Cyclin-dependent kinase 7 inhibitors

Abstract

The present invention relates to novel compounds of formula I, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which exhibit the properties of a CDK7 inhibitor, as well as to a pharmaceutical composition containing said compounds, methods for treating diseases or disorders, and the use of said compounds or composition as pharmaceutical preparations for treating diseases or disorders.

Description

[0001] Cyclin-dependent kinase 7 inhibitors

[0002] Field of technology

[0003] The present invention relates to novel inhibitors of cyclin-dependent protein kinase 7 (CDK7), to pharmaceutically acceptable salts, solvates or stereoisomers thereof, pharmaceutical compositions containing these compounds, to methods for treating diseases or disorders and the use of these compounds as pharmaceuticals for treating diseases or disorders.

[0004] State of the art

[0005] Cyclin-dependent kinase 7 (CDK7) is an enzyme widely expressed in various tissues of the body, which is a member of the cyclin-dependent protein kinase (CDK) family. Together with cyclin H and MAT1, CDK7 forms a CDK-activating complex that regulates the progression of cell cycle phases by phosphorylating other CDKs. CDK7 is an obligatory component of the transcription factor TFIIH. The latter is involved in transcription initiation and DNA repair processes. Thus, CDK7 plays a critical role in the regulation of the cell cycle and gene transcription (Ganuza et al. Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. EMBO J. 2012;31(ll):2498-510; Larochelle et al. Cyclin-dependent kinase control of the initiation-to- elongation switch of RNA polymerase II. Nat Struct Mol Biol. 2012; 19(11): 1108-15).

[0006] Uncontrolled proliferation and changes in transcription processes are properties characteristic of malignant tumor cells. CDK7 over-activation has been found in many cancer types and correlates with aggressive disease progression and poor prognosis, such as gastric cancer, esophageal squamous cell carcinoma, ER+ and triple-negative breast cancer, and hepatocellular carcinoma (Liu et al. Cyclin-dependent kinase 7 (CDK7) expression in human hepatocellular carcinoma: association with HCC progression, prognosis and cell proliferative capacity. Transl Cancer Res. 2018;7(3):472-479; Wang et al. Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis. Exp Mol Pathol. 2016;100(3):514-21; Patel et al. Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2016;22(23): 5929-5938; Li et al.Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in TripleNegative Breast Cancer. Cancer Res. 2017;77(14):3834-3845; Zhang et al. Low expression of cyclinH and cyclin-dependent kinase 7 can decrease the proliferation of human esophageal squamous cell carcinoma. Dig Dis Sci. 2013;58(7):2028-37). Inhibition of CDK7 is able to exert an antitumor effect by reducing the rate of cell proliferation, as well as influencing the transcription of genes involved in the malignant transformation of cells, such as ovarian cancer cells, T-cell acute lymphoblastic leukemia, neuroblastoma, glioma, small cell lung cancer and others (Chipumuro et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014; 159(5): 1126-1139, Kwiatkowski et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511(7511):616-20, Greenall at al.Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma. Oncogenesis. 2017;6(5):e336, Christensen et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014 Dec 8;26(6):909-922). In addition, protein inhibition potentiates genomic instability and reduces PD-L1 expression, which promotes the activation of antitumor immune responses (Zhang et al. CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer Cell 2020;37(l):37-54.e9, Wang et al. CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38a / MYC / PD-Ll signaling in non-small cell lung cancer. J Hematol Oncol. 2020;13(l):99).

[0007] Thus, there is a need to develop new compounds that target CDK7 preferentially and may provide a better benefit / risk ratio in the treatment of diseases associated with increased CDK7 activity.

[0008] Description of the invention

[0009] Below are definitions of terms used in the description of this invention.

[0010] Optionally substituted at one, two, three, four or more positions means that the described group may be substituted at one, two, three, four or from one to six positions by any one or any combination of radicals.

[0011] An "annelated compound" or "fused compound" is a polycyclic compound that shares two adjacent atoms. Examples of condensed compounds include, but are not limited to, naphthalene, quinoline, tetrahydroquinoline, isoquinoline, quinoxaline, 1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroquinoline, indole, dihydroindole, 1H-pyrrolo[2,3-b]pyridine, 1H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H,SHpyrrolo[2,3-c]azepine, 1H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,7H,8H-pyrrolo[2,3-c]azepine, 1H,6H,7H,8H-pyrrolo[2,3-c]azepine, 1H,8H-pyrrolo[2,3-c]azepine, 7H,8H-pyrrolo[2,3-c]azepine, IH, 4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,7H,8H,9H-pyrrolo o [2,3-c]azocine, 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,8H,9H-pyrrolo[2,3-c]azocine, 9H-pyrrolo[2,3-c]azocine,

[0012] 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole, 1H-1,3-benzodiazole, azaspiro[3.5]nonane, azaspiro[2.5]octane, 1H,2H,3H,4H,5H,6H-pyrrolo[2,3-1 [1,4]oxazepine, 3,4,6,13- tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-1(10),2,4,11-tetraen-11-yl, 1,4-diazatricyclo[7.1.1.0 3 , 7 ]undeca-3(7), 5-dienyl.

[0013] "Alkyl" means an aliphatic hydrocarbon group, linear or branched, 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, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl. Alkyl may have substituents, which may be the same or different.

[0014] "Cycloalkyl" means a fully saturated carbocyclic ring containing 3-10 carbon atoms in the ring. Cycloalkyl may have substituents, which may be the same or different. Cycloalkyl may be annelated with aryl, heteroaryl, heterocyclyl. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups such as bicycloheptyl or bicyclooctyl.

[0015] "Alkenyl" means a hydrocarbon group, linear or branched, with 2 to 12 carbon atoms in the chain, more preferably with 2 to 6 carbon atoms in the chain, which contains one or more carbon-carbon double bonds. Alkenyl may have substituents, which may be the same or different.

[0016] "Aryl" means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl and anthrylene. Aryl may have substituents, which may be the same or different. Aryl may be annelated with a heterocycle, cycloalkyl, heteroaryl.

[0017] "Alkyloxy", "Alkoxy" or "alkyloxy group" 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, n-butoxy, tert-butoxy, iso-butoxy.

[0018] "Amino group" means R'R"N- group.

[0019] "Aminocarbonyl" means the -C(=O)NR"'R"" group.

[0020] Examples of R', R", R'", R"" include, but are not limited to, substituents selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroalkyl, or R' and R" together with the nitrogen atom to which they are attached can form a 4-7-membered heterocyclyl or heteroaryl.

[0021] "Alkylsulfonyl" (-8(O)2-(C1-C6)alkyl) means "alkyl" or "cycloalkyl" as defined above, appended to the corresponding molecular moiety through a sulfonyl group -SO2-. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, etc.

[0022] "Alkylsulfonamide" (-NH-8(O)2-(C1-C6)alkyl) means an "alkyl" or "cycloalkyl" group as defined above, attached to the corresponding molecular moiety through a sulfonamide group -NH-SO2-. Examples of alkylsulfonamides include, but are not limited to, methylsulfonamide, ethylsulfonamide, propylsulfonamide, cyclopropylsulfonamide, etc.

[0023] "Dialkylphosphine oxide" or "dialkylphosphoryl" (-P(O)((C1-C6)alkyl)2) means "alkyl" or "cycloalkyl" as defined above, attached to the corresponding molecular moiety through a phosphoryl group. Examples of dialkylphosphine oxide include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, methylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide, etc.

[0024] The term "oxo" as used herein refers to the radical =0.

[0025] "Lower alkyl" means a linear or branched alkyl of 1 to 4 carbon atoms.

[0026] "Halo" or "Halogen" (Hal) means fluorine, chlorine, bromine or iodine.

[0027] "Heterocycle", "heterocyclyl", "heterocyclic ring" means a monocyclic or polycyclic system comprising from 3 to 11 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom, such as nitrogen, oxygen, sulfur. The heterocycle may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms present in the heterocycle may be oxidized to N-oxide, S-oxide or S-dioxide. The heterocycle may be saturated, partially unsaturated or unsaturated. Heterocyclyl may be represented by a bridged compound with one, two or three -CH2- groups; or be annelated with a 4-5 membered heteroaryl, in which one, two or three carbon atoms are replaced by nitrogen atoms. The heterocycle may be annelated with cycloalkyl, aryl or heteroaryl. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azepane, azabicycloheptane, oxane, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin, 1H,4H,5H,6H- r3-pyrrolopi,[2, 1,2,3,4-tetrahydroquinoxaline, tetrahydroquinoline, 1,2- dihydroquinoline, dihydroindole, azaspiro[3.5]nonane, azaspiro[2.5]octane, 5H,6H,7H,8H,9H- [azepno,3olo ,2,4]a[ 5H,6H,7H-[ 1 ,2,4]triazolo[4,3 -a]azepino, 1 - azabicyclo[4.1.1]octano, 1-azabicyclo[4.1.1]oct-3-enyl, et al.

[0028] "Heteroaryl", "heteroarylyl", "heteroaryl ring" means an aromatic monocyclic or polycyclic system comprising from 5 to 11 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, sulfur or oxygen. The nitrogen atom located in the heteroaryl can be oxidized to an N-oxide. Heteroaryl can have one or more substituents, which can be the same or different. Heteroaryl can be annelated with cycloalkyl, aryl or heterocyclyl. Examples of heteroaryls include, but are not limited to, 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-c1]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimidine, pyridazine, isooxazole, isothiazole, tetrazole, oxazole, 1,2,4-oxadiazole, thiazole, pyrazole, furazan, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-thiadiazole, 2H-1,2,3,4-tetrazole quinoxaline, imidazo[1,2-a]pyridine, indole, benzimidazole, quinoline, imidazole, thienopyridine, quinazoline, naphthyridine, thienopyrimidine,imidazopyridine, quinoline, isoquinoline, quinoxaline, indole, 1H-pyrrolo[2,3-b]pyridine, 1H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine, 1H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,7H,8H-pyrrolo[2,3-c]azepine, 1H,6H,7H,8H-pyrrolo[2,3-c]azepine, 7H,8H-pyrrolo[2,3-c]azepine, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,8H,9H-pyrrolo[2,3-c]azocine, 9H-pyrrolo[2,3-c]azocine, 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole, 1H-1,3-benzodiazole, 1H,2H,3H,4H,5H,6H-pyrrolo[2,3-1][1,4]oxazepine, 3,4,6,13-tetraazatricyclo[8.3.0.0, 2 , 6 ]trideca- 1(10), 2, 4, 11 -tetraenyl, 1,4-diazatricyclo[7.1.1.0 3 , 7 ]undeca-3(7), 5-dienyl, etc.

[0029] "Substituent" means a chemical radical that is attached to a molecular backbone (scaffold, fragment).

[0030] "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 those commonly used in pharmaceuticals that are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, and the like. Other solvents can be used as intermediate solvates in the preparation of more desirable solvates, such as MeOH, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (K)-propylene glycol, 1,4-butanediol, and the like.

[0031] The term "hydrate" refers to a complex in which the solvent molecule is water.

[0032] 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 moieties (groups, fragments), if the two atoms joined by the bond are considered as part of a larger substructure.

[0033] The chemical bond in the compounds of the present invention, shown as "

[0034] " denotes a double bond, with the configuration of the substituents corresponding to the formula.

[0035] The chemical bond in the compounds of the present invention is shown as "e" е " denotes a double bond, which can have either a cis or trans configuration.

[0036] The term "stereoisomers" refers to compounds that have identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, and diastereomers.

[0037] The term "standard processing" includes extraction; action with solutions of acids, alkalis and / or salts to neutralize or otherwise change the pH and / or remove interfering components; filtration through celite, silica gel and other materials; addition of an inert carrier (celite, silica gel); removal of volatile components and solvents under vacuum.

[0038] The term "excipient" is used herein to describe any ingredient other than the compound(s) of the present invention.

[0039] "Pharmaceutical composition" means a composition comprising a compound according to the invention and at least one excipient. The excipient can be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and receiving means, delivery means, such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavors, aromas, antibacterial agents, fungicides, lubricants, regulators of prolonged delivery, 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 sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances.Protection against the action of microorganisms can be provided by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, sorbic acid and the like. The composition can also include isotonic agents, such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents that slow down the absorption of the active principle, such as 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 grinding and distributing agents are starch, alginic acid and its salts, silicates and the like.Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethyleneglycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in unit administration form as a mixture with traditional pharmaceutical carriers. Suitable unit administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

[0040] "Pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of acids and bases claimed in the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of the compounds, or specially prepared. In particular, salts of bases can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts obtained in this manner are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, formates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19).Salts of the claimed acids can also be specially obtained by reacting the purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. Amines and amino acids with sufficient basicity to form a stable salt and suitable for use in medicine (in particular, they must have low toxicity) are selected as organic bases from which salts of the claimed acids can be obtained.Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. In addition, tetraalkylammonium hydroxides can be used for salt formation, such as choline, tetramethylammonium, tetraethylammonium and the like. The main amino acids - lysine, ornithine and arginine - can be used as amino acids.

[0041] "Medicine (drug, medicine)" is a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, granules, capsules, injections, ointments and other finished forms, intended to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others. "Treat", "treatment" and "therapy" refer to a method of alleviating or eliminating a biological disorder and / or at least one of its accompanying symptoms. The term "alleviate" a disease, illness or condition means a decrease in the severity and / or frequency of symptoms of the disease, disorder or condition. In addition, references in this document to "treatment" include references to curative, palliative and preventive therapy.

[0042] "Prevention", "preventive therapy" refers to a set of measures aimed at preventing the occurrence, eliminating risk factors or early detection of a disease or disorder, its progression, worsening of the course, exacerbation, relapse, complications or other consequences.

[0043] In one aspect, the subject of prevention or treatment or the patient is a mammal, preferably a human subject. The said subject may be male or female of any age.

[0044] The term "disorder" or "disease" means any condition that can be improved in its manifestations or improved in the prognosis of a subject with the condition as a result of treatment according to the present invention. The definition of this term includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to developing the disorder. Non-limiting examples of diseases to be treated include an oncological disease selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing estrogen and / or progesterone receptors, HER2-negative breast cancer, small cell lung cancer,metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, head and neck squamous cell cancer, oral cancer, oral squamous cell cancer, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal carcinoma, retinoblastoma, multiple myeloma; autoimmune disease selected from the group consisting of axial spondylitis,antiphospholipid syndrome, vasculitides (ANCA-associated vasculitides including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA),familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); an infectious inflammatory disease or a non-infectious inflammatory disease selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection,graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis,inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

[0045] A "therapeutically effective amount" is the amount of a therapeutic agent administered during treatment that will result in a reduction in the severity or elimination of the symptoms of the disease being treated.

[0046] 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,” “comprises,” or “containing,” are to be understood as including the stated whole or group of wholes, but not excluding any other whole or group of wholes.

