[<Dimidazol6-yl)azetidin-3-yl)(morpholino)methanone Azetidine-1 -yl-( 1 -(4(dimethylamino)phenyl)- 1Habenzo[<Dimidazol-6yl)methanone (3-Methoxyazetidin-1-yl)(1(4-methoxyphenyl)-1R-benzo[(Dimidazol-6yl)methanone (1-(1-(4-Methoxyphenyl)-1H-benzo[<Dimidazol-6-yl)azetidin-3-yl)(morpholino) methanone BCD-CDK81-7A BCD-CDK81-7 BCD-CDK81-8 BCD-CDK81-9 BCD-CDK81-10 BCD-CDK81-11 BCD-CDK81-12 \ _ Ν r-% 0 °^ ΌΡ> Χ^'-v F (1-(1-(4-(Dimethylamino)phenyl)-4-fluoro-1Habenzo[<Dimidazol-6-yl)azetidin-3-yl)(morpholino) methanone BCD-CDK8- 1-13 Ο /° V θχ? I (1-(1-(4-(1H-Pyrazol-4yl)phenyl)-7-fluoro-1Hbenzo[d]imidazol-6-yl)azetidin-3-yl)(morpholino) methanone BCD-CDK8- 1-14 .. 7' oPPO Methyl 4-(6-(azetidine-1-carbonyl)-7-fluoro-1H-benzo[d\imidazol-1-yl)benzoate BCD-CDK8- 1-15E 0. Ν-όη χι ν σ οΡ 4-(6-(azetidine-1-carbonyl)- 7-fluoro- 1H-benzo [<D and m and dazol- 1-yl)benzoic acid BCD-CDK8- 1-15A 0. y-NH ₂ ., ό 0¾) 4-(6-(azetidine-1-carbonyl)- 7-fluoro-1H-benzo[<Dimidazole- 1 -yl) benzamide BCD-CDK8- 1-15

- 13 041908

sl" (1-(4-(1-Methyl-1H-pyrazol-4yl)phenyl)-1Hbenzo[<7]imidazol-6yl)(piperidin-1-yl)methanone BCD-CDK8- 1-16 ^Ν '-ν ^/ ν/ & ^Ν υ7> °^ W \^-Ν F \ Ν-μ Λ . \- ⁿ vVn ΥΎ/> \ί^Ν °γ-ΟΗ Ο ν' 7 N ^Hr v^ ΤΎ/> θ V^ ^N (1-(1-(4-(1-Methyl-1Hpyrazol-4-yl)phenyl)- 1Habenzo\d\imidazol-6-yl)azetidin-3-yl)(morpholino) methanone Azetidin-1-yl(1-(4-(1-methyl1H-pyrazol-4-yl)phenyl)-1Hbenzo[<7]imidazol-6yl)methanone (1-(1-(4-(1-Methyl-1Hpyrazol-4-yl)phenyl)-4-fluoro1H-benzo[<7]imidazol-6-yl)azetidin-3-yl)(m orpholino) methanone 4-(6-( (2-(Chloromethyl)-3-oxo3-(phenylamino)propyl) amino)-4-fluoro-1Habenzo \d\ imidazol-1 -yl) benzamide BCD-CDK81-17 BCD-CDK81-18 BCD-CDK81-19 BCD-CDK81-20 BCD-CDK81-21A ζ V^/^Z ζ U P 4-(6-((2-(Chloromethyl)-3-oxo3-(phenylamino)propyl)amino)-4-fluoro-1Habenzo[d\imidazol-1-yl)benzoic acid BCD-CDK8- 1-21 Η °ν ^Ν χ° ¹¹ /k ο ο ο ΗΟ< C Ν Ι^ίΓΐ 4^ ^Ν (5)-4-(3-(3- Hydroxypyrrolidine-1 carbonyl)-1,7-naphthyridin-5yl)-R(methanesulfonyl)benzamide BCD-CDK83-1 ΗΝ-Ν ώ ^{0 ηο} ^/^ν 4^ (7?)-(5-(4-(1H-Pyrazol-4yl)phenyl)-1,7-naphthyridin-3 yl)(3-hydroxypyrrolidin-1 yl)methanone BCD-CDK8- 3-2 Ο ό 2=0 ^ζ ν5 (7?)-(5-(4-(dimethylamino) phenyl)-1,7-naphthyridin-3 yl)(3-hydroxypyrrolidin-1 yl) methanone BCD-CDK8- 3-3

- 14 041908

I About ύ /=° W /=\ (L)-(3-H hydroxypyrrolidin1-yl)(5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)methanone BCD-CDK8- 3-4 0 ό ^{0 ΗΟ} “^\ j ¹ Τι ι ί Ν (7?)-(3-Hidroxypyrrolidin1-yl)(5-(4-morpholinophenyl)1,7-naphthyridin-3yl1) methanone BCD-CDK8- 3-5 0^ ό (7?)-(3-hydroxypyrrolidine- 1 -yl) (5- (4-methoxyphenyl) - 1,7-naphthyridin-3-yl) methanone BCD-CDK8- 3-6 \ ο 7=0 ^η Ο (5-(4-(Dimethylamino)phenyl)1,7-naphthyridin-3-yl)(4methylpiperazin-1-yl) methanone BCD-CDK8- 3-8 \ Ν—Ν ί “'όο (1-(5-(4-(1-Methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)azetidin-3yl)(morpholino)methanone BCD-CDK8- 3-9 Η Os. ^N. And ° ο ο Cj ίΠ to J d Jk N ACmethylsulfonyl)-4-(3(piperidine-1-carbonyl)-1,7 naphthyridin-5-yl)benzamide BCD-CDK8- 3-11 Η %' ^Ν ^° Γ ⁰ XAS, . ί 0 N VA Τ ΌΟ JD-Dimethyl-1 -(5-(4((methylsulfonyl)carbamoyl)phenyl)-1,7-naphthyridin-3 yl)azetidine-3-carboxamide BCD-CDK8- 3-12 I ο ό %° A °Α (7?)-4-(3-(3-Hidroxy-pyrrolidine-1-carbonyl)-1,7naphthyridin-5-yl)-N(methanesulfonyl)benzamide BCD-CDK8- 3-13 \ Ν-Ν ώ ⁰ ΤΓ σ\ώ Azetidin-1 -yl-(5-(4-(1methyl-III-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl) methanone BCD-CDK8- 3-14 \ Ν-Ν ό ⁰ γνΑ^Α (3-Methoxyazetidin-1-yl(5(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl) methanone BCD-CDK8- 3-15 37

- 15 041908

\ NN Λ ⁰ οΛπό (5-(4-(1-Methyl-III-pyrazol-4yl)phenyl)-1,7-naphthyridin-3 yl)(pyrrolidin-1 yl)methanone BCD-CDK8- 3-16 b (1-(5-(4-(1-Methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)pyrrolidin-2-one BCD-CDK8- 3-17 \ NN ¹ [M oJr ^and vu N-(2-Methoxyethyl)-5-(4-(1methyl-1H-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-18 NN ώ ⁰ oy^YyS Gl k _N YN (R)-3 -(Methoxypyrrolidin-1 yl)(5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3 -yl)methanone BCD-CDK8- 3-19 \ NN ό ⁰ M (7?)-3-Hydroxypiperidin-1 yl)(5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridyl-3-yl)methanone BCD-CDK8- 3-20 \ NN 0 1 ? 1 m \ NN \ NN O ^{0 /0} '-^n'%<YYy ^H C, JL^n N^γ nh ₂ (R)-3-(Methoxypiperidin-1 yl)(5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)methanone A,A-Methyl-5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridine-3-carboxamide N, A-Diethyl- 5-(4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl)-1,7naphthyridine-3-carboxamide 8-Amino-A-(2-methoxyethyl)5-(4-(1-methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK83-21 BCD-CDK83-22 BCD-CDK83-23 BCD-CDK83-24 \ NN ό ⁰ ΔΓ/γ^Ύ+Υ ¹ 4Y' ⁿ A-(2-Methoxyethyl)-A-methyl5-(4-(1-methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-25

- 16 041908

NN nh ₂ (8-Amino-5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)(azetidin1-yl)methanone BCD-CDK8- 3-26 HH O ⁰ nh ₂ (8-Amino-5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3yl)(morpholino)methanone BCD-CDK8- 3-27 Ni/ o ⁰ 2-Methoxyethyl-5-[4-(methyl-1H-pyrazol-4-yl)phenyl]-1,7naphthyridine-3-carboxylate BCD-CDK8- 3-28 _NN / o 0 ^l ^' ^oL w nh ₂ 2 -Methoxy ethyl- 8 - amino - 5 - (4 (1 -methyl- 1H-pyrazol-4yl)phenyl) -1,7-naphthyridine-3 carboxylate BCD-CDK8- 3-29 N-N (4-Methylpiperazin-1-yl)(5(4-(1-methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridin-3yl)methanone BCD-CDK8- 3-30

NN O ⁰ νη ₂ (8-Amino-5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridin-3-yl)(4methylpiperazin-1 yl)methanone BCD-CDK8- 3-31 \ N—N o 9 ¹ IAJ N nh ₂ 8-Lmino-LC2-methoxyethyl)A-methyl-(5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7naphthyridine-3-carboxamide BCD-CDK8- 3-32 N-N (5-(4-(1-Methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridin-3yl)(morpholino)methanone BCD-CDK8- 3-33 \-NV α ^νΛ ο9 nh ₂ (8 - Amino-5 - (4 - (1 -methyl- 1Yapyrazol-4-yl) phenyl) -1,7 naphthyridin-3 -yl) (3 - methoxyazetidine) methanone BCD-CDK8- 3-34 \N-N N-(2-(Dimethylamino)ethyl)-N-methyl-5-(4-(1-methyl-lHpiprazol-4-yl)φenyl)-l,7naphthyridine-3-carboxamide BCD-CDK8- 3-35

- 17 041908

N-N G TV-Cycle opr opil-5-(4-(1methyl-III-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-37 ABOUT ZI 8-Amino-Λ-cyclopropyl-5(4-(1-methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-38 \ NN ⁰ Tw ACcyclopropyl methyl)-5-(4(1-methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-39 \ NN (j ⁰ < νψ νη ₂ 8-Amino-I- (Opropylmethyl cycle) - 5-(4-(1methyl-1H-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-40 0 ό ⁰ xO^J 5-(4(1H-Imidazol-1-yl)phenyl)-N-(2-methoxyethyl)1,7-naphthyridin-3-yl)carboxamide BCD-CDK8- 3-41 XNU<^ yf o =( ΖΙ G 8-Amino-L-(2-hydroxyethyl)5-(4-(1-methyl-1H-pyrazol-4 yl)phenyl)-1,7-naphthyridine-3-carbamide BCD-CDK8- 3-42 χχ Χν ^Ν Η (5-(4-(Dimethylamino)-3 hydroxyphenyl)- 1Hpyrrolo[2,3-b]pyridin-3-yl)(pyridin-2-yl)methanone BCD-CDK8- 4-1 1 U “χν^ΝΗ,νΧ^ L 1 /X / Ν- ^{7 ν} th 5-(Dimethylamino)-2-(3pico linoi l-1 N-pyrrolo [2,30]pyridin-5-yl)benzamide BCD-CDK8- 4-2 7 ^ζ ο C} ^χ (5-(3-Hydroxy-4morpholinophenyl)-1Hpyrrolo[2,3-ό]pyridin-3-yl)(pyridin-2-yl)methanone BCD-CDK8- 4-3 °\ / ^N ^> VocS HgM^O [j 5-Methoxy-2-(3-pico linoyl1 N-pyrrolo [2,3-b]pyridin-5 yl)benzamide BCD-CDK8- 4-4 I he -~χχ LH ^Ν Η 5 - (4 - (Dimethyl amino) - 3 hydroxyphenyl) - 1Hpyrrolo [2,3-b] pyridin-3 -yl) (pyridin-3 -yl) methanone BCD-CDK8- 4-5 L ζ τ \ 5-(Dimethylamino)-2-(3nicotinoyl-1H-pyrrolo[2,30]pyridin-5-yl)benzamide BCD-CDK84-6 7 /-ζ Ο 0 ¹ (5-(3-Hydroxy-4-morpholinophenyl)-1H-pyrrolo[2,3-b} pyridin-3-yl) (pyridin-3-yl) methanone BCD-CDK8- 4-7 ΧχΛ^ Τϊρ Η ₂ Ν^Ο Ν Ν 5-Methoxy-2-(3-nicotinoyl1 N-pyrrolo[2,3-b]pyridin-5yl)benzamide BCD-CDK8- 4-8

- 18 041908

1 OH (5 - (4 - (Dimethylamino) -3 - XX 0 /N hydroxyphenyl)- 1H- BCD-CDK8- oX pyrrolo[2,3-b]pyridin-3-yl) 4-9 H (pyridin-4-yl) methanone 1 Vh ₂ n^o o o/ ⁿ th N \d/ 5-(Dimethylamino)-2-(3I30NIK0TIN0IL-1Yapyrrolo[2,3-b]pyridin-5-yl)benzamide BCD-CDK8- 4-10 0-% 0 -ABOUT (5-(3-Hidroxy-4morpholinophenyl)-1H- BCD-CDK8- TX> pyrrolo[2,3-b]pyridine-3 - 4-11 ^N H yl)(pyridin-4-yl)methanone V ^x H ₂ L 0 ϋό ⁴ N^NH O 2-(3-Isonicotinoyl-1Hpyrrolo[2,3-6]pyridin-5-yl)5-methoxybenzamide BCD-CDK8- 4-12 0 5 -Methoxy-2 - (3 - (3 - L X 0./ 0 methoxybenzoyl) - 1H- BCD-CDK8- Or> pyrrolo[2,3-b]pyridin-5-yl) 4-13 h ₂ n^o ^N benzamide 1 X1 1 o Όλ ⁴ N^~N Ν=\ Ό (5 - (4 - (Dimethylamino) -3 methoxyphenyl) -1Hpyrrolo [2,3-0] pyridin-3 -yl) BCD-CDK8- 4-21 ^N H (pyridin-2-yl) methanone CI ^ ^NVO % ^NH Ό 5-(Dimethylamino)-2-(3picolinoyl-1H-pyrrolo[2,30]pyridin-5-yl)benzonitrile BCD-CDK8- 4-22 0% %Ny^ 0. L) N=\ AJ (5-(3-Methoxy-4morpholinophenyl)-1H- BCD-CDK8- 1 co pyrrolo[2,3-0]pyridin-3-yl) 4-23 ^N H (pyridin-2-yl) methanone V II N 0 yCd ^N №\ -M 5-Methoxy-2-(3-picolinoyl1H-pyrrolo[2,3-0]pyridin-5yl)benzonitrile BCD-CDK8- 4-24 1 (5 - (4- (Dimethylamino) -3 - Ά y Ό methoxyphenyl)-1H- BCD-CDK8- w pyrrolo[2,3-0]pyridin-3-yl) 4-25 Ν N ^IN H (pyridin-3 -yl) methanone T N O 5-(Dimethylamino)-2-(3nicotinoyl-1Н-pyrrolo[2,30]pyridin-5-yl)benzonitrile BCD-CDK8- 4-26 ₄ 0. L ΑΧ (5-(3-Methoxy-4morpholinophenyl)-1H- BCD-CDK8- 1 u? ^KT^N pyrrolo[2,3-0]pyridin-3-yl) 4-27 ^N H (pyridin-3 -yl) methanone Ύ N υϊ ABOUT 5-Methoxy-2-(3-nicotinoyl1 N-pyrrolo[2,3-0]pyridin-5yl)benzonitrile BCD-CDK8- 4-28 > X/ D (5-(4-(Dimethylamino)-3 methoxyphenyl)-1Hpyrrolo[2,3-0]pyridin-3-yl) BCD-CDK8- 4-29 ^N H (pyridin-2-yl) methanone

- 19 041908

1 θχ / N τχττ^ Wo II N ^H 5-(Dimethylamino)-2-(3isonicotinoyl-1Hpyrrolo[2,3-0]pyridin-5-yl)benzonitrile BCD-CDK8- 4-30 W^“ (5-(3-Methoxy-4morpholinophenyl)-1Hpyrrolo[2,3-b}pyridin-3-yl)(pyridin-4-yl)methanone BCD-CDK8- 4-31 ^°Ύ^1 left w 2-(3-Isonicotinoyl-1Нpyrrolo[2,3-0]pyridin-5-yl)5-methoxybenzonitrile BCD-CDK8- 4-32 OTT Υ ^Λ Ν ^N H (5-(4-Methoxyphenyl)-1Hpyrrolo[2,3-b]pyridin-3yl)(pyridin-4-yl)methanone BCD-CDK8- 4-33 0^ X about. H > To ^N H (5-(4-(Dimethylamino)phenyl)1 H-pyrrolo[2,3-b]pyridin-3yl)(3-methoxyphenyl)methanone BCD-CDK8- 4-34 0 o ₄ r\ TJo 1Ш ill K N Ν H 5 -Methoxy-2 - (3 - (3 methoxybenzoyl) - 1Hpyrrolo[2,3-0]pyridin-5-yl) benzonitrile BCD-CDK8- 4-35 0^% ^N.^. O / ^N== T tiTo TO On (5-(4-Morpholinophenyl)-1Hpyrrolo[2,3-b}pyridin-3-yl)(pyridin-2-yl)methanone BCD-CDK8- 4-36 W ^ΌχΟ o ^N (5-(4-Morpholinophenyl)-1Hpyrrolo[2,3-0]pyridin-3-yl)(pyridin-3-yl)methanone BCD-CDK8- 4-37 0^ T T^N OTo TO ABOUT (5-(4-Morpholinophenyl)-1Hpyrrolo [2,3-b] pyridin-3-yl) (pyridin-4-yl) methanone BCD-CDK8- 4-38 1 ^N OoJo ⁷ TO ^N (5-(4-(Dimethylamino)phenyl1 N-pyrrolo[2,3-0]pyridin-3yl)(pyridin-3-yl)methanone BCD-CDK8- 4-39 I 0 / N OcJr^ iTw N (5-(4-(Dimethylamino)phenyl1 N-pyrrolo[2,3-0]pyridin-3yl)(pyridin-4-yl)methanone BCD-CDK8- 4-40 0 O^NH ° ^L T1 T ^j to n-(Methylsulfonyl)-4-(4(piperidine-1-carbonyl) quinolin-6-yl) benzamide BCD-CDK8- 5-1 O Λ, ° ^L TT Ύ 40 N Cl 4-(4-(Piperidin-1 carbonyl)-2-chloroquinolin-6yl)-R-(methylsulfonyl) benzamide BCD-CDK8- 5-1S1 Oh । O O\^\ HN^N^T Thu (^)-1-((6-(4- (Dimethylamino)phenyl)quinol in-4-yl)(imino)methyl) pyrrolidin-3-ol BCD-CDK8- 5-2i

- 20 041908

—Ζ \ (7?)-(6 - (4 - (Dimethylamino) phenyl) quinolin-4-yl) (3 hydroxypyrrolidin-1 -yl) methanone BCD-CDK8- 5-2 0^ N Morpholino(6-(4morpholinophenyl)quinolin-4yl)methanimine BCD-CDK8- 5-3i 0 0 O R Morpholino(6-(4morpholinophenyl)quinolin-4yl)methanone BCD-CDK8- 5-3 I Z (6-(4-(1H-Pyrazol-4-yl)phenyl)quinolin-4-yl)(piperidin-1-yl)methanimine BCD-CDK8- 5-4i hn^00 05 N (6-(4-(1H-Pyrazol-4-yl) phenyl) quinolin-4-yl) (piperidin-1 -yl) methanone BCD-CDK8- 5-4 ABOUT ^11 Ο^'ΝΗ bye Ν 4-(4-(Azetidine-1 carbonyl) quinolin-6-yl)-A(methylsulfonyl) benzamide BCD-CDK8- 5-5 0 \H 0 ^<S 'NH Αχ Υ Axl N Cl 4-(4-(Azetidin-1-carbonyl)2-chloroquinolin-6-yl)-A(methylsulfonyl)benzamide BCD-CDK8- 5-5S1 \ NN L ⁰ 0030 N (4-(4-(1-Methyl-1H-pyrazol-4yl)phenyl)quinolin-6-yl)(pyrrolidin-1-yl)methanone BCD-CDK8- 6-12 \ N-N 1-(4-(4-(1-Methyl-1H-pyr azo l4-yl)phenyl)quinolin-6-yl)pyrrolidin-2-one BCD-CDK8- 6-13 \ Ν—N V ¹ D) ⁿ La Ν A-(2-Methoxyethyl)-4-(4-(1 methyl-\H- pyrazol-4-yl) phenyl)quinoline-6 carboxamide BCD-CDK8- 6-14

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

The 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 as follows:

dimethyl sulfoxide - DMSO

- 21 041908 (±)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthalene - BINAP

4-methylbenzenesulfonic acid - PTSA

4-dimethylaminopyridine - DMAP

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

-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 - SEMCl.

