RU2754441C2 - New cdk8/19 inhibitors - Google Patents

Abstract

FIELD: pharmaceutics.SUBSTANCE: described is a group of inventions including a compound by the formula Ior a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a method for inhibiting the biological activity of cyclin-dependent protein kinases CDK8/19 in a subject, a pharmaceutical composition intended for preventing or treating a disease or a disorder mediated by activation of a cyclin-dependent protein kinase CDK8/19, a method for treating a disease or a disorder mediated by activation of cyclin-dependent protein kinases CDK8/19, and an application of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for treating a disease or a disorder mediated by activation of cyclin-dependent protein kinases CDK8/19 in a subject in need of such treatment.EFFECT: invention expands the range of means for inhibiting the biological activity of cyclin-dependent protein kinases CDK8/19.21 cl, 9 tbl, 93 ex

Description

Technology area

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

State of the art

CDK8, along with the closely related isoform CDK19 in structural and functional characteristics, is an oncogenic kinase that regulates transcription (Xu, W. & L, JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452; Galbraith, MD, et al. (2010) CDK8: a positive regulator of transcription, Transcription. 1, 4-12; Firestein, R. & Hahn, WC (2009) Revving the Throttle on an oncogene: CDK8 takes the driver seat, Cancer Res 69, 7899-7901). In contrast to the more well-known members of the CDK family (such as CDK1, CDK2, and CDK4 / 6), CDK8 does not play a role in the regulation of the cell cycle, but knockout of the CDK8 gene in embryonic stem cells leads to the arrest of embryonic development (Adler, AS, et al. (2012) CDK8 maintains tumor de-differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139) due to its important role in the formation of the pluripotent stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). It should be noted that blocking CDK8 does not suppress the growth of normal cells (Adler, AS, et al. (2012) CDK8 maintains tumor de-differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139, Kapoor, A., et al. . (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109). The role of CDK8 in carcinogenesis is related to its unique function as a regulator of several transcription factors (Xu, W. & L, J.Y. (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452). High expression of CDK8 has been identified in colon cancer (Firestein, R., et al. (2010) CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival, Int. J. Cancer 126, 2863 -2873), melanoma (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109), while in these types of cancer, increased expression of CDK8 is observed in ~ 50 % of cases; a similar situation is observed in breast cancer and. ovarian 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 a poor prognosis in colon cancer (Gyorffy, V., et al. (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients, Breast Cancer Res . Treat. 123, 725-731).

Known mechanisms associated with CDK8 in cancer include upregulation of the Wnt / b-catenin pathway (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109; Alarcon , C, et al. (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways, Cell 139, 757-769), NF-kappaB-induced transcription (DiDonato, JA, et al. (2012) NF-kappaB and the link between inflammation and cancer, Immunol. Rev. 246, 379-400) and the TGF-beta signaling pathway (Acharyya, S., et al. (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis, Cell 150, 165-178). It has also been shown that CDK8 can maintain the pluripotent phenotype of embryonic stem cells, and that it may be associated with the phenotype of cancer stem cells (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). DNA damage chemotherapeutic drugs induce TNF-a, an activator of the transcription factor NFkB (Fabian et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol. 23, 329-336), in endothelial cells and in other stromal elements of the tumor microenvironment. Stromal TNF-a acts on tumor cells, where it induces NFkB-mediated production of the cytokines CXCL1 and CXCL2, which promote the survival and growth of tumor cells. CXCL 1/2 attracts myeloid cells to the tumor by binding to the CXCR2 receptor on the myeloid cell surface. The myeloid cells then secrete small calcium-binding proteins S 100A8 and A9, which are associated with chronic inflammation and tumor growth. S 100A8 / 9 acts on tumor cells, promoting both their metastasis and survival during chemotherapy (Huang, et al. (2012) MED 12 Controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling, Cell 151, 937-950).

A mechanism associated with CDK8 and CDK19 in autoimmune, inflammatory and allergic diseases is also known, in which chemical inhibition of CDK8 and CDK19 is able to induce Foxp3, a key transcription factor that controls Treg cell function, in an antigen-stimulated effector / memory, as well as naive CD4 + and CD8 + T cells (Akamatsu M. et al. (2019) Conversion of antigen-specific effector / memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8 / 19. Sei Immunol. 2019 Oct 25; 4 (40); Guo Z. et al. (2019) Inhibition of Cdk8 / Cdk19 Activity Promotes Treg Cell Differentiation and Suppresses Autoimmune Diseases. Front Immunol. 2019 Aug 20; 10: 1988; WO 2018139660; WO 2014194245; WO 2018027082).

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

Description of the invention

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

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

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

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

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

"Alkylsulfonyl" (-S (O) ₂ -C ₁ -C ₆ alkyl) means "alkyl", the definition of which is given above, attached to the corresponding fragment of the molecule through the sulfonyl group -SO ₂ -. Examples of alkylsulfonyls include, but are not limited to, methylsulfonyl, ethylsulfonyl, etc.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The term "disorder" means any condition that can be improved as a result of the treatment of the present invention. The definition of this term includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the occurrence of this disorder. Non-limiting examples of treatable diseases include cancers such as breast cancer, HER2 positive breast cancer, estrogen positive breast cancer (ER +), triple negative breast cancer (TNBC), ovarian cancer, metastatic ovarian cancer, stomach cancer, metastatic stomach cancer, endometrial cancer, salivary gland, lung, kidney, colon cancer, colorectal cancer, melanoma, metastatic melanoma, thyroid cancer, pancreatic cancer (PCa), prostate or bladder cancer, castration-refractory prostate cancer ; oncohematological diseases, leukemias, acute myeloid leukemia and lymphoid malignant neoplasms; neuronal, glial, astrocytal, hypothalamic and other granular, macrophage, epithelial, stromal and blastocoelic disorders; inflammatory, angiogenic and immunological disorders, autoimmune or allergic disorders, in particular IgA nephropathy; IgG4-related disease; IgG4-associated sclerosing disease; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); POEMS syndrome; agammaglobulinemia; axial spondioarthritis; axonal and neuronal neuropathy; allergic conjunctivitis; allergic rhinitis; amyloidosis; angiocentric eosinophilic fibrosis; ankylosing spondylitis; anti-GMB / anti-TMB nephritis; antisperm antibodies; antiphospholipid syndrome; Takayasu's arteritis; atopic dermatitis; autoimmune aplastic anemia; autoimmune inner ear disease; autoimmune hemolytic anemia; autoimmune hemolytic anemia with warm antibodies; autoimmune hyperlipidemia; autoimmune dysautonomy; autoimmune urticaria; autoimmune neuromyotonia (Isaacs syndrome); autoimmune retinopathy; autoimmune thrombocytopenic purpura; autoimmune testicular damage / autoimmune hypogonadism; autoimmune angioedema; autoimmune hepatitis; autoimmune diabetes; autoimmune immunodeficiency; autoimmune pericarditis; autoimmune progesterone dermatitis; autoimmune thyroiditis; diseases of incompatibility by blood groups; Addison's disease; Behcet's disease; Graves' disease (diffuse toxic goiter); Devik's disease (optic nerve neuromyelitis); Kawasaki disease; Castleman disease; Crohn's disease; Meniere's disease; Mucha-Habermann disease; Ormond's disease (retroperitoneal fibrosis); Raynaud's disease; Churg-Strauss disease; Chagas disease; Sjogren's disease; bullous pemphigoid; bullosa epidermolysis; vasculitis; vasculitis of the kidneys; vasculitis associated with antineutrophilic cytoplasmic antibodies; vesiculobullous dermatosis; temporal arteritis; temporal / giant cell arteritis; vitiligo; vitiligo and Wegener's granulomatosis; lupus nephritis; inflammatory aortic aneurysm; congenital heart block; vulgar pemphigus; gangrenous pyoderma; hemolytic anemia; hemorrhagic vasculitis; herpes gestational or gestational pemphigoid; dermatitis herpetiformis; gestational pemphigoid; giant cell arteritis (temporal arteritis); giant cell myocarditis; hypogammaglobulinemia; glomerulonephritis; granulomatosis with polyangiitis (Wegener's syndrome); woody conjunctivitis; dermatomyositis; dilated cardiomyopathy; discoid lupus; idiopathic recurrent macrohematuria; idiopathic inflammatory myopathy; idiopathic thrombocytopenic purpura; idiopathic inflammatory pseudotumor; idiopathic hypocomplementary tubulointerstitial nephritis; idiopathic pulmonary fibrosis; insulin-dependent diabetes mellitus (type 1); interstitial cystitis; true red cell aplasia; cardiomyopathy; contact dermatitis; Balo concentric sclerosis; hives; lichen planus / lichen sclerosus; leukocytoclastic vasculitis; limbic encephalitis; limited scleroderma (CREST syndrome); linear IgA-dependent bullous dermatosis; leafy pemphigus; Waldenstrom's macroglobulinemia; mediastinal fibrosis; myasthenic crisis; Lambert-Eaton myasthenic syndrome; myasthenia gravis; myasthenia gravis; microscopic polyangiitis; myositis; Coxsackie myocarditis; multifocal motor neuropathy; multifocal fibrosclerosis; narcolepsy; optic neuritis; undifferentiated connective tissue disease; neuromyelitis of the optic nerve (Devik's syndrome); neutropenia; nonspecific ulcerative colitis; nephritis associated with antibodies to the basement membrane of the tubules and glomeruli; opsoclonus; acute motor axonal neuropathy; acute hemorrhagic leukoencephalitis; acute disseminated encephalomyelitis; alopecia areata; palindromic rheumatism; paraneoplastic degeneration of the cerebellum; paraneoplastic syndrome; paraproteinemic polyneuropathy; paroxysmal nocturnal hemoglobinuria; pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS syndrome); conjunctival pemphigoid; pemphigoid of mucous membranes; primary biliary cholangitis (cirrhosis); primary sclerosing cholangitis; periaortitis; periarteritis; perivenous encephalomyelitis; peripheral neuropathy; peripheral uveitis; pernicious anemia; subacute bacterial endocarditis; polyglandular (polyendocrine) autoimmune syndrome 1 (candidopolyendocrine syndrome), 2 (Schmidt's syndrome), 3 types; polymyositis; polyneuropathy with organomegaly (POEMS syndrome); transverse myelitis; postinfarction syndrome; post-traumatic pericarditis; progesterone dermatitis; psoriasis; psoriatic arthritis; pemphigus; purple Schoenlein-Genoch; multiple sclerosis; reactive arthritis; graft versus host disease (GVHD); graft rejection due to antibodies to HLA; rheumatism; rheumatic fever; polymyalgia rheumatica; rheumatoid arthritis; reflex sympathetic dystrophy; refractory epilepsy; recurrent polychondritis; Cicatricial pemphigoid (RP) of the conjunctiva; sarcoidosis; type 1 diabetes mellitus; sympathetic ophthalmia; restless legs syndrome; Guillain-Barré syndrome; Goodpasture syndrome; Dressler's syndrome; Kawasaki syndrome; Kogan's syndrome; Lambert-Eaton syndrome; Mikulich's syndrome; Miller Fisher syndrome; Pari-Romberg syndrome (progressive facial hemiatrophy); Personage-Turner syndrome (neuralgic amyotrophy, idiopathic brachial plexopathy); postpericardiotomy syndrome; Reiter's syndrome; stiffness syndrome; Stiff-Person syndrome; Susak's syndrome; Tolosa-Hunt syndrome. (superior orbital fissure syndrome); cold agglutination syndrome (CAD); Sjogren's syndrome; Schmidt's syndrome; Evans syndrome; systemic lupus erythematosus; scleritis; scleroderma; scleroderma; lichen sclerosus; mixed connective tissue disease; mixed cryoglobulinemia; sporadic myositis with inclusions; Riedel's thyroiditis; Hashimoto's thyroiditis; thyroid ophthalmopathy; thyroid crisis; thrombotic thrombocytopenic purpura; thrombocytopenic purpura; uveitis; polyarteritis nodosa; erythema nodosum; universal alopecia; fetal and neonatal alloimmune thrombocytopenia; fibrosing alveolitis; fibromyalgia; cold hemagglutinin disease; Sydenham's chorea (small or rheumatic chorea); chronic Lyme disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic recurrent multifocal osteomyelitis; chronic sclerosing sialoadenitis (Küttner's inflammatory tumor); celiac disease; pure / true erythrocyte aplasia; experimental allergic encephalomyelitis; endocrine ophthalmopathy (thyroid ophthalmopathy, Graves ophthalmopathy, autoimmune ophthalmopathy); endometriosis; Hashimoto's encephalitis; encephalitis / encephalopathy associated with autoantibodies; eosinophilic fasciitis; eosinophilic esophagitis; essential mixed cryoglobulinemia; juvenile arthritis; juvenile diabetes (type 1 diabetes); juvenile myositis; juvenile rheumatoid arthritis; Moray's ulcer; ulcerative colitis.