[0047] Description of the Figures.

[0048] Figure 1 illustrates the dynamics of tumor growth of NCI-H69 xenografts in the control group and in the group receiving CDK7_1187 at a dose of 6 mg / kg QD for 21 days. Data are presented as arithmetic mean values ​​of tumor volumes ± standard error of the mean.

[0049] Note - *- p<0.05; statistically significant difference from the control group (Mann-Whitney test).

[0050] Detailed description of the invention

[0051] In one embodiment, the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0052] Ri is -C(Hа1)3, -CH(Hа1)2, -CH2Hа1, -Hal, -H, -NO2, -(C1-C6)alkyl unsubstituted or substituted by one or more Hal atoms, -O-(C1-C6)alkyl unsubstituted or substituted by one or more Hal atoms, -S-(C1-C6)alkyl unsubstituted or substituted by one or more Hal atoms;

[0053] R2, R3 each independently represents H, -(C1-C6)alkyl; or R2, R3 together form -(C3-C6)cycloalkyl unsubstituted or unsubstituted by one or more -(C1-C6)alkyl;

[0054] Li, L2 each independently represents a chemical bond, -NR5-, -O-, -S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R6b)i-3-, -P(O)(CH3)-, -O-(CH2)1-h-, -(CH2)1-h- O-, -NR 5a -(CH2)i.3-, -(CH2)i-3-NR 5a -, -C(O)-(CH2)1-3-, -(CH2)1-3-C(O)-, -C(O)-NH- or -NH- C(O)-;

[0055] A is a 6-10 membered aryl, unsubstituted or substituted by one or more R?; 6-10 membered aryl, unsubstituted or substituted by one or more R? a , condensed with -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs a ; 6-10 membered aryl, unsubstituted or substituted by one or more R-th, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; 6-10 membered aryl, unsubstituted or substituted by one or more R? c , condensed with 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N,0 or S, unsubstituted or substituted by one or more Rs c; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R?d; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, 0 or S, unsubstituted or substituted by one or more R? e , condensed with (C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs e ; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R?f, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rsf; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R? g; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R?h, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst;

[0056] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4aR4b, -P(O)(Ci-Ce alkyl)2, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C1-C6)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g; -C2-C6 alkenyl, unsubstituted or substituted by one or more R4h; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, condensed with phenyl, unsubstituted or substituted by one or more R4k; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, condensed with phenyl, unsubstituted or substituted by one or more R4m;

[0057] R4a, R4b, R4C, R4d, R4e, R4f, R4 g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, -P(0)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl,

[0058] R5, Rsa each independently represents -H, Ci-Ce alkyl,

[0059] Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0060] R7, R?a, R?b, R?c, R?d, R?e R?f R? gR?h each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(Ci-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0061] Rsa, Rsb, Rsc, Rsd, Rse Rsf Rsh each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0062] Hal represents an atom of F, Cl, Br, I.

[0063] In one embodiment, the present invention relates to a compound of formula I:

[0064] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0065] Ri is -C(На1)3, -CH(На1)2, -CH2На1, -Hal, -H, alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms Hal

[0066] R2, R3 each independently represents H, -(C-C6)alkyl; or R2, R3 together form -(C3-C6)cycloalkyl unsubstituted or unsubstituted by one or more -(C1-C6)alkyl;

[0067] Li, L2 each independently represents a chemical bond, -NR5-, -O-, -S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)ьз-, -(CH2)ьз- O-, -NR 5a -(CH2)i.3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH- C(O)-;

[0068] A is a 6-10 membered aryl, unsubstituted or substituted by one or more R?; 6-10 membered aryl, unsubstituted or substituted by one or more R? a , condensed with -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs a; 6-10 membered aryl, unsubstituted or substituted by one or more R-th, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; 6-10 membered aryl, unsubstituted or substituted by one or more R? c , condensed with 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N,0 or S, unsubstituted or substituted by one or more Rs c ; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R?d; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, 0 or S, unsubstituted or substituted by one or more R? e , condensed with (C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs e; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R?f, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rsf; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R? g ; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R?h, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR 4a R4b, -P(0)(C1-C6 alkyl)2, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C-C6)alkyl, unsubstituted or substituted by one or more R 4c ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R4d ; phenyl, unsubstituted or substituted by one or more R 4e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R ; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R 4g ; -C2-C6 alkenyl, unsubstituted or substituted by one or more R4h; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R4i; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, condensed with phenyl, unsubstituted or substituted by one or more R4k; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R4I, condensed with phenyl, unsubstituted or substituted by one or more R 4m ;

[0069] R 4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, R4I, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, -P(0)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl,

[0070] R5, Rsa each independently represents -H, Ci-Ce alkyl,

[0071] Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0072] R7, R?a, R?b, R?c, R?d, R?e R?f R?g R?h each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(Ci-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0073] Rsa, Rsb, Rsc, Rsd, Rse Rsf Rsh each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0074] Hal represents an atom of F, Cl, Br, I.

[0075] In one embodiment, the present invention relates to a compound of formula Lb: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0076] Ri is -C(На1)3, -CH(На1)2, -CH2На1, -Hal, -H, alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms Hal

[0077] R2, R3 each independently represents H, -(C-C6)alkyl; or R2, R3 together form -(C3-C6)cycloalkyl unsubstituted or unsubstituted by one or more -(C1-C6)alkyl;

[0078] Li, L2 each independently represents a chemical bond, -NR5-, -O-, -S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)ьз-, -(CH2)ьз- O-, -NR 5a -(CH2)i.3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH- C(O)-;

[0079] A is a 6-10 membered aryl, unsubstituted or substituted by one or more R?; 6-10 membered aryl, unsubstituted or substituted by one or more R? a , condensed with -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs a; 6-10 membered aryl, unsubstituted or substituted by one or more R-th, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; 6-10 membered aryl, unsubstituted or substituted by one or more R? c , condensed with 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N,0 or S, unsubstituted or substituted by one or more Rs c ; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R?a; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, 0 or S, unsubstituted or substituted by one or more R? e , condensed with (C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs e; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R?f, fused to 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rsf; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R? g ; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R?h, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst;

[0080] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(0)(C1-C6 alkyl)r, -S(O)2NH2, -S(0)2Ci-Ce alkyl, -(C1-C6)alkyl, unsubstituted or substituted by one or more R4 C; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g ; -Cr-C6 alkenyl, unsubstituted or substituted by one or more R41,; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R41, fused with phenyl, unsubstituted or substituted by one or more R41; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, fused with phenyl, unsubstituted or substituted by one or more R41

[0081] Vda, Vd, Vds, Ida, Vde, R-4f, B.4 g , Vd, B.4i, Vd], Vdk, B41, Vd ш each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)r, -P(0)(C1-C6 alkyl)r, morpholinyl, thiazolyl, phenyl,

[0082] B-5, B.5a each independently represents -H, Ci-Ce alkyl,

[0083] R-6, R-7 each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0084] R7, R?a, R?b, R?c, R?d, R?e R?f R?g R?h each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(Ci-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0085] Rsa, Rsb, Rsc, Rsd, Rse Rsf Rsh each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0086] Hal represents an atom of F, Cl, Br, I.

[0087] In one embodiment, the present invention relates to the S-isomer of the compound of formula I.

[0088] In one embodiment, the present invention relates to a compound wherein -A-L2-R4 is: where k,m each independently represents 0, 1,2 or 3,

[0089] Xi, Xg, X3, Xd, X5, X6 each independently represents a C atom, an N atom, CH, CH2, NH, S or O;

[0090] Yi, Yi, Yz, Ys, Ys each independently represents a C atom, an N atom or CH;

[0091] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)ьз-, -(CH2)ьз-O-, -NR 5a -(CH2)i.3-, -(CH2)i-3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH-C(O)-;

[0092] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(O)(C1-C6 alkyl)r, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C-C6)alkyl, unsubstituted or substituted by one or more R4 C; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more ^;-(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g ; -Cr-C6 alkenyl, unsubstituted or substituted by one or more Il; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rtj, fused with phenyl, unsubstituted or substituted by one or more R4k5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, fused with phenyl, unsubstituted or substituted by one or more R4m;

[0093] R 4a , R4b, R4C, R4d, R4e, R4f, R4g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)g, -P(0)(C1-Cb alkyl)g, morpholinyl, thiazolyl, phenyl,

[0094] R5, Rs a each independently represents -H, Ci-Ce alkyl,

[0095] Re a , Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Kb аand Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0096] R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0097] Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; Hal represents an F, Cl, Br, I atom.

[0098] In one embodiment, the present invention relates to a compound wherein -A-L2-R4 is: where p each independently represents 0 or 1 and q each independently represents 0, 1 or 2, with the total number of substituents on each ring being no more than 3; Xi, Xr, X3, Xg, X5, X6 each independently represents a C atom, an N atom, CH, CH2, NH, S or O;

[0099] Yi, Yi, Yz, Ys, Ys each independently represents a C atom, an N atom or CH;

[0100] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)ьз-, -(CH2)ьз-O-, -NR 5a -(CH2)i.3-, -(CH2)i-3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH-C(O)-;

[0101] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(0)(C1-Cb alkyl)g, - S(O)2NH2, -S(O)2CI-C6 alkyl, -(C-Cb)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g ; -Cr-C6 alkenyl, unsubstituted or substituted by one or more Il; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, fused with phenyl, unsubstituted or substituted by one or more R4k5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, fused with phenyl, unsubstituted or substituted by one or more R4m;

[0102] R 4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)g, -P(0)(C1-Cb alkyl)g, morpholinyl, thiazolyl, phenyl,

[0103] R5, Rs a each independently represents -H, Ci-Ce alkyl,

[0104] Re a , Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Re aand Reb, together with the C atom to which they are attached, form C3-C6 cycloalkyl, unsubstituted or unsubstituted by several -(C1-C6)alkyl; R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0105] Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0106] Hal represents an atom of F, Cl, Br, I.

[0107] In one embodiment, the present invention relates to a compound wherein -A-L2-R4 is

[0108] where k,m each independently represents 0, 1,2 or 3,

[0109] Ь2 is a chemical bond, -NR.5-, -О-, -S-, -S(O)-, -S(O)2-, -С(О)-, -С(О)О-, - C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -Р(О)(СН3)-, -О-(СН2)1-з-, -(СН2)Ьз-О-, -NR 5a -(CH2)i.3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH-C(O)-;

[0110] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(O)(Ci-Ce alkyl)2, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C1-Cb)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Cb alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more ^;-(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g; -C2-C6 alkenyl, unsubstituted or substituted by one or more R4; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rtj, condensed with phenyl, unsubstituted or substituted by one or more R4k5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, condensed with phenyl, unsubstituted or substituted by one or more R4m; R4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH, -NH2, -Hal, -CN, -Ci-C6 alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl;-C3-Cb cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)r, -P(0)(C1-C6 alkyl)r, morpholinyl, thiazolyl, phenyl,;

[0111] R5, Rsa each independently represents -H, Ci-Ce alkyl,

[0112] Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-Cb cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0113] R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C1-Cb)alkyl, unsubstituted or substituted by one or more -Hal;

[0114] Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl unsubstituted or substituted by one or more -Hal;

[0115] Hal represents an atom of F, Cl, Br, I.

[0116] In one embodiment, the present invention relates to a compound where -A-L2-R4 is

[0117] where p each independently represents 0 or 1 and q each independently represents 0, 1 or 2, with the total number of substituents on each ring not exceeding 3; b2 represents a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)1-3-, -(CH2)i-3-O-, -NR 5a -(CH2)i.3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)1.3-, -(CH2)1.3-C(O)-, -C(O)-NH- or -NH-C(O)-;

[0118] R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(0)(C1-C6 alkyl)2, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C-C6)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R 4e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R ; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R 4g; -Cr-C6 alkenyl, unsubstituted or substituted by one or more R4h; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R4i; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, fused with phenyl, unsubstituted or substituted by one or more R4k5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R4I, fused with phenyl, unsubstituted or substituted by one or more R 4m ;

[0119] R 4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, R4I, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)g, -P(0)(C1-Cb alkyl)g, morpholinyl, thiazolyl, phenyl,

[0120] R5, Rsa each independently represents -H, Ci-Ce alkyl,

[0121] Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls;

[0122] R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0123] Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal;

[0124] Hal is an atom of F, Cl, Br, I

[0125] In one embodiment, the present invention relates to a compound wherein Li, L2 each independently represent a chemical bond, -C(O)-, -CH2-, -CH(CH3)-, -C(CH3)2-, -C(CH2)2-, -CF2-, -S-, -S(O)-, -S(O)2-, -O-, -NH-, -NCH3-, -P(O)(CH3)-, -C(O)O-, -C(O)-NH- or -NH-C(O)-.

[0126] In one embodiment, the present invention relates to a compound wherein Ri is -H, -CF3, -CC13, -CHF2, -CH2F, -CHCh, -CH2CI, -NO2.

[0127] In one embodiment, the present invention relates to a compound wherein R2, R3 each independently represent -H, methyl, ethyl, propyl, or R2 and R3 together with the C atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl.

[0128] In one embodiment, the present invention relates to a compound wherein R4 is -H, (=0), -OH, -F, -Cl, -Br, -P(O)(C-C6 alkyl)r; -S(O)2NH2; -S(O)2-(C1-C6)alkyl; -(C1-C6)alkyl, unsubstituted or substituted by one or more (=0), -Hal, -CN, -S(O)2-(C1-C6)alkyl; -O-(C1-C6)alkyl, unsubstituted or substituted by one or more (=0), -CN, -Hal; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more (=0), -OH, -Hal, -CN; phenyl, unsubstituted or substituted by one or more -Hal, -CN, morpholine, -P(O)(CH3)r; 5-6 membered heterocyclyl with 1,2 or 3 heteroatoms selected from N or O, unsubstituted or substituted by -(C1-C6)alkyl, (=0), -Hal, -CN; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted (=0) by -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -Hal, -CN; 5-6 membered heteroaryl with 1 or 2 N atoms, unsubstituted or substituted by one or more (=0) -(C1-C6)alkyl, fused with phenyl;-ЫКдаКдь,;

[0129] P-4a, Kd each independently represents -H, (=0), morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

[0130] In one embodiment, the present invention relates to a compound wherein R4 is -H, -OH, (=0), -P(O)(CH3)2, -CH3, -CH2CH3, tert-butyl, -CH2CF3, -CH2CH2S(O)2CH3, -CF3, -Cl, -OCF3, -S(O)2NH2, -S(O)2CH3, phenyl unsubstituted or substituted with one or more -Hal, -CN; methylpiperazinyl, piperazinyl, imidazolyl, thiazolyl, methylpyrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholine, oxanyl, oxolanyl, cyclohexyl, cyclopentyl, cyclopropyl, oxazolyl, methyloxazolyl, dimethyloxazolyl, dihydropyridinyl, methyldihydropyridinyl, -MPaId,

[0131] Each of the groups independently represents -H, (=0), morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

[0132] In one embodiment, the present invention relates to a compound wherein Rg, Rd, R 4C , R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, R41, R-4m each independently represents -H, (=0) -CH3, morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

[0133] In one embodiment, the present invention relates to a compound wherein R5 is —H, -CH3.