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

Scheme 1

where X1, X ₃ each independently represents C(H)m, N, NH;

X1 is each independently C, CH, N;

L1 , L2 each independently represents a chemical bond, -C(R ₆ ) ₂ -, -O-, -C(O)-, -NH-, -C(=NR19)-;

n is 0, 1;

k is 0, 1;

m is 1, 2;

R1, _R3 are each independently H, Hal, cyano, C1-C6 alkyl;

R ₂ , R4 are each independently selected from the group consisting of

C ₁ -C6 alkyl, unsubstituted or substituted with one or more R ₁₄ substituents;

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

L ₃ , L4 each independently represents a chemical bond, -C(O)-, -O-, -CH2-, -NH-, -C(O)NR ₇ -, -C(=NH)-;

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

R ₅ is H; Hal; cyano; C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 alkyloxy C _r C6 alkyl; NR ₁₅ R ₁₆ ; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1-C6 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 _r C ₆ alkyl, C _r C ₆ alkyloxy, NR ₁₅ R ₁₆ ;

R ₆ is each independently H, Hal, hydroxy, C1-C6 alkyloxy;

R ₇ is each independently H, C1-C6 alkyl;

R8, R9 are each independently H, C1-C6 alkyl, -C(O)-NR ₂₁ R ₂₂ , -CN, -C(O)-OR ₂₀ ; or

R8 and R9 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 may be unsubstituted or substituted with 1 or 2 substituents selected from oxo, C1-C6 alkyl;

R ₁₀ is each independently selected from the group consisting of H, Hal, Ci-C ₆ alkyl, hydroxy, cyano, C1-C6 alkyloxy, C1-C6 alkyloxy C1-C6 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 C1-C6 alkyls; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and/or S, unsubstituted or substituted with one or more C1-C6 alkyl; -S(O) ₂ -C ₁ -C ₆ alkyl;

- 22 041908

Rn, 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 is each independently Hal, -C(O)NR ₁₇ R ₁₈ ;

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ , R ₁₈ each independently represents H, C ₁ -C ₆ alkyl; aryl unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1C6 alkyloxy;

R ₁₉ , R20 are each independently H, C1-C6 alkyl;

Y is each independently H, Hal, NH2, OH, -B(OH) ₂ , -CON(Me)-OMe, -C(O)Cl;

A, W is H, Hal, CN, -C(O)OH, -C(O)Cl.

In the case when OH, NH groups are present in the initial reagents, intermediate compounds, they can be protected by (2-(trimethylsilyl)ethoxy)methylacetal, trialkylsilyl or alkyl(diaryl)silyl protective groups.

The interaction between compound 1 and compound B with the formation of compound 2 can be carried out according to the reactions: Suzuki between aryl halide 1 and arylboronic 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 the amine B according to the methodology of making an amide bond in the presence of a base such as a trialkylamine (A=C(O)C1, Y=H). The synthesis of compound 3 from compound 2 and compound C can be carried out using the following reactions: Suzuki between aryl halide 2 and arylboronic 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 the amine C using the amide bond methodology in the presence of a base such as a trialkylamine (W=C(O)C1, Y=H); between carbonitrile 2 and amine C according to the methodology for obtaining 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 following reactions: Suzuki between aryl halide 4 and arylboronic 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 the amine C using the amide bond methodology in the presence of a base such as a trialkylamine (W=C(O)C1, Y=H); between carbonitrile 4 and amine C according to the methodology for obtaining amidines using organomagnesium reagents (W=CN, Y=H); between compound 4 and acid chloride С by acylation reaction (W=H, Y=C(O)C1); between aryl halide 4 and Weinreb amide C by the Grignard reaction (W=Hal, Y=C(O)N(Me)-OMe). The interaction between compound 5 and compound B with the formation of compound 3 can be carried out according to the reactions: Suzuki between aryl halide 5 and arylboronic 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 of obtaining an amide bond in the presence of a base such as a trialkylamine (a=c(O)ci, 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 X1, X ₂ , X ₃ , R1, R ₂ , R ₃ , L1, k, Hal, Y are as defined above.

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.

- 23 041908

Scheme 3

where X _b X ₂ , X ₃ , R^ R ₃ , R4, 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 following reactions: Suzuki between aryl halide 9 and arylboronic 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 obtained by reacting compound 10 with a strong acid such as HCl or trifluoroacetic acid. Compound 5' can be obtained from compound 11 by diazotization reaction with sodium nitrite and subsequent replacement of the diazonium group by halogen by reaction with an appropriate metal halide such as potassium iodide.

Compound 3' is a variant of compound 3 where L2 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 , R4, L ₁ , n, k, Hal, Y have the above meanings.

Compound 12 can be obtained 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 solution of alkali on heating. Compound 3' can be prepared by reacting carboxylic acid 13 with amine C using carbodiimide amide bond methodology.

Compound 3 is a variant of compound 3 where L2 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 , R4, 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 variant of compound 3 where L ₁ is -C(O)- and compound 14 can be converted to compound 3' according to Scheme 6.

- 24 041908

Scheme 6

where X1, X2, X ₃ , R1, R2, R ₃ , R4, L2, n, k, Y, Hal are as defined above.

Compound 15 can be obtained 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 solution of alkali. The reaction between compound 16 and compound B to form 3' can be carried out in the presence of a carbodiimide and a base.

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

Scheme 7

where R2, R4, L1, Y, Hal are as defined above.

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

This preparation 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 R1, R2, R ₃ , R4, L1, L2, Y, Hal are as defined above.

Reaction of compound 23 with amine C may be carried out in the presence of a base such as potassium or diisopropylethylamine tert-butoxide in DMSO to give compound 24. Compound 24 may be converted to compound 25 by reaction with compound B in the presence of a catalyst such as as a complex compound of palladium with organophosphorus ligands. Compound 26 can be prepared from compound 25 by hydrogen reduction on Pd/C followed by cyclization with an acid catalyzed trialkyl orthoester of formic acid. 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. Reaction of compound 29 and amine C to give compound 25 is carried out in a similar manner according to the methods described above and used for compound 24 from compound 23 and compound C. The conversion of compound 24 to compound 27 can be carried out in a similar 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 a similar 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 oxidant such as mchloroperbenzoic acid or hydrogen peroxide to give an N-oxide, followed by 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 initial reagents, intermediate compounds, they can be protected by (2-(trimethylsilyl)ethoxy)methylacetal, trialkylsilyl or alkyl(diaryl)silyl protective groups. Deprotection can be carried out in the final steps of the synthesis with a strong acid such as HCl or trifluoroacetic acid.

In the case when in the final structures the radicals R ₂ , R4 contain an ether group -COOC1C ₆ alkyl, then this ether group can be converted into a -COOH group by interaction with strong bases, such as lithium, sodium or potassium hydroxide, followed by treatment with an acid such as salt or lemon. Further, such a -COOH group can be converted into a functional group -C(O)NH ₂ by reaction with ammonium chloride in the presence of carbodiimide; or can be converted into a functional group -C(O)-NH-S(O) ₂ -C ₁ -C ₆ alkyl by reaction with C ₁ -C ₆ alkyl-S(O) ₂ NH ₂ . In the case when the radicals R ₂ , R4 contain the functional group CN in the final structures, it can be hydrolyzed into the functional group -C(O)NH ₂ . The NH group in a heterocyclic moiety, eg pyrazole, can be converted to an NC ₁ -C ₆ alkyl group with alkylating agents 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 into an OH group by reaction with AlCl ₃ when heated. The azetidine ring can be opened by the action of a hydrohalic acid such as hydrochloric acid to form a hydrogen halide addition product. Intermediates may optionally be prepared and isolated as acid salts, eg hydrochloride, trifluoroacetate and others, or with bases, eg sodium, potassium, ammonium trialkylammonium and other salts.

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

In one embodiment, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, MES, and one or more pharmaceutically acceptable excipients. In yet another embodiment of the invention, the pharmaceutical composition of this invention is for the prevention or treatment of a disease or disorder mediated by the activation of CDK8/19 cyclin-dependent protein kinases. In yet another embodiment of the invention, the pharmaceutical composition of this invention is for the prevention or treatment of a disease or disorder mediated by activation of CDK8/19 cyclin-dependent protein kinases, wherein the disease or disorder mediated by activation of CDK8/19 cyclin-dependent protein kinases is an oncological or hemato-oncological disease. In yet another embodiment, the pharmaceutical composition of the invention is for the prevention or treatment 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).

The pharmaceutical composition of the present invention contains, for example, from about 10% to about 100% active ingredients, preferably from about 20% to about 60% active ingredients. It is understood that the content of the active ingredient or ingredients in an individual dose of each dosage form does not necessarily constitute an effective amount, since the required effective amount can be achieved with the introduction of 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 skilled in the art and include substances such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The specific carrier, diluent or excipient used will depend on the means and purpose for which the compound of the present invention is being 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 (eg PEG400, PEG300), etc. and their mixtures. The compositions may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, lubricants, processing aids, colors, sweeteners, flavors, flavors, and other known additives. to obtain a good appearance of the medicinal product or to facilitate the manufacture of a pharmaceutical product (ie drug).

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

The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral administration of medicines - taking medicine through the mouth (Latin per os, oris), by swallowing the medicine. The compounds of the present invention may also be administered buccally, lingually or sublingually so that the compound enters the blood stream directly from the mouth.

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 those filled with liquid); chewable forms; gels; fast-dissolving dosage forms; films; suppositories; sprays; and buccal/mucoadhesive patches.

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

The compounds of the present invention may 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 introduces the pharmaceutical composition through the tissue disruption, typically resulting in direct entry into the bloodstream, muscle, or 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 through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is intended 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 useful. Regional perfusion is also provided.

Dosage forms of pharmaceutical compositions suitable for parenteral administration generally contain the active ingredient in association with a pharmaceutically acceptable carrier, eg sterile water or sterile isotonic saline. Such dosage forms may be formulated, packaged or sold in a form suitable for bolus administration or for continuous administration. Injectable dosage forms may be manufactured, packaged or

- 27 041908 sold in unit dosage form, for example, in 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, pulsatile, controlled, targeted, and programmed release.

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

In yet another embodiment, the present invention relates to a method of treatment as described above, 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).

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

As used herein, the terms co-administered, 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: the simultaneous administration of such a combination of a compound of this invention and a therapeutic agent to a patient who is 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 of this invention and a therapeutic agent to a patient in need of treatment when such components are formulated separately in different dosage forms, the introduction of which occurs at almost the same time to the specified patient, after which these components are released almost simultaneously, the sequential administration of such a combination of a compound of this invention and a therapeutic agent that of a patient in need of treatment, when such components are formulated separately from each other in separate dosage forms, which are taken in sequence in time by the specified patient with a significant time interval between each administration, after which these components are released at different times; as well as the 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 time, where each part can be entered in one or different ways.

Those skilled in the art will recognize that therapeutically effective dosages may vary when drugs are used in combination therapy. Methods for experimental determination of 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 dosing, i.e. administration of more frequent and smaller doses to minimize toxic side effects has been described in the literature. Combination treatment further includes intermittent treatment that starts and stops 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, of course, vary depending on the type of auxiliary drug used, the specific drug used, the disease or condition being treated, and so on.

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 benefit in the methods described in this patent, in which the pharmaceutical composition of the compound described in the present invention and/or combinations with other therapies are combined with genetic testing to determine whether whether the subject is a carrier of a mutated gene known to be associated with certain diseases or conditions.

Compounds that are inhibitors of CDK8/19 may be used in the treatments 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 anticancer agents include, without limitation, any of the following agents: alkylating agents, alkylated sulfonates, nitrosoureas, or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; anticancer antibiotics; topoisomerase inhibitors.

Examples of antimetabolites include, without limitation, folic acid analogs (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, calcium levofolinate) or pyrimidine analogs (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxouridine, azacitidine, enocytabine, carmofur, gemcitabine, sapacitabine, elacytarabine, doxifluridine), or purine analogs (eg, mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine), or asparaginase.

Examples of alkylating agents include, without limitation, mechloroethamine, cyclophosphamide, chlorambucil, menphalan, bendamustine, hexamethylimelamine, thiotepa, busulfan, carmustine, lomustine, laromustine, semustine, streptozocin, dacarbazine, ifosfamide, improsulfan, mitobronitol, mitolactol, nimustine, ranimustine, temozolom treosulfan, carboquine, apazichion, fotemustine, altretamine, glufosfamide, pipobroman, trofosfamide, uramustine, evophosphamide, VAL-083.

Examples of hormonal agents and hormone antagonists include, without limitation, prednisone, prednisolone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, diethylstilbestrol, estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, abarelix, abiraterone, biriancalutamide, buserelin, calusterone, , degarelix, dexamethasone, fluocortolone, fulvestrant, goserelin, histrelin, leuprorelin, mitotane, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin alfa, toremifene, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, epithioglutamine, dimizalustanol, ortereol , anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane.

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

Examples of anticancer antibiotics include, without limitation, doxorubicin, daunorubicin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pyrarubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plicamycin, peplomycin, mitomycin C, zinostatin, streptozocin.

Examples of topoisomerase inhibitors include, without limitation, irinotecan, topotecan, belotecan, teniposide, etoposide, voreloxin, amonafide.

Examples of anti-cancer agents include, without limitation, any of the following: microtubule-acting drugs such as taxanes (eg, paclitaxel, docetaxel, cabazitaxel, tezetaxel), vinca alkaloids (eg, vinorelbine, vinblastine, vincristine, vindesine, vinflunine); mitogen-activated protein kinase signaling inhibitors (eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmanin, or LY294002); mTOR inhibitors (eg sirolimus, temsirolimus, everolimus, ridaphorolimus); антитела (например, ритуксимаб, трастузумаб, алемтузумаб, бесилесомаб, цетуксимаб, деносумаб, ипилимумаб, бевацизумаб, пертузумаб, ниволумаб, офатумумаб, панитумумаб, тозитумомаб, катумаксомаб, элотузумаб, эпратузумаб, фарлетузумаб, могамулизумаб, нецитумумаб, нимотузумаб, обинутузумаб, окаратузумаб, ореговомаб, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, EDM-525797); kinase inhibitors (fosmatanib, entosplenib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dasatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, bosutinib, axitinib, afatinib, alicertib, dacomibidinabicyclinib, dacomibractinib, dacomibrazifenib , nintedanib, lenvatinib, linifanib, linsitinib, masitinib, motesanib, neratinib, orantinib, ponatinib, radotinib, tipifarnib, tivantinib, tivozanib, trametinib, apatinib, ibrutinib, acalabrutinib, cobimetinib, fedratinib, brivanib alaninate, cediranib, icatinib, icatinib rigosertib, pimacertib, buparlisib, idelicib, midostaurin, perifosine, XL-647); photosensitizers (eg thalaporfin, temoporfin, sodium porfimer); cytokines (eg, aldesleukin, interferon alfa, interferon alfa-2a, interferon alfa-2b, celloleukin, tasonermin, recombinant interleukin-2, oprelvekin, recombinant interferon beta-1a); vaccines (eg picibanil, sipuleucel-T, witespen, emepepimut-S, oncoVACS, rindopepimut, troVACS, MGN-1601, MGN-1703); bisantren, decitabine, mitoxantrone, procarbazine, trabectedin, amsacrine, brostallicin, miltefosine, romidepsin, plitidepsin, eribulin, ixabepilone, fosbretabulin, denileukin diftitox, ibritumomab tiuxetan, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab-ozogamicin, afliberocycin, gemtuzumab-ozogamicin , edotreotide, inotuzumab-ozogamicin, naptumomab estafenatox, vintafolide, brentuximab vedotin, bortezomib, ixazomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, zoledronic acid, ibandronic acid, pamidronic acid, alitretinoin, tretinoin, peretinoin,

- 29 041908 bexarotene, tamibarotene, imiquimod, lentinan, mifamurtide, romurtide, pegaspargasa, pentostatin, endostatin, sizofiran, vismodegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide, etanidazole, ganetespib, idronoxyl, iniparib, lonidazole, promodazole, nimorazole , telotristat, belinostat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicin, reolisin, retaspimicin, 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 CDK8/19 cyclin-dependent protein kinases in a subject in need of such treatment.

In yet 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 activation of CDK8/19 cyclin-dependent protein kinases. , which is an oncological or hemato-oncological disease.

In 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 gastric cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa). In any of the above treatments, the subject may be a human.

The compounds of the present invention will be administered in an amount effective to treat the condition in question, i. 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 a stand-alone treatment or is administered in combination with one or more additional therapies.

Drug 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 dosage uniformity. Unit dosage form, as used herein, refers to physically discrete units suitable as unit doses for patients/subjects to be treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier.

In addition, it should be understood that for any particular patient, specific administration schedules will need to be adjusted over time according to individual need and at the discretion of the healthcare professional who administers or supervises the administration of the compositions, and that the concentration ranges given in this specification are 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 conditions of the patient, severity of the condition, route of administration, and the particular compound of the present invention used. Thus, the dosing regimen may vary widely, but may be determined regularly using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may 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 modes are well known in the relevant field of technology and will be clear to a person skilled in the art after reading the ideas disclosed in this document.

Typically, doses used to treat an adult human 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, may be reduced, depending on the symptoms, to a level at which relief of the disease, disorder, or condition is maintained. Patients may, however, require intermittent treatment over time for any recurrence of symptoms.

The above spectrum is only suggestive, as the number of variables in relation to an individual treatment regimen is large, and significant deviations from these recommended values are not uncommon. These dosages may be varied depending on a variety of variables, not limited to the activity of the compound being used, the disease or condition being treated, the route of administration, the requirement 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 given. These examples are provided 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 referenced in this specification are incorporated herein by reference. Although the above invention has been described in some detail by way of illustration and example in order to avoid ambiguous interpretation, it will be quite clear to those skilled in the art based on the ideas disclosed in this invention that certain changes and modifications can be made without deviating from the essence and scope of the attached options. implementation of the invention.

Examples

Example 1 Process for the preparation of the compound BCD-CDK8-1-6e

Stage 1

Potassium tert-butoxide (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 hours, then poured into 500 ml of water. The suspension was filtered, the precipitate was washed with water, dissolved in ethyl acetate, washed with 0.1 M HCl solution. The solvent was distilled off in vacuo. Product 1-1-3 was isolated by silica gel column chromatography using hexane-ethyl acetate (8:2) as an orange powder as an eluent. Yield 1.33 g (55%).

Stage 2. Obtaining compound 1-1-2.

