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

Abstract

The invention relates to new compounds of formula 1.5a or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which have CDK8/19 inhibitor properties, to a pharmaceutical composition containing these compounds, and their use as pharmaceutical preparations for the treatment of diseases or disorders.

Description

Field of technology

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

State of the art

CDK8, along with its closely related structural and functional isoform CDK19, is an oncogenic kinase that regulates transcription (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’s seat, Cancer Res 69, 7899–7901). In contrast to better known members of the CDK family (such as CDK1, CDK2, and CDK4/6), CDK8 does not play a role in cell cycle regulation, but knockout of the CDK8 gene in embryonic stem cells results in embryonic developmental arrest (Adler, A. S., et al. (2012) CDK8 maintains tumor 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 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 associated with its unique function as a regulator of several transcription factors (Xu, W. & L., J. Y. (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439–452). High expression of CDK8 was detected 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), and in these types of cancer, increased expression of CDK8 is observed in ~ 50% of cases; A similar situation is observed in breast cancer (Broude E., et al. (2015) Expression of CDK8 and CDK8-interacting genes as potential biomarkers in breast cancer, Curr. Cancer Drug Targets, 15(8), 739-749). Increased expression of CDK8 is associated with an unfavorable 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, 725-731).

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), transcription induced by the growth factor NF-kB (DiDonato, J. A., et al. (2012) NF-kappaB and the link between inflammation and cancer, Immunol. Rev. 246, 379–400), and the TGF-beta signaling pathway (Acharyya, S., et al. (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis, Cell 150, 165–178). It has also been shown that CDK8 can maintain the pluripotent phenotype of embryonic stem cells and that it can be associated with the cancer stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547–551). Chemotherapeutic drugs that cause DNA damage induce TNF-α, an activator of the transcription factor NFKB (Fabian et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol. 23, 329–336), in endothelial cells and other stromal elements of the tumor microenvironment. Stromal TNF-α acts on tumor cells, where it induces NFγB-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 S 100A8 and A9, which are associated with chronic inflammation and tumor growth. S 100A8/9 act on tumor cells, promoting both their metastasis and survival during chemotherapy (Huang, et al. (2012) MED12 Controls the response to multiple cancer drags through regulation of TGF-β receptor signaling, Cell 151, 937-950).

At present, the search for new compounds that inhibit cyclin-dependent protein kinases CDK8/19 seems relevant.

Description of the invention

Below are definitions of terms used in the description of this invention.

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

Cycloalkyl means a fully saturated carbocyclic ring containing 3-10 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, and 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 ring system containing 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthranyl, and others. Aryl may have substituents on the ring system, which may be identical or different. Aryl may be annelated to a nonaromatic ring system or a heterocycle.

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

Amino group means an R'RN- group, substituted or unsubstituted, optionally by identical substituents R' and R.

Alkylsulfonyl (-S(O) ₂ - _C1 - _C6 alkyl) means an alkyl group, as defined above, attached to the corresponding molecular moiety through a sulfonyl group, -SO2-. Examples of alkylsulfonyls include, but are not limited to, methylsulfonyl, ethylsulfonyl, etc.

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

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

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

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

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

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

A substituent is a chemical radical that is attached to a molecular backbone (scaffold, fragment).

A solvate is a molecular complex of a compound of the present invention, including its pharmaceutically acceptable salts, with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceuticals and 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.

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 joined 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 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 structure but differ in the spatial arrangement of atoms or groups. Stereoisomers can include geometric isomers, enantiomers, and diastereomers.

A diastereomer is a stereoisomer with two or more chiral centers, 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 and cannot be superposed in space.

The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomers that lacks optical activity. The enantiomers can be separated from a racemic mixture using chiral separation methods, such as supercritical fluid chromatography (SFC).

The compounds of the invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that 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, 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 indicate the absolute configuration of the molecule about its chiral center(s). A particular stereoisomer may 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 spatial isomerism caused by the lack of rotation around a single bond, such as in biphenyls, dinaphthyls, and others.

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

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

A pharmaceutical composition is a composition comprising a compound according to the invention and at least one excipient. The excipient may be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and receiving agents, delivery vehicles, such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, aromatizers, antibacterial agents, fungicides, lubricants, and sustained delivery regulators, the selection and ratio of which depend on the nature and route of administration and dosage. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition can also include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged action of the composition can be ensured by agents that delay the absorption of the active principle, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents, and delivery vehicles include 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 disintegrating and dispensing agents 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 polyethyleneglycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in unit administration form as a mixture with traditional 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, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

A pharmaceutically acceptable salt means a relatively non-toxic salt of a compound of the present invention. Salts of the compounds provided herein can be prepared from inorganic or organic acids and bases. Examples of salts thus prepared are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like; salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum, salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine (A 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). The amino acids lysine, ornithine and arginine can be used as amino acids.

A medicinal product (drug) is a substance (or 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 prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

Treat, cure, and therapy refer to a method of alleviating or eliminating a biological disorder and/or at least one of its associated symptoms. The term "alleviate" means to reduce the severity and/or frequency of symptoms of the disease, disorder, or condition. Furthermore, references to treatment in this document include references to curative, palliative, and preventive 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 by treatment according to the present invention. This term is defined to include chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to developing the disorder. Non-limiting examples of diseases that can 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 cancer, salivary gland cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, melanoma, metastatic melanoma, thyroid cancer, pancreatic cancer, prostate cancer or bladder cancer; hemato-oncological diseases, leukemias, acute myeloid leukemia and lymphoid malignancies; neuronal, glial, astrocytic, hypothalamic and other granular, macrophage, epithelial, stromal and blastocoelic disorders; inflammatory, angiogenic and immunological disorders.

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

In the present description and in the following claims, unless the context otherwise requires, the words have, include and contain, or variations thereof such as has, having, includes, including, contains or containing, are to be understood as including the stated whole or group of wholes, but not excluding any other whole or group of wholes.

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, where X1 is N, C, CH;

X ₂ , X ₃ , X4 each independently represents 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 represents 0, 1, 2;

R1, _R3 , _R13 each independently represents H, Hal, cyano, C1-C6 alkyl, _NH2 ;

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

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

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

L ₃ , L ₄ each independently represents a chemical bond, -C(O)-, -O-, -CH ₂ -, -NH-, -C(O)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, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, NR 15 R 16 ; 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, NR ₁₅ R ₁₆ ;

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

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

R ₈ , R ₉ each independently represents 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, wherein the heterocyclic ring formed by R ₈ and R ₉ may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C1-C6 alkyl;

R ₁₀ are 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 alkyl; -S(O) ₂ -C1-C ₆ alkyl;

R11, R ₁₂ each independently represents H; C1-C6 alkyl, unsubstituted or substituted by hydroxy, _C3 - _C6 cycloalkyl, -NR _23a R _24a ; C _{r C6} alkoxy _C1 - _C6 alkyl; _C3 - _C6 cycloalkyl;

R ₁₄ each independently represents 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, _CrC6 alkyl; aryl, _{unsubstituted} or substituted with _one or more substituents selected from the group consisting of Hal, _CrC6 alkyl, _C1C6 alkoxy;

each independently represents a single bond or a double bond;

Hal represents chlorine, bromine, iodine, fluorine.

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

In another embodiment, the present invention relates to a compound of formula I, wherein L1, _L2 each independently represents a chemical bond, -C(O)-, -C(O)-O-, -NH-, -C(=NH)-.

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

where X ₄ represents C(H) _m , N;

m represents 0, 1;

X1 represents 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 each independently represents 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 by one or more R ₁₄ substituents;

X ₅ , X6, X ₇ each independently represents 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 -C6 alkyl; C ₁ -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-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 each independently represents H, C1-C6 alkyl;

R8, R ₉ each independently represents 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, wherein the heterocyclic ring formed by _R8 and _R9 may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C1-C6 alkyl;

R ₁₀ are each independently selected from the group consisting of H, Hal, C-C6 alkyl, hydroxy, cyano, _CrC6 alkyloxy, _CrC6 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 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 alkyl; -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 each independently represents 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 represents chlorine, bromine, iodine, fluorine.

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

In another embodiment, the present invention relates to a compound of formula I.1, wherein L1, L ₂ each independently represents a chemical bond, -C(O)-, -C(O)-O-, -NH-, -C(=NH)-.

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

where X1 represents C, CH, N;

X1, X ₃ each independently represents 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 represents 0, 1;

R1, _R3 , _R13 each independently represents H, Hal, cyano, C1-C6 alkyl, _NH2 ;

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

- 6 041908

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

X ₅ , X ₆ , X7 each independently represents 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; _{C1 - C6} alkyl; _C1 - _C6 alkyloxy; C1 _{- C6} alkyloxy _C1 - _C6 alkyl; _NR15R16 ; aryl _, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, _CrC6 alkyl, _CrC6 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, _CrC6 alkyl, _{CrC6 alkyloxy} , _{NR15R16 ;}

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

R7, R7 _a each independently represents 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, wherein the heterocyclic ring formed by R ₈ and R ₉ may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C _r C ₆ alkyl;

R ₁₀ are each independently selected from the group consisting of H, Hal, _CrC6 alkyl, hydroxy, _cyano , _C1 - _C6 alkyloxy, _CrC6 alkyloxy _CrC6 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} 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 alkyl; -S(O) ₂ -C1- _C6 alkyl;

R11 _{, R12} each independently represents H; _C1 - _C6 alkyl, _{unsubstituted} or substituted by hydroxy, _{C3 - C6} cycloalkyl, _-NR23aR24a ; _{CrC6alkoxyCrC6} alkyl; _C3 - _C6 cycloalkyl _;

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

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

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

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

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

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

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

where L _1? L ₂ , R ₂ , R3, R4 have the above meaning.

- 7 041908

In 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 ;

X _1? 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 represents 0, 1;

m represents 1, 2;

R1, _R3 , _R13 each independently represents H, Hal, cyano, _C1 - _C6 alkyl, NH2;

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

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

X ₅ , X ₆ , X ₇ each independently represents 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, _Cr C ₆ alkyl, _Cr C ₆ alkyloxy;

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

R8, R9 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, wherein the heterocyclic ring formed by R ₈ and R ₉ may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C _r C ₆ alkyl;

R ₁₀ are each independently selected from the group consisting of H, Hal, _CrC6 alkyl, hydroxy, _cyano , _C1 - _C6 alkyloxy, _CrC6 alkyloxy _CrC6 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 _CrC6 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 alkyl; -S(O) ₂ - _C1 - _C6 alkyl _;

R11, R ₁₂ each independently represents H; _{CrC6 alkyl} , unsubstituted or _substituted by hydroxy, _{C3 - C6} cycloalkyl, _-NR23aR24a ; _CrC6 alkoxy _CrC6 alkyl _{; C3} - _C6 cycloalkyl;

R ₁₄ each independently represents 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, _Cr C ₆ alkyl; aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of Hal, _Cr C ₆ alkyl, _Cr C6 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 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 have the above meaning.