[0134] In one embodiment, the present invention relates to a compound wherein Rea and Reb each independently represent -H, -F, -CH3, or Rea and Reb together with the C atom to which they are attached represent cyclopropyl.

[0135] In one embodiment, the present invention relates to a compound wherein R7, R?a, R?b, R?c, R?d, R?e R?f R?g R?h each independently represents (=0), -Hal, -CH3; -OCH3; -CHah; -OCHah.

[0136] In one embodiment, the present invention relates to a compound wherein Rsa, Rsb, Rsc, Rsd, Rse Rsf Rsh each independently represents (=0), -Hal, -CH3; -OCH3; -CHah; -OCHah.

[0137] The compounds described in the present invention may be prepared as and / or may be used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, the following: acid salts formed by reacting the compound in free base form with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acids, etc.; or with an organic acid such as formic, acetic, propionic, caproic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, trifluoroacetic, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic acids, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylene-bis-3-hydroxy-2-ene-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, etc.

[0138] The corresponding counterions of the pharmaceutically acceptable salts can be analyzed and identified using a variety of techniques including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductive plasma coupling, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0139] Salts are recovered using at least one of the following techniques: filtration, precipitation with a precipitating agent followed by filtration, evaporation of the solvent or, in the case of aqueous solutions, lyophilization. It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition salt forms or crystalline forms thereof, in particular solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and can be formed during a crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described in this patent can be readily prepared or formed in the processes 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, solvated forms are considered equivalent to unsolvated forms when describing the compounds and methods provided by the present invention.

[0140] The compounds described in the present invention may be presented in various forms, including, but not limited to, unstructured forms, milled forms, and nanoparticles. In addition, the compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include crystals with different structures of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, different infrared spectra, melting points, different densities, hardnesses, crystalline forms, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, the degree of crystallization, and storage temperature, may cause one crystalline form to predominate.

[0141] Screening and characterization of pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished by a variety of methods, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption and microscopy. Thermal analysis methods are directed toward the study of 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 weight loss, find the glass transition temperature or study compatibility with an excipient. 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 techniques 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, FTIR, UVIS and NMR (liquid and solid). The various microscopy techniques include but are not limited to: polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray (EDX), ambient scanning electron microscopy with EDX (gas or water vapor), IR microscopy and Raman microscopy.

[0142] In another embodiment, the present invention relates to compounds selected from the group consisting of:

[0143]

[0144]

[0145] The present invention also relates to a method for inhibiting the biological activity of cyclin-dependent protein kinases CDK7 in a subject, comprising contacting cyclin-dependent protein kinases CDK7 with a compound of the present invention.

[0146] The CDK7 inhibitory compounds can be used for the manufacture of medicaments for the treatment of any of the pathological conditions described herein, for example, the compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers will be useful in the prevention or treatment of diseases or medical conditions associated with an increase in CDK7 activity exclusively or in part, for example, an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease. Examples of an oncological disease that can be treated using the above compounds are selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC),HER2-negative breast cancer expressing estrogen and / or progesterone receptors, HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, head and neck squamous cell cancer, oral cancer, oral squamous cell cancer, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma,primary peritoneal cancer, retinoblastoma, multiple myeloma, but not limited to.,

[0147] Examples of an autoimmune disease are selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitides (ANCA-associated vasculitides including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis, but are not limited to them.

[0148] Examples of autoinflammatory disease are selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD),TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome), but are not limited to them.,

[0149] Examples of an infectious inflammatory or non-infectious inflammatory disease are selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis,diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis,

[0150] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0151] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0152] In another embodiment of the invention, the pharmaceutical composition of the invention is intended for the prevention or treatment of a disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7. In another embodiment of the invention, the pharmaceutical composition of the invention is intended for the prevention and treatment of a disease or disorder associated with an increase in the activity of cyclin-dependent protein kinase CDK7, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7 is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease.

[0153] In another embodiment of the present invention, a pharmaceutical composition comprising the compounds of the present invention is intended for the prevention or treatment of an oncological disease selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing estrogen and / or progesterone receptors, HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, squamous cell cancer of the head and neck, oral cancer, oral squamous cell cancer, hepatobiliary cancer,hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis,mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis,pharyngitis and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult Still's disease (AOSD), TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); infectious inflammatory or non-infectious inflammatory disease selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia,desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis,sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.,

[0154] In another embodiment of the present invention, a pharmaceutical composition containing the compounds of the present invention is intended for the prevention or treatment of an oncological disease that is breast cancer, metastatic breast cancer, HEK2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing receptors for estrogen and / or progesterone HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0155] The pharmaceutical composition of the present invention may contain, for example, from about 5% to about 100% by weight of active ingredients, from about 10% to about 100% of active ingredients, from about 10% to about 60% of active ingredients. It is understood that the content of the active ingredient or ingredients in an individual dose of each dosage form does not necessarily constitute an effective amount, since the necessary effective amount can be achieved by administering several unit dosage forms.

[0156] A typical composition is prepared by mixing a compound of the present invention and a carrier, diluent, or excipient. Suitable carriers, diluents, fillers are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or filler 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 a major component, and ethanol, propylene glycol, polyethylene glycols (e.g. PEG400, PEG300), etc., and mixtures thereof. The compositions may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, glidants, processing aids, colorants, sweeteners, flavors, aromas, and other known additives to obtain a good appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to facilitate the manufacture of a pharmaceutical product (i.e., a drug). The manufacture of pharmaceutical compositions should preferably comply with GMP (good manufacturing practice) requirements.

[0157] The pharmaceutical compositions may also include salts, solvates and hydrates of the compounds of the present invention, or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent).

[0158] The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract and / or buccally, lingually or sublingually enters the bloodstream directly from the oral cavity.

[0159] Dosage forms suitable for oral administration include solid, semi-solid, and liquid systems such as tablets; granules; soft or hard capsules containing multi- or nanoparticulates, liquids, or powders; lozenges (including liquid-filled); chewables; gels; rapidly dissolving dosage forms; films; suppositories; sprays; and buccal / mucoadhesive patches. More preferred dosage forms for oral administration are tablets, granules, and capsules.

[0160] Liquid dosage forms include suspensions, solutions, syrups and elixirs. Such dosage forms may be used as fillers in soft or hard capsules (e.g., of gelatin or hydroxypropyl methylcellulose) and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying and / or suspending agents. Liquid dosage forms may also be prepared by reconstitution of a solid, e.g., from a sachet.

[0161] The compounds of the present invention may also be administered parenterally. As used herein, the term "parenteral administration" of a pharmaceutical composition includes any route of administration that involves physically breaking the integrity of a subject's tissue and introducing the pharmaceutical composition through the tissue break, typically resulting in direct entry into the bloodstream, into a muscle, or into an internal organ. Thus, parenteral administration includes, but is not limited to, administering the pharmaceutical composition by injecting the composition, by introducing the composition through a surgical incision, by applying the composition through a tissue-penetrating non-surgical wound, and the like.Specifically, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intra-articular injection or infusion; and renal dialysis infusion techniques. Intratumoral delivery, such as intratumoral injection, may also be useful. Regional perfusion is also contemplated.

[0162] Dosage forms of pharmaceutical compositions suitable for parenteral administration typically contain the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic solution. Such dosage forms can be prepared, packaged in a form suitable for bolus administration or for continuous administration. Injectable dosage forms can be prepared, packaged in unit dosage form, such as ampoules, or in multi-dose containers containing a preservative. Dosage forms for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous bases, pastes and the like.

[0163] The compounds of the present invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture or as particles with mixed components, for example mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler such as a pressurized aerosol container, pump, spray, nebulizer (preferably an atomizer that uses the principle of electrohydrodynamics to produce a fine mist) or nebulizer, with or without a suitable propellant, or as nasal drops.

[0164] The pressurized container, pump, spray, nebulizer or atomizer typically contains a solution or suspension of the compound of the invention, including, for example, a suitable substance for dispersing, solubilizing or extending the release of the active substance, a propellant as a solvent. Before use as a dry powder or suspension, the drug is typically micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid purification to form nanoparticles, high pressure homogenization or spray drying.

[0165] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base and a potency modifier.

[0166] A suitable solution formula for use in a sprayer that uses the principle of electrohydrodynamics to produce a fine mist may contain a suitable dose of the compound of the invention per actuation, and the volume per actuation may vary, for example, from 1 µl to 100 µl.

[0167] Suitable flavoring agents such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharinate may be added to the dosage forms of the present invention intended for inhalation / intranasal administration.

[0168] Dosage forms may be designed for immediate and / or modified release. Modified release dosage forms include delayed, sustained, pulsatile, controlled, targeted and programmed release.

[0169] In one embodiment, the present invention relates to a prophylaxis or method of treating a disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7, which comprises administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition of the present invention to a subject in need of such treatment or prophylaxis.

[0170] In another embodiment, the present invention relates to the prevention or method of treating a disease or disorder, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7 is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease.

[0171] In another embodiment, the present invention relates to the prevention or method of treating a disease or disorder, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7 is an oncological disease selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing estrogen and / or progesterone receptors, HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer,head and neck squamous cell carcinoma, oral cavity cancer, oral squamous cell carcinoma, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis,Graves' disease, asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous and articular syndrome (CINCA), Majid syndrome,mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); an infectious inflammatory or non-infectious inflammatory disease selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia,giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, rheumatic polymyalgia, hepatitis, cholangitis,progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.,

[0172] In another embodiment, the present invention relates to the prevention or method of treating a disease or disorder, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent protein kinases CDK7 is an oncological disease selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing receptors for estrogen and / or progesterone HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0173] It is understood that the compounds of the present invention can be used in prophylaxis, methods of treatment as described above, can be used in treatment as described above, and / or can be used in the manufacture of medicinal products (medicines) for treatment as described above.

[0174] In one embodiment, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as described above, for the treatment of a disease or disorder associated with increased CDK7 activity in a subject in need of such treatment.

[0175] In one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as described above, for the treatment of a disease or disorder associated with an increase in CDK7 activity, wherein the disease or disorder associated with an increase in CDK7 activity is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease.

[0176] In another embodiment, the present invention relates to the use described above, wherein the disease or disorder associated with an increase in CDK7 activity is an oncological disease selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing estrogen and / or progesterone receptors, HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, head and neck squamous cell cancer, oral cancer, oral squamous cell cancer, hepatobiliary cancer,hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis,mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis,pharyngitis and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult Still's disease (AOSD), TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); an infectious inflammatory or non-infectious inflammatory disease selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia,hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis,necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.,

[0177] In another embodiment, the invention relates to the use described above, wherein the oncological disease is selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing receptors for estrogens and / or progesterone HEK2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0178] The compounds of the present invention may be administered alone or in combination with one or more other drugs or monoclonal antibody drugs (or any combination thereof). Thus, the pharmaceutical compositions, methods and uses of the invention also encompass embodiments of combinations (co-administration) with other active agents.

[0179] As used herein, the terms "co-administration," "co-administered," or "in combination with" referring to the compounds with one or more other therapeutic agents are intended to mean, refer to, or include:

[0180] • the simultaneous administration to said patient of such a combination of a compound of the present invention and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form from which said components are released substantially simultaneously,

[0181] • the simultaneous administration of such a combination of a compound of the present invention and a therapeutic agent to a patient in need of treatment, wherein such components are formulated separately in different dosage forms, the administration of which occurs at substantially the same time to said patient, whereupon said components are released substantially simultaneously in said patient,

[0182] • sequential administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment, wherein such components are formulated separately from one another in separate dosage forms which are administered sequentially in time to said patient with a significant time interval between each administration, wherein said components are then released at different times in said patient; and • sequential administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment, wherein such components are formulated together in a single dosage form from which the release of said components occurs in a controlled manner, wherein they are then simultaneously, sequentially or jointly released at the same time and / or at different times to said patient, wherein each part may be administered by the same or different routes.

[0183] 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 therapy regimens are described in the literature. For example, the use of uniform dosing, i.e., administering more frequent and smaller doses to minimize toxic side effects, is described in the literature. Combination therapy also includes intermittent treatment, which is started and stopped at different times in accordance with the patient's treatment plan. In the combination therapy described in this patent, the dosages of the co-administered compounds may vary depending on the type of adjuvant drug used, the specific drug used, the disease or condition being treated, etc.

[0184] The antitumor treatment described above may be used as a single therapy or in combination with surgery or radiation therapy or drug therapy. Such therapy may be administered concurrently, simultaneously, sequentially or separately with treatment with a compound of the invention and may include one or more agents from the following categories of antitumor agents: antiproliferative / antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents, alkylated sulfonates, nitrosoureas or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; antitumor antibiotics; topoisomerase inhibitors.

[0185] Examples of antimetabolites include, but are not limited to, folate antagonists (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, calcium levofolinate) or pyrimidine antagonists (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxouridine, azacitidine, enocitabine, carmofur, gemcitabine, sapacitabine, elacytarabine, doxifluridine) or purine antagonists (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine) or asparaginase.

[0186] Examples of alkylating agents include, but are not limited to, mechlorethamine, cyclophosphamide, chlorambucil, menphalan, bendamustine, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, laromustine, semustine, streptozocin, dacarbazine, ifosfamide, improsulfan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, treosulfan, carbochion, apazichion, fotemustine, altretamine, glufosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, VAL-083.

[0187] Examples of hormonal agents and hormonal antagonists include, but are not limited to, hydrocortisone, dexamethasone, prednisone, prednisolone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, diethylstilbestrol, estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, fluocortolone, fulvestrant, goserelin, histrelin, leuprorelin, mitotane, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin-alpha, toremifene, triptorelin, diethylstilbestrol, akolbifen, danazol, deslorelin, epithiostanol, orteronel, enzalutamide, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane.

[0188] Examples of platinum compounds include, but are not limited to, cisplatin, carboplatin, oxaliplatin, eptaplatin, miriplatin hydrate, lobaplatin, nedaplatin, picoplatin, satraplatin.

[0189] Examples of antitumor antibiotics include, but are not limited to, doxorubicin, daunorubicin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pirarubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plicamycin, peplomycin, mitomycin C, zinostatin, streptozocin.

[0190] Examples of topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, belotecan, teniposide, etoposide, voreloxin, amonafide.