Trifluoroacetic acid (0.70 ml, 7.5 mmol) was added 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. The mixture was stirred for 12 h, after which the solvent was distilled off in vacuo. The residue was dried in a rotary evaporator vacuum 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 acetate palladium(II) (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 0.1M HCl solution, saturated solutions of NaHCO ₃ and NaCl. The organic phase was concentrated in vacuo. Product 1-1-1 was isolated by silica gel column chromatography 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), trimethylorthoformate (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 hours Then the suspension was filtered through celite, the filtrate was concentrated in vacuo. The product was isolated by column chromatography on silica gel using hexane-ethyl acetate (1:1) as eluent. The reaction product BCD-CDK8-1-6e was obtained as a colorless powder. Yield 159 mg (85%).

Example 2 Production Method for BCD-CDK8-1-6a

BCD-CDK8-1-be 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°C for 2 h. The methanol was distilled off in a vacuum, the aqueous solution was washed with ethyl acetate, and the aqueous phase was brought to a neutral medium with a 0.1 M HCl solution.

- 31 041908

The suspension was filtered. The product BCD-CDK8-l-6a was obtained as a colorless powder. Yield 164 mg (62%).

Example 3 Production Method for BCD-CDK8-1-1

BCD-CDK8-1-6a

BCD-CDK8-1-1

EDCHC1 (42 mg, 0.22 mmol) was added to a suspension of BCD-CDK8-l-6a (70 mg, 0.17 mmol), methanesulfonamide (17 mg, 0.18 mmol), and DMAP (27 mg, 0.22 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The product was isolated by silica gel column chromatography using dichloromethane-methanolformic acid (9:1:0.1) as a colorless powder as eluent. Yield 55 mg (66%). The compound was further purified by preparative chromatography.

Example 4 Method for the preparation of the compound BCD-CDK8-1-6

BCD-CDK8-1-6a

BCD-CDK8-1-6

To a solution of BCD-CDK8-l-6a (71 mg, 0.17 mmol), HOBt (37 mg, 0.24 mmol), NH ₄ C1 (28 mg, 0.53 mmol), DIPEA (45 μl, 0.26 mmol) in 5 ml of DMF was added EDCHC1 (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 silica gel column chromatography using dichloromethane-methanol (95:5->92:8) as a colorless powder as eluent. Yield 60 mg (85%). The compound was further purified by preparative chromatography.

Example 5 Method for the preparation of the compound BCD-CDK8-1-2

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 EDCHC1 (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-fluoro-nitrobenzene.

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

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

Step 5: Preparation of the BCD-CDK8-1-2 Compound

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

Example 6 Process for the preparation of the BCD-CDK8-1-3 compound

-32041908

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)- N-pyrazole (11.5 g, 35.4 mmol) (obtained according to the method 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 100 ml of THF and 50 ml of water were stirred at 70° C. under an inert atmosphere for 10 hours. THF was distilled off in vacuo, 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 silica gel column chromatography using hexane-ethyl acetate (8:2) as an eluent 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 hours 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 of DMSO was heated at 90°С for 30 h. the mixture was poured into 100 ml of water. The suspension was filtered, the precipitate was washed with water, dissolved in ethyl acetate, washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. The product 1-3-2 was isolated by silica gel column chromatography using hexane-ethyl acetate (2:1) as an orange powder as an eluent. Yield 712 mg (53%).

Step 5 Compound 1-3-1 was prepared analogously to BCD-CDK8-1-6e (Example 1, Step 4) using Compounds 1-3-2 instead of Compound 1-1-1.

Step 6: preparation of the BCD-CDK8-1-3 compound.

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°C 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 silica gel column chromatography using dichloromethane-ethyl acetate-methanol (20:5:1) as a colorless powder as eluent. Yield 132 mg (56%).

Example 7 Method for preparing the 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°C. 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 hours, then concentrated in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol (96:4) as a colorless powder as eluent. Yield 52 mg (61%).

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

- 33 041908

Step 1 Compound 1-4-3 was prepared analogously to compound 1-3-2 (Example 6, Step 4) using 4-bromo-2-fluoro-nitrobenzene instead of compound 1-3-3.

Step 2 Compound 1-4-5 was prepared analogously 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 prepared analogously 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 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 analogously 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 the compound BCD-CDK8-1-17

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

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

Step 1 Compound 1-5-2 was prepared analogously 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 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 the 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 the compound BCD-CDK8-1-9

- 34 041908

Step 1 Compound 1-9-2 was prepared analogously to 1-3-2 (Example 6, step 4) using 4-bromo-2-fluoronitrobenzene instead of 1-3-3 and N,N-dimethyl-p-phenylenediamine instead of 1- 3-4.

Step 2 Compound 1-9-1 was prepared analogously 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 analogously 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 the compound BCD-CDK8-1-10

Step 1 Compound 1-10-1 was prepared analogously to 1-3-2 (Example 6, Step 4) using 1-2-4 instead of 1-3-3 and N,N-dimethyl-p-phenylenediamine instead of 1- 3-4.

Step 2 Compound BCD-CDK8-1-10 was prepared analogously 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 the compound BCD-CDK8-1-11

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

Step 2 Compound 1-11-1 was prepared analogously to 1-3-2 (Example 6, Step 4) using 1-112 instead of 1-3-3 and 4-methoxyaniline instead of 1-3-4.

Step 3 Compound BCD-CDK8-1-11 was prepared analogously 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 the compound BCD-CDK8-1-12

Step 1 Compound 1-12-2 was prepared analogously to 1-3-2 (Example 6, Step 4), using 4-bromo-2-fluoro-nitrobenzene instead of 1-3-3 and 4-methoxyaniline instead of 1-3-4.

Step 2 Compound 1-12-1 was prepared analogously to 1-1-1 (Example 1, Step 3) using 1-122 instead of 1-1-3 and 1-4-4 instead of 1-1-2.

Step 3 Compound BCD-CDK8-1-12 was prepared analogously 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 the preparation of the compound BCD-CDK8-1-7e

- 35 041908

Step 1 Compound 1-7-2 was prepared analogously to compound 1-1-3 (Example 1, Step 1) using 4-bromo-2,6-difluoro-nitrobenzene instead of 4-bromo-2-fluoro-nitrobenzene.

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

Step 3 BCD-CDK8-1-7e was prepared analogously to 1-1-1 (Example 1, Step 3) using 1-7-1 instead of 1-1-3.

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

Compound BCD-CDK8-1-7a was prepared analogously 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 the compound BCD-CDK8-1-7

Connection BCD-CDK8-1-7 was obtained similarly to the connection BCD-CDK8-1-6 (example 4), using BCD-CDK8-1-7a instead of BCD-CDK8-1-6a.

Example 19 Method for preparing the 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 BCD-CDK8-1-6e (Example 1, Step 4) using Compound 1-8-3 instead of Compound 1-1-1.

Step 3 Compound 1-8-1 was prepared analogously 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 analogously 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 the compound BCD-CDK8-1-19

- 36 041908

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 the compound BCD-CDK8-1-13

Step 1 Compound 1-13-2 was prepared analogously to 1-3-2 (Example 6, step 4) using 4-bromo-2,6-difluoronitrobenzene instead of 1-3-3 and N,N-dimethyl-p-phenylenediamine instead 1-3-4.

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

Step 3 BCD-CDK8-1-13 was prepared analogously 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 the 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 of DMSO was heated at 110°C for 5 h. The reaction mixture was poured into 100 ml of water. The suspension was filtered, the precipitate was washed with water, dissolved in ethyl acetate, washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. The product was isolated by silica gel column chromatography using hexane-ethyl acetate (1:1) as an orange powder as an eluent. Yield 794 mg (81%).

Step 3 Compound 1-14-1 was prepared analogously to 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 the 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 the compound BCD-CDK8-1-15e

- 37 041908

Step 1 Compound 1-15-2 was prepared analogously 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-fluoro-nitrobenzene.

Step 3 Compound BCD-CDK8-1-15e was prepared analogously 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 the compound BCD-CDK8-1-15a

Compound BCD-CDK8-1-15a was prepared analogously 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 the compound BCD _- CDK8-1-15

BCD-CDK8-1-15a 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 the compound BCD-CDK8-1-21a

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

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

Connection BCD-CDK8-1-21 was obtained similarly to the connection BCD-CDK8-1-6 (example 4), using BCD-CDK8-1-21a instead of BCD-CDK8-1-6a.

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

- 38 041908

pH

BCD-CDK8-5-2

Stage 1

PBr ₃ (0.909 ml, 9.59 mmol) was added to a solution of 6-iodo-4-hydroxyquinoline (2.00 g, 7.38 mmol) in 25 mL of DMF while cooling with an ice bath. Then the reaction mixture was brought to room temperature and stirred for 3 hours. Then 300 ml of water was added, extracted with ethyl acetate (3x150 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 concentrating 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 of 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° C. for 6 hours. Then 250 ml of water was added, extracted with ethyl acetate (3x150 ml). The organic layers were separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The 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. temperature. Next, the resulting mixture was stirred at 100°C for 1 hour. Poured into water, the precipitated crystals were filtered off, washed with water, obtaining the product 5-2-2 in the form of a yellow powder. Yield 236 mg (94%).

Stage 4

To 5-2-2 (430 mg, 1.57 mmol) dissolved in 10 ml of ethanol was added a solution of KOH (264 mg, 4.71 mmol) in 5 ml of water. The reaction mixture was refluxed for 60 hours. Then a 1M HCl solution was added to pH 4. The precipitated 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 DMF. EDC-HCl (138 mg, 0.564 mmol) was added in portions 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 (3x70 ml). The organic layers were separated, washed with saturated NaCl solution, dried with 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 the compound BCD-CDK8-5-2i

pH

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) (obtained according to the method described in WO 2003/045315) in 3 ml of dry THF in an inert atmosphere with cooling ice bath. The mixture was kept for 1 hour 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 kept 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 (3x30 ml). The organic layers were separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The 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 a 4M solution of HC1 in 1,4-dioxane was added, and kept for 16 h at room temperature. At the end of the reaction, 0.25 ml of a 7 M solution of NH ₃ in methanol was added with stirring, then the solvents were distilled off. The product BCD-CDK8-5-21 was isolated by column chromatography on silica gel, eluent dichloromethane-XH ₃ in methanol (7M) (15:1) as a yellow powder. Yield 236 mg (94%).

Example 31 Method for preparing the 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-morpholinephenylboronic 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 BCD-CDK8-5-3 was prepared analogously to 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 Method for preparing the compound BCD-CDK8-5-31

Compound BCD-CDK8-5-31 was prepared analogously to compound 5-21-1 (Example 30, step 1) using compound 5-3-2 instead of compound 5-2-2 and butyldimethylsilyloxy)pyrrolidine morpholine.

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

(R)-3-(third place

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 of DMF with stirring and cooling with an ice bath. The reaction mixture was brought to room temperature and kept for 15 minutes. Then 2-(trimethylsilyl)ethoxymethyl chloride (3.36 g, 0.02 mol) was added. After 1 h, poured into 300 ml of water, extracted with ethyl acetate (3x100 ml). The organic layers were separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ The reaction product 5-4-5 was obtained as a light yellow powder after the solution was concentrated 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 1 ,4-dioxane was added under inert atmosphere with stirring palladium(II) acetate (35 mg, 0.158 mmol). The reaction mixture was kept at 80°C for 30 min. Next, 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 (3x150 ml). The organic layers are separated

-40041908 washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product 5-4-4 was isolated by column chromatography on silica gel, eluent 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 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)- 3hydroxypyrrolidine.

Stage 6

5-4-1 (57 mg, 0.111 mmol) was dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid was added while cooling with an ice bath. The solution was stirred for 16 hours at room temperature. Next was added 50 ml of a saturated solution of Na ₂ CO ₃ was extracted with dichloromethane (3x30 ml). The organic layers were separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The product BCD-CDK85-4 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 for the preparation of the 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 The BCD-CDK8-5-4i compound was prepared analogously to the BCD-CDK8-5-4 compound (Example 33, Step 6) using compound 5-4i-1 instead of compound 5-4-1.

Example 35 Method for the preparation of the compound BCD-CDK8-5-6

Step 1 Compound 5-6-2 was prepared analogously to compound 5-2-3 (Example 29, step 2) using 6-iodo-4-hydroxyquinoline instead of 5-2-4 and 4-methoxyphenylboronic acid instead of 4-hydrochloride. (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 a suspension of 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 added 50 ml of water, extracted with ethyl acetate (3x30 ml). The organic layers were separated, washed with saturated NaCl solution, dried with Na ₂ SO ₄ . The product BCD-CDK8-5-6 was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (98:2). Yield 76 mg (75%).

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

BCD-CDK8-5-7 was prepared analogously to BCD-CDK8-5-2 (Example 29, Step 5) using (S)-3-hydroxypyrrolidine hydrochloride instead of (R)-3-hydro

- 41 041908 xypyrrolidine.

Example 37 Method for preparing the 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, 4 ml of a 4 M HCl solution in 1,4-dioxane was added with cooling, and kept for 72 h at room temperature. At the end of the reaction, 0.25 ml of a 7 M solution of NH ₃ 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 dichloromethaneNH ₃ in methanol (7M) (15:1). Yield 70 mg (78%).

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

Step 1 Compound 5-8-4 was prepared analogously to compound 5-2-3 (Example 29, Step 2) using 1-bromo-4-iodobenzene instead of 5-2-4 and 1-methyl-4-( 4,4,5,5-tetramethyl-1,3,2dioxoborolan-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 BCD-CDK8-5-8 was prepared analogously to 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 the 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 the compound BCD-CDK8-5-1Cl

- 42 041908

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 boiled for 10 h in 15 ml of acetic acid. The suspension was filtered, 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%).

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

Stage 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 the 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 using silica gel column chromatography, eluent hexane-ethyl acetate (3:1). Yield 457 mg (30%).

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

Step 6 BCD-CDK8-5-1C1 Compound Was Prepared (Example 3) Using 5-1Cl-1 Instead of BCD-CDK8-1-6a

Example 41 Preparation of BCD-CDK8-5-1 Compound Similar to BCD-CDK8-1-1 Compound

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 under a hydrogen atmosphere at a pressure of 8 atm for 3 h. after concentration, the product was isolated as a white powder by preparative chromatography. Yield 100 mg (85%).

Example 42 Method for preparing the 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 analogously to BCD-CDK8-1-6a (Example 2) using compound 5-5Cl-2 instead of BCD-CDK8-1-6e.

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

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

- 43 041908

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 the compound BCD-CDK8-6-1

BCD-CDK8-5-5CI BCD-CDK8-5-5

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

Step 2 Compound 6-1-1 was prepared analogously to compound 5-2-3 (Example 29, Step 2) using compound 6-1-2 instead of compound 5-2-4 and 4-morpholinephenylboronic 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. Next, the reaction mixture was poured into 50 ml of water, a saturated solution was added

Na ₂ CO ₃ to pH 8, the product was extracted with ethyl acetate (3x50 ml). The combined extract was washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product BCD-CDK8-6-1 was isolated as a yellow-orange powder using silica gel column chromatography, eluent dichloromethanemethanol (97:3). Yield 61 mg (57%).

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

Stage 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°C for 3 hours. Next, the volatile components 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°C. The reaction mixture was kept at room temperature for 6 hours. After concentration, the product 6-2-4 was isolated as a white powder using silica gel column chromatography, eluent hexane-ethyl acetate-dichloromethane (3:2:2). Yield 850 mg (72%).

Step 3 Compound 6-2-3 was prepared 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 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

- 44 041908 mg, 2.28 mmol) in 6 ml of water. The reaction mixture was refluxed for 2 h, methanol was distilled off, and a 0.1 M solution

HCl to pH 4. The suspension was filtered, the precipitate was washed with water to give the product 6-2-2 as a gray powder. Yield 795 mg (87%).

Stage 5

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 as a white powder using silica gel column chromatography, eluent dichloromethane-methanol (94:6). Yield 90 mg (23%).

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

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

Stage 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 hours. Next, the solvent was distilled off, and a 7M solution of NH ₃ in methanol was added to the residue at 05°C. After concentration, the product 6-3-3 was isolated as a yellow liquid using silica gel column chromatography, eluent dichloromethane-NH ₃ in methanol (7M) (99:1). Yield 433 mg (63%).

Step 2 Compound 6-3-2 was prepared analogously to 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 prepared 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 the compound BCD-CDK8-6-4

Step 1 Compound 6-4-2 was prepared analogously to 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 the compound BCD-CDK8-6-5

- 45 041908

Step 1 Compound 6-5-3 was prepared analogously to 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 prepared 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 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 the compound BCD-CDK8-6-6

Step 1 Compound 6-6-3 was prepared analogously to 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 prepared analogously 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 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 the compound BCD-CDK8-6-7

Step 1 Compound 6-7-1 was prepared 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 the compound BCD-CDK8-6-8

Step 1. Compound 6-8-1 was prepared analogously to compound 5-2-3 (Example 29, step 2), using compound 6-3-2 instead of compound 5-2-4 and 4-morpholinephenylboronic acid instead of hydro- 46 041908 4-(dimethylamino)phenylboronic acid rochloride.

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 the compound BCD-CDK8-6-9

Step 1 Compound 6-9-4 was prepared analogously 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 prepared analogously 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 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 the compound BCD-CDK8-6-10

Compound BCD-CDK8-6-10 was prepared analogously 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 the 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 the compound BCD-CDK8-6-12

Step 1 Compound 6-12-1 was prepared analogously 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 the compound BCD-CDK8-6-13

- 47 041908

was obtained similarly to the connection BCD-CDK8-5-6 (example 35,

Step 1 Compound 6-13-1 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 the 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 the preparation of the compound BCD-CDK8-3-1

Stage 1

To 5-bromo-1,7-naphthyridine-3-carboxylic acid (1.00 g, 3.95 mmol) (obtained according to the method described in WO 2015/014768) was added SOCl ₂ (5 ml, 60 mmol) and one drop of DMF. The reaction mixture was refluxed for 5 h, after which the volatile components were removed under reduced pressure. 5 ml of MTBE was added to the residue, concentrated, and the residue was dried in a rotary evaporator vacuum. 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 under nitrogen at -5°C. The resulting mixture was stirred at room temperature for 5 hours. After that, the reaction mass was washed with 1M HCl solution and extracted with dichloromethane. The organic layer was separated, washed with saturated NaCl solution, dried over Na ₂ SO ₄ . The product 3-1-4 was isolated as a white powder 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) under nitrogen at room temperature. The resulting mixture was heated at 70°C for 5 hours. After that, the reaction mass was concentrated in a vacuum. The product 3-1-3 was isolated as a white powder by column chromatography on silica gel, eluent dichloromethane-methanol (98:2). Exit

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 1M HCl solution was added to pH 4. The suspension was filtered, the precipitate was washed with water (3x20 ml), dried in vacuum to constant weight, obtaining the 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) under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 24 hours. The product 3-1-1 as 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 a 4M solution of HCl in diethyl ether. After two days the reaction mixture was filtered, washed with diethyl ether (2x20 ml). The product BCD-CDK8-3-1 was isolated as a white powder by column chromatography on silica gel, eluent dichloromethane-methanol (9:1). Yield 59 mg (96%).

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

COOMe

Step 1 Compound 3-13-4 was prepared analogously 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 analogously to compound BCD-CDK8-3-1 (Example 58, Step 6) using 3-13-1 instead of 3-1-1

Example 60 Method for preparing the compound BCD-CDK8-3-2 he

3-1-5 3-2-2

3-2-1

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

- 49 041908

Example 61 Method for preparing the 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-methoxycarbonylphenylboronic acid.

Example 62 Method for preparing the 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 the compound BCD-CDK8-3-5

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

Example 64 Method for preparing the 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 the 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 BCD-CDK8-3-8 was prepared analogously to 3-1-3 (Example 58, Step 3) using 3-8-1 instead of 3-1-4 and 4-(dimethylamino)phenylboronic acid instead of 4-methoxycarbonylphenylboronic acid.