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

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

Detailed description of the invention

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

X is selected from O, NR ₉ ;

Y is selected from N, C, CH;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

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

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₄ , R ₅ , R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals R ₁₇ or

R ₄ and R ₅ together represent an oxo group, or R ₄ and R ₅ together with R ₆ and Y represent a 5-6 membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from N, S or O, 5-6 membered heteroaryl with 1, 2 or 3 ring heteroatoms selected from N, S or O

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₉ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ is C ₁ -C ₆ alkyl, unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₄ and R ₅ are H or are collectively oxo.

In one embodiment, X is O or NH.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, R ₄ , R ₅ , R ₆ and Y together are triazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, morpholinyl, furanyl, thienyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

X is selected from O, NR ₉ ;

Y is selected from N, C, CH;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₄ , R ₅ , R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₇

or

R ₄ and R ₅ together represent an oxo group, or R ₄ and R ₅ together with R ₆ and Y represent a 5-6 membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from N, S or O, 5-6 membered heteroaryl with 1, 2 or 3 ring heteroatoms selected from N, S or O

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₉ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ are each independently H, C ₁ -C ₆ alkyl;

R ₁₇ represents C ₁ -C ₆ alkyl unsubstituted or substituted by Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₄ and R ₅ are H or are collectively oxo.

In one embodiment, X is O or NH.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, R ₄ , R ₅ , R ₆ and Y together are triazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, morpholinyl, furanyl, thienyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

X is selected from O, NR ₉ ;

Y is selected from N, C, CH;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals R ₁₇

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₉ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ is C ₁ -C ₆ alkyl, unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

X is selected from O, NR ₉ ;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₄ , R ₅ , R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₇

or

R ₄ and R ₅ together represent an oxo group

or

R ₇ and R ₈ together represent an oxo group;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals R ₁₇

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₉ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ is C ₁ -C ₆ alkyl, unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

Y is selected from N, C, CH;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₄ , R ₅ , R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₇

or

R ₄ and R ₅ together represent an oxo group, or R ₄ and R ₅ together with R ₆ and Y represent a 5-6 membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from N, S or O, 5-6 membered heteroaryl with 1, 2 or 3 ring heteroatoms selected from N, S or O, or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ is C ₁ -C ₆ alkyl, unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, R ₄ , R ₅ , R ₆ and Y together are triazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, morpholinyl, furanyl, thienyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

Y is selected from N, C, CH;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals R ₁₇

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ is C ₁ -C ₆ alkyl, unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

where n, m are each independently selected from 0, 1, 2, 3;

p, q are each independently selected from 0, 1;

Z is selected from O, NR ₁₀ ;

R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals;

R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals;

R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals R ₁₇

or

R ₇ and R ₈ together represent an oxo group;

R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ ; C ₁ -C ₆ alkyl-C (O) -C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ;

R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , each independently represents H, C ₁ -C ₆ alkyl;

R ₁₇ represents C ₁ -C ₆ alkyl unsubstituted or substituted with Hal, hydroxy, amino, carboxy, carboxamide;

представляет собой одинарную связь или двойную связь.

represents a single bond or double bond.

In one embodiment, R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl.

In one embodiment, R ₁ is N, N-dimethylacetamide, methyl.

In one embodiment, R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl.

In one embodiment, R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl.

In one embodiment, where R ₇ and R _{8 are} each H or are collectively an oxo group.

The compounds described in the present invention can be obtained in the form and / or can be used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: acid salts formed by reacting a free base compound with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acids, etc .; or with an organic acid such as acetic, propionic, nylon, cyclopentanpropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, trifluoroacetic, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-1-carboxylic acid, glucose methylene-bis-3-hydroxy-2-ene-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, etc.

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

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

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

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

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

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

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate thereof, and one or more pharmaceutically acceptable excipients. In yet another embodiment, the pharmaceutical composition of this invention is intended for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19. In yet another embodiment of the invention, the pharmaceutical composition of this invention is intended for the prevention or treatment of a disease or disorder mediated by the activation of the cyclin-dependent protein kinase CDK8 / 19, where the disease or disorder mediated by the activation of the cyclin-dependent protein kinase CDK8 / 19 is an oncological, oncohematological, autoimmune, inflammatory or allergic disease.

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

A typical composition is prepared by mixing a compound of the present invention and one or more excipients. Examples of excipients include, but are not limited to, diluents, carriers, fillers. Suitable carriers, diluents, fillers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend on the means and purpose for which the compound of the present invention is used. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to a mammal. In general, safe solvents are aqueous solvents such as water and other solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water as the main component and ethanol, propylene glycol, polyethylene glycols (eg, PEG400, PEG300), etc., and mixtures thereof. The compositions can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, glidants, processing aids, colorants, sweeteners, fragrances, flavors, and others. known additives to obtain a good appearance of a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug).

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

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

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

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

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

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

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

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

In yet another embodiment, the present invention relates to a method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, which is a cancer, hematological cancer, autoimmune, inflammatory or allergic disease, which comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to this invention, to a subject in need of such treatment, in a therapeutically effective amount.

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

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

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

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

• simultaneous administration of such a combination of a compound 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 almost the same time to the specified patient, after which these components are released almost simultaneously,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In another embodiment, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 by a compound of the present invention or a pharmaceutically acceptable salt, or a pharmaceutical composition containing such a compound, to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such a compound, for the treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 in a subject in need of such treatment, where the disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological, oncohematological, autoimmune, inflammatory or allergic disease, with an oncological or oncohematological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, HER2-positive breast cancer, hormone-dependent breast cancer, triple negative breast cancer (TNBC), prostate cancer, castration- refractory prostate cancer, metastatic ovarian cancer, metastatic stomach cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa); the autoimmune, inflammatory, or allergic disease is IgA nephropathy; IgC4-related disease; unrelated sclerosing disease; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); POEMS syndrome; agammaglobulinemia; axial spondioarthritis; axonal and neuronal neuropathy; allergic conjunctivitis; allergic rhinitis; amyloidosis; angiocentric eosinophilic fibrosis; ankylosing spondylitis; anti-GMB / anti-TMB nephritis; antisperm antibodies; antiphospholipid syndrome; Takayasu's arteritis; atopic dermatitis; autoimmune aplastic anemia; autoimmune inner ear disease; autoimmune hemolytic anemia; autoimmune hemolytic anemia with warm antibodies; autoimmune hyperlipidemia; autoimmune dysautonomy; autoimmune urticaria; autoimmune neuromyotonia (Isaacs syndrome); autoimmune retinopathy; autoimmune thrombocytopenic purpura; autoimmune testicular damage / autoimmune hypogonadism; autoimmune angioedema; autoimmune hepatitis; autoimmune diabetes; autoimmune immunodeficiency; autoimmune pericarditis; autoimmune progesterone dermatitis; autoimmune thyroiditis; diseases of incompatibility by blood groups; Addison's disease; Behcet's disease; Graves' disease (diffuse toxic goiter); Devik's disease (optic nerve neuromyelitis); Kawasaki disease; Castleman disease; Crohn's disease; Meniere's disease; Mucha-Habermann disease; Ormond's disease (retroperitoneal fibrosis); Raynaud's disease; Churg-Strauss disease; Chagas disease; Sjogren's disease; bullous pemphigoid; bullosa epidermolysis; vasculitis; vasculitis of the kidneys; vasculitis associated with antineutrophilic cytoplasmic antibodies; vesiculobullous dermatosis; temporal arteritis; temporal / giant cell arteritis; vitiligo; vitiligo and Wegener's granulomatosis; lupus nephritis; inflammatory aortic aneurysm; congenital heart block; vulgar pemphigus; gangrenous pyoderma; hemolytic anemia; hemorrhagic vasculitis; herpes gestational or gestational pemphigoid; dermatitis herpetiformis; gestational pemphigoid; giant cell arteritis (temporal arteritis); giant cell myocarditis; hypogammaglobulinemia; glomerulonephritis; granulomatosis with polyangiitis (Wegener's syndrome); woody conjunctivitis; dermatomyositis; dilated cardiomyopathy; discoid lupus; idiopathic recurrent macrohematuria; idiopathic inflammatory myopathy; idiopathic thrombocytopenic purpura; idiopathic inflammatory pseudotumor; idiopathic hypocomplementary tubulointerstitial nephritis; idiopathic pulmonary fibrosis; insulin-dependent diabetes mellitus (type 1); interstitial cystitis; true red cell aplasia; cardiomyopathy; contact dermatitis; Balo concentric sclerosis; hives; lichen planus / lichen sclerosus; leukocytoclastic vasculitis; limbic encephalitis; limited scleroderma (CREST syndrome); linear IgA-dependent bullous dermatosis; leafy pemphigus; Waldenstrom's macroglobulinemia; mediastinal fibrosis; myasthenic crisis; Lambert-Eaton myasthenic syndrome; myasthenia gravis; myasthenia gravis; microscopic polyangiitis; myositis; Coxsackie myocarditis; multifocal motor neuropathy; multifocal fibrosclerosis; narcolepsy; optic neuritis; undifferentiated connective tissue disease; neuromyelitis of the optic nerve (Devik's syndrome); neutropenia; nonspecific ulcerative colitis; nephritis associated with antibodies to the basement membrane of the tubules and glomeruli; opsoclonus; acute motor axonal neuropathy; acute hemorrhagic leukoencephalitis; acute disseminated encephalomyelitis; alopecia areata; palindromic rheumatism; paraneoplastic degeneration of the cerebellum; paraneoplastic syndrome; paraproteinemic polyneuropathy; paroxysmal nocturnal hemoglobinuria; pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS syndrome); conjunctival pemphigoid; pemphigoid of mucous membranes; primary biliary cholangitis (cirrhosis); primary sclerosing cholangitis; periaortitis; periarteritis; perivenous encephalomyelitis; peripheral neuropathy; peripheral uveitis; pernicious anemia; subacute bacterial endocarditis; polyglandular (polyendocrine) autoimmune syndrome 1 (candidopolyendocrine syndrome), 2 (Schmidt's syndrome), 3 types; polymyositis; polyneuropathy with organomegaly (POEMS syndrome); transverse myelitis; postinfarction syndrome; post-traumatic pericarditis; progesterone dermatitis; psoriasis; psoriatic arthritis; pemphigus; purple Schoenlein-Genoch; multiple sclerosis; reactive arthritis; graft versus host disease (GVHD); graft rejection due to antibodies to HLA; rheumatism; rheumatic fever; polymyalgia rheumatica; rheumatoid arthritis; reflex sympathetic dystrophy; refractory epilepsy; recurrent polychondritis; Cicatricial pemphigoid (RP) of the conjunctiva; sarcoidosis; type 1 diabetes mellitus; sympathetic ophthalmia; restless legs syndrome; Guillain-Barré syndrome; Goodpasture syndrome; Dressler's syndrome; Kawasaki syndrome; Kogan's syndrome; Lambert-Eaton syndrome; Mikulich's syndrome; Miller Fisher syndrome; Pari-Romberg syndrome (progressive facial hemiatrophy); Personage-Turner syndrome (neuralgic amyotrophy, idiopathic brachial plexopathy); postpericardiotomy syndrome; Reiter's syndrome; stiffness syndrome; Stiff-Person syndrome; Susak's syndrome; Tolosa-Hunt syndrome (superior orbital fissure syndrome); cold agglutination syndrome (CAD); Sjogren's syndrome; Schmidt's syndrome; Evans syndrome; systemic lupus erythematosus; scleritis; scleroderma; scleroderma; lichen sclerosus; mixed connective tissue disease; mixed cryoglobulinemia; sporadic myositis with inclusions; Riedel's thyroiditis; Hashimoto's thyroiditis; thyroid ophthalmopathy; thyroid crisis; thrombotic thrombocytopenic purpura; thrombocytopenic purpura; uveitis; polyarteritis nodosa; erythema nodosum; universal alopecia; fetal and neonatal alloimmune thrombocytopenia; fibrosing alveolitis; fibromyalgia; cold hemagglutinin disease; Sydenham's chorea (small or rheumatic chorea); chronic Lyme disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic recurrent multifocal osteomyelitis; chronic sclerosing sialoadenitis (Küttner's inflammatory tumor); celiac disease; pure / true erythrocyte aplasia; experimental allergic encephalomyelitis; endocrine ophthalmopathy (thyroid ophthalmopathy, Graves ophthalmopathy, autoimmune ophthalmopathy); endometriosis; Hashimoto's encephalitis; encephalitis / encephalopathy associated with autoantibodies; eosinophilic fasciitis; eosinophilic esophagitis; essential mixed cryoglobulinemia; juvenile arthritis; juvenile diabetes (type 1 diabetes); juvenile myositis; juvenile rheumatoid arthritis; Moray's ulcer; ulcerative colitis.

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

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

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

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

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

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

All publications, patents, and patent applications mentioned in this specification are incorporated by reference in this document. Although the above invention has been described in some detail, it will be readily apparent to those skilled in the art based on the teachings disclosed in this invention that certain changes and modifications can be made without departing from the spirit and scope of the appended embodiments.