- 8 041908

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

where L1, L2, R1, R2, R3, R4 have the above meaning.

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

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

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

I.10

where X1, _X2 , _X3 , L1, _L2 , R1, _R2 , _R3 , R4, n, k have the above meaning.

In another embodiment, the present invention relates to a compound of formula I, I.1-I.10, wherein R ₅ is H; Hal; cyano; 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 by one or more substituents selected from the group consisting of Hal, C1-C6 alkyl, C1-C6 alkyloxy, NR ₁₅ R ₁₆ .

In another embodiment, the present invention relates to a compound of formula I, I.1-I.10, wherein R ₁₀ are 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 alkyl; 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 represents chlorine, bromine, iodine, fluorine.

In 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, where X1 is N, C, CH;

X ₂ , X ₃ , X ₄ each independently represents 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 represents 0, 1,2;

R1, _R3 , _R13 each independently represents H, Hal, cyano, Ci- _C6 alkyl;

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

- 9 041908

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

X ₅ , X ₆ , X7 each independently represents 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-C ₆ alkyl; C1-C ₆ alkyloxy; C1-C ₆ alkyloxy C1-C ₆ 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 each independently represents 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, wherein the heterocyclic ring formed by R ₈ and R ₉ may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C _r C ₆ alkyl;

R ₁₀ are each independently selected from the group consisting of H, Hal, _CrC6 alkyl, hydroxy, _cyano , _C1 - _C6 alkyloxy, _CrC6 alkyloxy _CrC6 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 _CrC6 alkyl; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N, O and/or S, unsubstituted or substituted with one or _{more CrC6} alkyl; -S( _O ) _{2 -C1} - _C6 alkyl;

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

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

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ 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-C ₆ alkyl, C1C ₆ alkyloxy; R ₁₉ , R ₂₀ each independently represents H, C1-C6 alkyl;

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

Hal represents chlorine, bromine, iodine, fluorine.

In another embodiment, the present invention relates to a compound of formula Ia, wherein R1, _R3 each independently represents H, Hal.

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

In 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 represents 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, wherein R1, _R3 each independently represents H, Hal.

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

The compounds described in the present invention may be prepared as and/or administered in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, the following: acid salts formed by reacting the compound in free base form with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acid, 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-ene-1-carboxylic, glucoheptonic, 4,4'-methylene-bis-3-hydroxy-2-ene-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, etc.; salts of bases formed by the interaction of the compound in the form of a free acid with a pharmaceutically acceptable inorganic base, such as a hydroxide, carbonate or bicarbonate of a metal or ammonium cation, or with an organic base. Cations of pharmaceutically acceptable salts 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, primary, secondary or tertiary amine (e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine), substituted amine, including natural 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.

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

Salts are regenerated using at least one of the following techniques: filtration, precipitation with a precipitating agent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. It should 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 can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described in this patent can be readily prepared or formed by the methods described in the present invention. Furthermore, the compounds provided by the present invention can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms in describing the compounds and methods provided by the present invention.

The compounds described in this invention can be presented in a variety of forms, including, but not limited to, structureless forms, milled forms, and nanoparticles. Furthermore, the compounds described in this 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, crystalline forms, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, the degree of crystallization, and storage temperature, can determine the dominance of one crystalline form.

Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished by a variety of methods, including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analytical methods focus on the study of thermochemical decomposition or thermophysical processes, including, but not limited to, polymorphic transitions, and are used to analyze the relationship between polymorphic forms, determine weight loss, find the glass transition temperature, or study filler compatibility. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulating differential scanning calorimetry (MDSC), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG/IR). Crystallographic methods include, but are not limited to, single-crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques used include, but are not limited to, Raman spectroscopy, FTIR, UVIS, and NMR (liquid and solid). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), ambient scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

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

Formula Name Cipher He 1 -(1 -(4-((Methylsulfonyl) / ν° carbamoyl)phenyl)-1R- BCD-CDK8- ίί /ГЛ ⁰ benzo[d\imidazol-6-yl)-Ya- 1-1 YΎ/> phenylazetidine-3 - N carboxamide O. n Ύχ 4-(6-Azetidine-1-carbonyl)- ο Ο BCD-CDK8- 1 I- benzo[d\imidazol-1-yl)- 1-2 ζ^^ζ Ρ 0 A-(methylsulfonyl)benzamide o- (1-(4-(1Я-Pyrazol-4- Cj yl)phenyl)-1Я- BCD-CDK8- oW benzo[<Dimidazol-6yl)(piperidin-1-yl)methanone 1-3 /Ϊ ^Η (1 -(1 -(4-(1R-pyrazole-4- U yl)phenyl)-1Я- BCD-CDK8- benzo[<Dimidazole-6- 1-4 O J Tχ > yl)azetidine-3- (morpholino)methanone O (1-(4-(1Я-Pyrazol-4- G/ yl)phenyl)-1Я- BCD-CDK8- Λ benzo[<Dimidazole-6- 1-5 oVx> ΧχΧ^Ν yl)(azetidin-1-yl)methanone 0. UH Methyl-4-(6-(3-(phenyl Η X Ο carbamoyl)azetidin-1-yl)- BCD-CDK8- u_Jy 1 I-benzo[d\ themidazol-1 - 1-6E XX? (sil) benzoate Ooh- HE 4-(6-(3- Q ϊ O (phenylcarbamoyl)azetidine-1 - BCD-CDK8- ^H Vn^. X yl)-1Y-benzo[<Dimidazole-1- 1-6A ΎΎ /> XX N ( ... 0. γ-ΝΗ ₂ 1 -(1 -(4-Carbamoylphenyl)- 1R- Q1 O benzo[</]imidazol-6-yl)-Ya- BCD-CDK8- - at Yr phenylazetidine-3 - 1-6 γχ> carboxamide fl U Methyl-4-(6-(3- ίΆ (phenylcarbamoyl)azetidine-1 - BCD-CDK8- G ( / (4-fluoro-1Ya-) 1-7E Ύ T/> Xj^-N benzo[J]imidazole-1 - F (sil) 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' L Co ο \ίΤ^Ν rv Ρ W 4-(-6-(3- (Phenylcarbamoyl)azetidin-1-yl)-4-fluoro-1H-benzo[<D]imidazol-1-yl)benzoic acid 1-(1-(4-Carbamoylphenyl)-4fluoro-1H-benzo[<D]imidazol-6-yl)-A-phenyl azetidine-3-carboxamide (1-(1-(4-(1H-Pyrazol-4-yl)phenyl)-4-fluoro-1H-benzo[<D]imidazol-6-yl)azetidin-3-yl)(morpholino)methanone (1-(1-(4-(Dimethylamino)phenyl)-1H-benzo[<Dimidazol-6-yl)azetidin-3-yl) (morpholino)methanone Azetidin-1-yl-(1 -(4(dimethylamino)phenyl)- 1-benzo[<Dimidazol-6yl)methanone (3 -Methoxyazetidin-1 -yl)( 1 (4 -methoxyphenyl) -1 benzo[(Dimidazol-6yl)methanone (1 -(1 -(4-Methoxyphenyl)-1Nabenzo[<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^'-ν F (1 -(1 -(4 -(Dimethylamino) phenyl)-4-fluoro-1-benzo[<Dimidazol-6-yl) azetidin-3-yl)(morpholino) methanone BCD-CDK8- 1-13 Ο / ° V θχ? I (1-(1-(4-(1H-Pyrazol-4-yl)phenyl)-7-fluoro- 1H-benzo[y]imidazol-6-yl) azetidin-3-yl)(morpholino) methanone BCD-CDK8- 1-14 .. 7' orrO Methyl 4-(6-(azetidin-1 carbonyl)-7-fluoro-1-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-1R-benzo[<Dimidazole- 1-yl)benzamide BCD-CDK8- 1-15

- 13 041908

sL» (1 -(4-(1 -Methyl-1R-pyrazol-4yl)phenyl)-1Rbenzo[<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 Ν ^Hr v^ ΤΎ/> θ V^ ^N (1-(1-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)-1H-benzo[<7]imidazol-6-yl)azetidin-3-yl)(morpholino) methanone Azetidin-1-yl(1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-benzo[<7]imidazol-6-yl)methanone (1-(1-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)-4-fluoro-1H-benzo[<7]imidazol-6-yl)azetidin-3-yl)(morpholino) methanone (1-(1-(4-(1-Methyl-1H-pyrazol-4-yl)phenyl)-7-fluoro-1H-benzo[<7]imidazol-6-yl)azetidin-3-yl)(morpholino) methanone 4-(6-((2-(Chloromethyl)-3-oxo3 -(phenylamino)propyl) amino)-4 -fluoro-1-benzo\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 ΡΡ 4-(6-((2-(Chloromethyl)-3-oxo3-(phenylamino)propyl)amino)-4-fluoro-1-benzo[d\imidazol-1-yl)benzoic acid BCD-CDK8- 1-21 Η °ν ^Ν χ° ¹¹ /к ο ο ο ΗΟ<· C Ν Ι^ίΓΐ 4^ ^Ν (5)-4-(3-(3- Hydroxypyrrolidine-1-carbonyl)-1,7-naphthyridine-5-yl)-Ya(methanesulfonyl)benzamide BCD-CDK83-1 ΗΝ-Ν ώ ^{0 ηο} ^/^ν 4^ (7?)-(5-(4-(1R-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 О ύ /=° W /=\ (L)-(3-H hydroxypyrrolidin-1-yl)(5-(4-(1-methyl-1-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)methanone BCD-CDK8- 3-4 0 ό ^{0 ΗΟ} “^\ j ¹ Τι ι ί Ν (7?)-(3-G hydroxypyrrolidin1-yl)(5-(4-morpholinophenyl)1,7-naphthyridin-3yl1)methanone BCD-CDK8- 3-5 0^ ό (7?)-(3-hydroxypyrrolidin- 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)-1,7-naphthyridin-3-yl)azetidin-3-yl)(morpholino)methanone BCD-CDK8- 3-9 Η Os. ^Ν. And ° ο ο Cj ίΠ to J d Jk Ν AC(Methylsulfonyl)-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 YAD-Dimethyl-1-(5-(4((methylsulfonyl)carbamoyl )phenyl)-1,7-naphthyridine-3 yl)azetidine-3-carboxamide BCD-CDK8- 3-12 I ο ό %° A °Α (7?)-4-(3-(3-H-hydroxypyrrolidine-1-carbonyl)-1,7-naphthyridin-5-yl)-Y(methanesulfonyl)benzamide BCD-CDK8- 3-13 \ Ν-Ν ώ ⁰ ΤΓ σ\ώ Azetidin-1-yl-(5-(4-(1-methyl-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- SH-pyrazol-4yl)phenyl)-1,7-naphthyridin-3 yl)(pyrrolidin-1 yl)methanone BCD-CDK8- 3-16 ъ (1-(5-(4-(1-Methyl-1Hpyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl) pyrrolidin-2-one BCD-CDK8- 3-17 \ NN ¹ [Μ oJr ^й vu N- (2-Methoxyethyl)-5-(4-(1-methyl-1 N-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-1-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)methanone BCD-CDK8- 3-19 \ NN ό ⁰ M (7?)-3-G hydroxypiperidin-1 yl)(5-(4-(1-methyl-1-Pyrazol-4-yl)phenyl)-1,7naphthyridyl-3-yl)methanone BCD-CDK8- 3-20 \NN 0 1 ? 1 m\NN. \ NN \ NN O ^{0 /0} '-^n'%<YYy ^H C, JL^n Ν^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-1-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)(azetidin-1-yl)methanone BCD-CDK8- 3-26 НН О ⁰ nh ₂ (8-Amino-5-(4-(1-methyl-1-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)(morpholino)methanone BCD-CDK8- 3-27 Ni/ about ⁰ 2-Methoxyethyl-5-[4-(methyl-1-Pyrazol-4-yl)phenyl]-1,7-naphthyridine-3-carboxylate BCD-CDK8- 3-28 _NN / o 0 ^l ^' ^oЛ ш 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-1 N-pyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)methanone BCD-CDK8- 3-30