Example 66 Process for the preparation of BCD-CDK8-3-9 compound

- 50 041908

Step 1. 5-bromo-1,7-naphthyridine-3-carboxylic acid (2.22 g, 8.78 mmol) (prepared according to the method 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 boiled for 8 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in 50 ml of ethyl acetate, washed with water (2x40 ml), saturated NaHCO ₃ solution (50 ml) and saturated NaCl solution (50 ml). The organic layer was dried with Na ₂ SO ₄ . The product 3-9-4 was isolated as a light yellow powder by column chromatography on silica gel, eluent dichloromethane-methanol (96:4). Yield 1.64 g (58%).

Step 2 Compound 3-9-3 was prepared analogously 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.

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

Step 4. To a solution of compound 3-9-2 (169 mg, 0.50 mmol) in 1 ml of 6 M HCl solution was added a solution of NaNO ₂ (52 mg, 0.75 mmol) in 0.5 ml of H ₂ O at -5°C. After 1 h, a solution of KI (415 mg, 2.50 mmol) in 0.5 ml H ₂ O was added. After 1 h, the reaction mixture was heated to 80°C and stirred for 3 h. The reaction mixture was poured into a saturated Na ₂ SO ₃ solution, extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with NaCl solution, dried over Na ₂ SO ₄ . The product 3-9-1 was isolated as a yellow powder by column chromatography on silica gel, eluent dichloromethane-methanol (98:2). Yield 132 mg (64%).

Step 5 Compound BCD-CDK8-3-9 was prepared analogously 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 1-12.

Example 67 Method for preparing the 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 the compound BCD-CDK8-3-12

- 51 041908

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 prepared 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 from Journal of Medicinal Chemistry, 53(9), 3645-3674; 2010) instead of compound 11-2.

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 Method for preparing the 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 (obtained by the method described in WO 2015/014768) instead of 5-2-4 and 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 the compound BCD-CDK8-3-15

Compound BCD-CDK8-3-15 was prepared analogously 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 the compound BCD-CDK8-3-16

- 52 041908

Compound BCD-CDK8-3-16 was prepared analogously to the compound using pyrrolidine instead of azetidine hydrochloride and a fluorobenzoic acid compound.

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

Compound BCD-CDK8-3-17 was prepared similarly to the compound using 3-9-1 instead of 1-1-3 and 2-pyrollidone instead of 1-1-2.

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

1-2-4 (example 5, step 1), 3-14-1 instead of 4-nitro-31-1-1 (example 1, step 3),

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-3fluorobenzoic acid.

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

Stage 1

NaH (1.51 g, 63 mmol) was added to a solution of 5-bromo-3-iodo-1H-pyrollo[2,3]pyridine (6.78 g, 21 mmol) in 70 ml of THF while cooling in an ice bath. The suspension was stirred for 15 min, after which SEMCl (4.1 ml, 23.1 mmol) was added. The reaction mass was left to mix overnight. Then 250 ml of water was added and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried over MgSO ₄ . Product 4-24-3 was isolated as a light yellow viscous liquid by silica gel column chromatography using 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°С. 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 method described in Bioorganic and Medicinal Chemistry Letters, 19(16), 4639-4642; 2009). After 20 min the reaction mass was diluted with 200 ml of a saturated solution of NH ₄ Cl, the product was extracted with ethyl acetate. The organic layer was dried over MgSO ₄ . The product 4-24-2 was isolated as a light yellow powder using silica gel column chromatography in ethyl acetate-hexane (1:9). Yield 1.90 g (64%).

- 53 041908

Stage 3

Bis(pinacolato)diborane (449 mg, 1.77 mmol), potassium acetate (139 mg, 1.41 mmol), XPhos ( 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), ) ₄ (115 mg, 0.117 mol) and 0.5 mL of water. The reaction mass 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 over MgSO ₄ Product 4-24-1 was isolated as a light yellow powder using silica gel column chromatography in 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 while cooling with an ice bath. The reaction mass was stirred for 8 h at room temperature. Then diluted with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over 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 the preparation of the compound BCD-CDK8-4-4

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

Example 76 Method for preparing the 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 the 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 the compound BCD-CDK8-4-32

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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 method 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 the compound BCD-CDK8-4-12

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

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

Step 1. N -bromosuccinimide (3.71 g, 20.8 mmol) while 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 over MgSO ₄ . The product was used without further purification. Yield 3.5 g (77%).

Step 2 Compound 4-21-1 was prepared analogously 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 the compound BCD-CDK8-4-1

AlCl ₃ (296 mg, 2.22 mmol) was added to a solution of the 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 using silica gel column chromatography in dichloromethane-methanol (95:5). Yield 46 mg (52%).

Example 82 Method for preparing the 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.

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

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

Example 84 Method for preparing the 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 BCD-CDK8-4-29 was prepared analogously to BCD-CDK8-4-24 (Example 74, Step 4) using compound 4-29-1 instead of compound 4-24-1.

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

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

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

Stage 1

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 mass 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 over 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

POCl ₃ (1.71 ml, 18 mmol) was added to a suspension of compound 4-22-3 (2.97 g, 12 mmol) in 35 ml of chloroform. The reaction mass was stirred at the boil. After 2.5 h the solvent was removed under reduced pressure, the residue was poured into ice water, NaHCO ₃ was added. The reaction product was extracted with ethyl acetate, the organic layer was dried over MgSO4. The reaction product was isolated as a white powder using silica gel column chromatography in 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 analogously 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 the compound BCD-CDK8-4-2

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

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Example 88 Method for preparing the 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 the 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 the compound BCD-CDK8-4-30

Step 1 Compound 4-30-1 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 4-32-2 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 the compound BCD-CDK8-4-10

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

Example 92 Method for preparing the compound BCD-CDK8-4-23

Stage 1

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

Stage 2

N-bromosuccinimide (3.15 g, 18 mmol) was added to a solution of compound 4-23-3 (3.35 g, 17 mmol) in 40 ml of acetonitrile at a temperature of -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 using silica gel column chromatography, eluent hexane-ethyl acetate (95:5). Yield 4.28 g (92%).

Step 3 Compound 4-23-1 was prepared analogously to compound 4-24-1 (Example 74, Step 3),

- 57 041908 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 the compound BCD-CDK8-4-3

Compound BCD-CDK8-4-3 was prepared analogously 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 the compound BCD-CDK8-4-27

Step 1 Compound 4-27-1 was prepared analogously 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 the 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 the compound BCD-CDK8-4-31

Step 1 Compound 4-31-1 was prepared analogously 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 the 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 the compound BCD-CDK8-4-35

Stage 1. AlCl ₃ (2.71 g, 20.3 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2.3]pyridine (1.00 g, 5.07 mmol) in 30 ml of dichloroethane, the resulting suspension was stirred for 15 min, then a solution of acid chloride was added. -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 a vacuum. Ice water and saturated NaHCO ₃ solution were added to the residue. The suspension was filtered, the precipitate was dried in a vacuum oven, obtaining the reaction product in the form of a white powder. Yield 928 mg (56%).

Step 2 Compound 4-35-2 was prepared 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 BCD-CDK8-4-35 was prepared analogously to BCD-CDK8-4-24 (Example 74, Step 4) using compound 4-35-1 instead of compound 4-24-1.

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

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

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

Step 1 Compound 4-33-1 was prepared analogously 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 the 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 BCD-CDK8-4-34 was prepared analogously to BCD-CDK8-4-24 (Example 74, Step 4) using compound 4-34-1 instead of compound 4-24-1.

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

Step 1 Compound 4-36-1 was prepared analogously to compound 5-2-3 (Example 29, Step 2) using compound 4-24-2 instead of compound 5-2-4 and 4-morpholinephenylboronic acid instead of 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 the compound BCD-CDK8-4-37

Step 1 Compound 4-37-1 was prepared analogously to compound 5-2-3 (Example 29, step 2) using 4-28-2 instead of 5-2-4 and 4-morpholinephenylboronic acid instead of 4(dimethylamino)phenylboronic hydrochloride acids.

Step 2: Compound BCD-CDK8-4-37 was prepared similarly to Compound BCD-CDK8-4-24

- 59 041908 (example 74, stage 4), using compound 4-37-1 instead of 4-24-1.

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

Step 1 Compound 4-38-1 was prepared analogously to compound 5-2-3 (Example 29, step 2) using 4-32-2 instead of 5-2-4 and 4-morpholinephenylboronic acid instead of 4(dimethylamino)phenylboronic hydrochloride acids.

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

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

was obtained analogously to compound 5-2-3 (example 29, stage 2),

Step 1. Compound 4-39-1 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 the 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 BCD-CDK8-4-40 was prepared analogously to BCD-CDK8-4-24 (Example 74, Step 4) using compound 4-40-1 instead of 4-24-1.

Example 107 Method for preparing the 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 min under cooling and then another 30 min at room temperature. Next, methyl iodide (9 µL, 0.150 mmol, 1.7 equiv.) was added dropwise with stirring and cooling with a water bath; after 5 min, the reaction mixture was brought to room temperature. After 1 hour, 10 ml of water was poured in and extracted with ethyl acetate (2x15 ml). The organic layers were washed with saturated NaCl solution, dried over 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 the compound BCD-CDK8-3-20

Compound BCD-CDK8-3-20 was prepared analogously to compound 1-2-4 (Example 5, step 1) using compound 3-14-1 in place of 4-nitro-3-fluorobenzoic acid and (S)-3-hydroxypiperidine hydrochloride in place of hydrochloride Azetidine.

Example 109 Method for preparing BCD-CDK8-3-21 compound

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Compound BCD-CDK8-3-21 was prepared analogously to compound BCD-CDK8-3-19 (example

107) using BCD-CDK8-3-20 connection instead of BCD-CDK8-3-4

Example 110 Method for preparing the 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 in place of 4-nitro-3-fluorobenzoic acid and dimethylamine hydrochloride in place of azetidine hydrochloride.

Example 111 Method for preparing the 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 the compound BCD-CDK8-3-24

Stage 1

Compound BCD-CDK8-3-18 (110 mg, 0.283 mmol, 1.00 equiv.) was dissolved in 5 ml of dichloromethane and sprinkled with portions of m-chloroperbenzoic acid (66 mg, 0.326 mmol, 1.15 equiv.). After 1 h, 15 ml of water and 5 ml of dichloromethane were poured in, 1 M 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 over Na ₂ SO ₄ . The reaction product was isolated as a yellow powder by silica gel column chromatography using ethyl acetate-dichloromethane-methanol (5:4.7:0.3) as eluent. Yield 65 mg (57%).

Stage 2

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

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

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Compound BCD-CDK8-3-25 was prepared analogously to compound BCD-CDK8-3-19 (example

107) using BCD-CDK8-3-18 instead of BCD-CDK8-3-4 and DMF instead of THF as solvent.

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

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

Example 115 Method for preparing the 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 in place of 4-nitro-3-fluorobenzoic acid and morpholine in place of azetidine hydrochloride.

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

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

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

Example 117 Method for preparing the 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 in place of 4-nitro-3-fluorobenzoic acid and 2-methoxyethanol in place of azetidine hydrochloride.

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

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

Step 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 h at room temperature. Ethanolamine (20 mg 0.323 mmol) was added to the resulting solution. After an hour of stirring, additional ethanolamine (30 mg, 0.484 mmol) was added. After 1.5 h of stirring, the reaction mixture was poured into water, the product was extracted with ethyl acetate, dried with 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 the 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 in place of 4-nitro-3-fluorobenzoic acid and N-methylpiperazine in place of azetidine hydrochloride.

Example 120 Method for preparing the 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 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 similarly to BCD-CDK8-1-6a (Example 2) using compound 3-31-2 instead of BCD-CDK8-1-6e

Step 4 BCD-CDK8-3-31 was prepared analogously to 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 the 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 BCD-CDK8-3-24 (Example 112, Step 2) using Compound 3-32-1 instead of Compound 3-24-1.

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Example 122 Method for preparing the 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 the compound BCD-CDK8-3-35

Compound BCD-CDK8-3-35 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,N,N'-trimethylethylenediamine instead of azetidine hydrochloride.

Example 124 Method for preparing the 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 in place of 4-nitro-3-fluorobenzoic acid and cyclopropylamine in place of azetidine hydrochloride.

Example 125 Method for preparing the 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 BCD-CDK8-3-38 was prepared analogously to BCD-CDK8-3-24 (Example 112, Step 2) using compound 3-38-1 instead of compound 3-24-1.

Example 126 Method for preparing the 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 in place of 4-nitro-3-fluorobenzoic acid and cyclopropylmethanamine in place of azetidine hydrochloride.

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

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Step 1 Compound 3-40-1 was prepared analogously 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 the 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 the compound BCD-CDK8-3-41

Stage 1

Nitrogen was passed through a suspension of benzotriazole (84 mg, 0.7 mmol, 0.2 equiv) and copper (I) iodide (135 mg, 0.7 mmol, 0.2 equiv) in 20 ml of DMSO for 30 min. Then 1-bromo-4-iodobenzene (1.00 g, 3.5 mmol, 1 equiv.), imidazole (265 mg, 3.8 mmol, 1.1 equiv.) and potassium tert-butoxide (595 mg, 5.3 mmol, 1.5 equiv.) were added. The reaction mixture was stirred in a closed flask for 3 h 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 (2x50 ml). The organic layer was separated, washed with water, dried over Na ₂ SO ₄ . The product was isolated as a gray powder using silica gel column chromatography, eluent hexane-ethyl acetate (7:3). Yield 430 mg (55%).

Stage 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.

Stage 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 compound 5- 4-5.

Example 130 Analysis of Compounds Obtained

The purity and structure of the obtained compounds were confirmed by LC/MS chromatography-mass spectrometry and ^2H NMR spectroscopy (Table 1).

Equipment data:

Chromato-mass spectrometry _____________________________________

Name Manufacturer, country Agilent Triple Quad LC/MS Liquid Chromatograph: Agilent USA Agilent 1200 autosampler Agilent 1200 column thermostat Agilent 1200 degasser Agilent 1200 autosampler thermostat Agilent 6410 QQQ MS Detector Agilent 1200 UV Detector Agilent 1200 pump

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NMR spectrometer

Name Manufacturer, country Model, main characteristics NMR spectrometer Germany A VANCE III, 400 MHz

Table. 1 Analytical data for compound examples

Cipher ESIMS. [M+N] ⁺ NMR 0, md BCD-CDK81-1 490.2 Ή NMR (400 MHz, DMSCMO δ 12.95-11.55 (br s, 1H), 10.09 (s, 1H), 8.85 (s, 1H), 8.20 (d, J= 8.6 Hz, 2H), 7.91 (d, J= 8.6 Hz, 2H), 7.67 (d, J= 8.7 Hz, 1H), 7.62 (d, J= 7.7 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.05 (t, J = 7.4 Hz , 1H), 6.69-6.60 (m, 2H), 4.16-4.07 (m, 2H), 4.02-3.96 (m, 2H), 3.77-3.68 (m, 1H), 3.42 (s, 3H). BCD-CDK81-2 399.0 Ή NMR (400 MHz, DMSCMO δ 8.66 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.3, 1.1 Hz, 1H), 4.33 (s, 2H), 4.08 (s, 2H), 2.92 (s, 3H), 2.362.25 (m, 2H ). BCD-CDK81-3 372.1 Ή NMR (400 MHz, DMSCMO δ 13.04 (s, 1H), 8.66 (s, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.87 (d, J= 8.5 Hz, 2H), 7.82 ( d, J= 8.3 Hz, 1H), 7.67 (d, J= 8.5 Hz, 2H), 7.59 (s, 1H), 7.32 (dd,J=8.3,1.2 Hz, 1H), 3.71-3.25 (m, 4H ), 1.60-1.50 (m, 6H). BCD-CDK81-4 429.2 Ή NMR (400 MHz, DMSCMO δ 13.03 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.62 ( d, J= 8.4 Hz, 2H), 7.58 (d, J= 9.0 Hz, 1H) 6.52-6.50 (m, 2H), 4.05 (t, 2H), 3.91 (t, 2H), 3.853.78 (m, 1H), 3.58-3.54 (m, 4H), 3.47-3.45 (m, 2H), 3.35-3.32 (m, 2H). BCD-CDK81-5 344.1 Ή NMR (400 MHz, DMSCMO δ 13.05 (s, 1H), 8.69 (s, 1H), 8.28-8.06 (m, 2H), 7.88 (d, J= 8.4 Hz, 2H), 7.85-7.79 (m, 2H ), 7.67 (d, J= 8.4 Hz, 2H), 7.58 (dd, J= 8.6,0.8 Hz, 1H), 4.32 (m, 2H), 4.06 (m, 2H), 2.312.20 (m, 2H) . BCD-CDK81-6E 427.2 Ή NMR (400 MHz, DMSO-^) δ 10.08 (s, 1H), 8.41 (s, 1H), 8.17 (d, J= 8.5 Hz, 2H), 7.86 (d, J= 8.5 Hz, 2H), 7.63 - 7.60 (m, 3H), 7.31 (t, 2H), 7.05 (t, 1H), 6.64 (d, J= 1.8 Hz, 1H), 6.56 (dd, J= 8.6,1.8 Hz, 1H),