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

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

Abbreviations used in the present description, including those set forth in the illustrative diagrams and the following examples, are well known to the average person skilled in the art. Some of the abbreviations are used like the following:

DMF - N, N-dimethylformamide;

THF - tetrahydrofuran;

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

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

MTBE - methyl tert-butyl ether;

TMEDA - N, N, N ', N'-tetramethylethane-1,2-diamine;

Pd (dppf) Cl ₂ * DCM - bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane;

HATU - 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide of hexafluorophosphate.

Examples of

Example 1. Synthesis of block A

Scheme 1. Synthesis of fragment A3

Example 1.1. Synthesis of compound A1

NaH in the form of a 60% suspension in mineral oil (1.45 g, 36.2 mmol) was added to 60 ml of DMF, stirred for 15 min, 4-methoxybenzyl alcohol (5.10 g, 36.2 mmol) was added, heated to 90 ° С in a nitrogen atmosphere, stirred for 30 min. , cooled to 20 ° С, 4-bromo-2-fluoro-1-iodobenzene (10.0 g, 32.9 mmol) was added. The reaction mass was stirred at 90 ° С for 5 h, cooled, poured into 300 ml of water, extracted with ethyl acetate (4 × 80 ml), washed with the extract with water (4 × 30 ml), saturated NaCl solution (30 ml), dried over Na ₂ SO ₄ , the solvent was distilled off in a vacuum, the residue was recrystallized from isopropanol. 10.4 g (75.8%) of product A1 was obtained.

Example 1.2. Synthesis of compound A2

1-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl) -1H-pyrazole (6.26 g, 29.5 mmol), A1 (10.00 g, 22.7 mmol), Cs ₂ CO ₃ (14.92 g, 45.3 mmol), Pd (dppf) Cl ₂ * DCM, (0.56 g, 0.68 mmol), dioxane (100 ml), and water (40 ml) were placed in a screw cap vessel. Nitrogen was bubbled through the reaction mass for 15 min, the vessel was closed and heated with stirring in a nitrogen atmosphere for 6 h at 100 ° C. After the completion of the reaction, the reaction mixture was cooled to room temperature, applied to silica gel, the product was isolated by column chromatography on silica gel, eluent hexane-ethyl acetate (8: 2), then (7: 3). The resulting yellowish oil was treated with a mixture of 40 ml of MTBE and 120 ml of hexane, the precipitate was filtered off, washed with hexane (30 ml), and dried in air. Received 5.77 g (69.0%) A2.

Example 1.3. Synthesis of compound A3

Nitrogen was bubbled through a suspension of A2 (3.00 g, 7.64 mmol), bispinacolatodiborane (2.97 g, 11.5 mmol) and KOAc (1.55 g, 15.27 mmol) in 45 ml dioxane for 10 minutes, then Pd (dppf) Cl ₂ * DCM ( 0.40 g, 0.50 mmol). The reaction mixture was stirred at 100 ° C in a nitrogen atmosphere for 3 hours, filtered through a celite layer, washed with 10 ml of dioxane, and the solvent was removed from the filtrate under reduced pressure. The product was purified by column chromatography on silica gel using ethyl acetate-hexane (8: 2) as eluent. The oily substance obtained after removal of the solvent was treated with a mixture of hexane and MTBE, and the precipitate was filtered off. Got 2.80 g (89%) A3.

Scheme 2 Synthesis of the A8 fragment

Example 1.4. Synthesis of compound A4

4- (4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl) -1H-pyrazole (2.00 g, 10.1 mmol), ethyl chloroacetate (3.75 g, 30.3 mmol), K ₂ CO ₃ (4.19 g, 30.3 mmol) in 30 ml of DMF was stirred in a nitrogen atmosphere at 50 ° С for 6 h. The reaction mixture was filtered, the solvent was removed under reduced pressure, the residue was dissolved in dichloromethane, dried over Na ₂ SO ₄ , the solvent was removed. Received 2.70 g (95%) A4 in the form of a yellow oily substance.

Example 1.5. Synthesis of compound A5

A4 (1.00 g, 3.39 mmol), A1 (1.42 g, 3.39 mmol), Cs ₂ CO ₃ (2.23 g, 6.78 mmol), Pd (PPh ₃ ) ₄ , (0.20 g, 0.17 mmol), in a mixture of 30 ml of dioxane , placed in a jar with a screw cap. Nitrogen was bubbled through the reaction mass for 15 min, the vessel was closed and heated with stirring in a nitrogen atmosphere for 12 h at 90 ° C. After the completion of the reaction, the reaction mixture was cooled to room temperature, applied to silica gel, the product was isolated by column chromatography on silica gel, eluent hexane - ethyl acetate - methanol (4: 1: 0.01). Received 0.88 g (58%) A5.

Example 1.6. Synthesis of compound A6

A5 (0.70 g, 1.41 mmol) was dissolved in 10 ml of THF, and a solution of LiOH (0.022 g, 0.51 mmol) in 20 ml of water was added to the resulting solution. The reaction mixture was stirred at 20 ° С for 1 h, THF was removed under reduced pressure, the pH of the remaining aqueous solution was adjusted to 3. The precipitate that formed was filtered off, washed successively with a small amount of ice-cold ethanol and ether, and dried. Received 0.48 g (89%) A6.

Example 1.7. Synthesis of compound A7

A6 (0.20 g, 0.48 mmol), dimethylamine hydrochloride (0.12 g, 0.72 mmol), HATU (0.28 g, 0.72 mmol), triethylamine (0.10 g, 0.96 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol) in 30 ml dichloromethane was stirred at room temperature for 2 h. After the completion of the reaction, the reaction mixture was applied to silica gel, the product was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (96: 3). Received 0.18 g (85%) A7.

Example 1.8. Synthesis of compound A8

Nitrogen was bubbled through a suspension of A7 (0.23 g, 0.49 mmol), bispinacolatodiborane (0.197 g, 0.74 mmol) and KOAc (0.10 g, 0.98 mmol) in 25 ml of dioxane for 15 minutes, then Pd (dppf) Cl ₂ * DCM ( 0.02 g, 0.025 mmol). The resulting mixture was stirred at 90 ° C under nitrogen atmosphere for 12 hours. The reaction mass was concentrated under reduced pressure, 30 ml of water was added to the residue, extracted with ethyl acetate (3 × 30 ml), the combined organic extracts were dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure, the product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (1: 2). Received 0.20 g (83%) A8.

Example 2. Synthesis of block B

Scheme 3

Example 2.1. Synthesis of compound B1-1

Cyclopropylmethylamine (3.00 g, 41.3 mmol) was dissolved in 15 ml of dichloromethane, a solution of di-tert-butyl dicarbonate (7.25 g, 33.1 mmol) in 30 ml of dichloromethane was added under cooling in an ice bath, the reaction mixture was stirred for 20 h at room temperature, the solvent and the excess amine was removed under reduced pressure. Received 6.40 g (113.0%) B1-1. The product was used in the next step without further purification.

Example 2.2 Synthesis of compound B1-2

It was synthesized similarly to B1-1 from 2-methoxyethylamine (6.00 g, 79.1 mmol) with a yield of 11.0 g (99.3%).

Example 2.3 Synthesis of Compound B2-1

NaH in the form of a 60% suspension in mineral oil (0.61 g, 15.2 mmol) was added with cooling in an ice bath in a nitrogen atmosphere to a solution of B1-1 (2.00 g, 11.7 mmol) in 30 ml of DMF. The reaction mixture was stirred at room temperature for 1 h, 4-bromobutyl acetate (2.96 g, 15.2 mmol) was added and stirred in a nitrogen atmosphere at 60 ° С for 6 h, cooled, added 100 ml of water, extracted with ethyl acetate (4 × 70 ml ), washed with water (3 × 30 ml) and saturated NaCl solution (30 ml). The product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (1:20). Received 1.34 g (40.2%) B2-1.

Example 2.4 Synthesis of compound B2-2

It was obtained similarly to B2-1 from B1-2 (1.00 g, 5.52 mmol) and 3-bromopropyl acetate (1.07 g, 6.08 mmol) with a yield of 1.24 g (81.5%).

Example 2.5 Synthesis of Compound B2-3

It was obtained similarly to B2-1 from B1-2 (3.00 g, 17.1 mmol) and 4-bromobutyl acetate (3.34 g, 17.1 mmol) with a yield of 2.02 g (44.4%).

Example 2.6 Synthesis of Compound B3-1

To a solution of B2-1 (1.33 g, 4.66 mmol) in 30 ml of dichloromethane, a 4N solution of HCl in dioxane (5.83 ml, 23.3 mmol) was added under cooling with ice water. The reaction mixture was stirred at room temperature for 20 h, the solvents were removed under reduced pressure, the residue was dissolved in 15 ml of water, the pH was adjusted to 8 with solid NaHCO ₃ , the product was extracted with dichloromethane (5 × 50 ml), dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure. Received 0.73 g (85.0%) B3-1.

Example 2.7 Synthesis of Compound B3-2

It was obtained similarly to B3-1 from B2-2 (1.24 g, 4.50 mmol) with a yield of 0.53 g (67.2%).

Example 2.8 Synthesis of Compound B3-3

It was obtained similarly to B3-1 from B3-2 (2.09 g, 7.22 mmol) with a yield of 1.03 g (75.3%).

Example 3. Synthesis of block C

Scheme 4

Example 3.1. Synthesis of compound C1

Diisopropylethylamine (36.9 g, 0.28 mol) and diphenylphosphoryl azide (55.6 g, 0.20 mol) were added to a solution of 2-chloropyridinecarboxylic acid (30.0 g, 0.19 mol) in 160 ml of toluene. The reaction mixture was stirred at room temperature for 2.5 hours, tert-butyl alcohol (20.1 g, 0.28 mol) was added and stirred for another 1.5 h at 80 ° С, cooled, washed with 20 ml water, dried over Na ₂ SO ₄ , the solvents were removed at reduced pressure. The product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (1: 9). Received 35.7 g (84.2%) C1.

Example 3.2. Synthesis of compound C2

A solution of C1 (35.7 g, 0.14 mol) and TMEDA (41.5 g, 0.35 mol) in 500 ml of tetrahydrofuran, cooled to -75 ° С, and a 2.5 M solution of BuLi in hexane (142 ml, 0.35 mol) was added dropwise so that the temperature of the reaction mixture did not rise above -64 ° C. The resulting mixture was stirred at -70 ° C for 1 hour, then heated for 30 minutes to -50 ° C and cooled again to -75 ° C. Ethyl formate (42.4 g, 0.57 mol) was added to the reaction mixture from a dropping funnel over 16 seconds, stirred for 1 h at -70 ° C, heated to -40 ° C, 10 ml of methanol and 150 ml of 15% NaCl solution were added, the organic layer was separated and washed with a saturated NaCl solution, dried over Na ₂ SO ₄ , the solvents were removed under reduced pressure. The product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (2: 8). Received 29.2 g (81.2%) C2.

Example 3.3. Synthesis of compound C3

To a solution of C2 (29.2 g, 0.11 mol) and ethyl 3,3-diethoxypropionate (32.5 g, 0.162 mol) in 220 ml of chloroform, trifluoroacetic acid (149 g, 1.30 mol) was added dropwise at 0 ° С. The reaction mass was boiled for 2 hours, the solvent was removed under reduced pressure. To the residue was added 200 ml of methyl tert-butyl ether, the formed precipitate was filtered off and dried. Received 22.5 g (98%) C3.

Example 3.4. Synthesis of compound C4

To a suspension of C3 (22.5 g, 0.103 mol) in 220 ml of tetrahydrofuran, a solution of LiOH (6.90 g, 0.162 mol) in 100 ml of water was added. The reaction mixture was stirred for 1 h, the solvent was removed under reduced pressure, 1N HCl solution was added to the residue until pH 2, the precipitate was filtered off and dried. Received 18.5 g (93.0%) C4.

Example 3.5 Synthesis of Compound C5-1

To a suspension of С4 (0.753 g, 3.96 mmol) in SOCl ₂ (4.76 g, 39.6 mmol), 0.3 ml of DMF was added and the reaction mixture was boiled for 4 h, SOCl _{2 was} removed under reduced pressure, the residue was concentrated with MTBE, then dissolved in 15 ml dichloromethane, cooled with stirring in an ice bath under nitrogen atmosphere. To the reaction mixture was added dropwise a solution of B3-1 (0.734 g, 3.96 mmol) and Et ₃ N (2.11 g, 19.8 mmol) in 8 ml of dichloromethane, stirred at room temperature for 20 h. The product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (1: 1). 1.14 g (76.4%) C5-1 was obtained.

Example 3.6. Synthesis of compound С5-2

It was obtained similarly to C5-1 from B3-2 (0.53 g, 3.02 mmol) and C4 (0.58 g, 3.02 mmol) with a yield of 0.89 g (81.0%).