NN O ⁰ νη ₂ (8-Amino-5-(4-(1-methyl-1Hpyrazol-4-yl)phenyl)-1,7-naphthyridin-3-yl)(4-methylpiperazin-1-yl)methanone BCD-CDK8- 3-31 \ Ν—Ν o 9 ¹ IAJ N nh ₂ 8-Lmino-LC2-methoxyethyl)A-methyl-(5-(4-(1-methyl-1-Pyrazol-4-yl)phenyl)-1,7naphthyridine-3-carboxamide BCD-CDK8- 3-32 N-N (5-(4-(1-Methyl-1R-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- 1Napyrazol-4-yl)phenyl)-1,7naphthyridin-3 -yl)(3 - methoxyazetidine)methanone BCD-CDK8- 3-34 \ N-N N-(2-(Dimethylamino)ethyl)-Nmethyl-5-(4-(1-methyl-lπyrazol-4-yl)phenyl)-l,7naphthyridine-3-carboxamide BCD-CDK8- 3-35

- 17 041908

N-N g TV-Cycle opil- 5-(4-(1-methyl-3-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3-carboxamide BCD-CDK8- 3-37 About ZI 8-Amino-Λ-cyclopropyl-5(4-(1-methyl-1R-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-38 \ NN ⁰ T w ACCCyclopropyl methyl)-5 -(4(1-methyl-1R-pyrazol-4yl)phenyl)-1,7-naphthyridine-3 carboxamide BCD-CDK8- 3-39 \ NN (j ⁰ < νψ νη ₂ 8-Amino-1- (propylmethyl cyclopropionate) - 5-(4-(1-methyl-1-pyrazol-4-yl)phenyl)-1,7-naphthyridine-3-carboxamide BCD-CDK8- 3-40 0 ό ⁰ xO^J 5-(4(1 Y-Imidazol-1-yl)phenyl)-L-(2-methoxyethyl)1,7-naphthyridin-3-yl) carboxamide BCD-CDK8- 3-41 ХНУ<^ yf о =( ZI G 8-Amino-L-(2-hydroxyethyl)5-(4-(1-methyl-1 N-pyrazol-4 yl)phenyl)-1,7-naphthyridine-3-urea BCD-CDK8- 3-42 χχ Χν ^Ν Η (5-(4-(Dimethylamino)-3-hydroxyphenyl)- 1-pyrrolo[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-(3picolinoyl-1-pyrrolo[2,30]pyridin-5-yl)benzamide BCD-CDK8- 4-2 7 ^ζ ο C} ^χ (5-(3-Hydroxy-4-morpholinophenyl)-1-pyrrolo[2,3-ό]pyridin-3-yl) (pyridin-2-yl)methanone BCD-CDK8- 4-3 °\ / ^Ν ^> VocS НгМ^О [j 5-Methoxy-2-(3-picolinoyl-1 N-pyrrolo[2,3-b]pyridin-5-yl)benzamide BCD-CDK8- 4-4 I he -~χχ ЛХ ^Н Н 5-(4-(Dimethyl amino)-3 hydroxyphenyl)-1Yapyrrolo[2,3-b]pyridin-3-yl) (pyridin-3-yl)methanone BCD-CDK8- 4-5 Л ζ τ \ 5-(Dimethylamino)-2-(3-nicotinoyl-1 N-pyrrolo[2,30]pyridin-5-yl)benzamide BCD-CDK84-6 7 /-ζ Ο 0 ¹ (5-(3-Hydroxy-4morpholinophenyl)-1R-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-nicotinoyl-1 N-pyrrolo[2,3 -b]pyridin-5 yl)benzamide BCD-CDK8- 4-8

- 18 041908

1 HE (5 -(4 -(Dimethylamino)-3 - XX 0 / N hydroxyphenyl)- 1Я- 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 Y N \d/ 5-(Dimethylamino)-2-(3I30NIK0TIN0YL-1Ypyrrolo[2,3-b]pyridin-5-yl)benzamide BCD-CDK8- 4-10 0% 0 -ABOUT (5-(3-H hydroxy-4-morpholinophenyl)-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-1H-pyrrolo[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 Y benzamide 1 X1 1 about Όλ ⁴ N^~N N=\ Ό (5-(4-(Dimethylamino)-3 methoxyphenyl)-1Hpyrrolo[2,3-0]pyridin-3-yl) BCD-CDK8- 4-21 ^N H (pyridin-2-yl)methanone CI ^ ^N V O% ^N H Ό 5-(Dimethylamino)-2-(3picolinoyl-1 H-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 Й No. -M 5-Methoxy-2-(3-picolinoyl-1 H-pyrrolo[2,3-0]pyridin-5-yl)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 N N ^IN H (pyridin-3-yl)methanone T N O 5-(Dimethylamino)-2-(3nicotinoyl-1H-pyrrolo[2,30]pyridin-5-yl)benzonitrile BCD-CDK8- 4-26 ₄ 0. L U A.X. (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-nicotinoyl-1 N-pyrrolo[2,3-0]pyridin-5-yl)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-4-morpholinophenyl)-1-pyrrolo[2,3-b}pyridin-3-yl) (pyridin-4-yl)methanone BCD-CDK8- 4-31 ^°Ύ^1 lew w 2-(3-Isonicotinoyl-1H-pyrrolo[2,3-0]pyridin-5-yl)5-methoxybenzonitrile BCD-CDK8- 4-32 ОТТ Υ ^Λ Ν ^N H (5 -(4-methoxyphenyl)-1Hpyrrolo[2,3-b]pyridin-3yl)(pyridin-4-yl)methanone BCD-CDK8- 4-33 0^ । X o. G > To ^N H (5-(4-(Dimethylamino)phenyl)1 H-pyrrolo[2,3 -b ]pyridin-3 yl)(3 -methoxyphenyl)methanone BCD-CDK8- 4-34 0 o ₄ r\ TJo 1Ш ill К N Ν H 5-Methoxy-2-(3-(3 methoxybenzoyl)- 1-pyrrolo[2,3-0]pyridin-5-yl) benzonitrile BCD-CDK8- 4-35 0^% ^N.^. O / ^N== T tiTo TO On (5-(4-Morpholinophenyl)-1-pyrrolo[2,3-b}pyridin-3-yl) (pyridin-2-yl)methanone BCD-CDK8- 4-36 W ^ΌχΟ o ^N Й (5-(4-Morpholinophenyl)-1Yapyrrolo[2,3-0]pyridin-3-yl) (pyridin-3-yl)methanone BCD-CDK8- 4-37 0^ T T^N OTo TO O (5-(4-Morpholinophenyl)-1-pyrrolo[2,3-Ь]pyridin-3-yl) (pyridin-4-yl)methanone BCD-CDK8- 4-38 1 ^N OoJo ⁷ TO ^N Й (5-(4-(Dimethylamino)phenyl1-Pyrrolo[2,3-0]pyridin-3-yl)(pyridin-3-yl)methanone BCD-CDK8- 4-39 I 0 / N OcJr^ iTw N N (5-(4-(Dimethylamino)phenyl1-Pyrrolo[2,3-0]pyridin-3-yl)(pyridin-4-yl)methanone BCD-CDK8- 4-40 0 O^NH ° ^L T1 T ^j to Y-(Methylsulfonyl)-4-(4(piperidine-1-carbonyl)quinolin-6-yl)benzamide BCD-CDK8- 5-1 О Λ, ° ^Л TT Ύ 40 N Cl 4-(4-(Piperidine-1-carbonyl)-2-chloroquinolin-6-yl)-N-(methylsulfonyl) benzamide BCD-CDK8- 5-1С1 OH । o O\^\ HN^N^T TH (^)-1-((6-(4- (Dimethylamino)phenyl)quinol in-4-yl)(imino)methyl) pyrrolidin-3-ol BCD-CDK8- 5-2i

- 20 041908

—Z \ (7?)-(6 -(4 -(Dimethylamino) phenyl)quinolin-4-yl)(3 hydroxypyrrolidin-1 -yl) methanone BCD-CDK8- 5-2 0^ N Morpholino(6-(4-morpholinophenyl)quinolin-4yl)methanimine BCD-CDK8- 5-3i 0 0 O R Morpholino(6-(4-morpholinophenyl)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 O ^11 O^'ΝΗ тю Ν 4-(4-(Azetidine-1-carbonyl)quinolin-6-yl)-A(methylsulfonyl)benzamide BCD-CDK8- 5-5 0 \Н 0 ^<S 'NH Αχ Υ Axl N Cl 4 -(4 -(Azetidin-1-carbonyl)2-chloroquinolin-6-yl)-A(methylsulfonyl)benzamide BCD-CDK8- 5-5С1 \ 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-pyrazol4-yl)phenyl)quinolin-6-yl)pyrrolidin-2-one BCD-CDK8- 6-13 \ N—N V ¹ G) ⁿ La N A-(2-Methoxyethyl)-4-(4-(1 methyl-\H-pyr azol-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 methods by which the compounds of the present invention can be prepared. The starting materials can be obtained from commercial sources or prepared using conventional methods known to those skilled in the art. It will also be apparent to those skilled in the art that the selective protection and deprotection steps, as well as the order in which these steps are performed, can be performed in varying orders, depending on the nature of the substituents, to successfully complete the synthesis presented below.