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4.09 (t, 2H), 3.97 (t, 2H), 3.90 (s, 3H), 3.76–3.65 (m, 1H). BCD-CDK81-6A BCD-CDK81-6 BCD-CDK81-7E BCD-CDK81-7A BCD-CDK81-7 BCD-CDK8- 1-8 413.1 412.2 445.1 431.2 430.1 447.2 Ή NMR (400 MHz, DMSO-<A) δ 10.13 (s, 1H), 8.39 (s, 1H), 8.15 (s, 2H), 7.81 (s, 2H), 7.62 (s, 3H), 7.31 (s , 2H), 7.05 (s, 1H), 6.64 (s, 1H), 6.56 (s, 1H), 4.09 (s, 2H), 3.97 (s, 2H), 3.72 (s, 1H). Ή NMR (400 MHz, DMSCMO δ 10.08 (s, 1H), 8.98 (s, 1H), 8.20-8.10 (m, 3H), 7.84 (dd, J= 8.4, 2.4 Hz, 2H), 7.69 (dd , J = 8.7, 2.5 Hz, 1H), 7.62 (d, J = 7.0 Hz, 2H), 7.54 (s, 1H), 7.31 (t,J=6.6Hz, 2H), 7.05 (t, J= 6.7 Hz , 1H), 6.70 (d, J= 8.7 Hz, 1H), 6.61 (s, 1H), 4.19-4.06 (m, 2H), 4.05-3.94 (m, 2H), 3.79-3.67 (s, 1H). Ή NMR (400 MHz, DMSO-J ₆ ) δ 10.06 (s, 1H), 8.42 (s, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.62 (d, J= 7.7 Hz, 2H), 7.31 (t, J= 7.9 Hz, 2H), 7.05 (t, J= 7.4 Hz, 1H), 6.49-6.33 (m, 2H), 4.12-4.05 (m , 2H), 4.01–3.94 (m, 2H), 3.91 (s, 3H), 3.75–3.65 (m, 1H).ΉNMR (400 MHz, DMSO-J ₆ ) δ 13.17 (s, 1H), 10.06 , 1H), 8.41 (s, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.31 (t , J = 7.9 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.48-6.36 (m, 2H), 4.11-4.07 (m, 2H), 3.99-3.96 (m, 2H), 3.76- 3.65 (m, 1H), Ή NMR (400 MHz, DMSO-<A) δ 10.06 (s, 1H), 8.38 (s, 1H), 8.15-8.07 (m, 3H), 7.77 (d, J= 8.6 Hz , 2H), 7.62 (d, J= 7.6 Hz, 2H), 7.48 ( s, 1H), 7.31 (t, J= 7.9 Hz, 2H), 7.06 (t, 7.3 Hz, 1H), 6.45-6.37 (m, 2H), 4.09 (m, 2H), 3.97 (m, 2H), 3.75-3.64 (m, 1H). ΉNMR (400 MHz, DMSCMO <5 13.04 (s, 1H), 8.368.25 (m, 2H), 8.04 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.5 Hz, 2H), 6.37 (dd, J = 12.6, 1.3 Hz, 1H), 6.31 (d, J = 1.5 Hz, 1H), 4.10–4.05 (m, 2H), 3.96–3.88 (m, 2H), 3.87 -3.75 (m, 1H), 3.61-3.52 (m, 4H), 3.49-3.43 (m, 2H), 3.43-3.38 (m, 2H). BCD-CDK81-9 406.3 Ή NMR (400 MHz, DMSO-<A) δ 8.11 (s, 1H), 7.55 (d, J= 8.6 Hz, 1H), 7.39 (d, J= 8.9 Hz, 2H), 6.90 (d, J= 9.0 Hz, 2H), 6.48 (dd, J = 8.6, 2.1 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 4.03 (t, 2H), 3.88 (t, 2H), 3.843.77 (m , 1H), 3.58–3.54 (m, 4H), 3.47–3.45 (m, 2H), 3.35–3.32 (m, 2H), 2.98 (s, 6H). BCD-CDK81-10 321.1 Ή NMR (400 MHz, DMSO-<A) δ 8.50 (s, 1H), 7.76 (d,J=8.4Hz, 1H), 7.69 1.1 Hz, 1H), 7.53 (dd, J= 8.4,1.4 Hz, 1H), 7.43 (d,J= 8.9 Hz, 2H), 6.92 (d, J- 9.0 Hz, 2H), 4.31 (m, 2H), 4.06 (m, 2H), 3.01 ( s, 6H), 2.34-2.22 (m, 2H). BCD-CDK81-11 338.2 Ή NMR (400 MHz, DMSO-^) δ 8.53 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.72 (s, 1H), 7.59-7.53 (m, 3H), 7.18 (d, J= 8.9 Hz, 2H), 4.45 (s, 1H), 4.28-4.20 (m, 2H), 4.09 (s, 1H), 3.88 (s, 4H), 3.24 (s, 3H). BCD-CDK81-12 393.2 Ή NMR (400 MHz, DMSO-A) <5 8.18 (s, 1H), 7.577.53 (m, 3H), 7.17 (d, J= 8.9 Hz, 2H), 6.49 (dd, J = 8.6,2.1 Hz , 1H), 6.40 (d, J = 2.0Hz, 1H), 4.O3 (t, 2H), 3.89 (t, 2H), 3.85 (s, 3H), 3.84–3.77 (m, 1H), 3.613. 53 (m, 4H), 3.49-3.43 (m, 2H), 3.34 (t, 2H). BCD-CDK81-13 424.3 Ή NMR (400 MHz, DMSO-dk) δ 8.01 (s, 1H), 7.35 (d, J= 8.9 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.24 (dd, J = 12.3, 1.3 Hz, 1H), 6.13 (d, J = 1.5 Hz, 1H), 4.073.98 (m, 2H), 3.94-3.86 (m, 2H), 3.85-3.74 (m, 1H), 3.62-3.54 (m , 4H), 3.51–3.43 (m, 2H), 3.37–3.30 (m, 2H), 3.02 (s, 6H). BCD-CDK81-14 447.2 Ή NMR (400 MHz, DMSCMO δ 13.03 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.79 (d,J= 8.4 Hz, 2H), 7.57 ( dd, J = 8.5, 2.1 Hz, 2H), 7.43 (d, J = 8.6 Hz, 1H), 6.60 (t, J= 8.4 Hz, 1H), 4.13 (t, 2H), 4.01 (t, 2H), 3.85-3.78 (m, 1H), 3.55 (s, 4H), 3.47-3.45 (m, 2H), 3.33 (s, 2H).

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BCD-CDK81-15E 354.2 Ή NMR (400 MHz, DMSO-20 δ 8.68 (s, 1H), 8.16 (d, J= 8.6 Hz, 2H), 7.84 (dd, J= 8.6,2.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.3, 6.0 Hz, 1H), 4.06–4.00 (m, 4H), 3.92 (s, 3H), 2.29–2.18 (m, 2H). BCD-CDK81-15A BCD-CDK81-15 BCD-CDK81-16 BCD-CDK81-17 BCD-CDK81-18 BCD-CDK81-19 340.2 339.1 386.2 443.4 358.2 461.2 Ή NMR (400 MHz, DMSO-20 δ 8.59 (s, 1H), 8.14 (d, J- 8.5 Hz, 2H), 7.76 (dd,.J- 8.5,2.5 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.3, 6.0 Hz, 1H), 4.08–4.03 (m, 4H), 2.32–2.24 (m, 2H). Ή NMR (400 MHz, DMSO-J5) δ 8.57 (s, 1H), 8.148.02 (m, 3H), 7.71 (dd, J= 8.5, 2.4 Hz, 2H), 7.63 (d, /= 8.4 Hz, 1H), 7.44 (s, 1H), 7.38-7.31 (m, 1H), 4.123.98 (m, 4H), 2.36-2.21 (m, 2H). Ή NMR (400 MHz, DMSO-20 δ 8.66 (s, 1H), 8.26 (s, 1H), 7.98 (d, J= 0.7 Hz, 1H), 7.83-7.81 (m, 3H), 7.68 (d, J = 8.6 Hz, 2H), 7.59 (d, J= 0.8 Hz, 1H), 7.32 (dd, J = 8.3, 1.4 Hz, 1H), 3.97 (s, 3H), 3.70-3.34 (m, 4H), 1.66 -1.41(m, 6H). Ή NMR (400 MHz, DMSO-/5) δ 8.26 (d, J = 13.7 Hz, 2H), 7.97 (s, 1H), 7.80 (d,/ = 8.5 Hz, 2H), 7.62 (d,/ = 8.5 Hz, 2H), 7.58 (d, J= 8.9 Hz, 1H), 6.54-6.48 (m, 2H), 4.09-4.02 (m, 2H), 3.95-3.88 (m, 5H), 3.86-3.76 (m, 1H), 3.61-3.53 (m, 4H), 3.49-3.44 (m, 2H). Ή NMR (400 MHz, DMSO-/5) δ 8.69 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.87-7.80 (m, 4H), 7.68 (d, J = 8.6 Hz , 2H), 7.58 (dd,/= 8.5,1.4 Hz, 1H), 4.39-4.27 (m, 2H), 4.12-4.00 (m, 2H), 3.91 (s, 3H), 2.33-2.21 (m, 2H ). Ή NMR (400 MHz, DMSO-O δ 8.30 (s, 1H), 8.25 (d,/= 0.7 Hz, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.80 (d, J= 8.6 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 6.36 (dd, J = 12.6, 1.8 Hz, 1H), 6.31 (d, J = 1.8 Hz, 1H), 4.094.01 (m, 2H), 3.96-3.90 (m, 2H), 3.90 (s, 3H), 3.873.76 (m, 1H), 3.61-3.50 (m, 4H), 3.49-3.40 (m, 2H), 3.36-3.30 (m, 2H ). BCD-CDK81-20 461.3 Ή NMR (400 MHz, DMSO-Zd) δ 8.23 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.607.54 (m, 2H), 7.43 (d,/=8.6 Hz, 1H), 6.6O (t,/= 8.4 Hz, 1H), 4.17-4.09 (m, 2H), 4.05-3.98 (m, 2H), 3.90 (s, 3H), 3.86-3.77 (m, 1H), 3.60-3.53 (m, 4H), 3.493.43 (m, 2H), 3.36 - 3.32 (m, 2H). BCD-CDK81-21A 467.1 Ή NMR (400 MHz, DMSO-/,) δ 13.17 (s, 1H), 10.10 (s, 1H), 8.32 (s, 1H), 8.12 (d,/ = 8.5 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.56 (d, / = 7.6 Hz, 2H), 7.27 (t, / = 7.9 Hz, 2H), 7.04 (t, / = 7.4 Hz, 1H), 6.62 (s, 1H), 6.56 (d, /= 13.3 Hz, 1H), 6.17 (t, /= 5.7 Hz, 1H), 3.923.74 (m, 2H), 3.53-3.40 (m, 1H), 3.28 (s, 1H), 3.183 .06(m, 1H). BCD-CDK81-21 466.2 Ή NMR (400 MHz, DMSO-O δ 10.10 (s, 1H), 8.30 (s, 1H), 8.11-8.09 (m,/= 8.6 Hz, 3H), 7.74 (d,/= 8.6 Hz, 2H), 7.61-7.55 (m, 2H), 7.49 (s, 1H), 7.32-7.25 (m, 2H), 7.05 (t,/= 7.4 Hz, 1H), 6.61 (d,/ = 1.7 Hz, 1H), 6.57 (dd, / = 13.3, 1.6 Hz, 1H), 6.15 (m, 1H), 3.93–3.81 (m, 2H), 3.52–3.41 (m, 1H), 3.29 (s, 1H), 3.20–3.08 (m , 1H). BCD-CDK83-1 441.1 Ή NMR (400 MHz, DMSO-/0 δ 9.49 (s, 1H), 9.19 (m, 1H), 8.69 (s, 1H), 8.31 (dd, /= 6.0, 1.1 Hz, 1H), 8.15 (d, /= 8.2 Hz, 2H), 7.57 (dd,/= 8.2, 3.0 Hz, 2H), 5.09, 5.02 (2d, /= 3.8 Hz, 1H, rotamers), 4.33, 4.25 (2s, 1H, rotamers), 3.23 -3.59 (m, 4H), 2.91 (s, 3H), 1.83-1.99 (m, 2H). BCD-CDK83-2 386.1 Ή NMR (400 MHz, DMSO-/0 δ 13.03 (s, 1H), 9.48 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.36 (d,/= 2.9 Hz, 1H) , 8.32 (s, 1H), 8.05 (s, 1H), 7.85 (d, / = 7.4 Hz, 2H), 7.59 (dd, / = 8.0, 2.1 Hz, 2H), 5.01 (dd, /= 28.6, 3.6 Hz, 1H), 4.40-4.18 (m, 1H), 3.68-3.14 (m, 4H), 2.06-1.66 (m, 2H). BCD-CDK83-3 363.1 Ή NMR (400 MHz, DMSO-J ₆ ) δ 9.40 (s, 1H), 9.17 (t, 1H), 8.61 (s, 1H), 8.38 (m, 1H), 7.43 (m, 2H), 6.93 (d ,/ = 8.8 Hz, 2H), 5.01 (dd,/= 32.7, 3.7 Hz, 1H),

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4.30 (d,/=36.4 Hz, 1H), 3.67-3.20 (m, 4H), 3.01 (s, 6H), 2.01-1.76 (d, 2H). BCD-CDK83-4 400.1 Ή NMR (400 MHz, DMSCMO δ 9.46 (s, 1H), 9.17 (t,/=2.1 Hz, 1H), 8.67 (s, 1H), 8.36 (d,/= 4.3 Hz, 1H), 8.22 (d, /= 2.1 Hz, 1H), 7.93 (d,/ = 1.2 Hz, 1H), 7.78 (d,/= 7.3 Hz, 2H), 7.57 (dd,/= 8.2,2.2 Hz, 2H), 5.00 (dd, /= 25.8, 3.7 Hz, 1H), 4.40-4.21 (m, 1H), 3.91 (s, 3H), 3.67-3.40 (m, 4H), 2.04-1.73 (m, 2H). BCD-CDK83-5 405.1 'H NMR (400 MHz, DMSO-J5) δ 9.41 (s, 1H), 9.16 (s, 1H), 8.61 (s, 1H), 8.36 (s, 1H), 7.46 (d,/= 7.5 Hz, 2H ), 7.16 (d, /= 8.5 Hz, 2H), 5.13-4.88 (br d, 1H), 4.32 (m, 1H), 3.80 (m, 4H), 3.68-3.38 (m, 5H), 3.26 (m , 4H), 2.04–1.79 (m, 2H). BCD-CDK83-6 350.1 'H NMR (400 MHz, DMSO-/0 δ 9.46 (s, 1H), 9.19 (t, 1H), 8.66 (s, 1H), 8.31 (m, 1H), 7.55 (m, 2H), 7.18 (d , / = 8.4 Hz, 2H), 5.05, 4.97 (2d, / = 3.8 Hz, 1H, rotamers), 4.35, 4.25 (2s, 1H, rotamers), 3.87 (s, 3H), 3.65–3.19 (m, 4H ), 2.03–1.75 (m, 2H). BCD-CDK83-8 376.2 Ή NMR (400 MHz, DMSO-/0 δ 9.39 (s, 1H), 9.07 (d,/= 1.9 Hz, 1H), 8.61 (s, 1H), 8.28 (d,/= 1.3 Hz, 1H), 7.43 (d,/= 8.7 Hz, 2H), 6.93 (d,/ = 8.8 Hz, 2H), 3.66 (m, 2H), 3.40 (m, 2H), 3.01 (s, 6H), 2.39 (m, 2H) , 2.29 (m, 2H), 2.20 (s, 3H). BCD-CDK83-9 455.2 'H NMR (400 MHz, DMSO-J5) δ 9.11 (s, 1H), 8.53 (d,/= 2.7 Hz, 1H), 8.33 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H ), 7.75 (d,/= 8.3 Hz, 2H), 7.54 (d,/= 8.3 Hz, 2H), 6.80 (d,/= 2.4 Hz, 1H), 4.30-4.21 (m, 2H), 4.20-4.12 (m, 2H), 3.96-3.86 (m, 1H), 3.90 (s, 3H), 3.60-3.52 (m, 4H), 3.51-3.44 (m, 2H), 3.36-3.27 (m, 2H). BCD-CDK83-11 439.2 Ή NMR (400 MHz, DMSO-/0 δ 12.30 (s, 1H), 9.53 (s, 1H), 9.12 (d,/= 1.8 Hz, 2H), 8.71 (s, 1H), 8.128.20 (m, 3H), 7.77 (d, /= 8.2 Hz, 2H), 3.61 (s, 2H), 3.41 (s, 3H), 3.35 (2H in H ₂ O signal), 1.61 (d, / = 3.9 Hz, 4H) , 1.47 (d,/= 1.7 Hz, 2H). BCD-CDK83-12 454.1 'H NMR (400 MHz, DMSO-/0 δ 13.12-11.51 (br s, 1H), 9.19 (s, 1H), 8.58 (d, /= 2.6 Hz, 1H), 8.37 (s, 1H), 8.13 ( d,/= 8.4 Hz, 2H), 7.73 (d,/= 8.4 Hz, 2H), 6.68 (d,/= 2.4 Hz, 1H), 4.33-4.23 (m, 2H), 4.21-4.11 (m, 2H ), 3.98-3.86 (m, 1H), 3.41 (s, 3H), 2.89 (s, 3H), 2.85 (s, 3H). BCD-CDK83-13 441.2 'H NMR (400 MHz, DMSO-/0 δ 12.25 (br s, 1H), 9.49 (s, 1H), 9.22 - 9.14 (m, 1H), 8.69 (s, 1H), 8.298.24 (m, 1H ), 8.18 (d,/= 7.8 Hz, 2H), 7.79-7.71 (m, 2H), 4.40-4.32,4.30-4.23 (2m, 1H, rotamers), 3.633.16 (m, 4H), 3.40 (s , 3H), 2.05–1.77 (m, 2H). BCD-CDK83-14 370.2 Ή NMR (400 MHz, DMSO-J ₆ ) δ 9.49 (d, / = 0.6 Hz, 1H), 9.26 (d, / = 2.0 Hz, 1H), 8.71 (s, 1H), 8.44 (d, / = 1.9 Hz, 1H), 8.28 (s, 1H), 8.00 (d,/= 0.5 Hz, 1H), 7.81 (d,/= 8.3 Hz, 2H), 7.60 (d,/= 8.3 Hz, 2H), 4.364. 32 (m, 2H), 4.12-4.08 (m, 2H), 3.92 (s, 3H), 2.332.26 (m, 2H). BCD-CDK83-15 400.2 Ή NMR (400 MHz, DMSO-/,) δ 9.49 (s, 1H), 9.27 (d,/ = 1.8 Hz, 1H), 8.71 (s, 1H), 8.46 (d,/= 0.9 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.81 (d, /= 8.1 Hz, 2H), 7.61 (d, / = 8.1 Hz, 2H), 4.50-4.48 (m, 1H), 4.33-4.23 (m, 2H), 4.20-4.18 (m, 1H), 3.95-3.87 (m, 4H), 3.22 (s, 3H). BCD-CDK83-16 384.2 Ή NMR (400 MHz, DMSO-J ₆ ) δ 9.48 (s, 1H), 9.21 (s, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.98 (s , 1H), 7.87-7.72 (m, 2H), 7.69-7.50 (m, 2H), 3.91 (s, 3H), 3.30-3.36 (m, 4H), 2.00-1.73 (m, 4H). BCD-CDK83-17 370.1 'H NMR (400 MHz, DMSO-/0 δ 9.44 (d, /= 2.5 Hz, 1H), 9.35 (d, / = 0.8 Hz, 1H), 8.58 (dd, / = 2.5, 0.8 Hz, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 7.99 (d,/= 0.8 Hz, 1H), 7.78 (d,/= 8.5 Hz, 2H), 7.58 (d,/= 8.4 Hz, 2H), 4.00 (t, /= 7.0 Hz, 2H), 3.91 (s, 3H), 2.55 (t, /= 8.1 Hz, 2H), 2.18-2.06 (m, 2H). BCD-CDK83-18 388.2 Ή NMR (400 MHz, DMSO-J5) δ 9.51 (s, 1H), 9.46 (d,/= 1.7 Hz, 1H), 9.11 (br s, 1H), 8.73 (s, 1H), 8.70