Example 3.7. Synthesis of compound С5-3

It was obtained similarly to C5-1 from B3-3 (0.70 g, 3.68 mmol) and C4 (0.69 g, 3.68 mmol) with a yield of 0.96 g (68.7%).

Example 3.8. Synthesis of compound С6-1

Through a suspension of C5-1 (1.69 g, 4.49 mmol), tert-butyl carbamate (0.797 g, 6.74 mmol), Cs ₂ CO ₃ (2.96 g, 8.98 mmol), BINAP (0.577 g, 0.90 mmol), Pd (OAc) ₂ (0.103 g, 0.45 mmol) in 40 ml of dioxane, an intense stream of nitrogen was passed for 10 min, heated with stirring in a nitrogen atmosphere at 90 ° С for 2.5 h. The reaction mixture was cooled, the product was isolated by column chromatography on silica gel, the eluent was ethyl acetate. Received 1.02 g (49.6%) C6-1.

Example 3.9. Synthesis of compound С6-2

It was obtained similarly to C6-1 from C5-2 (0.85 g, 2.32 mmol) with a yield of 0.66 g (63.8%).

Example 3.10. Synthesis of compound C6-3

It was obtained similarly to C6-1 from C5-3 (0.92 g, 2.42 mmol) with a yield of 0.51 g (45.8%).

Example 3.11. Synthesis of compound С7-1

To a solution of С6-1 (1.02 g, 2.23 mmol) in 30 ml of dichloromethane, a 4N solution of HCl in dioxane (5.6 ml, 22.6 mmol) was added with stirring. The reaction mixture was stirred for 20 h at room temperature, concentrated under reduced pressure, the residue was dissolved in a mixture of 50 ml of dichloromethane and 50 ml of saturated NaHCO ₃ solution, the organic layer was separated, the aqueous layer was extracted with dichloromethane (3 × 30 ml), the organic layers were combined, washed 10 ml of water, dried over Na ₂ SO ₄ . The product was isolated by column chromatography on silica gel, eluent ethyl acetate-methanol (9: 1). 0.57 g (71.9%) С7-1 was obtained.

Example 3.12. Synthesis of compound С7-2

It was obtained similarly to C7-1 from C6-2 (0.66 g, 1.48 mmol) with a yield of 0.36 g (70.3%).

Example 3.13. Synthesis of compound С7-3

It was obtained similarly to C7-1 from C6-3 (0.42 g, 0.82 mmol) with a yield of 0.16 g (54.1%).

Example 3.14. Synthesis of compound С8-1

N-bromosuccinimide (0.316 g, 1.76 mmol) was added to a solution of С7-1 in (0.57, 1.60 mmol) in 15 ml of dichloroethane. The reaction mixture was stirred for 20 h at room temperature, 50 ml of dichloromethane was added, washed with 20 ml of water, dried over Na ₂ SO ₄ . The product was isolated by column chromatography on silica gel using ethyl acetate as eluent. Received 0.62 g (89.5%) C8-1.

Example 3.15. Synthesis of compound С8-2

It was obtained similarly to C8-1 from C7-2 (0.34 g, 0.98 mmol) with a yield of 0.29 g (69.5%).

Example 3.16. Synthesis of compound С8-3

It was obtained similarly to C8-1 from C7-3 (0.31 g, 0.60 mmol) with a yield of 0.27 g (99%).

Scheme 5. Synthesis of block C for candidates CDK8-macro-4 and CDK8-macro-13b

Example 3.17. Synthesis of compound С5-4

Synthesis of 4-aminobutyl acetate hydrochloride. 4-bromobutyl acetate (1.50 g, 7.69 mmol) and NaN ₃ (1.52 g, 23.1 mmol) in DMF (15 ml) were stirred at room temperature for 20 h, water (50 ml) was added, the product (4-azidoacetate) was extracted with MTBE (3 × 50 ml), washed with 20 ml of water, dried, the solvent was removed under reduced pressure, the residue was dissolved in 20 ml of THF, triphenylphosphine (4.05 g, 15.4 mmol) was added, stirred for 12 h, water (0.346 g, 19.2 mmol) was added, stirred for 8 h , the solvent was removed under reduced pressure, 30 ml of 2N HCl was added, extracted with ethyl acetate (2 × 20 ml), the aqueous layer was separated, concentrated, the residue was treated with a mixture of acetone and isopropanol (5: 1), the precipitate was filtered off and dried. 1.10 (85.3%) 4-aminobutyl acetate hydrochloride was obtained.

Synthesis of compound C5-4. To a suspension of С4 (0.600 g, 3.16 mmol) in SOCl ₂ (3.79 g, 31.6 mmol), 0.5 ml of DMF was added and the reaction mixture was boiled for 4 h, SOCl _{2 was} removed under reduced pressure, the residue was concentrated with MTBE, then dissolved in 10 ml dichloromethane, cooled with stirring in an ice bath under nitrogen atmosphere. To the reaction mixture was added dropwise a solution of 4-aminobutyl acetate hydrochloride (0.620 g, 3.70 mmol) and triethylamine (1.60 g, 15.8 mmol) in 7 ml of dichloromethane, stirred at room temperature for 20 h.The product was isolated by column chromatography on silica gel, eluent ethyl acetate -hexane (7: 3). Received 0.35 g (34.5%) C5-4.

Example 3.18. Synthesis of compound С5-13b

C5-13b was prepared analogously to C5-4 using 5-amino-3-oxabutyl acetate in 65% yield.

Example 3.19. Synthesis of compound C6-4.

NaH (as a 60% suspension in mineral oil) (0.065 g, 1.63 mmol) was added to a solution of С5-4 (0.35 g, 1.09 mmol) in 5 ml of DMF, stirred for 1 h, methyl iodide (0.325 g, 2.18 mmol), stirred for 20 h at room temperature, added 20 ml of water, extracted with ethyl acetate (5 × 20 ml), washed with water (4 × 10 ml), dried. The product was isolated by column chromatography on silica gel, eluent ethyl acetate-hexane (7: 3). Received 0.27 g (72.8%) C6-4.

Example 3.20. Compound C6-13b was synthesized similarly to C6-4 using C5-13b in 51.2% yield.

Example 3.21. Synthesis of compound C7-4

Through a suspension of С5-1 (1.38 g, 3.69 mmol), 4-methoxybenzylamine (0.62 g, 4.43 mmol), Cs ₂ CO ₃ (2.06 g, 6.27 mmol), BINAP (0.23 g, 0.37 mmol), Pd (OAc) ₂ (0.042 g, 0.18 mmol) in 40 ml of dioxane was passed an intense stream of nitrogen for 10 min, heated with stirring in a nitrogen atmosphere at 100 ° С for 2.5 h. The reaction mixture was cooled, the product was isolated by column chromatography on silica gel, the eluent was ethyl acetate. Received 1.48 g (91.9%) C6-1.

Example 3.22. Synthesis of compound С7-13b was obtained similarly to С7-4, using С6-13b with a yield of 32.3%)

Example 3.23. Synthesis of compound С8-4

A solution of С7-4 (1.48 g, 3.39 mmol) in CF ₃ COOH (17.1 g, 150 mmol) was stirred at 40 ° С for 20 h, volatile components of the reaction mixture were removed to dryness under reduced pressure, and 20 ml of a 5% solution was added to the residue NaHCO ₃ , stirred for 30 min, the precipitate was filtered off, washed with water, dried. Received 0.87 g (80.9%).

Example 3.24. Synthesis of compound С8-13b was obtained similarly to С8-4, using С7-13b with a yield of 97.3%

Example 3.25 Synthesis of Compound C9-4

N-bromosuccinimide (0.17 g, 0.95 mmol) was added in small portions to a suspension of С8-4 (0.25 g, 0.79 mmol) in 10 ml of dichloroethane at 0 ° С, the reaction mixture was stirred for 40 min at 20 ° С, 50 ml of dichloromethane was added , washed with 10 ml of water, dried over Na ₂ SO ₄ . The product was isolated by column chromatography on silica gel, eluent: dichloromethane-methanol (98: 2). Received 0.20 g (64.0%) C9-4.

Example 3.26. Synthesis of compound С9-13b was obtained analogously to С8-4, using С7-13b, yield 34.0%.

Example 4. Synthesis of macrocycles

Scheme 6. Synthesis of CDK8-macro-2, 4, 6, 7 candidates

Example 4.1. Synthesis of compound D1-1.

Argon was bubbled through a suspension of C8-1 (0.20 g, 0.46 mmol), A3 (0.232 g, 0.55 mmol), Cs ₂ CO ₃ (0.302 g, 0.92 mmol) in a mixture of 10 ml of dioxane and 4 ml of water for 15 minutes, then Pd (dppf) Cl ₂ * DCM (0.02 g, 0.025 mmol) was added, the reaction mixture was stirred in a nitrogen atmosphere at 90 ° С for 4 h. The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (99: 1). 0.3 g (> 100%) of D1-1 was obtained, the product was used in the next step without further purification.

Example 4.2. Synthesis of compound D2-1.

To a solution of D1-1 (0.330 g, 0.50 mmol) in 4 ml of THF was added LiOH (0.218 g, 5.10 mmol) in 4 ml of water at 20 ° С, stirred for 5 h, water was added to the reaction mixture, the pH was adjusted to 6 with a solution of 1 M HCl, extracted with dichloromethane, dried over Na ₂ SO ₄ . The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (95: 5). Received 0.183 g (59%) D2-1.

Example 4.3. Synthesis of compound D4-1.

Trifluoroacetic acid (0.171 g, 1.5 mmol) was added to a solution of D2-1 (0.183 g, 0.30 mmol) in 10 ml of dichloromethane, the reaction mixture was stirred for 2 h at 20 ° С. The solvent was removed under reduced pressure, the residue was dissolved in a mixture of 4 ml of THF and 4 ml of water, LiOH (0.065 g, 2.70 mmol) was added at 20 ° С, stirred for 20 h, 20 ml of water was added to the reaction mixture, the pH was adjusted to 7 with 1M solution HCl, extracted with dichloromethane, dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure. 0.20 g (> 100%) of D4-1 was obtained, the product was used in the next step without further purification.

Example 4.4. Synthesis of compound CDK8-macro-2.

To a solution of D4-1 (0.060 mg, 0.11 mmol) and triphenylphosphine (0.087 mg, 0.33 mmol) in 6 ml of toluene in an argon atmosphere was added dropwise a solution of diisopropyl azodicarboxylate (0.067 g, 0.33 mmol) in 1 ml of toluene at 20 ° С and stirred within 18 hours. The solvent was removed under reduced pressure, the product was isolated using preparative HPLC. Received 0.010 g (20%) CDK8-macro-2 in the form of a lyophilisate.

Example 4.5. Synthesis of compound D1-2.

Argon was bubbled through a suspension of C9-4 (0.05 g, 0.12 mmol), A3 (0.08 g, 0.18 mmol), Cs ₂ CO ₃ (0.08 g, 0.24 mmol) in a mixture of 1 ml of dioxane and 0.3 ml of water for 5 minutes, then Pd (dppf) Cl ₂ * DCM (0.005 g, 0.01 mmol) was added, the reaction mixture was stirred in a nitrogen atmosphere at 95 ° С for 5 h. The product was isolated by column chromatography on silica gel, eluent dichloromethane-methanol (98: 2). Received 0.03 g (42%) D1-2.

Example 4.6. Synthesis of compound D3.

Trifluoroacetic acid (0.2 ml, 0.74 mmol, 5 eq) was added to a solution of D1-2 (0.030 g, 0.05 mmol) in 1.5 ml of dichloromethane, the mixture was stirred for 20 h at room temperature, the solvent was removed under reduced pressure, 10 ml of a saturated solution of NaHCO _{3 was added} and 20 ml EtOAc. The aqueous layer was extracted with 20 ml EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (96: 4). Received 0.024 g (99%) D3.

Example 4.7. Synthesis of compound D4-2.

A solution of LiOH (0.006 g, 0.15 mmol) in 0.5 ml of water was added to a suspension of D3 (0.024 g, 0.05 mmol) in 1 ml, the reaction mixture was stirred for 1 h, volatile components were removed under reduced pressure, and a 4M HCl solution was added to the residue. methanol to pH 6. The solvents were removed under reduced pressure, the residue was concentrated with acetonitrile 4 times. Received 0.022 g (99.0%) D4-2.

Example 4.8. Synthesis of compound CDK8-macro-4.

Diisopropyl azodicarboxylate (0.045 g, 0.22 mmol) was added to a solution of D4-2 (0.022 g, 0.04 mmol) and triphenylphosphine (0.059 mg, 0.22 mmol) in 3 ml of THF in an argon atmosphere at 0 ° С. The reaction mixture was stirred at 35 ° С for 4 h. The solvents were removed under reduced pressure, the product was isolated using preparative HPLC. Received 0.008 g (42%) CDK8-macro-4 in the form of a lyophilisate.

Example 4.9. Synthesis of compounds D1-3 and D2-3.