The abbreviations used in this description, including those given in the illustrative diagrams and subsequent examples, are well known to those of ordinary skill in the art. Some of the abbreviations used are 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.

The 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 each independently represents C, CH, N;

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

n represents 0, 1;

k represents 0, 1;

m represents 1, 2;

R1, _R3 each independently represents 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 by one or more R ₁₄ substituents;

X ₅ , X ₆ , X ₇ each independently represents 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 each independently represents H, Hal, hydroxy, C1-C6 alkyloxy;

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

R8, R9 each independently represents 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, wherein the heterocyclic ring formed by _R8 and _R9 may be unsubstituted or substituted with 1 or 2 substituents selected from an oxo group, C1-C6 alkyl;

R ₁₀ are 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 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 alkyl; -S(O) ₂ -C ₁ -C ₆ alkyl;

- 22 041908

Rn, R ₁₂ each independently represents H, hydroxy, C ₁ -C6 alkyl, C1-C6 alkoxy, C ₁ -C6 alkyloxy C1-C6 alkyl;

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

R ₁₅ , R ₁₆ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ 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 each independently represents H, C1-C6 alkyl;

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

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

In cases where the initial reagents or intermediate compounds contain OH and NH groups, they can be protected by (2-(trimethylsilyl)ethoxy)methylacetal, trialkylsilyl or alkyl(diaryl)silyl protecting groups.

The reaction between compound 1 and compound B to form compound 2 can be carried out according to the following reactions: Suzuki between aryl halide 1 and aryl boronic acid B in the presence of a palladium catalyst and a base (A=Hal, Y=-B(OH) ₂ ); Buchwald-Hartwig between aryl halide 1 and amine B in the presence of a palladium catalyst and a base (A=Hal, Y=H); between carboxylic acid 1 and amine B using the methodology for obtaining an amide bond with the participation of carbodiimide (A=COOH, Y=H); between carboxylic acid chloride 1 and amine B using the methodology for obtaining an amide bond in the presence of a base such as a trialkylamine (A=C(O)Cl, Y=H). The synthesis of compound 3 from compound 2 and compound C can be accomplished using the following reactions: Suzuki reaction between aryl halide 2 and aryl boronic acid C in the presence of a palladium catalyst and a base (W=Hal, Y=-B(OH) ₂ ); Buchwald-Hartwig reaction 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 using the methodology for obtaining an amide bond with the participation of carbodiimide (W=COOH, Y=H); between carboxylic acid chloride 2 and amine C using the methodology for obtaining an amide bond in the presence of a base such as a trialkylamine (W=C(O)Cl, Y=H); between carbonitrile 2 and amine C using 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 accomplished by the following reactions: Suzuki reaction between aryl halide 4 and aryl boronic acid C in the presence of a palladium catalyst and a base (W=Hal, Y=-B(OH) ₂ ); Buchwald-Hartwig reaction 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 using the amide bond preparation methodology with carbodiimide (W=COOH, Y=H); between carboxylic acid chloride 4 and amine C using the amide bond preparation methodology in the presence of a base such as a trialkylamine (W=C(O)Cl, Y=H); between carbonitrile 4 and amine C using the amidine preparation methodology using organomagnesium reagents (W=CN, Y=H); between compound 4 and acid chloride C by the acylation reaction (W=H, Y=C(O)Cl); 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 to form compound 3 can be accomplished by the reactions: Suzuki between aryl halide 5 and aryl boronic acid B in the presence of a palladium catalyst and a base (A=Hal, Y=B(OH) ₂ ); Buchwald-Hartwig between aryl halide 5 and amine B in the presence of a palladium catalyst and a base (A=Hal, Y=H); between carboxylic acid 5 and amine B by the methodology of obtaining an amide bond with the participation of carbodiimide (A=COOH, Y=H); between carboxylic acid chloride 5 and amine B by 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, _X2 , _X3 , R1, _R2 , _R3 , L1, k, Hal, Y have the above values.

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 _Ь X ₂ , X ₃ , R^ R ₃ , R4, L ₂ , n, k, Hal, Y have the above values.

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

Compound 3' is a variant of compound 3 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 values.

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

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 values.

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 have the above values.

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

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

Scheme 7

where R2, R4, L1, Y, Hal have the above values.

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

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

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

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

Scheme 8

where R1, R2, R ₃ , R4, L1, L2, Y, Hal have the above meanings.

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

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

Scheme 9

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

When the starting reagents or intermediates contain OH or NH groups, they can be protected with (2-(trimethylsilyl)ethoxy)methylacetal, trialkylsilyl, or alkyl(diaryl)silyl protecting groups. Removal of the protecting group can be accomplished in the final stages of the synthesis with a strong acid such as HCl or trifluoroacetic acid.

In the case where the R ₂ , R4 radicals in the final structures contain the -COOC1C ₆ alkyl ether group, this ether group can be converted into the -COOH group by reaction with strong bases such as lithium, sodium or potassium hydroxide, followed by treatment with an acid such as hydrochloric or citric acid. Further, such a -COOH group can be converted into the -C(O)NH ₂ functional group by reaction with ammonium chloride in the presence of carbodiimide; or it can be converted into the -C(O)-NH-S(O) ₂ -C ₁ -C ₆ alkyl functional group by reaction with C ₁ -C ₆ alkyl-S(O) ₂ NH ₂ . In the case where the R ₂ , R4 radicals in the final structures contain the CN functional group, it can be hydrolyzed into the -C(O)NH ₂ functional group. The NH group in a heterocyclic moiety, such as in pyrazole, can be converted into an NC ₁ -C ₆ alkyl group using alkylating reagents such as methyl iodide, ethyl bromide, isopropyl iodide, in the presence of a base such as sodium hydride. The -OC ₁ -C ₆ alkyl group can be converted into an OH group by reaction with AlCl ₃ upon heating. The azetidine ring can be opened by the action of a hydrohalic acid such as hydrochloric acid to form a hydrogen halide addition product. The intermediate compounds can optionally be obtained and isolated as acid salts, such as hydrochloride, trifluoroacetate, and others, or with bases, such as sodium, potassium, ammonium, trialkylammonium, and other salts.

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

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

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 the individual dose of each dosage form does not necessarily constitute an effective amount, since the required effective amount can be achieved by administering several unit dosage forms.

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

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

The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral administration of drugs is the ingestion of a drug through the mouth (Latin: per os, oris), by swallowing the drug. The compounds of the present invention can also be administered buccally, lingually, or sublingually, so that the compound enters the bloodstream directly from the oral cavity.

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

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

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 involves physically breaking the integrity of the tissue of a subject and introducing the pharmaceutical composition through the tissue break, 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 introducing 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 contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intra-articular 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 typically comprise the active ingredient in association with a pharmaceutically acceptable carrier, such as sterile water or a sterile isotonic solution. Such dosage forms may be manufactured, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable dosage forms may be manufactured, packaged, or

- 27 041908 are sold in unit dosage form, such as ampoules or 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 designed 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 cyclin-dependent protein kinases CDK8/19, 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 the present invention to a subject in need of such treatment.

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

In another embodiment, the present invention relates to a method of treatment 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 understood that the compounds of the present invention may be used in methods of treatment as described above, may be used in a treatment as described above, and/or may be used in the manufacture of a medicament for a treatment as described above.

As used herein, the terms co-administration, co-administered, and in combination with, referring to the present 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 in need of treatment, when such components are formulated together in a single dosage form from which said components are released substantially simultaneously, the 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 administration of which occurs at substantially the same time to said patient, after which said components are released substantially simultaneously, 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 separately from one another in separate dosage forms, which are taken sequentially in time to said patient with a significant time interval between each administration, after which said components are released at different times; and also the sequential administration of such a combination of a compound of the present 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 said components occurs in a controlled manner, after which they are released simultaneously, sequentially or jointly at the same time and/or different times, where each part can be administered by the same or different routes.

Those skilled in the art recognize that therapeutically effective dosages may vary when drugs are used in combination therapy. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination therapy regimens are described in the literature. For example, the use of uniform dosing, i.e., administering smaller and more frequent doses to minimize toxic side effects, is described in the literature. Combination therapy also includes intermittent treatment, which is started and stopped at different times according to the patient's treatment plan. In the combination therapy described in this patent, the dosages of the co-administered compounds undoubtedly vary depending on the type of adjuvant used, the specific drug used, the disease or condition being treated, etc.

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

Compounds that are CDK8/19 inhibitors can be used in the treatment methods 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 anticancer agents. Examples of anticancer agents include, but are not limited to, any of the following: alkylating agents, alkylated sulfonates, nitrosoureas, or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; antitumor antibiotics; and topoisomerase inhibitors.

Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, calcium levofolinate) or pyrimidine analogs (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxouridine, azacitidine, enocitabine, carmofur, gemcitabine, sapacitabine, elacytarabine, doxifluridine), or purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine), or asparaginase.

Examples of alkylating agents include, but are not limited to, mechlorethamine, cyclophosphamide, chlorambucil, menphalan, bendamustine, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, laromustine, semustine, streptozocin, dacarbazine, ifosfamide, improsulfan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, treosulfan, carbochion, apazichion, fotemustine, altretamine, glufosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, VAL-083.

Examples of hormonal agents and hormonal antagonists include, but are not limited to, prednisone, prednisolone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, diethylstilbestrol, estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, fluocortolone, fulvestrant, goserelin, histrelin, leuprorelin, mitotane, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin-alpha, toremifene, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane.

Examples of platinum compounds include, but are not limited to, cisplatin, carboplatin, oxaliplatin, eptaplatin, miriplatin hydrate, lobaplatin, nedaplatin, picoplatin, satraplatin.

Examples of antitumor antibiotics include, but are not limited to, doxorubicin, daunorubicin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pirarubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plicamycin, peplomycin, mitomycin C, zinostatin, streptozocin.