[0191] Examples of antineoplastic agents include, but are not limited to, any of the following: microtubule-active agents such as taxanes (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel, tesetaxel), vinca alkaloids (e.g., vinorelbine, vinblastine, vincristine, vindesine, vinflunine); mitogen-activated protein kinase signaling inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002); mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus, ridaforolimus); antibodies (eg, prolgolimab, rituximab, trastuzumab, alemtuzumab, besilesomab, cetuximab, denosumab, ipilimumab, bevacizumab, pertuzumab, pembrolizumab, nivolumab, cemiplimab, durvalumab, atezolizumab, avelumab, ofatumumab, panitumumab, tositumomab, catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab,tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, rakotumomab, tabalumab, abituzumab); kinase inhibitors (fosmatanib, entospletenib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dasatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, bosutinib, axitinib, afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, nintedanib, lenvatinib, linifatinib, linsitinib, masitinib, motesanib, neratinib, orantinib, ponatinib, radotinib, tipifarnib, tivantinib, tivozanib, trametinib, apatinib, ibrutinib, acalabrutinib, cobimetinib, fedratinib, brivanib alaninate, cediranib, cabozantinib, icotinib, cipatinib, rigosertib, pimasertib, buparlisib, idelalisib, midostaurin, perifosine, tesevatinib); photosensitizers (for example, talaporfin, temoporfin, sodium porfimer); cytokines (eg, aldesleukin, interferon alfa, interferon alfa-2a, interferon alfa-2Ь, celmoleikin, tasonermin,recombinant interleukin-2, oprelvekin, recombinant interferon beta-1a); vaccines (eg, picibanil, sipuleucel-T, vitespen, emepepimut-S, oncoVAX, rindopepimut, troVAX, MGN-1601, MGN-1703); bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, amsacrine, brostallicin, miltefosine, romidepsin, plitidepsin, eribulin, ixabepilone, fosbretabulin, denileukin diftitox, ibritumomab tiuxetan, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab-ozogamicin, aflibercept, oportuzumab monatox, cintredequin besudox, edotreotide, inotuzumab-ozogamicin, naptumomab estaphenatox, vintafolide, brentuximab vedotin, bortezomib, ixazomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, zoledronic acid, ibandronic acid, pamidronic acid, alitretinoin, tretinoin, peretinoin, bexarotene, tamibarotene, imiquimod, lentinan, mifamurtide, romurtide, pegaspargase, pentostatin, endostatin, sisofiran, vismodegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide,etanidazole, ganetespib, idronoxyl, iniparib, lonidamine, nimorazole, procodazole, tasquinimod, telotristat, belinostat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, reolizin, retaspimycin, trebananib, virulizin.,

[0192] Thus, in a further embodiment of the invention, there is provided a pharmaceutical product comprising a compound of formula I or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, as defined above, in combination with an antitumor agent, as defined above, for the joint treatment of cancer.

[0193] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over a period of time, or the dose may be proportionately reduced or increased as the exigencies of the therapeutic situation dictate. It is especially advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for the patients / subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.The specification for the unit dosage forms of the present invention is generally dictated by and directly dependent on (a) the unique characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compound for the treatment of sensitivity in subjects.

[0194] Thus, it will be understood by those skilled in the art, based on the disclosure provided herein, that the doses and dosing regimens are adjusted according to methods well known in the therapeutic art. This means that the maximum tolerated dose can be readily established and the effective amount that provides a detectable therapeutic effect for the patient can also be determined, as well as the requirements for the time of administration of each agent to achieve a detectable therapeutic effect for the patient. Thus, although certain doses and dosing regimens are provided as examples herein, these examples in no way limit the doses and dosing regimens that may be needed for a patient in the practice of the present invention.

[0195] It should be noted that the dosage values ​​may vary depending on the type and severity of the condition to be alleviated, and may include one or more doses. It should also be understood that for any particular patient, specific administration regimens should be adjusted over time according to individual needs and at the discretion of the healthcare professional administering or supervising the administration of the compositions, and that the concentration ranges provided herein are provided by way of example only and are not intended to limit the scope or practice of the claimed compositions. In addition, the dosage regimen with the compositions of the invention may be based on a variety of factors, including the type of disease, age, weight, sex, health condition of the patient, severity of the condition, route of administration, and the particular compound of the invention used.Thus, the dosage regimen may vary widely, but may be determined regularly using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses individual dose increases that are determined by a skilled artisan. Determination of the required dose and regimens are well known in the relevant art and will be understood by a person skilled in the art after familiarization with the teachings disclosed herein.

[0196] Typically, doses used to treat an adult are usually in the range of 0.01-5000 mg per day, or 0.1-500 mg per day, or 0.1 to 100 mg per day.

[0197] As the patient's condition improves, a maintenance dose is administered if necessary. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on symptoms, to a level that maintains an alleviated state of the disease, disorder, or condition. Patients may, however, require intermittent treatment over time for any recurrence of symptoms.

[0198] The foregoing range is only suggestive since the number of variables in individual treatment regimens is large and significant deviations from these recommended values ​​are not unusual. These dosages may be modified depending on a variety of variables not limited to the activity of the compound employed, 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 treating physician.

[0199] For a better understanding of the invention, the following examples are given. These examples are given for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0200] The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes, which demonstrate methods by which the compounds of the present invention may be prepared. The starting materials may be obtained from commercial sources or prepared by conventional methods in the art known to those skilled in the art. It will also be apparent to those skilled in the art that the selective protection and deprotection steps, as well as the order in which these steps are carried out, may be performed in different orders, depending on the nature of the substituents, to successfully complete the synthesis presented below.

[0201] The abbreviations used in the present description, including those given in the illustrative diagrams and the following examples, are well known to those of ordinary skill in the art.

[0202] DIPEA - diisopropylethylamine; TBAF - tetrabutylammonium fluoride;

[0203] DMF - CM-dimethylformamide;

[0204] THF - tetrahydrofuran;

[0205] In IN AP - (±)-2,2'-is(diphenylphosphino)-1,G-dinaphthalene;

[0206] MTBE - methyl tert-butyl ether;

[0207] TMEDA - A, A, A', A'-tetramethylethane-l,2-diamine;

[0208] HATU - 1-[is(dimethylamino)methylene]-1 / / -1,2,3-triazolo[4,5-£>]pyridinium 3-oxide hexafluorophosphate;

[0209] NBS - A-bromosuccinimide;

[0210] TEA - triethylamine;

[0211] DMAP - 4-dimethylaminopyridine;

[0212] TFA - trifluoroacetic acid;

[0213] TIPS - triisopropylsilane; dppf - 1,G-is(diphenylphosphino)ferrocene; ac - acetyl;

[0214] Ьос - tert-butoxycarbonyl; pin - pinacolato;

[0215] HOBt - 1-hydroxybenzotriazole;

[0216] EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

[0217] PPA - polyphosphoric acid;

[0218] HPLC - high performance liquid chromatography;

[0219] Ph - phenyl;

[0220] HMDS - hexamethyldisilazane.

[0221] Examples.

[0222] Example 1. Synthesis of compound 1.6.

[0223] 1.5 1.6

[0224] Synthesis of compound 1.2

[0225] To a solution of 1.1 (4.00 g, 18.34 mmol) in 40 mL of dichloromethane were added TEA (4.28 g, 42.2 mmol), DMAP (0.679 g, 5.50 mmol) and benzenesulfonyl chloride (3.64 g, 21.7 mmol). The reaction mixture was stirred for 20 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 5.63 g (86%) of compound 1.2 were obtained.

[0226] Synthesis of compound 1.3

[0227] Compound 1.2 (2.5 g, 6.98 mmol), (BPin)2 (3.62 g, 13.96 mmol), KOAc (1.77 g, 17.45 mmol), Pd(dppf)C12 (0.417 g, 0.56 mmol) in 50 mL of 1,4-dioxane were stirred under nitrogen for 10 h at 100°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 2.16 g (76%) of compound 1.3 were obtained.

[0228] Synthesis of compound 1.5

[0229] Compound 1.3 (0.90 g, 2.0 mmol), pyrimidine 1.4 (0.692 g, 1.82 mmol), Na2CO3 (0.448 g, 4.18 mmol), Pd(dppf)Cl2 (0.136 g, 0.18 mmol) in a mixture of 18 mL of 1,4-dioxane and 6 mL of water were stirred under nitrogen for 4 h at 100°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.95 g (84%) of compound 1.5 was obtained.

[0230] Synthesis of compound 1.6

[0231] Compound 1.5 (0.90 g, 1.44 mmol) was dissolved in 9 ml of ethanol, NaOH (0.35 g, 8.64 mmol) and 9 ml of water were added. The reaction mixture was stirred at 60°C for 6 h, the solvent was removed, water was added to the residue until complete dissolution (10 ml), the pH of the mixture was adjusted to 3 with 10% citric acid solution. The formed precipitate was filtered, the residual solvents were removed in vacuo. 0.6 g (92%) of product 1.6 was obtained.

[0232] Example 2. Synthesis of compound 2.4.

[0233] Synthesis of compound 2.1

[0234] Compound 1.1 (9.08 g, 41.6 mmol) was dissolved in 90 ml of ethanol, NaOH (6.73 g, 167 mmol) and 45 ml of water were added. The reaction mixture was stirred at 70°C for 6 h, ethanol was removed in vacuo, water was added to the residue until complete dissolution, the pH of the mixture was brought to 3 НСconc., the precipitate was filtered off, washed with water, and the residual solvents were removed in vacuo. 7.1 g (90%) of compound 2.1 were obtained.

[0235] Synthesis of compound 2.2

[0236] Compound 2.1 (3.52 g, 18.5 mmol) was dissolved in 40 ml of dichloromethane, oxalyl chloride (9.41 g, 74.1 mmol) and 0.3 ml of DMF were added. The reaction mixture was stirred for 2 h, the volatiles were removed in vacuo, the residue was dissolved in 20 ml of dichloromethane and added while cooling in an ice bath to a solution of tert-butanol (2.77 g, 37.1 mmol) and TEA (15.0 g, 148 mmol) in 10 ml of dichloromethane, and the mixture was stirred for 20 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 3.7 g (81%) of compound 2.2 were obtained.

[0237] Synthesis of compound 2.3

[0238] To a solution of 2.2 (4.5 g, 18.3 mmol) in 50 mL of dichloromethane were added TEA (4.28 g, 42.2 mmol), DMAP (0.22 g, 1.79 mmol) and benzenesulfonyl chloride (3.24 g, 20.2 mmol). The reaction mixture was stirred for 20 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel.

[0239] We obtained 6.73 g (80%) of product 2.3.

[0240] Synthesis of compound 2.4

[0241] TFA (1.37 g, 12.0 mmol) was added to a solution of 2.3 (0.579 g, 1.50 mmol) in 12 ml of dichloromethane, and the reaction mixture was stirred for 20 h at room temperature. Volatile components were removed in vacuo. 0.43 g (95%) of product 2.4 was obtained.

[0242] Example 3 Synthesis of compounds CDK7 536, CDK7 537, CDK7 833, CDK7 835, CDK7 846, CDK7 847, CDK7 848, CDK7 849, CDK7 850, CDK7 851, CDK7 951, CDK7 997, CDK7 998, CDK7 1001, CDK7 1003.

[0243] Synthesis of compound 3.1

[0244] Compound 1.6 (0.065 g, 0.14 mmol), HATU (0.108 g, 0.28 mmol), cyclopropylamine (0.012 g, 0.21 mmol), DIPEA (0.073 g, 0.56 mmol) were dissolved in 0.6 ml of DMF and stirred for 20 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.035 g (51%) of compound 3.1 was obtained.

[0245] Synthesis of compound CDK7_951

[0246] Compound 3.1 (0.035 g, 0.07 mmol) was dissolved in TFA (0.403 g, 3.5 mmol) and stirred at 20°C for 20 h. TFA was distilled off under reduced pressure, the product was isolated by preparative HPLC. 0.015 g (54%) of compound CDK7_951 was obtained.

[0247] The following compounds were prepared similarly from compound 1.6 and the corresponding amines:

[0248] Example 4 Synthesis of compounds CDK7 538, CDK7 539, CDK7 834, CDK7 836, CDK7 837, CDK7 838

[0249] Synthesis of compound 4.2

[0250] Compound 2.4 (0.3 g, 0.91 mmol) was dissolved in 5 ml of dichloromethane, oxalyl chloride (0.289 g, 2.28 mmol) and 0.1 ml of DMF were added. The reaction mixture was stirred for 3 h. The volatiles were removed in vacuo, the residue was dissolved in 5 ml of dichloromethane and added dropwise with stirring and cooling in an ice bath to a solution of 4-aminopyridine (0.087 g, 0.91 mmol) and TEA (0.386 g, 3.64 mmol) in 5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.3 g (80%) of compound 4.2 was obtained.

[0251] Synthesis of compound 4.3 Compound 4.2 (0.10 g, 0.25 mmol), (BPin)2 (0.13 g, 0.50 mmol), KOAc (0.063 g, 0.63 mmol), Pd(dppf)C12 (0.021 g, 0.03 mmol) were dissolved in 2 mL of 1,4-dioxane and heated in a closed vessel with stirring under nitrogen atmosphere for 6 h at 100 °C. The reaction mixture was filtered through a pad of celite and the solvent was removed. Compound 1.4 (0.088 g, 0.33 mmol), X2CO3 (0.088 g, 0.82 mmol), Pd(dppf)Cl2 (0.025 g, 0.03 mmol), 5 ml of 1,4-dioxane and 1.7 ml of water were added to the residue. The reaction mixture was heated in a closed vessel under nitrogen atmosphere for 3 h at 100°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.075 g (44%) of compound 4.3 was obtained.

[0252] Synthesis of compound 4.4

[0253] An aqueous solution of NaOH (0.089 g, 2.2 mmol) was added to a solution of 4.3 (0.075 g, 0.11 mmol) in ethanol (1.5 ml) and the mixture was stirred for 3 h at 50°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.042 g (72%) of compound 4.4 was obtained.

[0254] Synthesis of compound CDK7 836

[0255] Compound 4.4 (0.042 g, 0.08 mmol) was dissolved in 2 ml of dichloromethane, TFA (0.092 g, 0.8 mmol) was added, the reaction mixture was stirred for 20 h at 20°C, the solvent was removed. The product was isolated by HPLC. 0.012 g (34%) of compound CDK7 836 was obtained.

[0256] The following compounds, shown in the table below, were obtained in a similar manner.

[0257] *The intermediate product was not isolated.

[0258] Synthesis of compound 4.5

[0259] Compound 2.1 (0.6 g, 3.16 mmol), / N-methylpiperazine (0.425 mL, 3.79 mmol), HATU (1.58 g, 4.11 mmol), DIPEA (1.11 mL, 6.32 mmol) were dissolved in 6 mL of DMF and stirred at room temperature for 20 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.86 g (99%) of compound 4.5 was obtained.