Argon was bubbled through a suspension of C8-2 (0.264 g, 0.62 mmol), A3 (0.313 g, 0.74 mmol), Cs ₂ CO ₃ (0.409 g, 1.24 mmol) in a mixture of 10 ml of dioxane and 4 ml of water for 15 minutes, then Pd (dppf) Cl ₂ * DCM (0.026 g, 0.03 mmol) was added, the reaction mixture was stirred under nitrogen atmosphere at 90 ° С for 8 h. The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (95: 5). Received 0.22 g (55%) D1-3 and 0.15 g (39%) D2-3.

Example 4.10. Synthesis of compound D4-3.

Trifluoroacetic acid (0.171 g, 1.5 mmol) was added to a solution of D2-3 (0.140 g, 0.21 mmol) in 5 ml of dichloromethane, the reaction mixture was stirred for 36 h at 20 ° С, concentrated under reduced pressure, the residue was dissolved in a mixture of 5 ml water and 5 ml of THF, LiOH (0.112 g, 4.7 mmol) was added, the reaction mixture was stirred for 20 h, 5 ml of water was added, brought to pH 7 with 1M HCl, the product was extracted with dichloromethane, dried over Na ₂ SO ₄ . The product was isolated using preparative HPLC. Received 0.070 g (69%) D4-3.

Example 4.11 Synthesis of Compound CDK8-macro-6.

It was obtained similarly to CDK8-macro-2 from D4-3 with a yield of 0.006 g (10%).

Example 4.12. Synthesis of compound D1-4 and D2-4.

Argon was bubbled through a suspension of C8-3 (0.377 g, 0.82 mmol), A3 (0.343 g, 0.82 mmol), Cs ₂ CO ₃ (0.537 g, 1.63 mmol) in a mixture of 16 ml of dioxane and 8 ml of water for 15 minutes, then Pd (dppf) Cl ₂ * DCM (0.034 g, 0.04 mmol) was added, the reaction mixture was stirred under nitrogen atmosphere at 90 ° С for 5 h. The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (95: 5). Received 0.21 g (38%) D1-4 and 0.20 g (39%) and D2-4.

Example 4.13. Synthesis of compound D4-4.

Received similarly to D4-3 from D2-4 with a yield of 0.040 g (45%) (after purification by preparative HPLC).

Example 4.14. Synthesis of compound CDK8-macro-7.

To a solution of D4-4 (0.040 g, 0.08 mmol) and triphenylphosphine (0.083 g, 0.41 mmol) in 4 ml of toluene in an argon atmosphere was added dropwise a solution of diisopropyl azodicarboxylate (0.108 g, 0.41 mmol) in 1 ml of toluene at 20 ° С and stirred for 2 hours. To the reaction mass was added 10 ml of water, extracted with ethyl acetate (3 × 50 ml), the combined organic layers were washed with saturated NaCl solution, dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure, the product was isolated using preparative HPLC. Received 0.013 g (34%) CDK8-macro-7 in the form of a lyophilisate.

Example 4.15. Synthesis of compound D1-5.

D1-5 was obtained similarly to D1-1 from C9-13b with a yield of 88.9%

Example 4.16. Synthesis of compound D3-5.

D3-5 obtained similarly to D3-2 from D1-5

Example 4.17. Synthesis of compound D4-5.

D4-5 was obtained similarly to D4-2 from D3-5c in 45% yield

Example 4.18. Synthesis of compound CDK8-macro-13b.

CDK8-macro-13b was obtained similarly to CDK8-macro-4 from D4-5 in the form of acetic acid salt with a yield of 46.3%

Scheme 7. Synthesis of CDK8-macro-13a

Example 4.19. Synthesis of compound D4-6.

D4-6 was obtained similarly from A8 from C5-13b with a total yield of 11.1%

Example 4.20 Synthesis of Compound D5.

_{I 2} (0.015 g, 0.06 mmol) was added to a solution of D4-6 (0.01 g, 0.02 mmol), imidazole (0.005 g, 0.07 mmol) and triphenylphosphine (0.015 g, 0.06 mmol) in 0.3 mL of DMF. The reaction mixture was stirred at 20 ° С for 3 h, 2 ml of water was added, extracted with dichloromethane (6 × 3 ml), the product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (95: 5). Received 0.0036 g (30%) D5.

Example 4.21. Synthesis of compound CDK8-macro-13a.

A solution of D5 (0.016 g, 0.03 mmol), K ₂ CO ₃ (0.007, 0.05 mmol), 18-crown-6 (0.014 g, 0.05 mmol) in DMF 3 ml was stirred in a nitrogen atmosphere at 20 ° С for 20 h. The product was isolated using preparative HPLC. Received 0.005 g (39.2%) CDK8-macro-13a.

Scheme 8. Synthesis of CDK8-macro-8

Example 4.22. Synthesis of compound D1-5 and D2-5.

Argon was bubbled through a suspension of C8-1 (0.150 g, 0.34 mmol), A1-5 (0.186 g, 0.38 mmol), Cs ₂ CO ₃ (0.227 g, 0.69 mmol) in a mixture of 10 ml of dioxane and 4 ml of water for 15 minutes, then Pd (dppf) Cl ₂ * DCM (0.014 g, 0.02 mmol) was added, the reaction mixture was stirred in a nitrogen atmosphere at 90 ° С for 6 hours.The product was isolated by column chromatography on silica gel, eluent dichloromethane, dichloromethane-methanol (80 :twenty). Received 0.085 g (34%) D1-5 and 0.100 g (43%) D2-5.

Example 4.23. Synthesis of compound D3-5.

Trifluoroacetic acid (0.59 g, 5.14 mmol) was added to a solution of D1-5 (0.085 g, 0.12 mmol) and D2-5 (0.100 g, 0.15 mmol) in 10 ml of dichloromethane, the reaction mixture was stirred for 4 h at 20 ° С, was concentrated under reduced pressure, the residue was dissolved in a mixture of 2 ml of water and 2 ml of THF, LiOH (0.220 g, 5.14 mmol) was added, the reaction mixture was stirred for 20 h, 5 ml of water was added, brought to pH 7 with 1 M HCl, the product extracted with dichloromethane. The aqueous layer was concentrated under reduced pressure, the residue was treated with a mixture of 5 ml of dichloromethane and 5 ml of methanol, the solution was filtered from inorganic salts, the solvents from the filtrate were removed under reduced pressure, the product was purified using preparative HPLC. Received 0.056 g (41%) D3-5.

Example 4.24. Synthesis of compound D4-5.

To a solution of D3-5 (0.056 g, 0.11 mmol), HATU (0.049 g, 0.13 mmol), dimethylamine hydrochloride (0.010 g, 0.13 mmol) in 4 ml of acetonitrile was added a solution of diisopropylethylamine (0.042 g, 0.32 mmol) in 1 ml of acetonitrile and stirred for 2 h at 20 ° C. The solvent was removed under reduced pressure, the product was purified using preparative HPLC. Received 0.010 g (17%) D4-5.

Example 4.25. Synthesis of compound CDK8-macro-8.

To a solution of D4-3 (0.010 g, 0.02 mmol) and triphenylphosphine (0.029 mg, 0.11 mmol) in 2 ml of toluene in an argon atmosphere was added dropwise a solution of diisopropyl azodicarboxylate (0.022 g, 0.11 mmol) in 1 ml of toluene at 20 ° С and stirred within 4 h, the solvent was removed under reduced pressure, the product was purified using preparative HPLC. Received 0.003 g (31%) CDK8-macro-8.

Scheme 9. Synthesis of CDK8-macro-1.

Example 4.26. Synthesis of compound D6-1.

To a suspension of С4 (1.50 g, 7.00 mol) in 15 ml of SOCl _{2 was} added 0.2 ml of dimethylformamide, stirred at reflux for 1 h, concentrated under reduced pressure, the residue was concentrated a second time with toluene, dissolved in 10 ml of THF, and added dropwise at 0 ° С and vigorous stirring to a mixture of cyclopropylmethylamine (0.50 g, 7.00 mmol), NaHCO ₃ (1.72 g, 0.02 mol), 55 ml of tetrahydrofuran and 18 ml of water. The reaction mixture was stirred for 0.5 h at 0 ° С and for 1 h at 20 ° С, the solvent was removed under reduced pressure, 20 ml of water was added to the residue, the precipitate was filtered off, and the precipitate was dried. Received 1.56 g (89.0%) D6-1.

Example 4.27. Synthesis of compound D6-2.

D6-2 was obtained similarly to C6-1 with a yield of 0.80 g (46.0%).

Example 4.28. Synthesis of compound D6-3.

To a solution of D6-2 (0.80 g, 2.30 mmol) in 15 ml of dichloromethane was added dropwise a 4M HCl solution in dioxane (7.00 ml, 28.0 mmol). The reaction mixture was stirred at 20 ° С for 20 h, the solvent was removed under reduced pressure, 10 ml of water was added, the mixture was adjusted to pH 9 with a saturated solution of NaHCO ₃ , the precipitate was filtered off, and dried. Received 0.55 g (98.0%) D6-3.

Example 4.29. Synthesis of compound D6-4.

To a suspension of D6-3 (0.55 g, 2.10 mmol) in 6 ml of dichloroethane, N-bromosuccinimide (0.48 g, 2.70 mmol) was added in small portions at 0 ° С. The reaction mixture was stirred for 2 h, the precipitate was filtered off and dried. Received 0.54 g (82.0%) D6-4.

Example 4.30. Synthesis of compound D6-5.

D6-5 Obtained similarly to D1-1 with a yield of 0.34 g (57.0%).

Example 4.31. Synthesis of compound D6-6.

D6-6 Obtained similarly to D2-2 with a yield of 0.25 g (98.0%).

Example 4.32. Synthesis of compound D6-7.

To a suspension of D6-6 (0.10 g, 0.24 mmol), (2Z) -4-chlorobut-2-en-1-ol (0.10 g, 0.97 mmol) and triphenylphosphine (0.1 3 g, 0.48 mmol) in 2.5 ml of THF according to diisopropyl azodicarboxylate (0.10 g, 0.48 mmol) was added to drops at 0 ° С in an argon atmosphere. The reaction mixture was stirred at 20 ° С for 20 h, the solvent was removed under reduced pressure. The product was isolated by column chromatography on silica gel, eluent dichloromethane-ethyl acetate-acetone (6: 2: 2). Received 0.10 g (82.0%) D6-7.

Example 4.33. Synthesis of compound CDK8-macro-1.

_{KI (0.07 g, 0.42 mmol) and K 2} CO ₃ (0.06 g, 0.42 mmol) were added to a suspension of D6-7 (0.08 g, 0.14 mmol) in 40 ml of acetonitrile, the reaction mixture was stirred at reflux for 5 h, the solvent was removed under reduced pressure. The product was isolated using preparative HPLC. Received 0.01 g (16.0%) CDK8-macro-1 in the form of a salt with formic acid.

Scheme 10. Synthesis of CDK8-macro-10.

Example 4.34. Synthesis of compound CDK8-macro-10.

NaBH4 (0.007 g, 0.18 mmol) was added to a solution of CDK8-macro-4 (0.025 g, 0.060 mmol) in 0.25 ml of pyridine, the reaction mixture was stirred for 3 h at 100 ° С in a nitrogen atmosphere. The product was isolated using preparative HPLC. Received 0.006 g (24.8%) CDK8-macro-10.

Scheme 11. Synthesis of CDK8-macro-17.

Example 4.35. Synthesis of compound A9.

A9 was obtained similarly to A3 from 5-bromo-2- (1-methyl-1H-pyrazol-4-yl) aniline. Yield 96.6%

Example 4.36. Synthesis of compound C10.

C10 was obtained similarly to C9-4 from C4 and methyl 4- (methylamino) butanoate hydrochloride with a total yield of 29.8%

Example 4.37. Synthesis of compound D7.

D7 was obtained similarly to D1-2 from C10 and A9 with a yield of 22.1%

Example 4.38. Synthesis of compound D7-1.

D7 (0.12 g, 0.26 mmol) and LiOH (0.028 g, 0.65 mmol) were stirred in a mixture of 2.2 ml of THF and 1.2 ml of water at 20 ° С for 2 h, the pH of the reaction mixture was adjusted to 7 with 1N HCl. The product was isolated by column chromatography on silica gel, eluent dichloromethane - methanol (1: 1). 0.15 g (124%) D7-1 was obtained, the product was used in the next step without further purification.

Example 4.39. Synthesis of compound CDK8-macro-17.

To a solution of HATU (0.124 g, 0.32 mmol) in 1 ml of DMF, a solution of D7-1 (0.110 g, 0.22 mmol) and diisopropylethylamine (0.141 g, 1.08 mmol) in 2.3 ml of DMF. After the end of the addition, the solution was stirred for another 0.5 h at the same temperature. The product was isolated using preparative HPLC. Received 0.05 g (52.6%) CDK8-macro-17.