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

Examples of anticancer agents include, but are not limited to, any of the following: microtubule-active agents such as taxanes (e.g., paclitaxel, docetaxel, cabazitaxel, tesetaxel), vinca alkaloids (e.g., vinorelbine, vinblastine, vincristine, vindesine, vinflunine); mitogen-activated protein kinase signaling inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002); mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus, ridaforolimus); antibodies (eg, rituximab, trastuzumab, alemtuzumab, besilesomab, cetuximab, denosumab, ipilimumab, bevacizumab, pertuzumab, nivolumab, ofatumumab, panitumumab, tositumomab, catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, EDM-525797); kinase inhibitors (fosmatanib, entospletenib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dasatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, bosutinib, axitinib, afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, motesanib, neratinib, orantinib, ponatinib, radotinib, tipifarnib, tivantinib, tivozanib, trametinib, apatinib, ibrutinib, acalabrutinib, cobimetinib, fedratinib, brivanib alaninate, cediranib, cabozantinib, icotinib, cipatinib, rigosertib, pimasertib, buparlisib, idelalisib, midostaurin, perifosine, XL-647); photosensitizers (eg, talaporfin, temoporfin, porfimer sodium); cytokines (eg, aldesleukin, interferon alfa, interferon alfa-2a, interferon alfa-2b, celmoleukin, tasonermin, recombinant interleukin-2, oprelvekin, recombinant interferon beta-1a); vaccines (eg, picibanil, sipuleucel-T, vitespen, emepipepimut-S, oncoVAX, rindopepimut, troVAX, MGN-1601, MGN-1703); bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, amsacrine, brostallicin, miltefosine, romidepsin, plitidepsin, eribulin, ixabepilone, fosbretabulin, denileukin diftitox, ibritumomab tiuxetan, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab-ozogamicin, aflibercept, oportuzumab monatox, cintredequin besudox, edotreotide, inotuzumab-ozogamicin, naptumomab estaphenatox, 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, pegaspargase, pentostatin, endostatin, sizofiran, vismodegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide, etanidazole, ganetespib, idronoxyl, iniparib, lonidamine, nimorazole, procodazole, tasquinimod, telotristat, belinostat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, reolizin, retaspimycin, trebananib, virulizin.

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

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

The compounds of the present invention will be administered in an amount effective for the treatment of the condition in question, i.e., at doses and for periods of time necessary to achieve the desired result. The therapeutically effective amount may vary depending on factors such as the specific condition being treated, the age, gender, and weight of the patient, and whether the compounds are administered as a stand-alone treatment or in combination with one or more additional therapies.

Dosage 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 a period of time, or the dose may be proportionally decreased or increased depending on the exigencies of the therapeutic situation. It is particularly advantageous to formulate oral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages for the patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

It should also be understood that for any given patient, specific administration regimens should be adjusted over time according to individual needs and at the discretion of the healthcare professional administering or supervising the administration of the compositions, and that the concentration ranges provided herein are provided as examples only and are not intended to limit the scope or practice of the claimed compositions. Furthermore, the dosage regimen for the compositions of the present invention may be based on various factors, including the type of disease, age, weight, gender, health condition of the patient, the severity of the condition, the route of administration, and the specific compound of the present invention used. Thus, the dosage regimen may vary widely, but can be determined regularly using standard methods. For example, doses can 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 escalations, which are determined by a skilled artisan. The determination of the required dosage and regimens are well known in the relevant art and will be understood by one skilled in the art after becoming familiar with the teachings disclosed herein.

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

As the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dosage, frequency, or both may be reduced, depending on symptoms, to a level that maintains a milder state of the disease, disorder, or condition. However, patients may require periodic treatment over the long term if symptoms recur.

The above range is only suggestive, as the number of variables in individual treatment regimens is large, and significant deviations from these recommended values are quite common. These dosages may be modified 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 individual subject's needs, the severity of the disease or condition being treated, and the judgment of the treating physician.

To better understand the invention, the following examples are provided. These examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

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

Examples

Example 1. Method for obtaining 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 h, then poured into 500 mL of water. The suspension was filtered, the precipitate was washed with water, dissolved in ethyl acetate, and washed with 0.1 M HCl solution. The solvent was distilled off in vacuo. Product 1-1-3 was isolated by column chromatography on silica gel using hexane-ethyl acetate (8:2) as an orange powder. Yield 1.33 g (55%).

Step 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 at 45°C and used in the next step without further purification.

Stage 3.

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

Stage 4.

A mixture of compound 1-1-1 (200 mg, 0.44 mmol), trimethyl orthoformate (5 mL, 46 mmol), p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol), and 10% wt. Pd/C (40 mg) in 30 mL of methanol was subjected to hydrogen gas bubbles at atmospheric pressure and 25°C for 4 h. The suspension was then filtered through celite, and 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. Method for obtaining BCD-CDK8-1-6a

BCD-CDK8-1-be BCD-CDK8-1 -6a

A solution of LiOH-H ₂ O (40 mg, 0.95 mmol) in 10 ml of water was added to a solution of BCD-CDK8-1-6e (270 mg, 0.63 mmol) in 20 ml of methanol. The solution was stirred at 100°C for 2 h. Methanol was distilled off in vacuo, 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. Method for obtaining 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 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol-formic acid (9:1:0.1) as a colorless powder. Yield 55 mg (66%). The compound was further purified by preparative chromatography.

Example 4. Method for obtaining 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), _NH4Cl (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 h. The reaction mixture was concentrated in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol (95:5 to 92:8) as a colorless powder. Yield 60 mg (85%). The compound was further purified by preparative chromatography.

Example 5. Method for obtaining the compound BCD-CDK8-1-2

EDCHC1 (1.45 g, 7.56 mmol) was added 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. The reaction mixture was stirred at room temperature for 12 h and washed with 1 M HCl solution and saturated NaHCO ₃ and NaCl solutions. The organic phase was concentrated in vacuo to give 1-2-4 as a colorless powder. Yield 1.0 g (82%).

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

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

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

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

Example 6. Method for obtaining the compound BCD-CDK8-1-3

-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)-III-pyrazole (11.5 g, 35.4 mmol) (prepared according to the procedure described in WO 2011/130146), Na ₂ CO ₃ (6.82 g, 64.3 mmol) and Pd(PPh ₃ ) ₄ (743 mg, 0.64 mmol) in a mixture of 100 ml THF and 50 ml water were stirred at 70°C under an inert atmosphere for 10 h. 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 column chromatography on silica gel 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 under a hydrogen atmosphere at 5 atm. After 5 h, the reaction mixture was filtered through Celite and 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°C for 30 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, and washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. The product 1-3-2 was isolated by column chromatography on silica gel using hexane-ethyl acetate (2:1) as an orange powder. Yield 712 mg (53%).

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

Step 6. Obtaining 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, 1 M 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 column chromatography on silica gel using dichloromethane-ethyl acetate-methanol (20:5:1) as an eluent as a colorless powder. Yield 132 mg (56%).

Example 7. Method for obtaining 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 warmed to room temperature. After 15 min at -20°C, methyl iodide (17 μL, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The product was isolated by column chromatography on silica gel using dichloromethane-methanol (96:4) as an eluent as a colorless powder. Yield 52 mg (61%).

Example 8. Method for obtaining 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-fluoronitrobenzene 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 compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-4-2 instead of compound 1-1-1.

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

Example 9. Method for obtaining 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 obtaining 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 compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-5-2 instead of compound 1-1-1.

Step 3. Compound BCD-CDK8-1-5 was prepared similarly 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 obtaining 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 obtaining 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 similarly to compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-9-1 instead of compound 1-1-1.

Example 13. Method for obtaining 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 similarly to compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-10-1 instead of compound 1-1-1.

Example 14. Method for obtaining 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 similarly to compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-11-1 instead of compound 1-1-1.

Example 15. Method for obtaining 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-fluoronitrobenzene 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 similarly to compound BCD-CDK8-1-6e (Example 1, Step 4), using compound 1-12-1 instead of compound 1-1-1.

Example 16. Method for obtaining 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-difluoronitrobenzene instead of 4-bromo-2-fluoronitrobenzene.

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

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

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

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

Example 18. Method for obtaining the compound BCD-CDK8-1-7

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

Example 19. Method for obtaining 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 compound 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 similarly to compound BCD-CDK8-1-3 (Example 6, Step 6), using compound 1-8-1 instead of compound 1-3-1.

Example 20. Method for obtaining 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 obtaining 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 of 1-3-4.

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

Step 3. Compound BCD-CDK8-1-13 was prepared 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 obtaining 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.

Step 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, and washed with 0.1 M HCl solution. The organic phase was concentrated in vacuo. The product was isolated by column chromatography on silica gel using hexane-ethyl acetate (1:1) as an orange powder. Yield 794 mg (81%).

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

Step 4. Compound BCD-CDK8-1-14 was prepared similarly 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 obtaining 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 obtaining 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-fluoronitrobenzene.

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

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

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

Example 26. Method for obtaining the compound BCD-CDK8-1-15 °уон °у-мн ₂ о ₽ Р_ ί ϊ Р □ ^N PP> 2x2?

BCD-CDK8-1-15a BCD-CDK8-1-15

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

Example 27. Method for obtaining compound BCD-CDK8-1-21a

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

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

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

Example 29. Method for obtaining 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. The reaction mixture was then brought to room temperature and stirred for 3 h. Then 300 mL of water was added and the mixture was extracted with ethyl acetate (3x150 mL). The organic layers were separated, washed with saturated solutions of Na ₂ CO ₃ and NaCl, and dried over Na ₂ SO ₄ . The reaction product 5-2-4 was obtained as a white powder after concentration of the solution in vacuo. Yield 2.38 g (97%).

Stage 2.

5-2-4 (700 mg, 2.10 mmol), 4-(dimethylamino)phenylboronic acid hydrochloride (464 mg, 2.31 mmol) and Cs ₂ CO ₃ (2.39 g, 7.34 mmol) were dissolved in 10 ml 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 h. Then 250 ml of water were added and the mixture was extracted with ethyl acetate (3x150 ml). The organic layers were separated, washed with a saturated NaCl solution, and dried over Na ₂ SO ₄ . Product 5-2-3 was isolated by column chromatography on silica gel, eluent hexane-ethyl acetate (9:1) as a yellow powder. Yield 514 mg (75%).

Stage 3.

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 was added Pd(PPh ₃ ) ₄ (90 mg, 0.078 mmol) under an inert atmosphere at room temperature. The resulting mixture was then stirred at 100°C for 1 h. The mixture was poured into water, the precipitated crystals were filtered off, and washed with water, yielding the product 5-2-2 as a yellow powder. Yield 236 mg (94%).