[0260] Synthesis of compound 4.6

[0261] To a solution of 4.5 (0.5 g, 1.84 mmol) in 15 mL of dichloromethane were added TEA (0.769 mL, 5.52 mmol), DMAP (0.023 g, 0.18 mmol) and benzenesulfonyl chloride (0.36 g, 2.02 mmol). The reaction mixture was stirred for 20 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.56 g (74%) of product 4.6 was obtained.

[0262] Synthesis of compound 4.7

[0263] Compound 4.6 (0.56 g, 1.36 mmol), (BPin)2 (0.698 g, 2.72 mmol), KOAc (0.413 g, 4.08 mmol), Pd(dppf)C12 (0.112 g, 0.14 mmol) in 12 mL of 1,4-dioxane were stirred under nitrogen for 10 h at 100°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.52 g (83%) of compound 4.7 was obtained.

[0264] Synthesis of compound 4.8

[0265] Boronic ester 4.7 (0.149 g, 0.32 mmol), pyrimidine 1.4 (0.1 g, 0.26 mmol), MagCO3 (0.07 g, 0.65 mmol), Pd(dppf)Cl2 (0.024 g, 0.03 mmol) in 2 ml of 1,4-dioxane and 0.7 ml of water were stirred under nitrogen for 4 h at 100°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.05 g (23%) of compound 4.8 was obtained.

[0266] Synthesis of compound 4.9

[0267] Compound 4.8 (0.05 g, 0.07 mmol), NaOH (0.065 g, 1.61 mmol) in 0.5 ml ethanol and 0.5 ml H2O were stirred at 50°C for 2 h. 2 ml 10% citric acid solution were added, extracted with ethyl acetate, and after removing the solvent in vacuo, 0.016 g (42%) of compound 4.9 was obtained.

[0268] Synthesis of compound CDK7 539

[0269] Compound 4.9 (0.016 g, 0.03 mmol) was dissolved in 1 ml of dichloromethane, 0.2 ml of 4 N HCl solution in 1,4-dioxane was added, the reaction mixture was stirred at 20°C for 18 h, the volatile components were removed in vacuo, and the product was isolated by preparative HPLC. 0.010 g (77%) of compound CDK7_539 was obtained.

[0270] Example 5. Synthesis of compound CDK7_535

[0271]

[0272] To a solution of compound 5.1 (0.45 g, 1.23 mmol) in 50 ml of THF was added with stirring under nitrogen atmosphere at -78°C 0.75 ml (1.84 mmol) of 2.5 M solution of w-butyl lithium in hexane, the mixture was stirred for 30 min, then benzoyl chloride (0.262 g, 1.84 mmol) was added and the mixture was stirred for another 30 min. After standard work-up, the product was isolated by column chromatography on silica gel. 0.3 g (62%) of compound 5.2 was obtained.

[0273] Synthesis of compound 5.3

[0274] Pyrrole 5.2 (0.126 g, 0.35 mmol), (BPin)2 (0.124 g, 0.48 mmol), KOAc (0.063 g, 0.63 mmol), Pd(dppf)C12 (0.012 g, 0.02 mmol) were dissolved in 5 ml of 1,4-dioxane and heated in a closed vessel for 7 h at 100°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.05 g (36%) of compound 5.3 was obtained.

[0275] Synthesis of compound 5.4

[0276] Boronic ester 5.3 (0.05 g, 0.1 mmol), pyrimidine 1.4 (0.027 g, 0.07 mmol), ISfeCCh (0.021 g, 0.2 mmol), Pd(dppf)C12 (0.007 g, 0.01 mmol) in 1.5 mL of 1,4-dioxane and 0.5 mL of water were stirred under nitrogen for 3 h at 90°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.04 g (62%) of compound 5.4 was obtained.

[0277] Synthesis of compound 5.5

[0278] Compound 5.5 was obtained similarly to compound 4.9 in 87% yield.

[0279] Synthesis of compound CDK7 535

[0280] Compound CDK7_535 was obtained similarly to compound 539 in 38% yield.

[0281] Example 6 Synthesis of compounds CDK7 845, CDK7 924, CDK7 959, CDK7 961, CDK7 1052.

[0282] Synthesis of compound 6.2

[0283] The compound was obtained similarly to compound 4.2 with a yield of 93%.

[0284] Synthesis of compound 6.3

[0285] Amide 6.2 (0.29 g, 1.00 mmol) and 0.97 g methanesulfonic acid (10 mmol) were stirred for 72 h at 20°C, 5 ml water were added to the reaction mixture while cooling, the mixture was stirred for 1 h, the precipitate was filtered off, washed with water, and the residual solvents were removed in vacuo. 0.19 g (84%) of compound 6.3 was obtained.

[0286] Synthesis of compound 6.4

[0287] TEA (0.26 g, 2.60 mmol), DMAP (0.01 g, 0.08 mmol) and benzenesulfonyl chloride (0.165 g, 0.92 mmol) were added to a solution of pyrrolopyridone 6.3 (0.19 g, 0.84 mmol) in 6 ml of dichloromethane, and the reaction mixture was stirred for 18 h at 20°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.26 g (73%) of compound 6.4 was obtained.

[0288] Synthesis of compound 6.5

[0289] Compound 6.4 (0.22 g, 0.60 mmol), (BPin)2 (0.31 g, 1.2 mmol), KOAc (0.153 g, 1.50 mmol), Pd(dppf)C12 (0.045 g, 0.06 mmol) in 5 mL of 1,4-dioxane were heated with stirring under nitrogen atmosphere for 7 h at 100°C. After standard workup, the product was isolated by column chromatography on silica gel. 0.14 g (59%) of compound 6.5 was obtained.

[0290] Synthesis of compound 6.6

[0291] Compound 6.5 (0.54 g, 1.30 mmol), pyrimidine 1.4 (0.495 g, 1.30 mmol), ISfeCCE (0.348 g, 3.25 mmol), Pd(dppf)C12 (0.97 g, 0.13 mmol) in a mixture of 12 mL of 1,4-dioxane and 4 mL of water were stirred under nitrogen for 4 h at 100°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.26 g (32%) of compound 6.6 was obtained.

[0292] Synthesis of compound 6.7

[0293] The compound was obtained similarly to compound 4.9 with a yield of 95%.

[0294] Synthesis of compound CDK7 845

[0295] The compound was obtained similarly to compound CDK7_539 with a yield of 38%.

[0296] The following compounds were obtained in a similar manner:

[0297] Example 7. Synthesis of compound CDK7_944

[0298] Compound 7.1 (2.30 g, 12.9 mmol), compound 7.2 (1.49 g, 12.9 mmol) and A 2CO3 (1.87 g, 0.065 mmol) were added to 23 mL of 1,4-dioxane and stirred for 5 h at 100°C. After standard workup, the product was isolated by column chromatography on silica gel. 3.00 g (82%) of compound 7.3 were obtained.

[0299] Synthesis of compound 7.4

[0300] Compound 7.3 (3.00 g, 8.5 mmol) and LiOH (0.630 g, 25.5 mmol) in a mixture of 15 mL of water and 30 mL of methanol were stirred for 8 h at 55 °C. Methanol was removed under reduced pressure, the pH of the mixture was adjusted to 2, the formed precipitate was filtered off and the residual solvents were removed in vacuo. 2.10 g (97%) of compound 7.4 were obtained.

[0301] Synthesis of compound 7.5

[0302] Compound 7.4 (1.070 g, 4.0 mmol), SOCh (0.980 g, 8.0 mmol) and DMF (0.015 g, 0.2 mmol) in 10 mL of dichloromethane were stirred for 2 h at 40°C. To the mixture was added 5 mL of 4N HCl solution in 1,4-dioxane and stirred for 16 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.540 g (99%) of compound 7.5 were obtained.

[0303] Synthesis of compound 7.6

[0304] Compound 7.5 (0.30 g, 2.09 mmol) was dissolved in 30 ml of THF, NaH (0.125 g, 3.13 mmol) was added to the resulting solution at 0°C and the mixture was stirred for 30 min at 0°C. Then TIPSC1 (0.540 g, 2.72 mmol) was added dropwise and stirred for 30 min at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.611 g (99%) of compound 7.6 was obtained. Synthesis of compound 7. 7

[0305] Compound 7.6 (0.611 g, 1.98 mmol) was dissolved in 20 ml of THF, a solution of NBS (0.356 g, 1.98 mmol) in 10 ml of THF was added at -78°C and the mixture was stirred for 30 min at -78°C and 30 min at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.735 g (100%) of compound 7.7 was obtained. Synthesis of compound 7.8

[0306] Compound 7.7 (0.625 g, 1.60 mmol) and 30% TBAF solution in tetrahydrofuran (1.59 g, 1.76 mmol) were mixed in 20 mL of THF. The mixture was stirred for 30 min at 25°C. After standard workup, the product was isolated by column chromatography on silica gel. 0.240 g (70%) of compound 7.8 was obtained.

[0307] Synthesis of compound 7.9

[0308] Compound 7.8 (0.240 g, 1.06 mmol) was dissolved in 30 ml of THF, NaH (0.064 g, 1.59 mmol) was added to the resulting solution at 0°C and the mixture was stirred for 30 min, benzenesulfonyl chloride (0.227 g, 1.27 mmol) was added and the mixture was stirred for 30 min at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.31 g (82%) of compound 7.9 was obtained.

[0309] Synthesis of compound 7.10

[0310] Compound 7.10 was obtained analogously to compound 1.3 in 80% yield.

[0311] Synthesis of compound 7.11

[0312] Compound 7.11 was obtained similarly to compound 1.5 in 65% yield.

[0313] Synthesis of compound 7.12

[0314] Compound 7.12 was obtained analogously to compound 1.6 with a yield of 97%.

[0315] Synthesis of compound CDK7 944

[0316] Compound CDK7_944 was obtained similarly to compound CDK7_951 with a yield of 60%.

[0317] Example 8. Synthesis of compound CDK7_929.

[0318] A solution of 4.6 g (0.026 mol) of compound 8.1 in 50 ml of THF was slowly added to a suspension of 2.00 g (0.053 mol) of LIAIH4 in 100 ml of THF with stirring and cooling. The reaction mixture was stirred for 5 h at 100°C, cooled to 0°C and 50 ml of water were added. After standard work-up, the product was isolated by column chromatography on silica gel. 0.5 g (12%) of compound 8.2 was obtained. Synthesis of compound 8.3

[0319] Compound 8.3 was obtained similarly to compound 6.2 in 70% yield. Synthesis of compound 8.4

[0320] Compound 8.4 was obtained similarly to compound 6.3 in 13% yield.

[0321] Synthesis of compound 8.5

[0322] Compound 8.5 was obtained similarly to compound 6.4 in 56% yield.

[0323] Synthesis of compound 8.6

[0324] Compound 8.6 was obtained similarly to compound 6.5 in 64% yield.

[0325] Synthesis of compound 8.7

[0326] Compound 8.7 was obtained similarly to compound 6.6 in 31% yield.

[0327] Synthesis of compound 8.8

[0328] Compound 8.8 was obtained similarly to compound 6.7 in 95% yield.

[0329] Synthesis of compound CDK7 929

[0330] Compound CDK7_929 was obtained similarly to compound CDK7_845 with a yield of 90%.

[0331] Example 9. Synthesis of compound CDK7_966

[0332] Synthesis of compound 9.2

[0333] Compound 9.1 (2.4 g, 8.87 mmol) was dissolved in 30 ml of methanol. 50 ml (44.5 g, 0.395 mmol) of 40% aqueous dimethylamine solution were added. The reaction mixture was stirred for 24 h, the solvent was removed, and the product was isolated by column chromatography on silica gel. 0.5 g (21%) of compound 9.2 was obtained.

[0334] Synthesis of compound 9.3

[0335] Compound 9.2 (0.40 g, 1.48 mmol) was dissolved in 10 ml of dichloromethane, a solution of NBS (0.38 g, 2.13 mol) in 10 ml of dichloromethane was added. The reaction mixture was stirred for 1 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.16 g (31%) of compound 9.3 was obtained.

[0336] Synthesis of compound 9.4

[0337] Compound 9.3 (0.05 g, 0.14 mmol), (BPin)2 (0.047 g, 0.18 mmol), KOAc (0.042 g, 0.42 mmol), Pd(dppf)C12 (0.01 g, 0.01 mmol) were dissolved in 1 ml of 1,4-dioxane and heated in a closed vessel for 1 h at 100° C. The reaction mixture was filtered through celite and the solvent was removed in vacuo. 0.055 g (99%) of the product was obtained as a brown oil.

[0338] Synthesis of compound 9.5

[0339] Compound 9.5 was obtained similarly to compound 1.5 with a yield of 93%.

[0340] Synthesis of compound CDK7 966

[0341] Compound CDK7_966 was obtained similarly to compound CDK7_951 with a yield of 69%.

[0342] Example 10. Synthesis of compound CDK7_972

[0343] Compound 10.2 was obtained from compound 10.1 similarly to compound 1.3 with a yield of 98%.

[0344] Synthesis of compound 10.3

[0345] Compound 10.3 was obtained similarly to compound 1.5 with a yield of 3%.

[0346] Synthesis of compound CDK7 972

[0347] Compound CDK7_972 was obtained similarly to compound CDK7_951 with a yield of 33%.

[0348] Example 11. Synthesis of compound CDK7 921 11.3 _

[0349] Synthesis of compound 11.2

[0350] Compound 11.2 was obtained similarly to compound 1.3 with a yield of 62%.

[0351] Synthesis of compound 11.3

[0352] Compound 11.3 was obtained similarly to compound 1.5 with a yield of 34%.

[0353] Synthesis of compound CDK7 921

[0354] Compound CDK7_921 was obtained similarly to compound CDK7_951 with a yield of 34%.

[0355] Example 12. Synthesis of compound CDK7_901

[0356] Synthesis of compound 12.2

[0357] Compound 12.2 was obtained similarly to compound 1.3 with a yield of 87%.

[0358] Synthesis of compound 12.3

[0359] Compound 12.3 was obtained similarly to compound 1.5 with a yield of 46%.

[0360] Synthesis of compound CDK7 901

[0361] Compound CDK7_901 was obtained similarly to compound CDK7_951 with a yield of 89%.

[0362] Example 13. Synthesis of compound CDK7_766. _

[0363] Synthesis of compound 13.2

[0364] Boronic ester 13.1 (0.04 g, 0.17 mmol), pyrimidine 1.4 (0.059 g, 0.15 mmol), Pd(OAc)2 (0.003 g, 0.015 mmol), PPy3 (0.008 g, 0.03 mmol), N2CO3 (0.05 g, 0.46 mmol) in 0.37 mL of 1,4-dioxane and 0.04 mL of water were stirred at 100°C under nitrogen for 8 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.046 g (68%) of compound 13.2 were obtained.