Example 5. Analysis of the obtained compounds.

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

Equipment data:

Example 6. Determination of the stability of compounds in human blood plasma.

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

The stability of the compounds was evaluated. The compounds described herein are chemically stable in human plasma (Table 4).

Example 7. Determination of enzymatic stability.

Analysis of the enzymatic stability of the compounds described in the present invention made it possible to assess their resistance to the action of enzymes of phase I of biotransformation in liver microsomes and S9 fractions of human liver.

The rate of enzymatic degradation of the compound in liver microsomes was determined by keeping a reaction mixture containing 0.5 mg / ml of pooled human liver microsomes (XenoTech, USA, cat. # H2620) in a solid-state thermostat at 37 ° C, 10 μM compound, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat. # NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer (pH 7.4). The rate of enzymatic degradation of the compound in human liver S9 fractions was determined by keeping in a solid-state thermostat at 37 ° C a reaction mixture containing 0.5 mg / ml of pooled S9 human liver fractions (XenoTech, USA, cat # Н0610), 10 μM compound, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat # NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer, pH = 7.4.

The reaction was stopped with acetonitrile at the rate of 100 μL of acetonitrile per 100 μL of the reaction mixture. After stopping the reaction, the samples were centrifuged for 10 minutes at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent1200 chromatograph (Agilent, United States). Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. A graph of the dependence of the logarithm of the area of the peak of the substance on time was built. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the half-life of the drug T _1/2 and the decomposition rate CL _int were calculated:

Based on the data obtained, it was concluded that the candidates are enzymatic in microsomes of the human liver and S9 fractions of the human liver. The compounds of the present invention showed sufficient resistance to the action of liver microsome enzymes and human liver S9 fractions, and had an enzymatic degradation rate CL _int less than 47 μl / min / mg and 24 μl / min / mg, respectively. The results are shown in Table 5.

Example 8. Determination of chemical stability

The chemical stability of the compounds described in this patent was determined in artificial intestinal juice and artificial gastric juice.

SIF without enzymes was used as artificial intestinal juice, pH = 6.5 (Sigma Ireland, cat # 55331). An enzyme-free SGF concentrate, pH = 1.4 (Sigma Ireland, cat # 01651) was used as artificial gastric juice. The candidate stock solution (10 mM in DMSO) was diluted with SIF / SGF working solution to a concentration of 10 μM (test solution). The test solution was kept in a solid-state thermostat for 2 hours at a temperature of 37 ° C. By HPLC using an Agilent 1200 chromatograph (Agilent, USA), the peak areas of the compounds in the test samples corresponding to the initial test time (before exposure) and the final test time (after incubation in a solid-state thermostat for 2 hours at 37 ° C) were determined. Chromatographic analysis was performed in a gradient elution mode at a flow rate of 1 ml / min. The amount of substance in the sample was determined in% after thermostating.

The stability of the compounds was evaluated. The compounds described herein are chemically stable in artificial biological environments (Table 6).

Example 9. Affinity of compounds for recombinant CDK8 protein in complex with Cyclin C in vitro.

The ability of the compounds described in this patent to bind to the CDK8 protein was determined using the LanthaScreen method (ThermoFisher). A FRET signal was detected proportional to the amount of CDK8-bound fluorescently labeled ligand (Tracer 236), which competes with the inhibitor for the ATP binding site. Measurements were performed in a reaction volume of 15 μl using a 384-well plate (Corning Inc, Cat. # CLS4513). The CDK8 / Cyclin C enzyme (ThermoFisher, cat. # PR7261B) was mixed with Anti-His-tag-Biotin (ThermoFisher, cat. # PV6090), Streptavidin-Eu (ThermoFisher, cat. # PV6025) antibodies and added to the plate wells 5 μl each. The final concentrations of the substances were: CDK8 / Cyclin C - 5 nM, Streptavidin-Eu - 3 nM, Anti-His-tag-Biotin - 3 nM. Staurosporin was used as a control inhibitor, and a 0.1% dimethyl sulfoxide (DMSO) solution in a reaction buffer containing 250 mM HEPES (pH 7.5), 50 mM MgCl2, 5 mM EGTA, and 0.05% Brij-35 was used as a blank.

The investigated inhibitors and controls were added to the corresponding wells in 5 μl. The plate was incubated at room temperature for 20 minutes. After the incubation period, 5 μl of a tracer solution (Alexa Fluor-647 (Kinase Tracer 236, ThermoFisher, cat. No. PV5592)) was added to the wells. The final concentration of the tracer was 10 nM. A reaction buffer was used as a negative control instead of a tracer solution. The plate was incubated for 40 minutes at 25 ° C, then the TR-FRET signal was measured according to the manufacturer's recommendations on a SPARK20 plate reader (Tecan, Switzerland) and recalculated for the amount of the kinase bound tracer. The IC ₅₀ value was determined using the SparkControl Magellan program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with optimization according to Levenberg-Markart (Table 7).

Example 10. 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 test on continuous cell cultures MV4-11 (biphenotypic myelomonocytic leukemia, ATCC® CRL-9591 ™), KG-1 (acute myelogenous leukemia, ATCC® CCL-246 ™) using an in vivo dye AlamarBlue (ThermoFisher Cat # DAL1100). Cells were grown in RPMI-1640 medium (PanEco, cat. No. C330p) supplemented with 10% FBS (Gibco, cat. No. 16140-071). On the day of setting, the cells were spun off, a cell suspension was prepared in fresh medium with 10% FBS (Gibco, cat. # 16140-071) and plated in 96-well culture plates (Corning, cat. # 3599) at 10 × 10 ³ cells per 100 μl of medium per well. Test compounds were dissolved in DMSO and diluted with 10% FBS medium (Gibco cat # 16140-071) to a final concentration ranging from 100 to 0 μM. Diluted compounds in a volume of 50 μl were then added to each well (the final concentration of DMSO was no more than 1%) and incubated at 37 ° С in an incubator with 5% СО ₂ for 120 h. After the end of incubation, 15 μl of AlamarBlue reagent was added to the wells (ThermoFisher, cat. No. DAL1100), the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), then they were additionally incubated for 3 to 5 h at 37 ° C in an incubator with 5% CO ₂ . The number of living cells was detected on an Infinite M200Pro microplate spectrophotometer (Tecan, Switzerland) by measuring the fluorescent signal at an excitation wavelength (λEx) of 540 nm and an emission wavelength (λEm) of 590 nm.

The IC ₅₀ value was determined using the Magellan program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with optimization according to Levenberg-Markart (Table 8).

Example 11. General cytotoxicity towards primary cells HepaRG in vitro.

General cytotoxicity studies of the CDK8 inhibitors of the present invention were performed on primary HepaRG cells (Gibco (Biopredic International), Cat. # HPRGC10). The day before placement, the cells were removed from the freeze and seeded into the wells of 96-well plates (Corning, cat. # 3599) at a concentration of 30 × 10 ³ cells in 100 μl of medium per well. Assay medium consisted of William's E without glutamine (Gibco, cat # 12551032) with GlutaMAX growth supplements (Gibco, cat # 35050061) and HepaRG Maintenance / Metabolism Medium Supplement (Gibco, cat # HPRG720). Growth supplements were added to the medium according to the protocol of the cell manufacturer. The next day, the test compounds were added to the wells of the plates with the cells in the concentration range from 200 to 0.03 μM and incubated for 72 h. The cell viability was assessed according to the method described above. The results are shown in Table 8.

Example 12. Inhibition of cytochromes.

The CDK8 inhibitors of the present invention were analyzed for their ability to reduce the fluorescent signal in the reaction between the recombinant CYP450 enzymes and specific Vivid substrates. The assays used were Vivid CYP1A2 Blue (ThermoFisher Scientific, Cat # P2863), Vivid CYP2C19 Blue (ThermoFisher Scientific, Cat # P2864) and Vivid CYP3A4 Green (ThermoFisher Scientific, Cat # P2857).

Before starting the analysis, lyophilized substrates EOMCC (1A2), EOMCC (2C19), and DBOMF (3A4) were dissolved in the required amount of anhydrous acetonitrile (Fisher Chemical, cat. No. A / 0627/17) to a concentration of 2 mM. Weighed portions of the compounds under study were dissolved in DMSO (Scharlab, cat. No. SU01651000) to a concentration of 10 mM, then titrated in DMSO from 10 mM to 3.2 μM with a step of 5.

The titrated samples were diluted 200 times in a single buffer solution I (for cytochromes 1A2 and 3A4) or II (for cytochrome 2C19). Subsequently, the samples were dispensed 40 μl into the wells of black flat-bottomed plates (Corning, cat. No. CLS3631).

A 1% mixture of CYP450 baculosomes and a 2% mixture of the reducing system were prepared in a buffer corresponding to each cytochrome (master mix), and 40 μl were added to the corresponding wells of a black plate. Incubate the plate at room temperature for 10 minutes. During incubation, a mixture of NADP and substrate was prepared in appropriate buffers and concentrations for each cytochrome, according to the manufacturer's recommendations. At the end of incubation, a mixture of substrate and NADP, 10 μL, was added to the corresponding wells of a black plate. The plates were mixed and incubated for 1-2 hours (depending on cytochrome).

After the incubation period, the fluorescence intensity of the reaction mixture was measured at the recommended excitation and emission wavelengths for different substrates in relative fluorescence units (RFU). The measurements were carried out on a Spark 20M microplate reader (Tecan, Switzerland).

The IC ₅₀ value was determined using the SparkControl Magellan program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with optimization according to Levenberg-Markart (Table 9).

Claims (60)

1. Compound of formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, where n, m are each independently selected from 0, 1, 2, 3; p, q are each independently selected from 0, 1; X is selected from O, NR ₉ ; Y is selected from N, C, CH; Z is selected from O, NR ₁₀ ; R ₁ represents H, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals R ₁₁ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₁ radicals; R ₂ , R _{3 are} each independently H, C ₁ -C ₆ alkyl; R ₆ is H, C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more R ₁₂ radicals; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₂ radicals; R ₄ , R ₅ , R ₇ , R _{8 are} each independently hydrogen, C ₁ -C ₆ alkyl unsubstituted or substituted with one or more R ₁₇ radicals, or R ₄ and R ₅ together represent an oxo group, or R ₄ and R ₅ together with R ₆ and Y represent a 5-6 membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from N, S or O, 5- 6-membered heteroaryl with 1, 2 or 3 ring heteroatoms selected from N, S or O, or R ₇ and R ₈ together represent an oxo group; R ₁₁ , R _{12 are} each independently hydroxy, C ₃ -C ₆ cycloalkyl, —NR ₁₃ , R ₁₄ C ₁ -C ₆ alkyl — C (O) —C ₁ -C ₆ alkyl; C (O) -C ₁ -C ₆ alkyl, C (O) -NR ₁₅ R ₁₆ ; R ₉ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₅ , R _{16 are} each independently H, C ₁ -C ₆ alkyl; R ₁₇ represents C ₁ -C ₆ alkyl unsubstituted or substituted by Hal, hydroxy, amino, carboxy, carboxamide;

represents a single bond or double bond. 2. A compound according to claim 1, which is a compound of formula II