Stage 4.

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

Stage 5.

5-2-1 (150 mg, 0.513 mmol), (R)-3-hydroxypyrrolidine hydrochloride (70 mg, 5.64 mmol), HOBt (110 mg, 0.718 mmol) and DIPEA (0.357 mL, 2.05 mmol) were dissolved in 3 mL of DMF. EDC-HCl (138 mg, 0.564 mmol) was added portionwise to the mixture while cooling with an ice bath and the mixture was stirred for 16 h at room temperature. 100 mL of water was added and the product was extracted with ethyl acetate (3x70 mL). The organic layers were separated, washed with saturated NaCl solution and dried over Na ₂ SO ₄ . The product BCD-CDK8-5-2 was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (97:3) as a light brown powder. Yield 89 mg (48%).

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

pH

Stage 1.

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

Stage 2.

5-2i-1 (330 mg, 0.694 mmol) was dissolved in 5 ml of dichloromethane and, while cooling with an ice bath, 3 ml of a 4 M solution of HCl in 1,4-dioxane were added, and the mixture was kept at room temperature for 16 h. After the reaction was complete, 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-NH ₃ in methanol (7 M) (15:1) as a yellow powder. Yield 236 mg (94%).

Example 31. Method for obtaining 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. Compound BCD-CDK8-5-3 was prepared similarly to compound BCD-CDK8-5-2 (Example 29, Step 5), using compound 5-3-1 instead of compound 5-2-1 and morpholine instead of (R)-3-hydroxypyrrolidine hydrochloride.

Example 32. Method for obtaining 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 morpholine (butyldimethylsilyloxy)pyrrolidine.

Example 33. Method for obtaining the compound BCD-CDK8-5-4

(R)-3-(third place

Stage 1.

To 4-(4-bromophenyl)-1H-pyrazole (3.00 g, 0.01 mol) in 10 ml of DMF with stirring and cooling in an ice bath was added NaH (834 mg, 0.021 mol) portionwise. The reaction mixture was brought to room temperature and kept for 15 min. Then 2-(trimethylsilyl)ethoxymethyl chloride (3.36 g, 0.02 mol) was added. After 1 h, the mixture was poured into 300 ml of water and extracted with ethyl acetate (3x100 ml). The organic layers were separated, washed with a saturated NaCl solution, and dried over Na ₂ SO _4. The reaction product 5-4-5 was obtained as a light yellow powder after concentration of the solution in vacuo. Yield 3.42 g (88%).

Stage 2.

To a suspension of 5-4-5 (557 mg, 1.58 mmol), bis(pinacolato)diborane (600 mg, 2.36 mmol), potassium acetate (464 mg, 4.73 mmol), XPhos (150 mg, 0.316 mmol) in 20 ml of 1,4-dioxane was added palladium(II) acetate (35 mg, 0.158 mmol) under an inert atmosphere with stirring. The reaction mixture was kept at 80°C for 30 min. Then 5-2-4 (500 mg, 1.50 mmol), Na ₂ CO ₃ (835 mg, 7.88 mmol), Pd(PPh ₃ ) ₄ (182 mg, 0.158 mmol) and 10 ml of water were added. The reaction mixture was stirred at 80°C for 3 h. Then 250 ml of water were added, the product was extracted with ethyl acetate (3x150 ml). The organic layers were separated,

-40041908 was washed with a saturated NaCl solution and 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 compound BCD-CDK8-5-2 (Example 29, Step 5), using compound 5-4-2 instead of compound 5-2-1 and piperidine instead of (R)-3hydroxypyrrolidine hydrochloride.

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 in an ice bath. The solution was stirred for 16 h at room temperature. Then 50 ml of a saturated Na ₂ CO ₃ solution were added, and the mixture was extracted with dichloromethane (3x30 ml). The organic layers were separated, washed with a saturated NaCl solution, and dried over 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 obtaining 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 (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine.

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

Example 35. Method for obtaining 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 compound 5-2-4 and 4-methoxyphenylboronic acid instead of 4-(dimethylamino)phenylboronic acid hydrochloride.

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.

Step 3. _Palladium(II ) acetate (4 mg, 5 mol%) was added 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 _Cs2CO3 (259 mg, 0.796 mmol) in 5 mL of 1,4-dioxane under an inert atmosphere. The reaction mixture was stirred at 80°C for 4 h. Then 50 mL of water were added and the mixture was extracted with ethyl acetate (3x30 mL). The organic layers were separated, washed with saturated NaCl solution and dried _{over Na2SO4} . 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 obtaining the compound BCD-CDK8-5-7

Compound BCD-CDK8-5-7 was prepared analogously to compound 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 obtaining 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 and, while cooling, 4 ml of a 4 M HCl solution in 1,4-dioxane was added. The mixture was kept at room temperature for 72 h. After the reaction was complete, 0.25 ml of a 7 M NH ₃ solution in methanol was added with stirring, then the solvents were distilled off. The product BCD-CDK8-5-7i was isolated by column chromatography on silica gel, eluent dichloromethane NH ₃ in methanol (7 M) (15:1). Yield 70 mg (78%).

Example 38. Method for obtaining 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 compound 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. Compound BCD-CDK8-5-8 was prepared similarly to compound BCD-CDK8-5-2 (Example 29, Step 5), using compound 5-8-1 instead of compound 5-2-1 and piperidine instead of (R)-3-hydroxypyrrolidine hydrochloride.

Example 39. Method for obtaining 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 obtaining the compound BCD-CDK8-5-1Cl

- 42 041908

Step 1. A mixture of 5-iodisatin (2.00 g, 7.32 mmol), malonic acid (838 mg, 8.06 mmol), and sodium acetate (751 mg, 9.16 mmol) was refluxed for 10 h in 15 mL of acetic acid. The suspension was filtered, and 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-methoxycarbonylphenylboronic acid instead of 4-(dimethylamino)phenylboronic acid hydrochloride.

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

Step 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 h. After concentration, the product 5-1Cl-2 was isolated as a light yellow powder by column chromatography on silica gel, eluent hexane-ethyl acetate (3:1). Yield 457 mg (30%).

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

Step 6. Compound BCD-CDK8-5-1C1 was prepared (Example 3) using 5-1Cl-1 instead of BCD-CDK8-1-6a

Example 41. A method for obtaining the compound BCD-CDK8-5-1 similar to the compound BCD-CDK8-1-1

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

Example 42. Method for obtaining 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 similarly to compound BCD-CDK8-1-6a (Example 2), using compound 5-5Cl-2 instead of compound BCD-CDK8-1-6e.

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

Example 43. Method for obtaining the compound BCD-CDK8-5-5

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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 obtaining the compound BCD-CDK8-6-1

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

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

Step 2. Compound 6-1-1 was 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 4-(dimethylamino)phenylboronic acid hydrochloride.

Step 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 h. The reaction mixture was then poured into 50 mL of water, and a saturated solution of

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 and dried over Na ₂ SO ₄ . The product BCD-CDK8-6-1 was isolated as a yellow-orange powder by column chromatography on silica gel, eluent dichloromethanemethanol (97:3). Yield 61 mg (57%).

Example 45. Method for obtaining 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 heated at 100°C for 3 h. Volatiles were then removed under reduced pressure. Product 6-2-5 was obtained as a beige powder and used in the next step without further purification. Yield 476 mg (100%).

Step 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 h. After concentration, the product 6-2-4 was isolated as a white powder by column chromatography on silica gel, eluent hexane-ethyl acetate-dichloromethane (3:2:2). Yield 850 mg (72%).

Step 3. Compound 6-2-3 was 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 hydrochloride.

Step 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 boiled for 2 hours, methanol was distilled off, and a 0.1 M solution was added.

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

Stage 5.

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

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

Example 46. Method for obtaining 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 maintained at 60°C for 10 h. Then the solvent was distilled off, and a 7M solution of NH ₃ in methanol was added to the residue at 05°C. After concentration, the product 6-3-3 was isolated as a yellow liquid by column chromatography on silica gel, eluent dichloromethane-NH ₃ in methanol (7 M) (99:1). Yield 433 mg (63%).

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

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

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 similarly 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 obtaining the compound BCD-CDK8-6-5

- 45 041908

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

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 hydrochloride.

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 similarly to compound 6-2-1 (Example 45, Step 5), using compound 6-5-1 instead of compound 6-2-2.

Example 49. Method for obtaining the compound BCD-CDK8-6-6

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

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 hydrochloride.

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 similarly to compound 6-2-1 (Example 45, Step 5), using compound 6-6-1 instead of compound 6-2-2.

Example 50. Method for obtaining 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 similarly 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 obtaining 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 4-(dimethylamino)phenylboronic acid hydrochloride.

Step 2. Compound BCD-CDK8-6-8 was prepared similarly 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 obtaining 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 hydrochloride.

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 similarly 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 obtaining 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 obtaining 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 obtaining 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 obtaining compound BCD-CDK8-6-13

- 47 041908

was obtained similarly to the compound 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 obtaining 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 obtaining the compound BCD-CDK8-3-1

Stage 1.

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

410 mg (58%).

Stage 4.

A solution of LiOH-H ₂ O (42 mg, 1.00 mmol) in 5 mL of water was added dropwise to a solution of 3-1-3 (410 mg, 0.67 mmol) in 10 mL of methanol. The resulting mixture was stirred for 8 h. Then 1 M HCl solution was added until pH 4. The suspension was filtered, the precipitate was washed with water (3x20 mL), and dried in vacuo to constant weight, yielding product 3-1-2 as a white powder. Yield 360 mg (87%).

Stage 5.

To a solution of 3-1-2 (219 mg, 0.364 mmol), methanesulfonamide (42 mg, 0.437 mmol), and DMAP (7 mg, 0.05 mmol) in 15 mL of dichloromethane was added EDC-HCl (91 mg, 0.473 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 24 h. The product 3-1-1 was isolated as a white powder 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, 4 ml of 4 M HCl solution in diethyl ether were added dropwise. After two days, the reaction mixture was filtered and washed with diethyl ether (2 x 20 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 obtaining 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 similarly to compound BCD-CDK8-3-1 (Example 58, Step 6), using 3-13-1 instead of 3-1-1

Example 60. Method for obtaining the compound BCD-CDK8-3-2 on

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

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Example 61. Method for obtaining 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-methoxycarbonylphenyl boronic acid.