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(s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.81 (d, J= 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 4.84-4.25 (m, 4H), 3.92 (s, 3H), 3.27 (s, 3H). BCD-CDK83-19 BCD-CDK83-20 BCD-CDK83-21 BCD-CDK83-22 BCD-CDK83-23 BCD-CDK83-24 BCD-CDK83-25 BCD-CDK83-26 BCD-CDK83-27 414.2 414.2 428.3 358.2 386.3 403.2 402.2 385.2 415.2 Ή NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H) , 7.84-7.74 (m, 2H), 7.65-7.55 (m, 2H), 4.083.93 (m, 1H), 3.91 (s, 3H), 3.66-3.41 (m, 4H), 3.26 (s, 1.5H ), 3.16 (s, 1.5H), 2.05–1.89 (m, 2H). Ή NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.10-9.04 (m, 1H), 8.68 (s, 1H), 8.34-8.20 (m, 2H), 7.98 (s, 1H), 7.84- 7.76 (m, 2H), 7.63-7.54 (m, 2H), 4.05-3.92 (m, 1H), 3.91 (s, 3H), 3.55-3.15 (m, 4H), 3.31 (in H ₂ O.3H signal ), 1.89–1.30 (s,4H). *H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.12 (d, J= 2.0 Hz, 1H), 8.69 (s, 1H), 8.30 - 8.28 (m, 1H), 8.26 (s, 1H ), 7.98 (s, 1H), 7.80 (d, J= 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 3.91 (s, 3H), 3.02 (s, 3H), 2.97 (s , 3H). Ή NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.09 (d, J = 2.0 Hz, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.21 (d, J = 1.1 Hz , 1H), 7.99-7.97 (m, 1H), 7.79 (d, J= 8.3 Hz, 2H), 7.59 (d, J= 8.3 Hz, 2H), 3.91 (s, 3H), 3.48-3.46 (m, 2H), 3.26-3.25 (m, 2H), 1.19-1.14 (m, 3H), 1.ΙΟΙ.06 (m, 3H). Ή NMR (400 MHz, DMSO) δ 9.24 (d, J = 1.7 Hz, 1H), 9.2 - 9.12 (m, 1H), 8.54 (d, J= 1.8 Hz, 1H), 8.23 (s, 1H), 7.93 (s, 2H), 7.71 (d, J= 8.1 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 7.22 - 7.11 (m, 2H), 3.90 (s, 3H), 3.50 -3.41 ( m, 4H), 3.26 (s, 3H). Ή NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 9.13–9.01 (m, 1H), 8.68 (s, 1H), 8.35–8.26 (m, 2H), 7.98 (s, 1H), 7.80 ( d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 3.91 (s, 3H), 3.61-3.54 (m, 4H), 3.38 (s, 3H), 3.01 (m, 4H ). Ή NMR (400 MHz, DMSO) δ 8.99 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.94 (s , 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.17 (br s, 2H), 4.33 (t, J= 7.6 Hz, 2H), 4.08 ( t, J= 7.7 Hz, 2H), 3.90 (s, 3H), 2.35-2.23 (m, 2H). Ή NMR (400 MHz, DMSO) δ 8.86 (d, J = 1.7 Hz, 1H), 8.21 (s, 1H), 8.16-8.10 (m, 1H), 7.95 (s, 1H), 7.93 (s, 1H) , 7.71 (d,J= 8.1 Hz, 2H), 7.46 (d,J=8.1 Hz, 2H), 7.20 (br s, 2H), 3.90 (s, 3H), 3.75-3.36 (m, 8H). BCD-CDK83-28 389.2 Ή NMR (400 MHz, DMSO) δ 9.56 (d, J = 0.7 Hz, 1H), 9.49 (d, J= 2.0 Hz, 1H), 8.85-8.82 (m, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 8.01 (d,J= 0.7 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H), 4.51-4.46 (m, 2H) , 3.92 (s, 3H), 3.77–3.66 (m, 2H), 3.30 (s, 3H). BCD-CDK83-29 404.2 Ή NMR (400 MHz, DMSO) δ 9.22 (d, J = 1.9 Hz, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.95 (s , 1H), 7.72 (d, J= 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.25 (s, 2H), 4.48-4.44 (m, 2H), 3.90 (s, 3H) , 3.69-3.65 (m, 2H), 3.29 (s, 3H). BCD-CDK83-30 207.2 [M+2H] ⁺ /2,413.3 Ή NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.11 (d, J= 1.9 Hz, 1H), 8.70 (s, 1H), 8.29-8.24 (m, 2H), 7.98 (s, 1H) , 7.80 (d, J = 8.2 Hz, 2H), 7.60 (d,J= 8.2 Hz, 2H), 3.91 (s, 3H), 3.75-3.6 (m, 2H), 3.5-3.3 (m, 2H), 2.45-2.20 (m, 4H), 2.20 (s, 3H). BCD-CDK83-31 214.6 [M+2H] ⁺ /2, 428.2 Ή NMR (400 MHz, DMSO) δ 8.83 (d, J = 1.5 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.70 (d, 8.0 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.16 (br s, 2H), 3.90 (s, 3H), 3.75–3.55 (m, 2H), 3.513.40 (m, 2H), 2.43–2.25 (m, 4H), 2.12 (s, 3H). BCD-CDK83-32 417.3 Ή NMR (400 MHz, DMSO, 80 °C) δ 8.81 (d, J = 1.9 Hz, 1H), 8.11 (s, 1H), 8.10 (d, J= 1.8 Hz, 1H), 7.95 (s, 1H) , 7.87 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 6.88 (br s, 2H), 3.91 (s, 3H), 3.613.39 (m, 4H), 3.18 (brs, 3H), 3.01 (s, 3H). BCD-CDK83-33 400.3 Ή NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.13 (d, J= 1.9 Hz, 1H), 8.70 (s, 1H), 8.34-8.30 (m, 1H), 8.27 (s, 1H) , 7.99 (s, 1H), 7.80 (d,J= 8.2 Hz, 2H), 7.60 (d, J= 8.2 Hz, 2H), 3.91 (s, 3H), 3.74-3.36 (m, 8H). BCD-CDK83-34 415.2 Ή NMR (400 MHz, DMSO) δ 8.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.94 (s , 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.18 (s, 2H), 4.52–4.42 (m, 1H), 4.324.20 (m, 2H), 4.19-4.10 (m, 1H), 3.90 (s, 3H), 3.903.85 (m, 1H), 3.22 (s, 3H).

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BCD-CDK83-35 415.3 Ή NMR (400 MHz, DMSO, 80 °C) δ 9.46 (s, 1H), 9.12-9.02 (m, 1H), 8.67 (s, 1H), 8.30-8.22 (m, 1H), 8.17 (s, 1H ), 7.91 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 3.92 (s, 3H), 3.47-3.25 (m, 2H), 3.00 (s, 3H), 2.50–2.35 (m, 2H), 2.05 (brs, 6H). BCD-CDK83-37 370.2 385.2 Ή NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 9.41 (d, /= 2.0 Hz, 1H), 8.97 (d, /=3.8Hz, 1H), 8.69 (s, 2H), 8.28 (s , 1H), 8.00 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H), 2.91-2.86 (m, 1H) , 0.75-0.72 (m, 2H), 0.61-0.59 (m, 2H). Ή NMR (400 MHz, DMSO) δ 9.14 (d, J = 1.8 Hz, 1H), 8.88 (d, J= 3.9 Hz, 1H), 8.51 (d, J= 1.9 Hz, 1H), 8.22 (s, 1H ), 7.96-7.92 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.15 (s, 2H), 3.91 (s, 3H), 2.89 -2.85 (m, 1H), 0.74-0.72 (m, 2H), 0.6ΙΟ. 59(m, 2H). Ή NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 9.46 (d, J =2.0 Hz, 1H), 9.10 (t, J =5.5 Hz, 1H), 8.72 (d,J = 1.2 Hz, 1H ), 8.69 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 3.92 (s , 3H), 3.21–3.17 (m, 2H), 1.08–1.01 (m, 1H), 0.470.43 (m, 2H), 0.26–0.22 (m, 2H). Ή NMR (400 MHz, DMSO) δ 9.19 (d, J = 1.8 Hz, 1H), 9.00 (t, J= 5.5 Hz, 1H), 8.55 (d, J= 1.9 Hz, 1H), 8.21 (s, 1H ), 7.97-7.91 (m, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.16 (s, 2H), 3.90 (s, 3H), 3.18 (t, J = 6.2 Hz, 2H), 1.04–1.02 (m, 1H), 0.460.43 (m, 2H), 0.25–0.23 (m, 2H). Ή NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.46 (d, J= 2.0 Hz, 1H), 9.12-9.03 (m, 1H), 8.72 (s, 1H), 8.69 BCD-CDK83-38 BCD-CDK83-39 BCD-CDK83-40 BCD-CDK83-41 384.2 399.3 374.2 (d,J = 1.1 Hz, 1H), 8.43 (s, 1H), 8.03–7.86 (m, 3H), 7.79 (d,/= 8.5 Hz, 2H), 7.18 (s, 1H), 3.52–3.42 ( m, 4H), 3.27 (s, 3H). Ή NMR (400 MHz, DMSO) δ 9.19 (d, J = 1.9 Hz, 2H), 8.90 (t,/= 5.5 Hz, 1H), 8.54 (d,/= 1.9 Hz, 2H), BCD-CDK8- 389.2 8.21 (s, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 3-42 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.19 (s, 2H), 4.80-4.75 (m, 1H), 3.89 (s, 3H), 3.56-3.50 (m, 2H), 3.41-3.35 (m, 2H). BCD-CDK8- 359.1 Ή NMR (400 MHz, DMSO-D) δ 12.68 (s, 1H), 9.31 4-1 (s, 1H), 9.00 (s, 1H), 8.80-8.76 (m, 2H), 8.58 (d,J = 2.2 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.67 (ddd, J = 6.8 , 4.8, 2.0 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.13 (dd,/ = 8.1, 2.0 Hz, 1H). 6.97 (d, J = 8.1 Hz, 1H), 2.75 (s, 6H). Ή NMR (400 MHz, DMSO-D) δ 12.69 - 12.59 (m, 1H), 8.97 (d,/=3.0Hz, 1H), 8.80 (dt,/ = 4.7,1.3 Hz, BCD-CDK8- 193.6 1H), 8.65 (d, J= 2.2 Hz, 1H), 8.33 (d, J= 2.2 Hz, 1H), 4-2 386.1 8.09 - 8.05 (m, 2H), 7.69 - 7.64 (m, 1H), 7.63 (s, 1H), 7.31 (d, J= 8.5 Hz, 1H), 7.26 (s, 1H), 6.94 (dd, J = 8.5,2.6 Hz, 1H), 6.88 (d,/= 2.5 Hz, 1H), 3.O1 (s, 6H). Ή NMR (400 MHz, DMSO-D) δ 12.69 (s, 1H), 9.36 BCD-CDK8- (s, 1H), 9.00 (s, 1H), 8.81 (s, 1H), 8.80 (s, 1H), 8.59 4-3 401.2 (d, J = 2.2 Hz, 1H), 8.11-8.04 (m, 2H), 7.20 (d, J = 2.1 Hz, 1H), 7.16 (dd,/=8.1, 2.1 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 3.82–3.72 (m, 4H), 3.08–2.96 (m, 4H). Ή NMR (400 MHz, DMSO-D) δ 12.68 (s, 1H), 8.99 BCD-CDK8- 187.1 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 8.15- 4-4 373.1 8.03 (m, 2H), 7.78 7.62 (m, 2H), 7.47 7.29 (m, 2H), 7.18-7.02 (m, 2H), 3.86 (s, 3H). Ή NMR (400 MHz, DMSO-D) δ 12.78 (s, 1H), 9.31 (s, 1H), 9.00 (dd, J = 2.3, 0.8 Hz, 1H), 8.82 (dd, J = BCD-CDK8- 180.1 4.8, 1.7 Hz, 1H), 8.67 (d,/=2.3 Hz, 1H), 8.60 (d,/ = 4-5 359.1 2.3 Hz, 1H), 8.27-8.16 (m, 2H), 7.60 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 7.18-7.09 (m, 2H), 6.97 (d,/= 8.1 Hz, 1H ), 2.75 (s, 6H). Ή NMR (400 MHz, DMSO-D) δ 12.73 (s, 1H), 8.98 (d,/= 1.6 Hz, 1H), 8.81 (dd,/= 4.8,1.6 Hz, 1H), 8.51 BCD-CDK8- 193.6 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.22- 4-6 386.1 8.17 (m, 2H), 7.65-7.57 (m, 2H), 7.28 (d, / = 8.5 Hz, 1H), 7.25 (s, 1H), 6.89 (dd, /= 8.6, 2.7 Hz, 1H), 6.83 (d,/= 2.7 Hz, 1H), 2.99 (s, 6H). 201.1 ΉNMR (400 MHz, DMSO-D) δ 12.85 (d, J= 2.4 Hz, BCD-CDK8- 1H), 9.05 (d,/ = 1.6 Hz, 1H), 8.86 (dd,/=4.9, 1.6 4-7 401.1 Hz, 1H), 8.69 (d,/= 2.2 Hz, 1H), 8.63 (d,/= 2.2 Hz, 1H), 8.32 (dt,/= 7.9,1.8 Hz, 1H), 8.27 (d,/= 3.0 Hz,

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1H), 7.69 (dd, J= 8.0, 5.2 Hz, 1H), 7.26-7.18 (m, 2H), 7.16-7.08 (m, 1H), 3.87-3.77 (m, 4H), 3.23-3.05 (m, 4H). Ή NMR (400 MHz, DMSO-0) δ 12.79 (s, 1H), 8.98 (d,/= 1.6 Hz, 1H), 8.81 (dd,/=4.8,1.5 Hz, 1H), 8.54 BCD-CDK84-8 373.2 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.248.18 (m, 2H), 7.71 (s, 1H), 7.60 (dd,/= 7.7, 4.9 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 7.12 (dd, J = 8.5, 2.7 Hz, 1H), 7.07 (d, J= 2.6 Hz, 1H), 3.86 ( s, 3H). Ή NMR (400 MHz, DMSO-0) δ 13.51-11.76 (br s, BCD-CDK84-9 180.2 359.3 1H), 9.32 (s, 1H), 8.81 (dd, /=4.3, 1.6 Hz, 2H), 8.66 (d, / = 2.2 Hz, 1H), 8.61 (d, / = 2.2 Hz, 1H), 8.20 ( s, 1H), 7.74 (dd,/= 4.4,1.6 Hz, 2H), 7.18–7.09 (m, 2H), 6.67 (d,/ = 8.0 Hz, 1H), 2.75 (s, 6H). Ή NMR (400 MHz, DMSO-/6) δ 12.79 (d, / = 2.6 Hz, 1H), 8.81 (d, / = 5.9 Hz, 2H), 8.51 (d, / = 2.1 Hz, BCD-CDK8- 386.1 1H), 8.34 (d,/= 2.2 Hz, 1H), 8.17 (d,/= 3.2 Hz, 1H), 4-10 7.73 (d,/= 6.0 Hz, 2H), 7.62 (s, 1H), 7.28 (d,/= 8.5 Hz, 1H), 7.25 (s, 1H), 6.89 (dd,/= 8.6, 2.7 Hz, 1H ), 6.83 (d, /= 2.7 Hz, 1H), 2.99 (s, 6H). Ή NMR (400 MHz, DMSO-0) δ 12.84 (s, 1H), 9.37 BCD-CDK84-11 201.0 401.1 (s, 1H), 8.83-8.77 (m, 2H), 8.68 (d, /= 2.2 Hz, 1H), 8.62 (d, /= 2.2 Hz, 1H), 8.21 (s, 1H), 7.77-7.70 ( m, 2H), 7.21-7.13 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 3.81-3.71 (m, 4H), 3.06-2.99 (m, 4H). Ή NMR (400 MHz, DMSO-0) δ 8.80 (d,/ = 5.7 Hz, BCD-CDK84-12 373.1 2H), 8.53 (d, /= 2.2 Hz, 1H), 8.36 (d, /= 2.2 Hz, 1H), 8.19 (s, 1H), 7.76-7.68 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (s, 2H), 7.12 (dd, /= 8.5, 2.7 Hz, 1H), 7.07 (d, /= 2.7 Hz, 1H), 3.86 (s, 3H). Ή NMR (400 MHz, DMSO-0) δ 12.67 (s, 1H), 8.53 BCD-CDK8- 402.1 (d,/= 2.1 Hz, 1H), 8.34 (d,/= 2.0 Hz, 1H), 8.13 (d, 4-13 /= 3.0 Hz, 1H), 7.72 (s, 1H), 7.52-7.44 (m, 1H), 7.437.37 (m, 2H), 7.34 (s, 1H), 7.33-7.30 (m, 1H), 7.20 (dd, J = 8.0, 2.3 Hz, 1H), 7.12 (dd, J = 8.5, 2.7 Hz, 1H), 7.06 (d,/ = 2.7 Hz, 1H), 3.85 (2s, 6H). Ή NMR (400 MHz, DMSO-0) δ 12.72 (s, 1H), 9.01 BCD-CDK84-21 187.1 373.1 (s, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.81 (d, / = 4.7 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.12-8.03 (m, 2H) , 7.70-7.64 (m, 1H), 7.27-7.21 (m, 2H), 7.00 (d,/= 7.9 Hz, 1H), 3.93 (s, 3H), 2.76 (s, 6H). Ή NMR (400 MHz, DMSO-/ ₆ ) δ 12.69 (s, 1H), 9.05 (d, /=3.1 Hz, 1H), 8.82-8.74 (m, 2H), 8.44 (d, J = BCD-CDK8- 368.1 2.3 Hz, 1H), 8.09 (dt, /=8.0, 1.2 Hz, 1H), 8.03 (td, / 4-22 = 7.6,1.7 Hz, 1H), 7.63 (ddd,/=7.5,4.7,1.4 Hz, 1H), 7.49 (d,/= 8.5 Hz, 1H), 7.17-7.08 (m, 2H), 3.06 (s, 6H). Ή NMR (400 MHz, DMSO-0) δ 12.62 (s, 1H), 9.01 (d,/ = 3.1 Hz, 1H), 8.83 (d,/= 2.2 Hz, 1H), 8.79 (d, BCD-CDK8- 415.2 /= 4.5 Hz, 1H), 8.61 (d,/= 2.1 Hz, 1H), 8.09 (d,/ = 4-23 7.7 Hz, 1H), 8.04 (td, / = 7.6, 1.6 Hz, 1H), 7.69-7.60 (m, 1H), 7.28-7.19 (m, 2H), 7.01 (d, / = 8.7 Hz, 1H), 3.95 (s, 3H), 3.82-3.74 (m, 4H), 3.09-3.01 (m, 4H). Ή NMR (400 MHz, DMSO-0) δ 12.87 (s, 1H), 9.08 BCD-CDK84-24 355.0 (d, /=3.1 Hz, 1H), 8.85-8.78 (m, 2H), 8.52 (d, J = 2.1 Hz, 1H), 8.12-8.03 (m, 2H), 7.71-7.65 (m, 2H), 7.61 (d,/= 2.7 Hz, 1H), 7.43 (dd,/= 8.7,2.7 Hz, 1H), 3.90 (s, 3H). ΉNMR (400 MHz, DMSO-/ ₆ ) δ 12.80 (s, 1H), 9.04- BCD-CDK84-25 187.1 373.1 8.94 (m, 1H), 8.82 (dd, /=4.8,1.7 Hz, 1H), 8.73-8.65 (m, 2H), 8.27-8.19 (m, 2H), 7.61 (ddd, /= 7.8, 4.9, 0.9 Hz, 1H), 7.28–7.17 (m, 2H), 7.00 (d,/ = 8.0 Hz, 1H), 3.93 (s, 3H), 2.76 (s, 6H). Ή NMR (400 MHz, DMSO-0) δ 12.91 (s, 1H), 9.01 (d,/= 1.5 Hz, 1H), 8.82 (dd,/=4.8,1.6 Hz, 1H), 8.65 BCD-CDK8- 368.2 (d,/= 2.2 Hz, 1H), 8.51 (d,/= 2.2 Hz, 1H), 8.30 (s, 4-26 1H), 8.26 - 8.20 (m, 1H), 7.61 (ddd,/= 7.9, 4.9, 0.6 Hz, 1H), 7.52 (d,/= 8.7 Hz, 1H), 7.22 (d,/= 2.7 Hz, 1H ), 7.16 (dd, /= 8.8, 2.8 Hz, 1H), 3.02 (s, 6H).