[0365] Synthesis of compound CDK7 766

[0366] Compound 13.2 (0.025 g, 0.05 mmol) was dissolved in 3 ml of dichloromethane, 0.2 ml of TFA was added, the mixture was stirred for 18 h at 20°C, the solvent was removed in vacuo, and the product was isolated by preparative HPLC. 0.008 g (40%) of compound CDK7_766 was obtained.

[0367] Example 14. Synthesis of compounds CDK7 809, CDK7 810, CDK7 811, CDK7 829, CDK7 830, CDK7 897

[0368] Synthesis of compound 14.1

[0369] Method A:

[0370] NaH (0.014 g, 0.302 mmol) was added to a solution of indole (0.031 g, 0.276 mmol) in 2 ml DMF, the mixture was stirred for 30 min, a solution of pyrimidine 1.4 (0.100 g, 0.263 mmol) in 1 ml DMF was added, the reaction mixture was stirred for 20 h, a saturated solution of NaHCOs was added, and the mixture was extracted with ethyl acetate. The product was isolated by column chromatography on silica gel using a hexane-ethyl acetate mixture (92:8) as an eluent. 0.081 mg (67%) of compound 14.1 was obtained.

[0371] Method Ь is similar to method A, instead of NaH K2CO3 was used, and instead of DMF MeCN, instead of stirring at room temperature the reaction mixture was heated at boiling until the initial reagents disappeared.

[0372] Synthesis of compound CDK7 809

[0373] Method A:

[0374] Compound 14.1 (0.063 g, 0.137 mmol) was dissolved in 1.5 ml of 7.65 M HCl solution in 1,4-dioxane. The reaction mixture was stirred for 18 h at 20° C. The solvent was removed in vacuo, the residue was treated with ether, the formed precipitate was filtered off and the residual solvents were removed in vacuo. 0.014 g (24%) of compound CDK7 809 were obtained as hydrochloride.

[0375] Method Ь is similar to method A, but TFA was used instead of 7.65 M HCl solution in 1,4-dioxane, and dichloromethane was used as a solvent.

[0376] The following compounds were prepared similarly:

[0377]

[0378] Example 15. Synthesis of compounds CDK7 548, CDK7 550, CDK7 735, CDK7 754,

[0379] CDK7 888, CDK7 891, CDK7 898, CDK7 900, CDK7 903, CDK7 904

[0380] 15.1 15.2 15.3 CDK7 548

[0381] Synthesis of compound 15.2

[0382] To a solution of tert-butyl Y-(2-hydroxyphenyl)carbamate (0.289 g, 1.38 mmol) in 3 ml of absolute ethanol was added DIPEA (0.214 g, 1.66 mmol). To the resulting mixture at 0°C was added a solution of compound 15.1 (0.300 g, 1.38 mmol) in 2 ml of absolute ethanol. The mixture was stirred at 0°C for 30 min, then at room temperature for 16 h. After standard work-up, the product was isolated by column chromatography on silica gel. Product 15.2 (0.45 g, 84%) was obtained.

[0383] Synthesis of compound 15.3

[0384] Compound 15.2 (0.445 g, 1.14 mmol), t / ?-butyl 3(5)-3-aminopiperidine carboxylate (0.229 g, 1.14 mmol) and DIPEA (0.221 mg, 1.71 mmol) in 2 ml of z-PrOH were stirred at room temperature for 16 h. After standard workup, the product was isolated by column chromatography on silica gel, then by preparative TLC. 0.057 g (9%) of compound 15.3 was obtained.

[0385] Synthesis of compound CDK7 548

[0386] To a solution of compound 15.3 (0.057 g, 0.107 mmol) in 1 ml of ethanol was added 1 ml of 7.65 M HCl solution in 1,4-dioxane. The mixture was stirred at room temperature for 12 h, the volatiles were removed, and the residue was recrystallized from a mixture of MTBE:acetone:PrOH (4:1:1). 0.015 g (yield 31%) of compound CDK7_548 was obtained as a hydrochloride.

[0387] The following compounds were prepared similarly:

[0388] Reaction conditions: 1st stage a: DIPEA, EtOH, rt; b: DIPEA, MeCN, rt or 40 °C

[0389] 2 stage a: a: DIPEA, z-PrOH, rt; b: DIPEA, z-PrOH, boiling; c: DIPEA, MeCN, room temp.; d: DIPEA, MeCN, boiling.

[0390] 3rd stage: a: HC1, 1,4-dioxane; b: TFA, dichloromethane.

[0391] Example 16. Getting the CDK7_991 connection

[0392]

[0393] Synthesis of compound 16.2

[0394] Obtained analogously to compound 4.2 from compound 16.1. Yield 64%.

[0395] Synthesis of compound 16.3

[0396] Compound 16.3 was obtained similarly to compound 1.2 with a yield of 92%.

[0397] Synthesis of compound 16.4

[0398] Compound 16.4 was obtained similarly to compound 1.3 with a yield of 38%.

[0399] Synthesis of compound 16.5

[0400] Compound 16.5 was obtained similarly to compound 1.5 with a yield of 32%.

[0401] Synthesis of compound 16.6

[0402] Compound 16.6 was obtained similarly to compound 4.5 with a yield of 99%.

[0403] Synthesis of compound CDK7 991

[0404] Compound CDK7_991 was obtained similarly to compound CDK7_951 with a yield of 26%.

[0405] Example 17. Obtaining compound CDK7 1017

[0406] Synthesis of compound 17.1

[0407] To a solution of 4-bromo-N,N-dimethyl-β-pyrrole-2-carboxamide (0.332 g, 1.45 mmol) in 15 ml of THF was added NaH (60% suspension in paraffin oil) (0.087 g, 2.17 mmol) at 0°C, the reaction mixture was stirred for 30 min, CH3! (0.270 g, 1.88 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 24 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.33 g (99%) of compound 17.1 was obtained.

[0408] Synthesis of compound 17.2

[0409] Compound 17.2 was obtained similarly to compound 1.3 with a yield of 98%.

[0410] Synthesis of compound 17.3 Compound 17.3 was obtained similarly to compound 1.5 with a yield of 40%.

[0411] Synthesis of compound CDK7 1017

[0412] Compound CDK7_1017 was obtained similarly to compound CDK7_951 with a yield of 10%.

[0413] Example 18. Synthesis of compound CDK7_953.

[0414] Compound 18.2 was obtained analogously to compound 8.3 from acid 2.1 and amine 18.1 in 71% yield.

[0415] Synthesis of compound 18.3

[0416] TFA (4.17 g, 36.2 mmol) was added to a solution of amide 18.2 (0.60 g, 1.81 mmol) in 5 ml of dichloromethane, the reaction mixture was stirred for 18 h at 20 °C, the volatiles were removed in vacuo, polyphosphoric acid (PPA) (9.34 g, 36.2 mmol) and phosphorus anhydride (1.05 g, 3.62 mmol) were added to the residue, the mixture was heated with stirring at 110 °C for 3 h, 10 g of ice was added, the mixture was stirred for 2 h, the precipitate was filtered off, washed with water, and the residual solvents were removed in vacuo. 0.32 g (69%) of compound 18.3 was obtained.

[0417] Synthesis of compound 18.4

[0418] NaBH4 (0.053 g, 1.32 mmol) was added to a solution of compound 18.3 (0.100 g, 0.33 mmol) in 3 ml of ethanol while cooling in an ice bath, the reaction mixture was stirred for 1 h at the same temperature, then for 72 h at 20°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.076 g (88%) of compound 18.4 was obtained.

[0419] Synthesis of compound 18.5

[0420] A 4N solution of HCl in 1,4-dioxane (0.19 ml, 0.76 mmol) was added to a solution of compound 18.4 (0.22 g, 0.76 mmol) in 11 ml of chloroform, and the reaction mixture was stirred for 3 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.14 g (77%) of product 18.5 was obtained.

[0421] Synthesis of compound 18.6

[0422] To a solution of compound 18.5 (0.14 g, 0.49 mmol) in 6 ml of dichloromethane were added TEA (0.52 g, 5.00 mmol), DMAP (0.024 g, 0.2 mmol) and benzenesulfonyl chloride (0.21 g, 1.18 mmol), the reaction mixture was stirred for 40 h at 20°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.15 g (78%) of product 18.6 was obtained.

[0423] Synthesis of compound 18.7

[0424] Compound 18.7 was synthesized analogously to 6.5 from 0.15 g of compound 18.6. After completion of borylation, the reaction mixture was filtered through a layer of silica gel, the solvent was removed, and 0.54 g of the product was obtained as a dark red oil containing 30% of the target compound 18.7, which was used in the next step without further purification.

[0425] Synthesis of compound 18.8

[0426] Compound 18.7 (0.54 g, 0.38 mmol), pyrimidine 1.4 (0.111 g, 0.29 mmol), XarCO3 (0.094 g, 0.88 mmol), Pd(dppf)Cl2 (0.022 g, 0.03 mmol) in a mixture of 6 ml of 1,4-dioxane and 2 ml of water were stirred under nitrogen for 3 h at 100° C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.081 g (43%) of compound 18.8 was obtained.

[0427] Synthesis of compound 18.9

[0428] Compound 18.9 was obtained analogously to compound 6.7 from 0.081 g of compound 18.8 in 91% yield.

[0429] Synthesis of compound 18.10

[0430] Pd / C 5% (0.25 g, 0.12 mmol) was added to a solution of compound 18.9 (0.06 g, 0.12 mmol) in 6 ml of methanol. The mixture was hydrogenated at atmospheric pressure for 3 h, the reaction mixture was filtered through a layer of celite, and the solvent was removed in vacuo. 0.033 g (54%) of compound 18.10 was obtained.

[0431] Synthesis of compound CDK7 953

[0432] TFA (0.346 g, 3 mmol) was added to a solution of compound 18.10 (0.033 g, 0.06 mmol) in 2 ml of dichloromethane, the reaction mixture was stirred at 20°C for 18 h, the volatiles were removed in vacuo, and the product was isolated by preparative HPLC. 0.009 g (36%) of compound CDK7_953 was obtained.

[0433] Example 19. Synthesis of compound 19.6.

[0434] Synthesis of compound 19.2

[0435] Aldehyde 19.1 (5.00 g, 34.9 mmol), 2,2-dimethoxyethane-1-amine (3.87 mL, 34.9 mmol), sodium triacetoxyborohydride (23.24 g, 105 mmol) were suspended in 150 mL of dichloromethane and stirred at room temperature for 24 h. After standard workup, the product was isolated by column chromatography on silica gel. 6.31 g (80%) of compound 19.2 were obtained.

[0436] Synthesis of compound 19.3

[0437] To a suspension of 4-bromo-1- / / -pyrrole-2-carboxylic acid (0.5 g, 2.63 mmol) in 5 ml of dichloromethane were added oxalyl chloride (0.451 ml, 5.26 mmol) and a drop of DMF, stirred for 2 h at room temperature, the volatiles were removed in vacuo, added to a solution of compound 19.2 (0.592 g, 2.63 mmol) and TEA in 5 ml of dichloromethane at 0 °C, stirred for 1 h. After standard work-up, the product was isolated by column chromatography on silica gel. 1.00 g (95%) of compound 19.3 were obtained.

[0438] Synthesis of compound 19.4

[0439] Compound 19.3 (2.68 g, 6.41 mmol) was dissolved in 15 mL of TFA and stirred for 6 days. Volatiles were removed in vacuo and the product was isolated by column chromatography. 1.78 g (83%) of compound 19.4 were obtained.

[0440] Synthesis of compound 19.5

[0441] Compound 19.5 was obtained analogously to compound 6.4 in 83% yield.

[0442] Synthesis of compound 19.6

[0443] Compound 19.5 (0.440 g, 0.880 mmol) was dissolved in 2 mL of TFA in a closed vessel and heated with stirring at 100°C for 30 h. The volatiles were removed and isolated by column chromatography. 0.22 g (71%) of compound 19.6 was obtained.

[0444] Example 20. Synthesis of compound CDK7_1105

[0445] Compound 19.6 (0.040 g, 0.110 mmol), cyclopropylboronic acid (0.029 g, 0.330 mmol), pyridine (0.018 mL, 0.220 mmol), triethylamine (0.081 mL, 0.550 mmol) in 4 mL of tetrahydrofuran were heated in a microwave reactor for 1 h at 150 °C. After standard workup, the product was isolated by column chromatography on silica gel. 0.042 g (98%) of compound 20.1 was obtained.

[0446] Synthesis of compound 20.2

[0447] Compound 20.1 (0.042 g, 0.100 mmol), (BPin)2 (0.039 g, 0.150 mmol), KOAc (0.051 g, 0.500 mmol), Pd(dppf)C12 (0.015 g, 0.020 mmol) were dissolved in 2 ml of 1,4-dioxane and heated in a closed vessel for 1 h at 100° C. The reaction mixture was filtered through celite and the solvent was removed in vacuo. 0.04 g (91%) of the product was obtained as a brown oil.

[0448] Synthesis of compound 20.3

[0449] Compound 20.2 (0.04 g, 0.090 mmol), pyrimidine 1.4 (0.034 g, 0.090 mmol), ISfeCCh (0.019 g, 0.180 mmol), Pd(dppf)C12 (0.010 g, 0.010 mmol) in a mixture of 2 mL of 1,4-dioxane and 0.5 mL of water were stirred under nitrogen for 1 h at 100°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.026 g (44%) of compound 20.3 was obtained.

[0450] Synthesis of compound 20.4 Compound 20.3 (0.026 g, 0.04 mmol), NaOH (0.105 g, 2.60 mmol) in 5 mL of methanol and 0.5 mL of water was stirred at room temperature for 3 h, filtered through celite, and the solvent was removed in vacuo. We obtained 0.02 g (95%) of compound 20.4.

[0451] Synthesis of compound CDK7 1105

[0452] Compound 20.4 (0.020 g, 0.04 mmol) was dissolved in 2 ml of TFA, the reaction mixture was stirred at 20°C for 18 h, the volatiles were removed in vacuo, re-evaporated with dichloromethane, the volatiles were removed in vacuo, and the product was isolated by preparative HPLC. 0.017 g (47%) of compound CDK7_1105 was obtained.

[0453] Synthesis of compound 21.1

[0454] To a solution of 2-chloropyrimidine (0.5 g, 4.28 mmol) in 10 ml of THF was added with stirring under nitrogen atmosphere at -78°C 2.23 ml (5.56 mmol) of 2.5 M solution of n-butyl lithium in hexane, stirred for 30 min, then tributyltin hydride (1.42 ml, 5.14 mmol) was added and stirred for another 30 min, the temperature was brought to room temperature, and stirred for 12 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.55 g (35%) of compound 21.1 was obtained.

[0455] Synthesis of compound 21.2

[0456] Compound 21.1 (0.089 g, 0.240 mmol), 1-benzenesulfonyl-4-bromo-2-iodo- 1 / / -pyrrole (0.1 g, 0.240 mmol), copper(I) iodide (0.014 g, 0.070 mmol), Pc1(PPy3)4 (0.028 g, 0.020 mmol) in DMF were heated in a closed vessel under an inert atmosphere for 4 h at 120° C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.035 g (40%) of compound 21.2 was obtained.