Example 62. Method for obtaining 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 obtaining 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 obtaining 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 obtaining 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. Compound BCD-CDK8-3-8 was prepared analogously to compound 3-1-3 (Example 58, Step 3), using compound 3-8-1 instead of compound 3-1-4 and 4-(dimethylamino)phenylboronic acid instead of 4-methoxycarbonylphenylboronic acid.

Example 66. Method for obtaining the compound BCD-CDK8-3-9

- 50 041908

Step 1. 5-Bromo-1,7-naphthyridine-3-carboxylic acid (2.22 g, 8.78 mmol) (prepared according to the procedure described in WO 2015/014768), DPPA (2.27 mL, 10.5 mmol), triethylamine (1.47 mL, 10.5 mmol) were suspended in anhydrous tert-butanol (50 mL). The mixture was refluxed for 8 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in 50 mL ethyl acetate, washed with water (2x40 mL), saturated NaHCO ₃ solution (50 mL), and saturated NaCl solution (50 mL). The organic layer was dried over Na ₂ SO ₄ . 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, 5 mL of 4 M HCl in diethyl ether was added with stirring. The reaction mixture was stirred for 1 h, then filtered, washed with diethyl ether, and dried in vacuo to constant weight. 3-9-2 was obtained. 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 of 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 solution of Na ₂ SO ₃ and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with a solution of NaCl and 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 compound 1-12.

Example 67. Method for obtaining 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 similarly to compound 3-1-1 (Example 58, Step 5), using compound 3-11-1 instead of 3-1-2.

Example 68. Method for obtaining 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 (prepared according to the procedure 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 similarly to compound 3-1-1 (Example 58, Step 5), using compound 3-12-1 instead of compound 3-1-2.

Example 69. Method for obtaining 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 ethyl 5-bromo-1,7-naphthyridine-3-carboxylate (prepared according to the procedure 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 obtaining 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 obtaining the compound BCD-CDK8-3-16

- 52 041908

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

Example 72. Method for obtaining 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-pyrolidone instead of 1-1-2.

Example 73. Method for obtaining the compound BCD-CDK8-3-18

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

The compound BCD-CDK8-3-18 was obtained similarly to the compound

1-2-4 (Example 5, Step 1), using 2-methoxyethylamine instead of azetidine hydrochloride and compound 3-14-1 instead of 4-nitro-3-fluorobenzoic acid.

Example 74. Method for obtaining 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 mixture was stirred overnight. Then 250 mL of water were added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated NaCl solution and dried over MgSO ₄ . The product 4-24-3 was isolated as a light yellow viscous liquid by column chromatography on silica gel 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°C. Then a 2.5 M solution of butyl lithium 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, N-methoxy-N-methylpyridine-2-carboxamide (990 mg, 5.90 mmol) (prepared according to the procedure described in Bioorganic and Medicinal Chemistry Letters, 19(16), 4639–4642; 2009) was added. After 20 min, the reaction mixture was diluted with 200 mL of saturated NH ₄ Cl solution, and the product was extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . Product 4-24-2 was isolated as a light yellow powder by column chromatography on silica gel in ethyl acetate-hexane (1:9). Yield 1.90 g (64%).

- 53 041908

Stage 3.

To a solution of 2-bromo-5-methoxybenzonitrile (250 mg, 1.18 mmol) dissolved in 1.5 ml of 1,4-dioxane were added 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 under an inert atmosphere at 85°C for 2.5 h. Compound 4-24-2 (510 mg, 1.18 mmol), Cs ₂ CO ₃ (1.15 g, 3.54 mmol), Pd(PPh ₃ ) ₄ (115 mg, 0.117 mol) and 0.5 ml of water were added to the resulting suspension. The reaction mass was stirred under an inert atmosphere for 6 h at 90°C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with MgSO _4. Product 4-24-1 was isolated as a light yellow powder by column chromatography on silica gel in acetone-hexane (2:8) system. 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 mixture was stirred for 8 h at room temperature. Then it was diluted with a saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried with MgSO ₄ . The reaction product BCD-CDK8-4-24 was isolated as a white powder by column chromatography in an acetone-hexane (5:5) system. Yield 157 mg (52%).

Example 75. Method for obtaining the compound BCD-CDK8-4-4

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

Example 76. Method for obtaining 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 similarly 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 obtaining 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 obtaining the compound BCD-CDK8-4-32

- 54 041908

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

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

Step 3. Compound BCD-CDK8-4-32 was prepared similarly 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 obtaining 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 obtaining the compound BCD-CDK8-4-21

Step 1. To a solution of 2-methoxy-N,N-dimethylaniline (3.00 g, 19.8 mmol) (prepared according to the procedure described in Angewandte Chemie International Edition, 55(23), 6776–6779, 2016) in 50 mL of acetonitrile was added N-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 similarly 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 obtaining the compound BCD-CDK8-4-1

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

Example 82. Method for obtaining 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 similarly to compound BCD-CDK8-4-24 (Example 74, Step 4), using compound 4-25-1 instead of compound 4-24-1.

- 55 041908

Example 83. Method for obtaining 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 obtaining compound BCD-CDK8-4-29

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

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

Example 85. Method for obtaining 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 obtaining the compound BCD-CDK8-4-22

Stage 1.

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

Stage 2.

To a suspension of compound 4-22-3 (2.97 g, 12 mmol) in 35 ml of chloroform was added POCl ₃ (1.71 ml, 18 mmol). The reaction mixture was stirred at reflux. After 2.5 h, the solvent was removed under reduced pressure, the residue was poured into ice water, and NaHCO ₃ was added. The reaction product was extracted with ethyl acetate, and the organic layer was dried with MgSO 4. The reaction product was isolated as a white powder by column chromatography on silica gel 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 similarly to BCD-CDK8-4-24 (Example 74, Step 4), using compound 4-22-1 instead of compound 4-24-1.

Example 87. Method for obtaining the compound BCD-CDK8-4-2

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

- 56 041908

Example 88. Method for obtaining 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 similarly 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 obtaining 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 obtaining 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 similarly 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 obtaining 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 obtaining the compound BCD-CDK8-4-23

Stage 1.

To a solution of o-methoxyaniline (2.50 g, 20 mmol) in 20 ml DMF were 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 h. Then 100 ml of water were 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 by column chromatography on silica gel, 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 -10°C. After 1 h, the solvent was distilled off in vacuo, the residue was dissolved in dichloromethane, washed with water, and dried over Na ₂ SO ₄ . The product was isolated as a dark gray powder by column chromatography on silica gel, 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 similarly 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 obtaining the compound BCD-CDK8-4-3

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

Example 94. Method for obtaining 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 similarly 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 obtaining 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 obtaining 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 similarly 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 obtaining 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 obtaining the compound BCD-CDK8-4-35

Step 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 m-methoxybenzoic acid chloride (862 mg, 5.07 mmol) in 10 mL of dichloroethane was added. The reaction mixture was stirred at the boiling point of the solvent for 1.5 h. The solvent was removed in vacuo. Ice water and a saturated solution of NaHCO ₃ were added to the residue. The suspension was filtered, the precipitate was dried in a vacuum oven, giving the reaction product as 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. Compound BCD-CDK8-4-35 was prepared similarly to compound BCD-CDK8-4-24 (Example 74, Step 4), using compound 4-35-1 instead of compound 4-24-1.

Example 99. Method for obtaining the compound BCD-CDK8-4-13

Compound BCD-CDK8-4-13 was prepared similarly 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 obtaining 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 4-(dimethylamino)phenylboronic acid hydrochloride.

Step 2. Compound BCD-CDK8-4-33 was prepared similarly 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 obtaining 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. Compound BCD-CDK8-4-34 was prepared similarly to compound BCD-CDK8-4-24 (Example 74, Step 4), using compound 4-34-1 instead of compound 4-24-1.

Example 102. Method for obtaining 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 hydrochloride.

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

Example 103. Method for obtaining 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 acid hydrochloride.

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

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

Example 104. Method for obtaining 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 acid hydrochloride.

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

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

was obtained analogously to compound 5-2-3 (example 29, step 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 similarly 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 obtaining 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. Compound BCD-CDK8-4-40 was prepared similarly to compound BCD-CDK8-4-24 (Example 74, Step 4), using compound 4-40-1 instead of 4-24-1.

Example 107. Method for obtaining 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 while cooling and then for another 30 min at room temperature. Then, while stirring and cooling with a water bath, methyl iodide (9 μl, 0.150 mmol, 1.7 equiv.) was added dropwise, and after 5 min the reaction mixture was brought to room temperature. After 1 h, 10 ml of water were poured in and the mixture was extracted with ethyl acetate (2x15 ml). The organic layers were washed with a saturated NaCl solution and 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 obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and (S)-3hydroxypiperidine hydrochloride instead of azetidine hydrochloride.

Example 109. Method for obtaining the compound BCD-CDK8-3-21

- 60 041908

Compound BCD-CDK8-3-21 was obtained similarly to compound BCD-CDK8-3-19 (example

107), using the BCD-CDK8-3-20 compound instead of BCD-CDK8-3-4

Example 110. Method for obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and dimethylamine hydrochloride instead of azetidine hydrochloride.

Example 111. Method for obtaining 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 obtaining 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 m-chloroperbenzoic acid (66 mg, 0.326 mmol, 1.15 equiv.) was added portionwise. After 1 h, 15 ml of water and 5 ml of dichloromethane were poured in, 1 M sodium hydroxide solution was added until 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 and dried over Na ₂ SO ₄ . The reaction product was isolated as a yellow powder by column chromatography on silica gel using ethyl acetate dichloromethane-methanol (5:4.7:0.3) as eluent. Yield 65 mg (57%).

Stage 2.

Compound CDK8-3-24-1 (30 mg, 0.074 mmol, 1.00 equiv.) was dissolved in 2 ml of pyridine and sprinkled with p-tosyl chloride (17 mg, 0.089 mmol, 1.20 equiv.). The mixture was left with stirring for 1 h at room temperature. The solvent was distilled off, 3 ml of ethanolamine was added to the reaction mixture, and 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 and dried in vacuo, giving the product as a yellow powder. Yield 25 mg (83%).

Example 113. Method for obtaining the compound BCD-CDK8-3-25

- 61 041908

Compound BCD-CDK8-3-25 was obtained similarly to compound BCD-CDK8-3-19 (example

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

Example 114. Method for obtaining the compound BCD-CDK8-3-26

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

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

Example 115. Method for obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and morpholine instead of azetidine hydrochloride.

Example 116. Method for obtaining 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 compound BCD-CDK8-3-33 instead of compound BCD-CDK8-3-18.

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

Example 117. Method for obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and 2-methoxyethanol instead of azetidine hydrochloride.