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BCD-CDK84-27 415.1 Ή NMR (400 MHz, DMSCMO δ 12.83 (s, 1H), 9.00 (d, J= 1.7 Hz, 1H), 8.82 (dd, J=4.8,1.4 Hz, 1H), 8.70 (dd, J = 4.2,2.1 Hz, 2H), 8.29-8.17 (m, 2H), 7.61 (dd, J = 7.8, 4.9 Hz, 1H), 7.30-7.22 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.79–3.73 (m, 4H), 3.06–2.99 (m, 4H). BCD-CDK84-28 355.1 ΉNMR (400 MHz, DMSCMO (5 12.97 (d, J = 2.3 Hz, 1H), 9.01 (d, J = 1.8 Hz, 1H), 8.82 (dd, J =4.8, 1.5 Hz, 1H), 8.68 (d, J= 2.2 Hz, 1H), 8.55 (d, J= 2.2 Hz, 1H), 8.34 (d, J= 3.1 Hz, 1H), 8.24 (dt,J=7.8,1.8 Hz, 1H), 7.67 (d, J= 8.7 Hz, 1H), 7.64-7.58 (m, 2H), 7.42 (dd, J = 8.7, 2.7 Hz, 1H), 3.90 (s, 3H). BCD-CDK84-29 187.1 373.1 Ή NMR (400 MHz, DMSCMO δ 12.85 (s, 1H), 8.81 (d, J = 3.3 Hz, 2H), 8.74-8.64 (m, 2H), 8.21 (s, 1H), 7.74 (d, J = 3.0 Hz, 2H), 7.30-7.18 (m, 2H), 7.00 (d, J= 7.5 Hz, 1H), 3.93 (s, 3H), 2.76 (s, 6H). BCD-CDK84-30 368.2 Ή NMR (400 MHz, DMSO-O δ 13.00 (s, 1H), 8.85 (d, J = 5.6 Hz, 2H), 8.64 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 22 Hz, 1H), 8.28 (d, J = 3.1 Hz, 1H), 7.83 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H) , 7.15 (dd, J= 8.8, 2.8 Hz, 1H), 3.02 (s, 6H). BCD-CDK84-31 415.3 Ή NMR (400 MHz, DMSCMO δ 12.91 (s, 1H), 8.85 (d, J = 5.9 Hz, 2H), 8.70 (s, 2H), 8.21 (d, J = 2.7 Hz, 1H), 7.85–7.80 ( m, 2H), 7.31-7.22 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.82-3.74 (s, 4H), 3.113.03 (d, J = 9.8Hz, 4H). BCD-CDK84-32 355.2 Ή NMR (400 MHz, DMSCMO δ 13.02 (s, 1H), 8.80 (dd, J = 4.4,1.5 Hz, 2H), 8.67 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.30 (s, 1H), 7.74 (dd,J = 4.5, 1.5 Hz, 2H), 7.66 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.42 ( dd, J = 8.7, 2.7 Hz, 1H), 3.89 (s, 3H). BCD-CDK84-33 330.1 Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 8.83 - 8.78 (m, 2H), 8.69 (d, J = 22 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H ), 8.22 (d, J = 3.1 Hz, 1H), 7.74 (dd, J = BCD-CDK84-34 BCD-CDK84-35 BCD-CDK84-36 BCD-CDK84-37 BCD-CDK84-38 BCD-CDK84-39 372.2 384.1 385.3 385.2 385.3 343.2 4.5, 1.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H). Ή NMR (400 MHz, DMSCMO δ 12.68 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.14 (s, 1H), 7.64 (d, J= 8.1 Hz, 2H), 7.49 ( t, J= 7.8 Hz, 1H), 7.42 (d, J= 7.3 Hz, 1H), 7.33 (s, 1H), 7.21 (d, J =1.6 Hz, 1H), 7.02 (d, J=1A Hz, 2H), 3.85 (s, 3H), 3.01 (s, 6H). Ή NMR (400 MHz, DMSCMO δ 12.86 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), δ 7.61 (d, J = 1.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.46-7.40 (m, J= 8.0 Hz, 2H), 7.34 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H). Ή NMR (400 MHz, DMSO) δ 12.60 (br s, 1H), 9.00 (s, 1H), 8.83–8.77 (m, 2H), 8.63 (d, J = 2.2 Hz, 1H), 8.12–8.05 (m , 2H), 7.71-7.62 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 3.85-3.70 (m, 4H), 3.23-3.14 (m, 4H). Ή NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 9.00 (d, J = 1.7 Hz, 1H), 8.82 (dd, J =4.8, 1.6 Hz, 1H), 8.69 (d, J = 2.2 Hz , 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.258.19 (m, 2H), 7.67-7.57 (m, 3H), 7.10 (d, J= 8.8 Hz, 2H), 3.84-3.72 ( m, 4H), 3.23-3.14 (m, 4H). Ή NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.848.76 (m, 2H), 8.67 (d, J = 9.4 Hz, 2H), 8.20 (s, 1H), 7.80-7.70 (m, 2H), 7.63 (d, J= 7.0 Hz, 2H), 7.10 (d, J = 12 Hz, 2H), 3.85-3.70 (m, 4H), 3.25-3.13 (m, 4H). Ή NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.99 (d, J = 1.5 Hz, 1H), 8.81 (dd, J =4.8, 1.6 Hz, 1H), 8.65 (dd, J = 12.0, 2.3 Hz, 2H), 8.23-8.18 (m, 2H), 7.637.55 (m, 3H), 6.87 (d, J= 8.9 Hz, 2H), 2.97 (s, 6H). BCD-CDK84-40 343.2 Ή NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.838.78 (m, 2H), 8.66 (d, J= 2.3 Hz, 1H), 8.64 (d, J= 2.3

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Hz, 1H), 8.18 (s, 1H), 7.76-7.71 (m, 2H), 7.58 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.9 Hz, 2H), 2.97 (s, 6H ). Ή NMR (400 MHz, DMSO-/0 δ 12.24 (br s, 1H), 8.99 (d, J = 4.3 Hz, 1H), 8.26–8.20 (m, 2H), 8.12 (d, BCD-CDK8- 438.2 J= 8.4 Hz, 2H), 8.00 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 5-1 7.53 (d, J = 4.3 Hz, 1H), 3.87-3.73 (m, 2H), 3.38 (s, 3H), 3.19-3.3.05 (m, 2H), 1.75-1.55 (m, 4H), 1.541. 22(m, 2H). Ή NMR (400 MHz, DMSO-V> δ 12.25 (s, 1H), 8.28 (dd, J= 8.8,2.0 Hz, 1H), 8.15 (d, J= 8.8 Hz, 1H), 8.11 BCD-CDK8- 472.1 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 1.8 Hz, 1H), 7.90 (d, 5-1C1 J= 8.4 Hz, 2H), 7.69 (s, 1H), 3.86-3.70 (m, 2H), 3.33 (s, 3H, in H ₂ 0 signal), 3.22-3.11 (m, 2H), 1.73-1.58 ( m, 4H), 1.56-1.24 (m, 2H). ^J H NMR (400 MHz, DMS0-/O δ 8.86 (d, J = 4.3 Hz, BCD-CDK8- 1H), 8.08 (s, 2H), 7.89 (s, 1H), 7.63 (d, J = 7.4 Hz, 5-2i 361.3 2H), 7.37 (d, J =4.3 Hz, 1H), 6.85 (m, 3H), 5.11-4.82 (m, 1H), 4.51-4.03 (m, 1H), 3.80-3.36 (m, 2H), 3.252 .56 (m, 8H), 2.14-1.58 (m, 2H). Ή NMR (400 MHz, DMSO-V) δ 8.91 (dd, J = 4.3, 0.8 Hz, 1H), 8.15–8.07 (m, 2H), 7.90–7.85 (m, 1H), BCD-CDK85-2 362.1 7.69-7.60 (m, 2H), 7.53-7.44 (m, 1H), 6.91-6.80 (m, 2H), 5.41-4.55 (m, 1H), 4.45-4.36, 4.26-4.16 (2m, rotamers, 1H) , 3.81-3.60 (m, 2H), 3.34-3.23 (m, 1H), 3.19-3.09, 2.99-2.90 (2m, rotamers, 1H), 2.98 (s, 6H), 2.11-1.71(m, 2H). Ή NMR (400 MHz, DMSO-V) δ δ 9.69-8.74 (br s 1H), 9.05 (d, J= 4.3 Hz, 1H), 8.21 (d,/ = 0.7 Hz, 2H), BCD-CDK8- 403.1 8.01 (s, 1H), 7.82 (d,/= 4.3 Hz, 1H), 7.76 (d,/=8.8 5-3i Hz, 2H), 7.10 (d,/= 8.8 Hz, 2H), 4.06-3.84 (m, 4H), 3.83-3.73 (m, 4H), 3.65-3.30 (m, 4H), 3.14-3.05 (m, 4H). BCD-CDK8- 404.2 Ή NMR (400 MHz, DMSO-/0 δ 8.92 (d,/= 4.3 Hz, 5-3 1H), 8.13 (d,/ = 1.2 Hz, 2H), 7.90–7.86 (m, 1H), 7.68 (d,/ = 8.8 Hz, 2H), 7.50 (d,/ = 4.3 Hz, 1H), 7.11 ( d, J = 8.9 Hz, 2H), 3.98-3.67 (m, 8H), 3.65-3.34 (m, 2H), 3.27-3.07 (m, 6H). Ή NMR (400 MHz, DMSO-/0 δ 13.04 (s, 1H), 8.92 BCD-CDK85-4i 382.2 (d, J = 4.3 Hz, 1H), 8.34-7.97 (m, 5H), 7.80 (d, J = 8.3 Hz, 2H), 7.74 (d,/ = 8.4 Hz, 2H), 7.43 (d,/= 4.3 Hz, 1H), 7.28, 6.67 (2 brs, 1H), 3.65-3.09 (m, 4H), 1.67-1.36 (m, 6H). ΉNMR (400 MHz, DMSO-/5) 13.02 (s, 1H), 8.95 (d, BCD-CDK85-4 383.2 J= 4.1 Hz, 1H), 8.37-7.87 (m, 5H), 7.86-7.69 (m, 4H), 7.50 (d, J = 4.1 Hz, 1H), 3.96-3.63 (m, 2H), 3.23-3.00 (m, 2H), 1.78-1.53 (m, 4H), 1.52-1.21 (m, 2H). Ή NMR (400 MHz, DMSO-/5) δ 12.26 (s, 1H), 9.00 BCD-CDK85-5 410.1 (d,/= 4.3 Hz, 1H), 8.37 (s, 1H), 8.26-8.18 (m, 2H), 8.13 (d,/ = 8.5 Hz, 2H), 7.97 (d,/ = 8.5 Hz, 2H) , 7.63 (d,/= 4.3 Hz, 1H), 4.26-4.16 (m, 2H), 4.06-3.96 (m, 2H), 3.43 (s, 3H), 2.35-2.22 (m, 2H). Ή NMR (400 MHz, DMSO-/0 δ 12.27 (s, 1H), 8.31 BCD-CDK85-5C1 444.1 (s, 1H), 8.28 (d, / = 8.8 Hz, 1H), 8.13 (d, /= 8.8 Hz, 1H), 8.12 (d, /= 8.2 Hz, 2H), 7.94 (d, / = 8.2 Hz , 2H), 7.75 (s, 1H), 4.29-4.13 (m, 2H), 4.13-3.97 (m, 2H), 3.35 (s, 3H), 2.37-2.18 (m, 2H). Ή NMR (400 MHz, DMSO-/5) δ 8.89 (d,/= 4.6 Hz, 1H), 8.11 (d,/= 8.8 Hz, 1H), 8.05 (dd,/= 8.8, 1.5 BCD-CDK8- 319.1 Hz, 1H), 7.96 (d,/ = 1.4 Hz, 1H), 7.73 (d,/ = 8.6 Hz, 5-6 2H), 7.48 (d, /= 4.7 Hz, 1H), 7.09 (d, / = 8.6 Hz, 2H), 3.98 (t, /= 6.8 Hz, 2H), 3.84 (s, 3H), 2.62 (t, / = 7.9 Hz, 2H), 2.34–2.25 (m, 2H). Ή NMR (400 MHz, DMSO-/0 δ 8.87 (s, 1H), 8.08 BCD-CDK85-7i 361.2 (s, 2H), 7.89 (s, 1H), 7.63 (s, 2H), 7.38 (s, 1H), 7.176.47 (s, 1H), 6.85 (d, /= 7.0 Hz, 2H), 5.21- 4.79 (m, 1H), 4.52-4.04 (m, 1H), 3.81-4.45 (m, 2H), 3.17-2.65 (m, 2H), 2.97 (s, 6H), 2.05-1.61 (m, 2H).

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BCD-CDK85-7 362.2 Ή NMR (400 MHz, DMSO-^) δ 8.90 (dd, J = 4.3, 0.7 Hz, 1H), 8.15-8.05 (m, 2H), 7.91-7.83 (m, 1H), 7.69-7.60 (m, 2H ), 7.51-7.43 (m, 1H), 6.92-6.80 (m, 2H), 5.11, 4.98 (2d, J = 3.1, 3.4 Hz, rotamers, 1H), 4.45-4.37, 4.25-4.17 (2m, rotamers, 1H), 3.81-3.60 (m, 2H), 3.34-3.23 (m, 1H), 3.18-3.09, 2.99-2.89 (2m, rotamers, 1H), 2.98 (s, 6H), 2.08-1.71 (m, 2H ). BCD-CDK85-8i 396.2 Ή NMR (400 MHz, DMSO-J5) δ 8.91 (d, J = 4.2 Hz, 1H), 8.22 (s, 1H), 8.15 (s, 2H), 8.07 (s, 1H), 7.95 (s, 1H) , 7.79-7.69 (m, 4H), 7.41 (d, J= 4.1 Hz, 1H), 7.08 (br s, 1H), 3.90 (s, 3H), 3.48-3.09 (m, 4H), 1.68-1.56 ( m, 2H), 1.52-1.36 (m, 2H), 1.31-1.20 (m, 2H). BCD-CDK85-8 397.1 Ή NMR (400 MHz, DMSO-J5) δ 8.95 (d, J= 4.3 Hz, 1H), 8.23 (s, 1H), 8.21-8.13 (m, 2H), 7.98-7.89 (m, 2H), 7.81- 7.70 (m, 4H), 7.50 (d, J= 4.3 Hz, 1H), 3.90 (s, 3H), 3.86-3.68 (m, 2H), 3.20-3.05 (m, 2H), 1.761.57 (m, 4H), 1.53-1.20 (m, 2H). BCD-CDK86-1 417.4 Ή NMR (400 MHz, DMSO-J5) 8.63 (d, J = 4.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.63 (dd, J = 9.2, 1.8 Hz, 1H), 7.46 ( d, J= 8.5 Hz, 2H), 7.28 (s, 1H), 7.25 (d,J= 4.4 Hz, 1H), 7.19 (d, J= 1.9 Hz, 1H), 7.12 (d, J= 8.5 Hz, 2H), 6.79 (s, 1H), 3.85-3.74 (m, 4H), 3.72 (d, J = 12.4 Hz, 2H), 3.28 - 3.19 (m, 4H), 2.78-2.64 (m, 2H), 2.32 -2.19 (m, 1H), 1.86-1.74 (m, 2H), 1.731.57 (m, 2H). BCD-CDK86-2 440.1 Ή NMR (400 MHz, DMSCMO $ 12-34 (s, 1H), 9.05 (d, J= 4.3 Hz, 1H), 8.24-8.07 (m, 3H), 7.99-7.90 (m, 1H), 7.89 (s , 1H), 7.77-7.65 (m, 2H), 7.59 (d, J= 4.2 Hz, 1H), 5.11-4.87 (m, 1H), 4.40-4.17 (m, 1H), 4.2O3.99 (m, 1H), 3.69-3.42 (m, 3H), 3.17 (s, 3H), 2.041.68 (m, 2H). BCD-CDK86-3 229.8 [M+2H] ²⁺ /2 Ή NMR (400 MHz, DMSO-J5) δ 8.66 (d, J = 4.4 Hz, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.64 (dd, J = 9.3, 2.6 Hz, 1H), 7.50 (m, 4H), 7.29 (d, J= 4.4 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J=2.5Hz, lH), 6.88(s, 1H), 3.57 (s,

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458.4 [M+H] ⁺ 2H), 3.35 (br, 2H, in _H2O signal), 2.96-2.84 (m, 2H), 2.51-2.25 (br, 8H), 2.18 (s, 3H), 2.12-2.01 (m, 2H ), 1.52–1.39 (w, 2H), 1.11 (s, 3H). BCD-CDK86-4 385.1 Ή NMR (400 MHz, DMSO-^) δ 13.00 (br s, 1H), 9.00 (d, J= 4.4 Hz, 1H), 8.28-7.90 (m, 2H), 8.21-8.09 (m, 2H), 7.98 (dd, J = 8.8, 1.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 9.4, 6.4 Hz, 3H), 4.50-4.35 (m, 1H), 4.32- 4.18 (m, 2H), 4.16-4.01 (m, 1H), 3.953.77 (m, 1H), 3.23 (s, 3H). BCD-CDK86-5 410.1 Ή NMR (400 MHz, DMSCMO 12-34 (s, 1H), 9.07 (d,J=4.3 Hz, 1H), 8.23-8.11 (m, 3H), 8.06-7.99 (m, 2H), 7.75 (d, J= 8.2 Hz, 2H), 7.61 (d,J=4.4Hz, 1H), 4.27 (t,J= 7.5 Hz, 2H), 4.06 (t,J= 7.7 Hz, 2H), 3.44 (s, 3H) , 2.33-2.21 (m, 2H). BCD-CDK86-6 440.4 Ή NMR (400 MHz, McOD-Y) δ 9.02 (d, J = 4.4 Hz, 1H), 8.24 (d, J= 8.6 Hz, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.95 (s , 1H), 7.89 (d,J=8.6 Hz, 1H), 7.74 (d, J= 8.1 Hz, 2H), 7.62 (d, J = ^A Hz, 1H), 3.86-3.45 (m, 8H), 3.42(s, 3H). BCD-CDK86-7 222.8 444.4 Ή NMR (400 MHz, DMSO-^) δ 8.67 (d, J= 4.4 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.64 (dd, J = 9.4, 2.5 Hz, 1H), 7.56 -7.46 (m, 4H), 7.30 (d, J= 4.4 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J= 2.5 Hz, 1H), 6.79 (s, 1H), 3.76-3.65 ( m, 2H), 3.57 (s, 2H), 2.77-2.63 (m, 2H), 2.50-2.30 (m, 8H), 2.30-2.19 (m, 1H), 2.18 (s, 3H), 1.83- 1.72 (m, 2H), 1.71-1.56 (m, 2H). BCD-CDK86-8 431.3 Ή NMR (400 MHz, DMSO-^) 8.62 (d, J = 4.4 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.62 (dd, J = 9.4, 2.5 Hz, 1H), 7.45 ( d, J= 8.6 Hz, 2H), 7.24 (d, J= 4.4 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J =2.5 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 3.83-3.73 (m, 4H), 3.433.32 (m, 2H), 3.28-3.18 (m, 4H), 2.99-2.83 (m, 2H), 2.16-2.02 ( m, 2H), 1.54-1.40 (m, 2H), 1.12 (s, 3H). BCD-CDK86-9 440.2 Ή NMR (400 MHz, DMSO-^) δ 9.02 (d, J = 4.4 Hz, 1H), 8.20-8.09 (m, 3H), 7.99-7.88 (m, 2H), 7.61-7.51 (m, 3H), 5.03, 4.97 (2d, J = 3.3 Hz, rotamers, 1H), 4.36-4.28, 4.27-4.20 (2m, rotamers, 1H), 3.66-3.40 (m, 3H), 3.49-3.32, 3.26-3.19 (2m, rotamers, 1H), 2.96 (s, 3H), 2.04-1.73 ( m, 2H). BCD-CDK86-10 399.1 1H NMR (400 MHz, DMSO-O δ 9.14 (d, J = 4.4 Hz, 1H), 8.35-8.31 (m, 2H), 8.28 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 8.7 ,1.8 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 4.4 Hz, 1H), 4.63-4.54 (m, 1H), 4.44-4.37 (m, 2H), 4.27-4.19 (m, 1H), 4.08 (s, 3H), 4.06-3.99 (m, 1H), 3.39 (s, 3H). BCD-CDK86-11 369.1 Ή NMR (400 MHz, DMSO-J5) δ 9.02 (d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 8.19–8.13 (m, 2H), 8.03–7.97 (m, 2H), 7.81 ( d, J = 8.1 Hz, 2H), 7.61-7.54 (m, 3H), 4.34-4.24 (m, 2H), 4.10-4.03 (m, 2H), 3.91 (s, 3H), 2.34-2.22 (m, 2H). BCD-CDK86-12 383.1 ^X H NMR (400 MHz, DMSO-Y) δ 8.98 (d, J = 4.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d,J= 8.7 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.93-7.85 (m, 2H), 7.77 (d,J=8.1 Hz, 2H), 7.54 (d, J= 8.1 Hz, 2H), 7.51 (d, J= 4.4 Hz, 1H), 3.92 (s, 3H), 3.56-3.34 (m, 4H), 1.96-1.78 (m, 4H). BCD-CDK86-13 369.1 ^X H NMR (400 MHz, DMSO-J5) δ 9.00 (d, J= 4.8 Hz, 1H), 8.30 (m, 3H), 8.19 (d, J= 9.1 Hz, 1H), 8.02 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.69–7.60 (m, 3H), 3.95–3.88 (m, 5H), 2.58–2.52 (m, 2H), 2.08 (qv, 2H). BCD-CDK86-14 387.2 Ή NMR (400 MHz, DMSO-^) δ 9.08 (d, J = 4.6 Hz, 1H), 8.83–8.76 (m, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H) , 8.26 (dd, J= 8.8,1.8 Hz, 1H), 8.20 (d, J= 8.8 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.65 (d, J= 4.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 3.92 (s, 3H), 3.51–3.39 (m, 4H), 3.26 (s, 3H).