[0457] Synthesis of compound 21.3

[0458] Compound 21.2 (0.051 g, 0.140 mmol), (BPf)g (0.073 g, 0.280 mmol), KOAc (0.035 g, 0.350 mmol), Pd(dppf)Cl2 (0.010 g, 0.010 mmol) were dissolved in 2 ml of 1,4-dioxane, heated in a closed vessel for 10 h at 110° C, the reaction mixture was filtered through celite and the solvent was removed in vacuo. 0.058 g (99%) of compound 21.3 were obtained as a brown oil.

[0459] Synthesis of compound 21.4

[0460] Compound 21.3 (0.058 g, 0.140 mmol), pyrimidine 1.4 (0.053 g, 0.140 mmol), XarCO3 (0.019 g, 0.018 mmol), Pd(dppf)Cl2 (0.031 g, 0.04 mmol) in a mixture of 2 ml of 1,4-dioxane and 1 ml of water were stirred under nitrogen atmosphere for 2 h at 110° C. After standard work-up, the product was isolated by column chromatography on silica gel.

[0461] 0.044 g (50%) of compound 21.4 was obtained.

[0462] Synthesis of compound 21.5

[0463] Compound 21.5 was obtained analogously to compound 6.7 in 99% yield.

[0464] Synthesis of compound CDK7 1062

[0465] Compound CDK7_1062 was obtained similarly to compound 6.7 in 37% yield.

[0466] Example 22. Synthesis of compound CDK7 1058

[0467] Synthesis of compound 22.2

[0468] Compound 19.6 (0.12 g, 0.34 mmol), 2-bromothiazole (0.1 g, 0.6 mmol), CuI (0.06 g, 0.3 mmol), K2CO3 (0.09 g, 0.65 mmol) in 2 ml of DMF were heated with stirring in a closed vessel at 130°C for 2 h, cooled to room temperature, 3M NaOH solution was added to pH 8, stirred at room temperature for 2 h, the solvent was removed in vacuo, and the product was isolated by column chromatography. 0.1 g of a mixture containing compound 22.1 was obtained as an oil. To this mixture were added 0.056 g (0.32 mmol) of benzenesulfonyl chloride, 0.008 g (0.06 mmol) of DMAP, 0.064 g (0.64 mmol) of triethylamine and 5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 18 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.015 g (16%) of compound 22.2 was obtained.

[0469] Synthesis of compound CDK7 1058

[0470] 0.015 g (0.21 mmol) of compound 22.2, (BPin)2 (0.012 g, 0.05 mmol), KOAc (0.01 g, 0.1 mmol), Pd(dppf)C12 (0.01 g, 0.01 mmol) and 1 ml of 1,4-dioxane were mixed, and the mixture was heated in a closed vessel for 1 h at 100 °C. After cooling, the reaction mixture was filtered through celite and the solvent was removed in vacuo. To the residue containing 22.3 was added pyrimidine 1.4 (0.011 g, 0.03 mmol), Na2CO3 (0.006 g, 0.06 mmol), Pd(dppf)Cl2 (0.01 g, 0.01 mmol) in a mixture of 1 mL of 1,4-dioxane and 0.5 mL of water. The resulting mixture was stirred under nitrogen for 2 h at 110 °C, the reaction mixture was filtered through celite and the solvent was removed in vacuo. The residue containing compound 22.4 was dissolved in 1.5 mL of ethanol, NaOH (0.12 g, 3.00 mmol) and 1 mL of water were added.The reaction mixture was stirred at 60°C for 6 h, the solvents were removed in vacuo, water was added to the residue until complete dissolution (1 ml), acidified with 10% citric acid solution to pH 4, extracted with ethyl acetate, and the volatiles were removed in vacuo. The residue was dissolved in 1 ml TFA, the reaction mixture was stirred at 20°C for 18 h, the volatiles were removed in vacuo, and the product was isolated using preparative HPLC. 1.3 mg (total yield 7%) of compound CDK7_1058 was obtained.

[0471] Example 23. Synthesis of compounds CDK7 1060, CDK7 1103.

[0472] Synthesis of compound 23.2

[0473] A mixture of 4-bromo-1H-pyrrole-2-carbonitrile (0.40 g, 2.29 mmol) (23.1), NH2OH HCI (0.804 g, 11.45 mmol) and TEA (1.6 ml, 11.45 mmol) in 20 ml of ethanol was refluxed with stirring for 1 h. After standard work-up, 0.465 g (99%) was obtained and used in the next step.

[0474] Synthesis of compound 23.3

[0475] EDC (0.137 g, 0.71 mmol), HOBt (0.073 g, 0.47 mmol) were suspended in 3 mL of 1,4-dioxane, 0.027 mL (0.47 mmol) of acetic acid was added and the mixture was stirred at room temperature under nitrogen atmosphere for 1 h. Then compound 23.2 (0.100 g, 0.47 mmol) in 3 mL of 1,4-dioxane was added and the mixture was stirred at room temperature for 12 h, and the volatiles were removed in vacuo. The intermediate product was obtained by column chromatography, dissolved in 2 mL of 1,4-dioxane, heated in a microwave reactor at 130 °C for 2 h, and the volatiles were removed in vacuo. The product was isolated by column chromatography on silica gel. 0.025 g (23%) of compound 23.3 was obtained.

[0476] Synthesis of compound 23.4

[0477] Compound 23.4 was obtained similarly to compound 1.2 in 71% yield.

[0478] Synthesis of compound 23.5

[0479] Compound 23.4 (0.044 g, 0.120 mmol), (BPin)2 (0.04 g, 0.16 mmol), KOAc (0.036 g, 0.36 mmol), Pd(dppf)C12 (0.009 g, 0.01 mmol) in 1 ml of 1,4-dioxane were heated with stirring under nitrogen atmosphere at 100 °C for 4 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.034 g (68%) of compound 23.5 was obtained.

[0480] Synthesis of compound 23.6

[0481] Compound 23.6 was obtained similarly to compound 20.3 in 41% yield.

[0482] Synthesis of compound CDK7 1060

[0483] Compound 23.6 (0.016 g, 0.02 mmol), NaOH (0.016 g, 0.40 mmol) in 0.5 mL of ethanol and 0.4 mL of water were stirred at room temperature for 4 h. After standard workup, the residue containing compound 23.7 was dissolved in 1 mL of dichloromethane, 0.058 mL of TFA was added, the reaction mixture was stirred at 20 °C for 18 h, the volatiles were removed in vacuo, and the product was isolated by preparative HPLC. 0.008 g (66%) of compound CDK7_1060 was obtained.

[0484] Similarly, compound CDK7_1103 was obtained using cyclopropylcarboxylic acid with a total yield of 1%.

[0485] Example 24. Synthesis of compounds CDK7 1061, CDK7 533.

[0486] Synthesis of compound 24.2

[0487] A mixture of pyridine 24.1 (0.304 g, 0.82 mmol), 1-(benzenesulfonyl)-4-bromo-2-iodo- 1 / / -pyrrole (0.228 g, 0.55 mmol), CuI (0.032 g, 0.16 mmol), PcI(PPy3)4 (0.064 g, 0.06 mmol) in 5 ml of 1,4-dioxane was heated with stirring under nitrogen at 100°C for 4 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.054 g (32%) of compound 24.2 was obtained.

[0488] Synthesis of compound 24.3

[0489] Compound 24.2 (0.064 g, 0.18 mmol), (BPin)2 (0.093 g, 0.36 mmol), KOAc (0.055 g, 0.54 mmol), Pd(dppf)C12 (0.04 g, 0.05 mmol) in 2 mL of 1,4-dioxane were heated with stirring under nitrogen at 100 °C for 4 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.074 g (99%) of compound 24.3 was obtained.

[0490] Synthesis of compound 24.4

[0491] Compound 3.3 (0.074 g, 0.18 mmol), pyrimidine 1.4 (0.069 g, 0.18 mmol), ISfeCCh (0.058 g, 0.54 mmol), Pd(dppf)C12 (0.04 g, 0.05 mmol) in a mixture of 2 mL of 1,4-dioxane and 1 mL of water were stirred under nitrogen at 100°C for 2 h. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.04 g (35%) of compound 24.4 was obtained.

[0492] Synthesis of compound 24.5

[0493] Compound 24.4 (0.04 g, 0.06 mmol), NaOH (0.024 g, 0.6 mmol) in a mixture of 3 ml of ethanol and 3 ml of water were stirred at room temperature for 1 h. After standard work-up, 0.029 g (99%) of compound 24.5 was obtained.

[0494] Synthesis of compound CDK7 1061

[0495] Compound CDK7_1061 was obtained similarly to compound CDK7_1060 with a yield of 44%. Compound CDK7_533 was similarly obtained using the corresponding boronic acid (conditions similar to the synthesis of compound 21.4) with a total yield of 22%.

[0496] Example 25. Synthesis of CDK7_1000 compounds

[0497] Synthesis of compound 25.2

[0498] To a solution of 4-bromo-β-pyrrole-2-carbonitrile 25.1 (0.130 g, 0.750 mmol) in 3 ml of tetrahydrofuran was added NaH (0.045 g, 1.13 mmol) at 0°C, stirred for 30 min, 0.217 ml (1.2 mmol) of SEMC1 was added, and the mixture was stirred at room temperature for 1 h. After standard workup, the volatiles were removed in vacuo. The residue was dissolved in 2.5 ml DMF, NaNi (0.058 g, 0.88 mmol), NH4CI (0.047 g, 0.88 mmol) were added, and the mixture was heated with stirring in a microwave synthesizer ampoule at 160°C for 2 h. 0.069 ml (1.10 mmol) of methyl iodide was added to the reaction mixture, and the mixture was stirred at room temperature for 12 h. Volatile components were removed and the product was isolated by column chromatography. To the residue containing compound 25.2 was added (BPsh)g (0.168 g, 0.66 mmol), KOAc (0.134 g, 1.32 mmol), Pd(dppf)Cl2 (0.025 g, 0.03 mmol) in 2 ml of 1,4-dioxane and heated with stirring under nitrogen atmosphere at 100°C for 4 h.After standard workup, the reaction mixture was filtered through a layer of silica gel and the volatiles were removed. The residue containing compound 25.3 was dissolved in a mixture of 3 ml of 1,4-dioxane and 1.5 ml of water, pyrimidine 1.4 (0.118 g, 0.310 mmol), XarCO3 (0.100 g, 0.930 mmol), Pd(dppf)Cl2 (0.069 g, 0.090 mmol) were added and the mixture was stirred under nitrogen for 1 h at 100 °C. After standard workup, the reaction mixture was filtered through a layer of silica gel and the volatiles were removed. To the residue containing compound 25.4, 1 ml of dichloromethane and 0.07 ml of TFA were added, the reaction mixture was stirred at 20 °C for 18 h, and the volatiles were removed in vacuo. The residue was dissolved in 1 ml of ethanol, NaOH (0.036 g, 0.90 mmol) and 1 ml of water were added, and the mixture was stirred at 20°C for 18 h. After standard work-up, the reaction product was isolated by preparative HPLC. 0.010 g (29%) of CDK7_1000 was obtained.

[0499] Example 26. Synthesis of compound CDK7_1124

[0500]

[0501] NBS (0.926 g, 122.87 mmol) was added to a solution of pyrrole-2-carbaldehyde 26.1 (0.5 g, 5.15 mmol) in 10 ml of THF at 0°C and the mixture was stirred for 15 min at 0°C. The solvent was removed in vacuo and the product was isolated by recrystallization. 0.446 g (50%) of compound 26.2 was obtained.

[0502] Synthesis of compound 26.3

[0503] To a solution of compound 26.2 (0.200 g, 1.06 mmol) in 10 ml of THF was added NaH (0.069 g, 1.72 mmol) at 0°C and stirred for 30 min, benzenesulfonyl chloride (0.222 ml, 1.72 mmol) was added and the mixture was stirred at room temperature for 1 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.270 g (75%) of compound 26.3 was obtained.

[0504] Synthesis of compound 26.4

[0505] Compound 26.3 (0.246 g, 0.78 mmol), 1,2-diaminobenzene (0.089 g, 0.78 mmol), Na2S20s (0.148 g, 0.78 mmol) in 6 mL DMF were stirred in a microwave reactor at 80 °C for 25 min. After standard workup, the reaction product was isolated by recrystallization. 0.100 g (32%) of compound 26.4 was obtained.

[0506] Synthesis of compound 26.5

[0507] To a solution of compound 26.4 (0.100 g, 0.25 mmol) in 5 ml of THF (or DMF) was added NaH (0.015 g, 0.38 mmol) at 0°C and stirred for 20 min, methyl iodide (0.045 g, 0.30 mmol) was added and the mixture was stirred at room temperature for 18 h. After standard work-up, the product was isolated by column chromatography on silica gel. 0.103 g (99%) of compound 26.5 was obtained.

[0508] Synthesis of compound 26.6

[0509] Compound 26.5 (0.110 g, 0.250 mmol), (BPsh)g (0.130 g, 0.500 mmol), KOAc (0.076 g, 0.75 mmol), Pd(dppf)C12 (0.056 g, 0.07 mmol) were mixed in 3 ml of 1,4-dioxane and heated in a closed vessel at 100°C for 4 h. After cooling, the reaction mixture was filtered through celite, the solvent was removed in vacuo. Pyrimidine 1.4 (0.095 g, 0.250 mmol), Na2CC>3 (0.08 g, 0.750 mmol), Pd(dppf)C12 (0.056 g, 0.07 mmol) in a mixture of 3 ml of 1,4-dioxane and 1.5 ml of water were added to the residue. The resulting mixture was stirred under nitrogen atmosphere for 4 h at 110 °C, the reaction mixture was filtered through celite and the solvent was removed in vacuo. The product was isolated by column chromatography on silica gel. 0.042 g (25%) of compound 26.6 was obtained.

[0510] Synthesis of compound 26.7

[0511] Compound 26.6 (0.042 g, 0.060 mmol), NaOH (0.048 g, 1.20 mmol) in 3 mL of ethanol and 3 mL of water were stirred at room temperature for 1 h. The solvent was removed in vacuo to yield 0.028 g (88%) of compound 26.7.

[0512] Synthesis of compound CDK7 1124

[0513] TFA (0.116 g, 1.50 mmol) was added to a solution of 26.7 (0.028 g, 0.05 mmol) in 12 ml of dichloromethane, and the reaction mixture was stirred for 16 h at room temperature. Volatile components were removed in vacuo. The product was isolated by preparative HPLC.