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

- 62 041908

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

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

Example 119. Method for obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and N-methylpiperazine instead of azetidine hydrochloride.

Example 120. Method for obtaining 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 compound BCD-CDK8-3-29 (Example 118, Step 2), using compound 3-31-3 instead of compound 3-29-1.

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

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

Example 121. Method for obtaining the compound BCD-CDK8-3-32

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

Step 2. Compound BCD-CDK8-3-32 was prepared similarly to compound 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 obtaining the compound BCD-CDK8-3-34

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

Step 2. Compound BCD-CDK8-3-34 was prepared similarly 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 obtaining 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 obtaining 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 instead of 4-nitro-3-fluorobenzoic acid and cyclopropylamine instead of azetidine hydrochloride.

Example 125. Method for obtaining 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 compound BCD-CDK8-3-37 instead of compound BCD-CDK8-3-18.

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

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

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

Example 127. Method for obtaining 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 compound BCD-CDK8-3-39 instead of compound BCD-CDK8-3-18.

Step 2. Compound BCD-CDK8-3-40 was prepared similarly 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 obtaining the compound BCD-CDK8-3-42

Compound BCD-CDK8-3-42 was prepared similarly 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 obtaining compound BCD-CDK8-3-41

Stage 1.

Nitrogen was bubbled 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 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 three times with ethyl acetate, the mother liquor was washed with water and NaCl solution (2x50 mL). The organic layer was separated, washed with water, and dried over Na ₂ SO ₄ . The product was isolated as a gray powder by column chromatography on silica gel, 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 similarly 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 the obtained compounds

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

Equipment data:

Chromatography-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 example compounds

Cipher ESI-MS. [M+H] ⁺ NMR 0, ppm 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, ZN), 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 Yu.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 (s, 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 the 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 the signal H ₂ O, 3H), 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 (br s, 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 (br s, 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 =9.8 Hz, 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 the 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+N] ⁺ 2H), 3.35 (w, 2H, in the H ₂ O signal), 2.96-2.84 (m, 2H), 2.51-2.25 (w, 8H), 2.18 (s, ZN), 2.12-2.01 (m, 2H), 1.52-1.39 (w, 2H), 1.11 (s, ZN). 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 in this paper was determined in artificial intestinal juice and human blood plasma.

SGF enzyme-free concentrate, pH 1.4, was used as artificial intestinal juice.

- 76 041908 (Sigma Ireland, cat#01651). The candidate stock solution (10 mM in DMSO) was diluted with a working solution of SGF 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 peak areas of the compounds in the test samples corresponding to the initial test time (before incubation) and the final test time (after incubation in a solid-state thermostat for 2 hours at a temperature of 37°C) were determined by HPLC using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was performed in gradient elution mode at a flow rate of 1 ml/min. The amount of substance in the sample was determined as a % after thermostatting.

Stability in human plasma was determined using pooled human plasma from ten healthy donors. The candidate stock solution (10 mM in DMSO) was diluted with pooled plasma to a concentration of 10 μM (test solution). The test solution was incubated in a solid-state thermostat for 4 hours at 37°C. Peak areas of the compounds in the test samples were determined by HPLC using an Agilent1200 chromatograph (Agilent, USA) at the initial test time (before incubation) and the final test time (after incubation in a solid-state thermostat for 4 hours at 37°C) with preliminary protein precipitation with acetonitrile. Chromatographic analysis was performed in gradient elution mode at a flow rate of 1 ml/min. The amount of substance in the sample was determined as % after incubation.

The stability of the compounds was assessed. The compounds described in this document have chemical stability values greater than 75%, i.e., they are chemically stable in the acidic environment of simulated gastric juice and in human blood plasma (Table 2).

Table 2. Results of determination of 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 incubating the reaction mixture containing 0.5 mg/ml pooled human liver microsomes (XenoTech, USA, cat# H2620), 10 μM compound, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat# NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer pH=7.4 in a solid-state thermostat at 37°C. The reaction was stopped with acetonitrile at a rate of 100 μl acetonitrile per 100 μl reaction mixture. After stopping the reaction, the samples were centrifuged for 10 min at 10,000 rpm. The supernatant was analyzed chromatographically using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was performed in gradient elution mode at a flow rate of 1 ml/min. A plot of the logarithm of the peak area versus time was plotted. The dependent coefficient of this line corresponded to the elimination constant k, which was used to calculate the half-life of the drug t _1/2 and the decomposition rate CL _int :

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) (Lininius protein) = ---------Based on the data obtained, a conclusion was made about the enzymatic stability of the candidates in human liver microsomes. The compounds of the present invention showed sufficient stability against the action of human liver microsomal enzymes and had an enzymatic degradation rate of Clint of less than 47 μl/min/mg. The results are presented in Table 3.

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Table 3. Results of determination of enzymatic stability of 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 s9 fractions of human liver

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

The rate of enzymatic degradation of the compound was determined by incubating the reaction mixture containing 0.5 mg/ml pooled S9 fractions of human liver (XenoTech, USA, cat#H0610), 10 μM compound, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat#NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer pH=7.4 in a solid-state thermostat at 37°C. The reaction was stopped with acetonitrile at the rate of 100 μl acetonitrile per 100 μl reaction mixture. After stopping the reaction, the samples were centrifuged for 10 min at 10,000 rpm. The supernatant was analyzed chromatographically using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was performed in gradient elution mode at a flow rate of 1 ml/min. A plot of the logarithm of the peak area versus time was plotted. The dependent coefficient of this line corresponded to the elimination constant k, which was used to calculate the half-life of the drug t _1/2 and the decomposition rate CL _int :

Elimination rate constant (k) = (— gradient)

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

Intnsic Clearance (CE^НЦЭш mg protein} * 1/2

Based on the data obtained, a conclusion was drawn regarding the enzymatic stability of the candidates in human liver S9 fractions. The compounds of the present invention demonstrated sufficient stability against liver S9 enzymes and exhibited an enzymatic degradation rate of Clint of less than 13 μL/min/mg. The results are presented in Table 4.

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Table 4. Results of determination of enzymatic stability of 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 permeability through a monolayer of Caco-2 cells allows us to evaluate the ability of substances to penetrate biological membranes through both active and passive transport.

Caco-2 intestinal epithelial cells were cultured in filter inserts (0.4 μm pore size, BD Falcon with High Density) for 21 days, after which the integrity of the monolayer was checked using Lucifer Yellow dye (Sigma-Aldrich, USA) according to the standard protocol. When setting up the A^B transfer (intestinal lumen-to-bloodstream transfer), solutions of the studied substances were added in a buffer with pH 6.5 (HBSS, 10 mM HEPES, 15 mM glucose solution) at a concentration of 10 μM to the upper chamber; the lower chamber was filled with a buffer with pH 7.4 (HBSS, 10 mM HEPES, 15 mM glucose solution, 1% BSA). When performing the VA transfer (bloodstream-intestinal lumen transfer), the upper chamber was filled with pH 6.5 buffer, and solutions of the test substances were added to the lower chamber at a concentration of 10 μM in pH 7.4 buffer. Propranolol, a highly permeable substance, was used as a control.

After incubation for 2 hours at 37°C in an atmosphere containing 5% _CO2 , the amounts of the test substances in the upper and lower chambers were determined by HPLC using an Agilent l200 chromatograph (Agilent, USA) with preliminary protein precipitation with acetonitrile. Chromatographic analysis was performed in gradient elution mode at a flow rate of 1 ml/min. 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 compound concentration in the original solution and in the samples from the wells of the upper and lower chambers was determined.

Permeability through the cell layer P _app was calculated using the formula

Рарр = (Qt) * V)/ (С ₍ 0) * t * Area), where

_Рар р - effective permeability constant, m/s

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

Area - membrane surface area (0.33 ^cm2 ), ^cm2 t - holding time (7200 s), s

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

C( _t ) is the concentration of the solution after 2 hours (in the A^B test, the concentration in the sample from the well of the lower chamber; in the B^A test, the concentration in the sample from the well of the upper chamber), μM

The efflux coefficient showed the ability of cells to eliminate a substance from the bloodstream. The value was calculated using the formula efflux = P _a pp b-a/ Papp A-B >

Where

P _{a p} a-b is the value of the direct analysis permeability A^B;

Раррв-А - the value of permeability of the reverse analysis В^А.

The compounds of the present invention demonstrated a high rate of direct intestinal-to-bloodstream transport, with an efflux coefficient of no more than 2, indicating that the Pgp transporter does not limit bioavailability. The results are presented in Table 5.

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

Connection number A - B, Rarr 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-based assay on continuous cell cultures of MV4-11 (biphenotypic myelomonocytic leukemia, ATCC® CRL-9591™), KG-1 (acute myelogenous leukemia, ATCC® CCL-246™), HL-60 (acute promyelocytic leukemia, ATCC® CCL-240™) cells using the vital dye AlamarBlue (ThermoFisher, #DAL1100). Cells were grown in RPMI-1640 medium (PanEco, #C330 p) supplemented with 10% FBS (Gibco, #16140-071), washed, and reseeded in 96-well culture plates (Corning, #3599) with 10χ ¹⁰³ cells in 100 μl of medium per well. The compounds to be tested 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 DMSO concentration was no more than 1%) and incubated at 37°C in an incubator with 5% CO ₂ for 120 h. After incubation, 15 μl of AlamarBlue reagent (ThermoFisher, #DAL1100) were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), then additionally incubated for 3 to 5 h at 37°C in an incubator with 5% CO ₂ . The number of living cells was detected on a microplate spectrophotometer (Tecan Infinite M200Pro, Switzerland), measuring the fluorescent signal at an excitation wavelength (XEx) of 540 nm and an emission wavelength (XEm) of 590 nm.

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

The CC ₅₀ value was determined in a cytotoxicity assay. The study was performed on HepG2 cells (hepatocellular carcinoma, ATCC® HB-8065™). Cells were seeded in 96-well plates (Corning, #3599) at a concentration of 20x10 ³ cells in 100 μl of medium per well and incubated for 72 h with the added compounds in a concentration range from 200 to 0.78 μM. Cell viability was assessed using the method described above. The results are presented in Table 6.

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

Number MV-4-11 Hep-G2 Number MV-4-11 Hep-G2 connections ICso, μM CC50, μM connections IC50, μM CC50, μM 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 specific activity of compounds in a cellular antiproliferative test on a panel of cell lines (KG-1, HL-60). Data are presented as average activity values obtained in several assays.

Connection number KG-1 HL-60 Connection number KG-1 HL-60 ICso, μM IC50, μM IC50, μM IC50, μM 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