Example 131 Determination of chemical stability

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

SGF without enzymes concentrate was used as artificial intestinal juice, pH=1.4

- 76 041908 (Sigma Ireland, cat#01651). 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. The HPLC method using an Agilent1200 chromatograph (Agilent, USA) was used to determine the peak areas of the compounds in the tested samples corresponding to the initial test time (before holding) and the final test time (after holding in a solid state thermostat for 2 h at 37°C). Chromatographic analysis was carried out 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 determination of stability in human plasma was performed using pooled human plasma taken from ten healthy donors. The candidate stock solution (10 mM in DMSO) was diluted with 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 Agilent1200 chromatograph (Agilent, USA) was used to determine the peak areas of the compounds in the tested samples corresponding to the initial test time (before holding) and the final test time (after holding in a solid-state thermostat for 4 h at a temperature of 37°C) with preliminary precipitation of proteins with acetonitrile . Chromatographic analysis was carried out 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 plasma (Table 2).

Table 2. Results of determining the chemical stability of compounds

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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.

The rate of enzymatic degradation of the compound was determined by keeping the reaction mixture containing 0.5 mg/ml of pooled human liver microsomes (XenoTech, USA, cat# H2620), 10 μm of the 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 min at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. We plotted the dependence of the logarithm of the peak area of the substance on time. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the drug half-life t _1/2 and the decomposition rate CL _int were calculated:

Elimination constant (k) = (-gradient)

Half life (min) = ---- _T . , volume of incubation (uL) λ ( uL mg) =---——-—:---— _; ----protein in the incubation {mg) . . . . Vx 0.693

Intrinsic Clearance{CL _u n){LlLininius protein) =--------Based on the data obtained, the enzymatic stability of candidates in human liver microsomes was concluded. The compounds of the present invention showed sufficient resistance to the action of human liver microsome enzymes and had a Clint enzymatic degradation rate of less than 47 μl/min/mg. The results are shown in table. 3.

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Table 3. Results of determining the enzymatic stability of the compounds

Connection number Stability in microsomes, Clint, µl/min/mg CDK8-1-3 24.8 CDK8-1-4 18.8 CDK8-1-6 23.4 CDK8-1-8 23.4 CDK8-1-12 3.0 CDK8-1-14 12.4 CDK8-l-17a 14.4 CDK8-1-18 14.6 CDK8-1-20 12.4 CDK8-3-8 18.0 CDK8-3-9 8.8 CDK8-3-14 13.6 CDK8-3-15 15.2 CDK8-3-16 27.8 CDK8-3-17 10.7 CDK8-3-18 10.4 CDK8-4-3 22.0 CDK8-4-5 26.6 CDK8-4-7 23.2

Connection number Stability in microsomes, Clint, µl/min/mg CDK8-4-9 21.6 CDK8-4-11 15.0 CDK8-4-23 12.8 CDK8-4-25 22.2 CDK8-4-26 17.6 CDK8-4-27 7.2 CDK8-4-28 6.8 CDK8-4-33 21.2 CDK8-4-34 24.2 CDK8-4-38 20.0 CDK8-4-39 23.6 CDK8-4-40 35.0 CDK8-5-4 37.0 CDK8-5-4i 19.0 CDK8-6-3 18.6 CDK8-6-4 16.2 CDK8-6-13 22.6 CDK8-6-14 I,8 - -

Example 133 Determination of Enzymatic Stability in Human Liver S9 Fractions

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 S9 enzymes of human liver fractions.

The rate of enzymatic degradation of the compound was determined by keeping the reaction mixture containing 0.5 mg/ml pooled human liver S9 fractions (XenoTech, USA, cat#H0610), 10 μm of the 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 min at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. We plotted the dependence of the logarithm of the peak area of the substance on time. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the drug half-life t _1/2 and the decomposition rate CL _int were calculated:

Elimination rate constant (k) = (- gradient)

Half life (dD (min) volume of incubation (uL) ( uL mg) =----:—:—-— _:: -----protein nt the incubation (me)

Intnnsic Clearance (SE^ncEsh mg protein} * 1/2

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

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Table 4. Results of determining the enzymatic stability of the compounds

Connection number Stability in S9, Clint, µl/min/mg CDK8-3-19 2.9 CDK8-3-20 6.5 CDK8-3-21 12.9 CDK8-3-22 3.0 CDK8-3-23 9.2 CDK8-3-24 4.6 CDK8-3-25 3.3 CDK8 3 26 3.25 CDK8 3 27 1.55 CDK8 3 32 3.8 CDK8 3 37 10.05 CDK8 3 39 10.3 CDK8 3 40 2.95 CDK8 3 42 0.5

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

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

Caco-2 intestinal epithelial cells were cultured in inserts with filters (0.4 µm pores, 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 a standard protocol. . When setting up the transfer of A^B (transfer "intestinal lumen - blood flow"), solutions of the test substances were added in 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 buffer pH 7.4 (HBSS, 10 mM HEPES, 15 mM glucose solution, 1% BSA). When setting up the VA transfer (blood-intestinal lumen transfer), the upper chamber was filled with pH 6.5 buffer, and solutions of the test substances were added in pH 7.4 buffer at a concentration of 10 μM to the lower chamber. Propranolol was used as a control as a high permeability substance.

After incubation for 2 h at 37°С in an atmosphere with 5% _CO2 , the amounts of the studied substances in the upper and lower chambers were determined by HPLC using an Agilentl200 chromatograph (Agilent, USA) with preliminary precipitation of proteins with acetonitrile. Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. The peak areas corresponding to the compounds were determined on the chromatograms. Based on the peak area values of the compounds in the calibration standards, the concentration of the compound in the stock solution and in the samples from the wells of the upper and lower chambers was determined.

The permeability through the layer of cells Р _app was calculated by the formula

Papp = (Qt) * V) / (C ₍ 0) * t * Area), where

Р _ar r - effective permeability constant, m/s

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

Area - membrane surface area (0.33 cm ² ), cm ² t - holding time (7200 s), s

C(o) - concentration of the initial solution, μM

C( _t ) - concentration of the solution after 2 hours (in the test А^В - concentration in the sample from the well of the lower chamber; in the test В^А - 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 according to the _formula

Where

P _app a-in - the value of the direct analysis permeabilityA^B;

Ppp-A - reverse analysis permeability B^A value.

The compounds of the present invention showed a high rate of direct intestinal lumen-to-blood transport, with an efflux coefficient not exceeding 2, indicating that the Pgp transporter does not impose a restriction on the bioavailability of the substance. The results are shown in table. 5.

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Table 5. Results. determining the permeability of compounds through a monolayer of Caco-2 cells

connection number A - B , Papp cm/s efflux CDK8-1-3 64.1 0.44 CDK8-1-8 19.7 2.9 CDK8-1-14 39.9 0.79 CDK8-3-14 39.8 1.35 CDK8-3-18 46.9 0.9 CDK8-3-24 17.0 1.1 CDK8-3-25 29.3 0.6 CDK8 3 26 53.7 0.3 CDK8 3 27 22.6 0.9 CDK8 3 32 24.9 0.7 CDK8 3 37 18.9 1.0 CDK8 3 39 22.3 0.8 CDK8 3 42 11.8 1.6 CDK8-4-5 87.6 0.12 CDK8-4-7 64.5 0.34 CDK8-4-11 13.9 1.54 CDK8-4-21 106.1 0.09 CDK8-4-23 36.9 0.14 CDK8-4-27 84.6 0.25 CDK8-4-28 68.9 0.03 CDK8-4-31 36.1 0.35 CDK8-4-33 13.4 1.5 CDK8-4-37 8.63 1.08 CDK8-4-38 13.9 0.28 CDK8-6-14 64.1 0.44

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 cell assay on continuous cell cultures 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 in vivo dye (ThermoFisher, #DAL1100). Cells were grown in RPMI-1640 medium (PanEco, #C330 p) supplemented with 10% FBS (Gibco, #16140-071), washed and replated on nutrient medium with 10% FBS (Gibco, #16140-071) at 96- well culture plates (Corning, #3599) at 10 x 10 ³ cells in 100 µl of medium per well. Test compounds were dissolved in DMSO and diluted with 10% FBS medium (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 hours. (ThermoFisher, #DAL1100), the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), then additionally incubated for 3 to 5 hours 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), measuring the fluorescent signal at an excitation wavelength (XEx) of 540 nm and an emission wavelength (XEm) of 590 nm.

The _IC50 value was determined using the Magellan 7.2 program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with Levenberg-Markart optimization (Table 7).

The value of SS ₅₀ was determined in the test for cytotoxicity. Studies were performed on HepG2 cells (hepatocellular carcinoma, ATCC® HB-8065™). Cells were plated in 96-well plates (Corning, #3599) at a concentration of ≈20χ10 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.

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Table 6. Results of the specific activity of the compounds in the cellular antiproliferative test on the cell line (MV-4-11) and the results of general toxicity on the HepG2 cell line. The data are presented as average activity values obtained in several settings.

Number MV-4-11 Hep-G2 Number MV-4-11 Hep-G2 connections ICso, mkM CC50, MKM connections IC50, mkM CC50, MKM CDK8-1-3 2.08 59.1 CDK8-4-9 2.10 >200 CDK8-1-4 0.70 >100 CDK8-4-11 1.33 >200 CDK8-1-5 1.24 81.1 CDK8-4-21 0.74 4.7 CDK8-1-6 1.64 >100 CDK8-4-23 0.10 >100 CDK8-1-7E >2.5 >100 CDK8-4-25 0.05 4.7 CDK8-1-8 3.92 >200 CDK8-4-26 1.28 >100 CDK8-1-12 3.38 >100 CDK8-4-27 0.05 >100 CDK8-1-14 0.24 >100 CDK8-4-28 >1 >200 CDK8-1-16 >2.5 >50 CDK8-4-31 0.61 >100 CDK8-l-17a 12.44 >100 CDK8-4-33 19.68 >100 CDK8-1-18 4.80 >100 CDK8-4-34 0.14 2.6 CDK8-1-20 >1 >200 CDK8-4-36 0.46 17.0 CDK8-3-4 7.51 76.4 CDK8-4-37 0.13 117.5 CDK8-3-8 7.52 >200 CDK8-4-38 0.39 >100 CDK8-3-9 10.04 >20 CDK8-4-39 0.19 >100 CDK8-3-14 0.20 >100 CDK8-4-40 5.56 >100 CDK8-3-15 2.45 >100 CDK8-5-4 9.56 66.1 CDK8-3-16 2.87 >100 CDK8-5-4i 4.32 >100 CDK8-3-17 8.85 >20 CDK8-5-8 3.73 >50 CDK8-3-18 0.19 >200 CDK8-6-3 3.18 >60 CDK8-4-3 1.49 >200 CDK8-6-4 7.79 66.6 CDK8-4-5 0.62 7.7 CDK8-6-13 19.74 >200 CDK8-4-7 0.39 >200 CDK8-6-14 11.72 >50 CDK8-3-19 0.912 >100 CDK8 3 28 0.871 48.4 CDK8-3-20 5.044 >100 CDK8-3-30 0.412 100.0 CDK8-3-21 0.764 >100 CDK8-3-32 0.010 20.7 CDK8-3-22 0.432 >100 CDK8-3-33 2.059 100.0 CDK8-3-23 0.413 >100 CDK8-3-35 1.844 77.4 CDK8-3-24 0.099 >200 CDK8-3-37 0.022 98.2 CDK8-3-25 0.134 >100 CDK8-3-39 0.055 50.2 CDK8-3-26 0.011 4.9 CDK8-3-40 0.009 200.0 CDK8-3-27 0.066 19.4 CDK8-3-41 0.572 200.0 - - - CDK8-3-42 0.028 15.9

Table 7. Results of the specific activity of the compounds in the cellular antiproliferative test in a panel of cell lines (KG-1, HL-60). The data are presented as average activity values obtained in several settings.

Connection number KG-1 HL-60 Connection number KG-1 HL-60 ICso, mkM IC50, mkM IC50, mkM IC50, mkM CDK8-1-3 27.60 81.44 CDK8-4-27 5.21 >100 CDK8-1-5 4.71 >60 CDK8-4-31 21.66 - CDK8-1-6 >10 8.18 CDK8-4-34 0.20 0.081 CDK8-1-14 23.25 33.94 CDK8-4-36 1.59 - CDK8-1-16 - 60.68 CDK8-4-37 5.00 - CDK8-1-18 2.13 >100 CDK8-4-38 60.00 - CDK8-3-14 0.05 69.76 CDK8-4-39 27.72 - CDK8-3-15 1.13 >60 CDK8-4-40 25.00 - CDK8-3-16 0.94 >60 CDK8-5-8 17.52 24.79 CDK8-3-17 3.93 46.48 CDK8-6-13 12.32 >60 CDK8-3-18 0.08 34.98 CDK8-6-14 9.60 66.45

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Claims (15)

Connection number KG-1 1Czo, mkM CDK8-3-26 0.003 CDK8-3-31 0.002 CDK8-3-32 <0.01 CDK8-3-34 0.005 CDK8-3-37 0.004 CDK8-3-38 <0.01 CDK8-3-39 0.005 CDK8-3-42 0.009 CLAIM 1. Compound of formula 1.5a or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, L _b L2 each independently represents a chemical bond, -C(O)-, -C(O)-O-; R ₃ , R ₁₃ are each independently H, NH2; R2 is selected from the group consisting of C1-C6 alkyl, unsubstituted or substituted with one R ₁₄ substituent; R ₄ is X ₅ , X6 are each independently CH; X ₇ represents C, while L4 - R ₁₀ replaces only X ₇ ; L ₃ is a chemical bond, -C(O)-, -O-; L4 is a chemical bond, -O-, -C(O)-NR _7a -; P=1; R ₅ is H; C1-C6 alkyl; C1-C6 alkyloxy; NR ₁₅ R ₁₆ ; 6-membered heterocyclyl with 2 heteroatoms selected from N and/or O; R ₆ , R _6a are each independently H, hydroxy, C1-C6 alkyloxy; R ₇ , R _7a are each independently H, C1-C6 alkyl; R8, R9 are each independently H; R ₁₀ is selected from the group consisting of C1-C6 alkyl, hydroxy, C1-C6 alkyloxy, -NR ₂₃ R ₂₄ ; 6-membered heterocyclyl with 2 heteroatoms selected from N and/or O; 5-membered heteroaryl with 2 N atoms, unsubstituted or substituted with one C1-C6 alkyl; -S(O) ₂ -C ₁ -C ₆ alkyl; R11 is H; C1-C6 alkyl, unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, -NR _23a R _24a ; C1-C6 alkoxy C1-C6 alkyl; C ₃ -C ₆ cycloalkyl; R12 is C1-C6 alkyl, unsubstituted or substituted with hydroxy, C ₃ -C ₆ cycloalkyl, -NR _23a R _24a ; C1-C6 alkoxy C1-C6 alkyl; C ₃ -C ₆ cycloalkyl; R ₁₄ is C1-C6 alkoxy; R ₁₅ , R ₁₆ , R ₂₃ , R ₂₄ , R _23a , R _24a each independently represents H, C1-C6 alkyl. 2. Connection according to claim 1, where R ₅ is H; C1-C6 alkyl; C ₁ -C ₆ alkyloxy; NR ₁₅ R ₁₆ ; 4-morpholinyl; R ₁₅ , R ₁₆ are each independently H, C1-C6 alkyl. 3. Connection according to claim 1, where R ₁₀ is selected from the group consisting of C1-C6 alkyl, hydroxy, C1-C6 alkyloxy, -NR ₂₃ R ₂₄ , 4-morpholinyl, imidazolyl, pyrazolyl, unsubstituted or substituted with one or more C ₁ -C ₆ alkyl; -S(O) ₂ -C ₁ -C ₆ alkyl; R2 ₃ , R24 are each independently H, C1-C6 alkyl. 4. The compound according to claim 1, where R ₃ represents H. - 83 041908 5. The compound according to claim 1, which is (S)-4-(3-(3-hydroxypyrrolidine-1-carbonyl)-1,7-naphthyridin-5-yl)-N-(methanesulfonyl)benzamide (BCD-CDK8 -3-1); (R)-(5-(4-(1 H-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 (BCDCDK8-3-3); (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 (BCDCDK8-3-5); (R)-(3-hydroxypyrrolidin-1-yl)(5-(4-methoxyphenyl)-1,7-naphthyridin-3-yl)methanone (BCD-CDK83-6) (5-(4-(dimethylamino)phenyl )-1,7-naphthyridin-3-yl)(4-methylpiperazin-1-yl)methanone (BCD-CDK8-3-8); (1 - (5- (4- ( 1 -methyl-1 H-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); T-dimethyl-1-(5-(4-((methylsulfonyl)carbamoyl)phenyl)-1,7-naphthyridin-3-yl)azetidine-3-carboxamide (BCD-CDK8-3-12); (R)-4-(3-(3-hydroxypyrrolidin-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-CDK83-14); (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-1 yl)methanone (BCDCDK8-3-16); (1 - (5 - (4- (1 -methyl-1 H-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 (BCDCDK8-3-18); (R)-3 - (methoxypyrrolidin-1 -yl) (5- (4- ( 1 -methyl-1 H-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-1 H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3 -yl) methanone (BCD- CDK8-3-21); N,N-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-22); H2diethyl-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3-carboxamide (BCD-CDK8-3-23); 8-αmino-N-(2-methoxyethyl)-5-(4-(1-methyl-1 H-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-1 H-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 (BCDCDK8-3-27); 2-methoxyethyl-5-[4-(methyl-1H-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-1 H-pyrazol-4-yl) phenyl) -1,7-naphthyridin-3 -yl) methanone (BCD-CDK8-3- thirty); (8-amino-5-(4-(1-methyl-1 H-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)(4-methylpiperazin-1 yl)methanone (BCD-CDK8 -3-31); 8-αmino-N-(2-methoxyethyl)-M-methyl-(5-(4-(1-methyl-1 H-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3carboxamide (BCD-CDK8 -3-32); (5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)(morpholino)methanone (BCD-CDK8-333); (8-amino-5-(4-(1-methyl-1 H-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-84 041908 CDK8-3-37); 8-aMHHo-N-cyclopropyl-5-(4-(1-methyl-1 H-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-1 H-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-CDK83-41); 8-amino-N-(2-hydroxyethyl)-5-(4-(1-methyl-1 H-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3-urea (BCD-CDK8-3- 42). 6. A method for inhibiting the biological activity of CDK8/19 cyclin-dependent protein kinases in a subject, comprising contacting the CDK8/19 cyclin-dependent protein kinases with a compound according to any one of claims 1-5. 7. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and is intended for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8/19 . 8. The pharmaceutical composition according to claim 7, wherein the disease is an oncological or hemato-oncological disease. 9. The pharmaceutical composition according to claim 8, wherein the oncological or hemato-oncological disease is selected from the group including 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). 10. A method of treating a disease or disorder mediated by activation of CDK8/19 cyclin-dependent protein kinases, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, to a subject in need of such treatment . 11. The method of claim 10 wherein the disease is an oncological or hemato-oncological disease. 12. The method of claim 11, 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). 13. The use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the treatment of a disease or disorder mediated by the activation of CDK8/19 cyclin-dependent protein kinases in a subject in need of such treatment. 14. Use according to claim 13, wherein the disease is an oncological or hemato-oncological disease. 15. Use according to claim 14, 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). Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2