where n, m, p, q, X, Y, Z, R ₁ R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R _{17 are as} defined above. 3. Connection according to PP. 1, 2, where R ₄ and R ₅ each independently represents H or R ₄ and R ₅ together is an oxo group. 4. The connection according to PP. 1, 2, where X is O or NH. 5. Connection according to PP. 1, 2, where R ₁ is N, N-di C ₁ -C ₆ alkyl acetamide, C ₁ -C ₆ alkyl. 6. A compound according to claim 5, wherein R ₁ is N, N-dimethylacetamide, methyl. 7. The connection according to PP. 1, 2, where R ₆ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl. 8. A compound according to claim 7 wherein R ₆ is H, methyl, cyclopropylmethyl, methoxyethyl. 9. Connection according to PP. 1, 2, where R ₄ , R ₅ , R ₆ and Y together represent triazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, morpholinyl, furanyl, thienyl. 10. The connection according to PP. 1, 2, where R ₇ and R ₈ each represent H or together - an oxo group. 11. The compound according to claim 1, which is: (Z) -1 ^8- amino-8- (cyclopropylmethyl) -2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene cyclononafan-5-en-9-one formate (CDK8-macro-1), (Z) -1 ^8- amino-8- (cyclopropylmethyl) -2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene cyclononafan-5-en-9-one (CDK8-macro-1a), 1 ^8- amino-8- (2-cyclopropylethyl) -2 ⁴ - (methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3 ) -benzene cyclononafan-9-one (CDK8-macro-2), 1 ^8- amino-8-methyl-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) - benzene cyclononafan-9-one (CDK8-macro-4), 1 ^8- amino-7- (2-methoxyethyl) -2 ⁴ - (methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3 ) -benzenecyclooctafan-8-one (CDK8-macro-6), 1 ^8- amino-8- (2-methoxyethyl) -2 ⁴ - (methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3 ) -benzene cyclononafan-9-one (CDK8-macro-7), 2- (4- (1 ^8- amino-8- (cyclopropylmethyl) -9-oxo-3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene cyclononafan-2 ⁴ - yl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (CDK8-macro-8), 1 ^8- amino-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene-cyclononaphan-9- he (CDK8-macro-9), 8-methyl-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene cyclononafan-1 ⁸ - amine (CDK8-macro-10), 1 ^8- amino-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3,6-dioxa-9-aza-1 (5,3) -naphthyridine-2 (1,3) -benzenecyclodecaphan- 10-one (CDK8-macro-13), 2- (4- (1 ^8- amino-10-oxo-3,6-dioxa-9-aza-1 (5,3) -naphthyridine-2 (1,3) -benzenecyclodecaphan-2 ⁴ -yl) -1Н -pyrazol-1-yl) -N, N-dimethylacetamide (CDK8-macro-13a), 1 ^8- amino-9-methyl-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3,6-dioxa-9-aza-1 (5,3) -naphthyridine-2 (1,3 ) -benzenecyclodecaphan-10-one acetate (CDK8-macro-13b), 1 ^8- amino-9-methyl-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3,6-dioxa-9-aza-1 (5,3) -naphthyridine-2 (1,3 ) -benzenecyclodecaphan-10-one (CDK8-macro-13c), 3 ⁴ - (1-methyl-1H-pyrazol-4-yl) -1 ¹ H-4-oxa-2 (3,5) -naphthyridine-1 (5,4) -triazole-3 (1,3) benzenecyclooctaphan -2 ⁸ -amine (CDK8-macro-15), 1 ^8- amino-8-methyl-2 ⁴ - (1-methyl-1H-pyrazol-4-yl) -3,8-diaza-1 (5,3) -naphthyridine-2 (1,3) -benzene cyclononafan- 4,9-dione (CDK8-macro-17), 2- (4- (1 ^8- amino-8-methyl-9-oxo-3-oxa-8-aza-1 (5,3) -naphthyridine-2 (1,3) -benzene-cyclononafan-2 ^4- yl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (CDK8-macro-19). 12. A method of inhibiting the biological activity of cyclin-dependent protein kinases CDK8 / 19 in a subject, which consists in contacting cyclin-dependent protein kinases CDK8 / 19 with a compound according to any one of claims. 1-11. 13. A pharmaceutical composition intended for the prevention or treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinase CDK8 / 19, and containing a therapeutically effective amount of a compound according to any one of claims. 1-11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 14. A pharmaceutical composition according to claim 13, intended for the prevention or treatment of a disease or disorder mediated by the activation of the cyclin-dependent protein kinase CDK8 / 19, wherein the disease or disorder mediated by the activation of the cyclin-dependent protein kinase CDK8 / 19 is an oncological, oncohematological, autoimmune, inflammatory or allergic disease. 15. The pharmaceutical composition according to claim 14, where oncological or oncohematological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, HER2-positive breast cancer, hormone-dependent breast cancer, triple negative breast cancer (TNBC), prostate cancer, castration- refractory prostate cancer, metastatic ovarian cancer, metastatic gastric cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa); the autoimmune, inflammatory, or allergic disease is IgA nephropathy; IgG4-related disease; IgG4-associated sclerosing disease; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); POEMS syndrome; agammaglobulinemia; axial spondioarthritis; axonal and neuronal neuropathy; allergic conjunctivitis; allergic rhinitis; amyloidosis; angiocentric eosinophilic fibrosis; ankylosing spondylitis; anti-GMB / anti-TMB nephritis; antisperm antibodies; antiphospholipid syndrome; Takayasu's arteritis; atopic dermatitis; autoimmune aplastic anemia; autoimmune inner ear disease; autoimmune hemolytic anemia; autoimmune hemolytic anemia with warm antibodies; autoimmune hyperlipidemia; autoimmune dysautonomy; autoimmune urticaria; autoimmune neuromyotonia (Isaacs syndrome); autoimmune retinopathy; autoimmune thrombocytopenic. purple; autoimmune testicular damage / autoimmune hypogonadism; autoimmune angioedema; autoimmune hepatitis; autoimmune diabetes; autoimmune immunodeficiency; autoimmune pericarditis; autoimmune progesterone dermatitis; autoimmune thyroiditis; diseases of incompatibility by blood groups; Addison's disease; Behcet's disease; Graves' disease (diffuse toxic goiter); Devik's disease (optic nerve neuromyelitis); Kawasaki disease; Castleman disease; Crohn's disease; Meniere's disease; Mucha-Habermann disease; Ormond's disease (retroperitoneal fibrosis); Raynaud's disease; Churg-Strauss disease; Chagas disease; Sjogren's disease; bullous pemphigoid; bullosa epidermolysis; vasculitis; vasculitis of the kidneys; vasculitis associated with antineutrophilic cytoplasmic antibodies; vesiculobullous dermatosis; temporal arteritis; temporal / giant cell arteritis; vitiligo; vitiligo and Wegener's granulomatosis; lupus nephritis; inflammatory aortic aneurysm; congenital heart block; vulgar pemphigus; gangrenous pyoderma; hemolytic anemia; hemorrhagic vasculitis; herpes gestational or gestational pemphigoid; dermatitis herpetiformis; gestational pemphigoid; giant cell arteritis (temporal arteritis); giant cell myocarditis; hypogammaglobulinemia; glomerulonephritis; granulomatosis with polyangiitis (Wegener's syndrome); woody conjunctivitis; dermatomyositis; dilated cardiomyopathy; discoid lupus; idiopathic recurrent macrohematuria; idiopathic inflammatory myopathy; idiopathic thrombocytopenic purpura; idiopathic inflammatory pseudotumor; idiopathic hypocomplementary tubulointerstitial nephritis; idiopathic pulmonary fibrosis; insulin-dependent diabetes mellitus (type 1); interstitial cystitis; true red cell aplasia; cardiomyopathy; contact dermatitis; Balo concentric sclerosis; hives; lichen planus / lichen sclerosus; leukocytoclastic vasculitis; limbic encephalitis; limited scleroderma (CREST syndrome); linear IgA-dependent bullous dermatosis; leafy pemphigus; Waldenstrom's macroglobulinemia; mediastinal fibrosis; myasthenic crisis; Lambert-Eaton myasthenic syndrome; myasthenia gravis; myasthenia gravis; microscopic polyangiitis; myositis; Coxsackie myocarditis; multifocal motor neuropathy; multifocal fibrosclerosis; narcolepsy; optic neuritis; undifferentiated connective tissue disease; neuromyelitis of the optic nerve (Devik's syndrome); neutropenia; nonspecific ulcerative colitis; nephritis associated with antibodies to the basement membrane of the tubules and glomeruli; opsoclonus; acute motor axonal neuropathy; acute hemorrhagic leukoencephalitis; acute disseminated encephalomyelitis; alopecia areata; palindromic rheumatism; paraneoplastic degeneration of the cerebellum; paraneoplastic syndrome; paraproteinemic polyneuropathy; paroxysmal nocturnal hemoglobinuria; pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS syndrome); conjunctival pemphigoid; pemphigoid of mucous membranes; primary biliary cholangitis (cirrhosis); primary sclerosing cholangitis; periaortitis; periarteritis; perivenous encephalomyelitis; peripheral neuropathy; peripheral uveitis; pernicious anemia; subacute bacterial endocarditis; polyglandular (polyendocrine) autoimmune syndrome 1 (candidopolyendocrine syndrome), 2 (Schmidt's syndrome), 3 types; polymyositis; polyneuropathy with organomegaly (POEMS syndrome); transverse myelitis; postinfarction syndrome; post-traumatic pericarditis; progesterone dermatitis; psoriasis; psoriatic arthritis; pemphigus; purple Schoenlein-Genoch; multiple sclerosis; reactive arthritis; graft versus host reaction (GVHD); graft rejection due to antibodies to HLA; rheumatism; rheumatic fever; polymyalgia rheumatica; rheumatoid arthritis; reflex sympathetic dystrophy; refractory epilepsy; recurrent polychondritis; scarring pemphigoid (RP) of the conjunctiva; sarcoidosis; type 1 diabetes mellitus; sympathetic ophthalmia; restless legs syndrome; Guillain-Barré syndrome; Goodpasture syndrome; Dressler's syndrome; Kawasaki syndrome; Kogan's syndrome; Lambert-Eaton syndrome; Mikulich's syndrome; Miller Fisher syndrome; Pari-Romberg syndrome (progressive facial hemiatrophy); Personage-Turner syndrome (neuralgic amyotrophy, idiopathic brachial plexopathy); postpericardiotomy syndrome; Reiter's syndrome; stiffness syndrome; Stiff-Person syndrome; Susak's syndrome; Tolosa-Hunt syndrome (superior orbital fissure syndrome); cold agglutination syndrome (CAD); Sjogren's syndrome; Schmidt's syndrome; Evans syndrome; systemic lupus erythematosus; scleritis; scleroderma; scleroderma; lichen sclerosus; mixed connective tissue disease; mixed cryoglobulinemia; sporadic myositis with inclusions; Riedel's thyroiditis; Hashimoto's thyroiditis; thyroid ophthalmopathy; thyroid crisis; thrombotic thrombocytopenic purpura; thrombocytopenic purpura; uveitis; polyarteritis nodosa; erythema nodosum; universal alopecia; fetal and neonatal alloimmune thrombocytopenia; fibrosing alveolitis; fibromyalgia; cold hemagglutinin disease; Sydenham's chorea (small or rheumatic chorea); chronic Lyme disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic recurrent multifocal osteomyelitis; chronic sclerosing sialoadenitis (Küttner's inflammatory tumor); celiac disease; pure / true erythrocyte aplasia; experimental allergic encephalomyelitis; endocrine ophthalmopathy (thyroid ophthalmopathy, Graves ophthalmopathy, autoimmune ophthalmopathy); endometriosis; Hashimoto's encephalitis; encephalitis / encephalopathy associated with autoantibodies; eosinophilic fasciitis; eosinophilic esophagitis; essential mixed cryoglobulinemia; juvenile arthritis; juvenile diabetes (type 1 diabetes); juvenile myositis; juvenile rheumatoid arthritis; Moray's ulcer; ulcerative colitis. 16. A method of treating a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19, comprising administering in a therapeutically effective amount of a compound according to any one of claims. 1-11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for a subject in need of such treatment. 17. A method for treating a disease or disorder according to claim 16, wherein the disease or disorder mediated by activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological, hematological, oncological, autoimmune, inflammatory or allergic disease. 18. A method of treating a disease or disorder according to claim 17, wherein the oncological or oncohematological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, HER2-positive breast cancer, hormone-dependent breast cancer, triple negative breast cancer (TNBC), prostate cancer, castration refractory prostate cancer, metastatic ovarian cancer, metastatic stomach cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PC); the autoimmune, inflammatory, or allergic disease is IgA nephropathy; IgG4-related disease; IgG4-associated sclerosing disease; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); POEMS syndrome; agammaglobulinemia; axial spondioarthritis; axonal and neuronal neuropathy; allergic conjunctivitis; allergic rhinitis; amyloidosis; angiocentric eosinophilic fibrosis; ankylosing spondylitis; anti-GMB / anti-TMB nephritis; antisperm antibodies; antiphospholipid syndrome; Takayasu's arteritis; atopic dermatitis; autoimmune aplastic anemia; autoimmune inner ear disease; autoimmune hemolytic anemia; autoimmune hemolytic anemia with warm antibodies; autoimmune hyperlipidemia; autoimmune dysautonomy; autoimmune urticaria; autoimmune neuromyotonia (Isaacs syndrome); autoimmune retinopathy; autoimmune thrombocytopenic purpura; autoimmune testicular damage / autoimmune hypogonadism; autoimmune angioedema; autoimmune hepatitis; autoimmune diabetes; autoimmune immunodeficiency; autoimmune pericarditis; autoimmune progesterone dermatitis; autoimmune thyroiditis; diseases of incompatibility by blood groups; Addison's disease; Behcet's disease; Graves' disease (diffuse toxic goiter); Devik's disease (optic nerve neuromyelitis); Kawasaki disease; Castleman disease; Crohn's disease; Meniere's disease; Mucha-Habermann disease; Ormond's disease (retroperitoneal fibrosis); Raynaud's disease; Churg-Strauss disease; Chagas disease; Sjogren's disease; bullous pemphigoid; bullosa epidermolysis; vasculitis; vasculitis of the kidneys; vasculitis associated with antineutrophilic cytoplasmic antibodies; vesiculobullous dermatosis; temporal arteritis; temporal / giant cell arteritis; vitiligo; vitiligo and Wegener's granulomatosis; lupus nephritis; inflammatory aortic aneurysm; congenital heart block; vulgar pemphigus; gangrenous pyoderma; hemolytic anemia; hemorrhagic vasculitis; herpes gestational or gestational pemphigoid; dermatitis herpetiformis; gestational pemphigoid; giant cell arteritis (temporal arteritis); giant cell myocarditis; hypogammaglobulinemia; glomerulonephritis; granulomatosis with polyangiitis (Wegener's syndrome); woody conjunctivitis; dermatomyositis; dilated cardiomyopathy; discoid lupus; idiopathic recurrent macrohematuria; idiopathic inflammatory myopathy; idiopathic thrombocytopenic purpura; idiopathic inflammatory pseudotumor; idiopathic hypocomplementary tubulointerstitial nephritis; idiopathic pulmonary fibrosis; insulin-dependent diabetes mellitus (type 1); interstitial cystitis; true red cell aplasia; cardiomyopathy; contact dermatitis; Balo concentric sclerosis; hives; lichen planus / lichen sclerosus; leukocytoclastic vasculitis; limbic encephalitis; limited scleroderma (CREST syndrome); linear IgA-dependent bullous dermatosis; leafy pemphigus; Waldenstrom's macroglobulinemia; mediastinal fibrosis; myasthenic crisis; Lambert-Eaton myasthenic syndrome; myasthenia gravis; myasthenia gravis; microscopic polyangiitis; myositis; Coxsackie myocarditis; multifocal motor neuropathy; multifocal fibrosclerosis; narcolepsy; optic neuritis; undifferentiated connective tissue disease; neuromyelitis of the optic nerve (Devik's syndrome); neutropenia; nonspecific ulcerative colitis; nephritis associated with antibodies to the basement membrane of the tubules and glomeruli; opsoclonus; acute motor axonal neuropathy; acute hemorrhagic leukoencephalitis; acute disseminated encephalomyelitis; alopecia areata; palindromic rheumatism; paraneoplastic degeneration of the cerebellum; paraneoplastic syndrome; paraproteinemic polyneuropathy; paroxysmal nocturnal hemoglobinuria; pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS syndrome); conjunctival pemphigoid; pemphigoid of mucous membranes; primary biliary cholangitis (cirrhosis); primary sclerosing cholangitis; periaortitis; periarteritis; perivenous encephalomyelitis; peripheral neuropathy; peripheral uveitis; pernicious anemia; subacute bacterial endocarditis; polyglandular (polyendocrine) autoimmune syndrome 1 (candidopolyendocrine syndrome), 2 (Schmidt's syndrome), 3 types; polymyositis; polyneuropathy with organomegaly (POEMS syndrome); transverse myelitis; postinfarction syndrome; post-traumatic pericarditis; progesterone dermatitis; psoriasis; psoriatic arthritis; pemphigus; purple Schoenlein-Genoch; multiple sclerosis; reactive arthritis; graft versus host reaction (GVHD); graft rejection due to antibodies to HLA; rheumatism; rheumatic fever; polymyalgia rheumatica; rheumatoid arthritis; reflex sympathetic dystrophy; refractory epilepsy; recurrent polychondritis; Cicatricial pemphigoid (RP) of the conjunctiva; sarcoidosis; type 1 diabetes mellitus; sympathetic ophthalmia; restless legs syndrome; Guillain-Barré syndrome; Goodpasture syndrome; Dressler's syndrome; Kawasaki syndrome; Kogan's syndrome; Lambert-Eaton syndrome; Mikulich's syndrome; Miller Fisher syndrome; Pari-Romberg syndrome (progressive facial hemiatrophy); Personage-Turner syndrome (neuralgic amyotrophy, idiopathic brachial plexopathy); postpericardiotomy syndrome; Reiter's syndrome; stiffness syndrome; Stiff-Person syndrome; Susak's syndrome; Tolosa-Hunt syndrome (superior orbital fissure syndrome); cold agglutination syndrome (CAD); Sjogren's syndrome; Schmidt's syndrome; Evans syndrome; systemic lupus erythematosus; scleritis; scleroderma; scleroderma; lichen sclerosus; mixed connective tissue disease; mixed cryoglobulinemia; sporadic myositis with inclusions; Riedel's thyroiditis; Hashimoto's thyroiditis; thyroid ophthalmopathy; thyroid crisis; thrombotic thrombocytopenic purpura; thrombocytopenic purpura; uveitis; polyarteritis nodosa; erythema nodosum; universal alopecia; fetal and neonatal alloimmune thrombocytopenia; fibrosing alveolitis; fibromyalgia; cold hemagglutinin disease; Sydenham's chorea (small or rheumatic chorea); chronic Lyme disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic recurrent multifocal osteomyelitis; chronic sclerosing sialoadenitis (Küttner's inflammatory tumor); celiac disease; pure / true erythrocyte aplasia; experimental allergic encephalomyelitis; endocrine ophthalmopathy (thyroid ophthalmopathy, Graves ophthalmopathy, autoimmune ophthalmopathy); endometriosis; Hashimoto's encephalitis; encephalitis / encephalopathy associated with autoantibodies; eosinophilic fasciitis; eosinophilic esophagitis; essential mixed cryoglobulinemia; juvenile arthritis; juvenile diabetes (type 1 diabetes); juvenile myositis; juvenile rheumatoid arthritis; Moray's ulcer; ulcerative colitis. 19. The use of a compound according to any one of claims. 1-11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 13 for the treatment of a disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 in a subject in need of such treatment. 20. Use according to claim 19, wherein the disease or disorder mediated by the activation of cyclin-dependent protein kinases CDK8 / 19 is an oncological, oncohematological, autoimmune, inflammatory or allergic disease. 21. Application according to claim 20, where oncological or oncohematological disease is selected from the group consisting of colorectal cancer, melanoma, metastatic melanoma, breast cancer, HER2-positive breast cancer, hormone-dependent breast cancer, triple negative breast cancer (TNBC), prostate cancer, castration- refractory prostate cancer, metastatic ovarian cancer, metastatic gastric cancer, leukemia, acute myeloid leukemia, pancreatic cancer (PCa); the autoimmune, inflammatory, or allergic disease is IgA nephropathy; IgG4-related disease; IgG4-associated sclerosing disease; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); POEMS syndrome; agammaglobulinemia; axial spondioarthritis; axonal and neuronal neuropathy; allergic conjunctivitis; allergic rhinitis; amyloidosis; angiocentric eosinophilic fibrosis; ankylosing spondylitis; anti-GMB / anti-TMB nephritis; antisperm antibodies; antiphospholipid syndrome; Takayasu's arteritis; atopic dermatitis; autoimmune aplastic anemia; autoimmune inner ear disease; autoimmune hemolytic anemia; autoimmune hemolytic anemia with warm antibodies; autoimmune hyperlipidemia; autoimmune dysautonomy; autoimmune urticaria; autoimmune neuromyotonia (Isaacs syndrome); autoimmune retinopathy; autoimmune thrombocytopenic purpura; autoimmune testicular damage / autoimmune hypogonadism; autoimmune angioedema; autoimmune hepatitis; autoimmune diabetes; autoimmune immunodeficiency; autoimmune pericarditis; autoimmune progesterone dermatitis; autoimmune thyroiditis; diseases of incompatibility by blood groups; Addison's disease; Behcet's disease; Graves' disease (diffuse toxic goiter); Devik's disease (optic nerve neuromyelitis); Kawasaki disease; Castleman disease; Crohn's disease; Meniere's disease; Mucha-Habermann disease; Ormond's disease (retroperitoneal fibrosis); Raynaud's disease; Churg-Strauss disease; Chagas disease; Sjogren's disease; bullous pemphigoid; bullosa epidermolysis; vasculitis; vasculitis of the kidneys; vasculitis associated with antineutrophilic cytoplasmic antibodies; vesiculobullous dermatosis; temporal arteritis; temporal / giant cell arteritis; vitiligo; vitiligo and Wegener's granulomatosis; lupus nephritis; inflammatory aortic aneurysm; congenital heart block; vulgar pemphigus; gangrenous pyoderma; hemolytic anemia; hemorrhagic vasculitis; herpes gestational or gestational pemphigoid; dermatitis herpetiformis; gestational pemphigoid; giant cell arteritis (temporal arteritis); giant cell myocarditis; hypogammaglobulinemia; glomerulonephritis; granulomatosis with polyangiitis (Wegener's syndrome); woody conjunctivitis; dermatomyositis; dilated cardiomyopathy; discoid lupus; idiopathic recurrent macrohematuria; idiopathic inflammatory myopathy; idiopathic thrombocytopenic purpura; idiopathic inflammatory pseudotumor; idiopathic hypocomplementary tubulointerstitial nephritis; idiopathic pulmonary fibrosis; insulin-dependent diabetes mellitus (type 1); interstitial cystitis; true red cell aplasia; cardiomyopathy; contact dermatitis; Balo concentric sclerosis; hives; lichen planus / lichen sclerosus; leukocytoclastic vasculitis; limbic encephalitis; limited scleroderma (CREST syndrome); linear IgA-dependent bullous dermatosis; leafy pemphigus; Waldenstrom's macroglobulinemia; mediastinal fibrosis; myasthenic crisis; Lambert-Eaton myasthenic syndrome; myasthenia gravis; myasthenia gravis; microscopic polyangiitis; myositis; Coxsackie myocarditis; multifocal motor neuropathy; multifocal fibrosclerosis; narcolepsy; optic neuritis; undifferentiated connective tissue disease; neuromyelitis of the optic nerve (Devik's syndrome); neutropenia; nonspecific ulcerative colitis; nephritis associated with antibodies to the basement membrane of the tubules and glomeruli; opsoclonus; acute motor axonal neuropathy; acute hemorrhagic leukoencephalitis; acute disseminated encephalomyelitis; alopecia areata; palindromic rheumatism; paraneoplastic degeneration of the cerebellum; paraneoplastic syndrome; paraproteinemic polyneuropathy; paroxysmal nocturnal hemoglobinuria; pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS syndrome); conjunctival pemphigoid; pemphigoid of mucous membranes; primary biliary cholangitis (cirrhosis); primary sclerosing cholangitis; periaortitis; periarteritis; perivenous encephalomyelitis; peripheral neuropathy; peripheral uveitis; pernicious anemia; subacute bacterial endocarditis; polyglandular (polyendocrine) autoimmune syndrome 1 (candidopolyendocrine syndrome), 2 (Schmidt's syndrome), 3 types; polymyositis; polyneuropathy with organomegaly (POEMS syndrome); transverse myelitis; postinfarction syndrome; post-traumatic pericarditis; progesterone dermatitis; psoriasis; psoriatic arthritis; pemphigus; purple Schoenlein-Genoch; multiple sclerosis; reactive arthritis; graft versus host reaction (RTGHC); graft rejection due to antibodies to HLA; rheumatism; rheumatic fever; polymyalgia rheumatica; rheumatoid arthritis; reflex sympathetic dystrophy; refractory epilepsy; recurrent polychondritis; scarring pemphigoid (RP) of the conjunctiva; sarcoidosis; type 1 diabetes mellitus; sympathetic ophthalmia; restless legs syndrome; Guillain-Barré syndrome; Goodpasture syndrome; Dressler's syndrome; Kawasaki syndrome; Kogan's syndrome; Lambert-Eaton syndrome; Mikulich's syndrome; Miller Fisher syndrome; Pari-Romberg syndrome (progressive facial hemiatrophy); Personage-Turner syndrome (neuralgic amyotrophy, idiopathic brachial plexopathy); postpericardiotomy syndrome; Reiter's syndrome; stiffness syndrome; Stiff-Person syndrome; Susak's syndrome; Tolosa-Hunt syndrome (superior orbital fissure syndrome); cold agglutination syndrome (CAD); Sjogren's syndrome; Schmidt's syndrome; Evans syndrome; systemic lupus erythematosus; scleritis; scleroderma; scleroderma; lichen sclerosus; mixed connective tissue disease; mixed cryoglobulinemia; sporadic myositis with inclusions; Riedel's thyroiditis; Hashimoto's thyroiditis; thyroid ophthalmopathy; thyroid crisis; thrombotic thrombocytopenic purpura; thrombocytopenic purpura; uveitis; polyarteritis nodosa; erythema nodosum; universal alopecia; fetal and neonatal alloimmune thrombocytopenia; fibrosing alveolitis; fibromyalgia; cold hemagglutinin disease; Sydenham's chorea (small or rheumatic chorea); chronic Lyme disease; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic recurrent multifocal osteomyelitis; chronic sclerosing sialoadenitis (Küttner's inflammatory tumor); celiac disease; pure / true erythrocyte aplasia; experimental allergic encephalomyelitis; endocrine ophthalmopathy (thyroid ophthalmopathy, Graves ophthalmopathy, autoimmune ophthalmopathy); endometriosis; Hashimoto's encephalitis; encephalitis / encephalopathy associated with autoantibodies; eosinophilic fasciitis; eosinophilic esophagitis; essential mixed cryoglobulinemia; juvenile arthritis; juvenile diabetes (type 1 diabetes); juvenile myositis; juvenile rheumatoid arthritis; Moray's ulcer; ulcerative colitis.