[0514] Received

[0515] Synthesis of compound 27.1

[0516] Compound 18.3 (0.250 g, 0.830 mmol) was dissolved in 15 ml of THF, NaH (0.037 g, 0.910 mmol) was added to the resulting solution at 0°C and the mixture was stirred for 10 min, benzenesulfonyl chloride (0.139 ml, 1.08 mmol) was added and the mixture was stirred for 1 h at room temperature. After standard work-up, the product was isolated by column chromatography on silica gel. 0.131 g (40%) of compound 27.1 were obtained. Synthesis of compound 27.2

[0517] Compound 27.1 (0.131 g, 0.310 mmol), (BPin)2 (0.157 g, 0.620 mmol), KOAc (0.094-0.930 mmol), Pd(dppf)C12 (0.023 g, 0.030 mmol) in 5 mL of 1,4-dioxane were stirred under nitrogen for 8 h at 100°C. After standard workup, the reaction product was isolated by column chromatography on silica gel. 0.06 g (43%) of compound 27.2 was obtained.

[0518] Synthesis of compound 27.3

[0519] Compound 27.3 was obtained similarly to compound 4.3 in 23% yield.

[0520] Synthesis of compound CDK7 1021

[0521] Compound 27.3 (0.021 g, 0.03 mmol), NaOH (0.012 g, 0.03 mmol) in 0.5 mL ethanol and 0.5 mL H2O was stirred at room temperature for 2 h. After standard workup, the residue containing compound 27.4 was dissolved in 1 mL dichloromethane, 0.093 mL TFA was added and the mixture was stirred at room temperature for 20 h. After standard workup, the product was isolated by preparative HPLC. 0.006 g (35%) of compound CDK7_1021 was obtained.

[0522]

[0523] Synthesis of compound 28.1

[0524] Compound 19.6 (0.071 g, 0.190 mmol), oxan-4-yl methanesulfonate (0.070 g, 0.380 mmol), CS2CO3 (0.125 g, 0.380 mmol) in a mixture of 1 mL DMF and 1 mL dimethoxyethane was heated with stirring at 90 °C for 40 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.058 g (70%) of compound 28.1 was obtained.

[0525] Synthesis of compound 28.2

[0526] Compound 28.1 (0.058 g, 0.120 mmol), (BPsh)g (0.050 g, 0.190 mmol), KOAc (0.039 g, 0.380 mmol), Pd(dppf)Cl2 (0.009 g, 0.010 mmol) were dissolved in 1 ml of 1,4-dioxane and heated in a closed vessel for 4 h at 110° C. After standard work-up, the product was isolated by column chromatography. 0.049 g (85%) of compound 28.2 was obtained.

[0527] Synthesis of compound 28.3

[0528] Compound 28.2 (0.049 g, 0.100 mmol), pyrimidine 1.4 (0.046 g, 0.120 mmol), XarCO3 (0.040 g, 0.370 mmol), Pd(dppf)Cl2 (0.030 g, 0.040 mmol) in a mixture of 1 ml of 1,4-dioxane and 0.5 ml of water were stirred under nitrogen for 1 h at 110° C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.040 g (57%) of compound 28.3 was obtained.

[0529] Synthesis of compound CDK7 1121

[0530] Compound 28.3 (0.040 g, 0.060 mmol), NaOH (0.121 g, 3.00 mmol) in a mixture of 1 mL ethanol and 1 mL H2O was stirred at room temperature for 2 h. After standard workup, the residue containing compound 28.4 was dissolved in 3 mL dichloromethane, 0.696 mL TFA was added and the mixture was stirred at room temperature for 18 h. After standard workup, the product was isolated by preparative HPLC. 0.003 g (11%) of compound CDK7_1121 was obtained.

[0531] Example 29. Synthesis of compound 29.5.

[0532] Synthesis of compound 29.1

[0533] Oxalyl chloride (5.94 mL, 67.9 mmol) and a drop of DMF were added to acid 2.1 (4.30 g, 22.6 mmol) in 60 mL of dichloromethane and the mixture was stirred at room temperature for 1 h. The volatiles were then removed, the residue was dissolved in 30 mL of dichloromethane and added dropwise to a solution of methyl 3-aminopropanoate hydrochloride (4.11 g, 29.4 mmol) and TEA (16.6 mL, 31 mmol) in 30 mL of dichloromethane at 0° C. The mixture was stirred at room temperature for 1 h. After standard work-up, it was isolated by column chromatography on silica gel. 5.70 g (92%) of compound 29.1 were obtained.

[0534] Synthesis of compound 29.2

[0535] Compound 29.1 (3.90 g, 12.8 mmol) was dissolved in 40 ml of ethanol, NaOH (1.08 g, 26.8 mmol) and 20 ml of water were added. The reaction mixture was stirred at room temperature for 18 h. After standard workup, 2.8 g (84%) of product 29.2 were obtained.

[0536] Synthesis of compound 29.3

[0537] A mixture of compound 29.2 (4.07 g, 14.8 mmol), PPA (38.2 g, 148 mmol), P2O5 (4.29 g, 14.8 mmol) was stirred at 110°C for 2 h. After standard workup, 3.51 g (97%) of compound 29.3 was obtained.

[0538] Synthesis of compound 29.4

[0539] Compound 29.3 (2.04 g, 6.72 mmol), triethylsilane (3.16 g, 26.9 mmol) in 31 mL TFA was stirred at room temperature for 20 h. After standard workup, 1.22 g (79%) of compound 29.4 was obtained.

[0540] Synthesis of compound 29.5

[0541] Compound 29.5 was obtained analogously to compound 2.3 in 50% yield.

[0542] Example 30. Synthesis of compound CDK7_955. Synthesis of compound 30.1

[0543] Compound 29.5 (0.346 g, 0.920 mmol), 4-iodo-1-methyl-1H-pyrazole (1.17 g, 5.52 mmol), CuI (0.088 g, 0.460 mmol), (17?,27?)-cyclohexane-1,2-diamine (0.107 g, 0.920 mmol) in 14 mL of 1,4-dioxane was heated with stirring at 120°C for 7 h. After standard workup, the product was isolated by column chromatography. 0.247 g (60%) of compound 30.1 was obtained.

[0544] Synthesis of compound 30.2

[0545] Compound 30.1 (0.130 g, 0.290 mmol), (BPin)2 (0.221 g, 0.870 mmol), KO Ac (0.132 g, 1.30 mmol), Pd(dppf)C12 (0.065 g, 0.09 mmol) were dissolved in 9 ml of 1,4-dioxane and heated in a closed vessel for 12 h at 110° C. After standard work-up, the product was isolated by column chromatography. 0.141 g (98%) of compound 34.2 were obtained. Synthesis of compound 30.3

[0546] Compound 30.2 (0.225 g, 0.12 mmol), pyrimidine 1.4 (0.059 g, 0.160 mmol), XarCO3 (0.039 g, 0.360 mmol), Pd(dppf)Cl2 (0.009 g, 0.01 mmol) in a mixture of 3 mL of 1,4-dioxane and 1 mL of water were stirred under nitrogen for 10 h at 100°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.060 g (70%) of compound 30.3 was obtained.

[0547] Synthesis of compound 30.4

[0548] Compound 30.3 (0.026 g, 0.04 mmol), NaOH (0.112 g, 2.80 mmol) in 5 mL of ethanol and 5 mL of water were stirred at room temperature for 1 h, filtered through celite, and the solvent was removed in vacuo. 0.08 g (99%) of compound 30.4 were obtained.

[0549] Synthesis of compound CDK7 955

[0550] Compound 30.4 (0.080 g, 0.14 mmol) was dissolved in 2 ml of dichloromethane, 0.217 ml of TFA was added, and the reaction mixture was stirred at 20°C for 20 h. After standard workup, the product was isolated by preparative HPLC. 0.043 g (65%) of compound CDK7 955 was obtained.

[0551] Synthesis of compound 30.5

[0552] Compound 29.5 (0.201 g, 0.53 mmol), cyclopropylboronic acid (0.141 g, 1.59 mmol), copper(II) acetate (0.147 g, 0.079 mmol), TEA (0.339 g, 3.18 mmol), DMAP (0.196 g, 1.59 mmol) in 5 mL of toluene were stirred at 100 °C for 12 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.098 g (44%) of product 30.5 was obtained.

[0553] Synthesis of compound 30.6

[0554] Compound 30.5 (1.00 g, 2.32 mmol), (BPin)2 (1.80 g, 6.96 mmol), KOAc (0.704 g, 6.96 mmol), Pd(dppf)C12 (0.139 g, 0.190 mmol) were dissolved in 30 ml of 1,4-dioxane and heated in a closed vessel for 24 h at 100° C. After standard work-up, the product was isolated by column chromatography. 0.700 g (66%) of compound 30.6 were obtained.

[0555] Example 31. Synthesis of compound CDK7_1122, CDK7_1225.

[0556]

[0557] Compound 30.2 (0.216 g, 0.440 mmol), pyrimidine 31.1 (0.125 g, 0.390 mmol), XarCO3 (0.124 g, 1.16 mmol), Pd(dppf)Cl2 (0.058 g, 0.08 mmol) in a mixture of 6 mL of 1,4-dioxane and 2 mL of water were stirred under nitrogen for 4 h at 120°C. After standard work-up, the product was isolated by column chromatography on silica gel. 0.114 g (46%) of compound 31.2 was obtained.

[0558] Synthesis of compound CDK7 1122

[0559] Compound 31.2 (0.171 g, 0.270 mmol), NaOH (0.109 g, 2.70 mmol) in 2 mL of ethanol and 1 mL of water was stirred at room temperature for 4 h. After standard workup, it was isolated by preparative HPLC. 0.028 g (21%) of compound CDK7 1122 was obtained.

[0560] Similarly, compound CDK7_1225 was obtained with a total yield of 69%.

[0561] Example 32. Synthesis of compound CDK7 1123.

[0562] Compound 32.2 was obtained similarly to compound 4.2 in 79% yield.

[0563] Synthesis of compound 32.3

[0564] Amide 32.2 (7.34 g, 20.5 mmol) and 27 ml of methanesulfonic acid (410 mmol) were stirred for 16 h at 20°C. After standard workup, 4.98 g (83%) of the compound were obtained

[0565] 32.3.

[0566] Synthesis of compound 32.4

[0567] To a solution of pyrrolopyridone 32.3 (5.00 g, 17.1 mmol) in 100 mL of dichloromethane were added DIPEA (6.68 g, 51.2 mmol), DMAP (1.05 g, 8.53 mmol) and benzenesulfonyl chloride (4.87 g, 27.3 mmol), and the reaction mixture was stirred at room temperature for 18 h. After standard work-up, the product was isolated by column chromatography on silica gel. 3.00 g (41%) of compound 32.4 were obtained.

[0568] Synthesis of compound 32.5

[0569] Compound 32.4 (1.50 g, 3.46 mmol), (BPin)2 (1.76 g, 6.92 mmol), KOAc (1.05 g,

[0570] 10.4 mmol), Pd(dppf)C12 (0.258 g, 0.350 mmol) in 20 mL of 1,4-dioxane was heated with stirring under nitrogen for 3 h at 100°C. After standard workup, the product was isolated by column chromatography on silica gel. Compound 32.5 (1.60 g, 96%) was obtained.

[0571] Synthesis of compound 32.6

[0572] Compound 32.5 (0.117 g, 0.230 mmol), pyrimidine 31.1 (0.110 g, 0.210 mmol), XarCO3 (0.067 g, 0.630 mmol), Pd(dppf)Cl2 (0.031 g, 0.040 mmol) in a mixture of 3 ml of 1,4-dioxane and 1 ml of water were stirred under nitrogen atmosphere for 18 h at 100°C. After standard work-up, 0.130 g (98%) of compound 32.6 was obtained.

[0573] Synthesis of compound CDK7 1123

[0574] Compound 32.6 (0.600 g, 0.960 mmol), NaOH (0.384 g, 9.60 mmol) in 18 mL of ethanol and 3 mL of water was stirred at 45 °C for 3 h. After standard workup, it was isolated by preparative HPLC. 0.106 g (23%) of CDK7_1123 was obtained.

[0575] Example 33. Synthesis of compound CDK7 1176, CDK7 1172, CDK7 1177, CDK7 1188.

[0576] Synthesis of compound 33.1

[0577] Compound 33.1 was obtained similarly to compound 30.1 in 83% yield.

[0578] Synthesis of compound 33.2

[0579] Compound 33.2 was obtained similarly to compound 30.2 in 99% yield.

[0580] Synthesis of compound 33.3

[0581] Compound 33.3 was obtained similarly to compound 30.3 in 53% yield.

[0582] Synthesis of compound 33.4

[0583] Compound 33.4 was obtained similarly to compound 30.4 in 99% yield.

[0584] Synthesis of compound CDK7 1176

[0585] Compound CDK7_1176 was obtained similarly to compound CDK7_955 in 70% yield.

[0586] The following compounds were obtained similarly:

[0587] *The conditions and methodology of this step are described in the synthesis of compound 30.5

[0588] Synthesis of compound 34.1

[0589] Method A:

[0590] Compound 34.1 was obtained analogously to compound 26.5 in 79% yield.

[0591] Method B:

[0592] Compound 34.1 was obtained similarly to 44.3 from compound 43.1 and Me! in an overall yield of 70.0%.

[0593] Synthesis of compound 34.2

[0594] Compound 34.2 was obtained similarly to compound 30.2 in 99% yield.

[0595] Synthesis of compound CDK7 1187

[0596] Compound 34.2 (0.069 g, 0.120 mmol), pyrimidine 31.1 (0.062 g, 0.120 mmol), XarCO3 (0.039 g, 0.360 mmol), Pd(dppf)Cl2 (0.013 g, 0.020 mmol) in a mixture of 2 mL of 1,4-dioxane and 1 mL of water were stirred under nitrogen for 6 h at 100°C. After standard work-up, the product was isolated by preparative HPLC. 0.05 g (10%) of compound CDK7 1187 was obtained.

[0597] Example 35. Synthesis of compounds CDK7 999, CDK7 1102. .

[0598] Synthesis of compound 35.1

[0599] Compound 35.1 was obtained similarly to compound 4.2 in 96% yield.

[0600] Synthesis of compound 35.2

[0601] Compound 35.1 was dissolved in 10 ml of acetonitrile, NaNi (0.136 g, 2.07 mmol) was added.

[0602] A solution of trifluoromethanesulfonic anhydride (0.570 g, 1.88 mmol) in 5 mL of acetonitrile was then added and the mixture was stirred at room temperature for 18 h. After standard workup, the product was isolated by column chromatography to yield 0.162 g (76%) of compound 35.2.

[0603] Synthesis of compound 35.3

[0604] Compound 35.3 was obtained similarly to compound 26.3 in 49% yield.

[0605] Synthesis of compound 35.4

[0606] Compound 35.4 was obtained similarly to compound 20.2 in 50% yield.

[0607] Synthesis of compound 35.5

[0608] Compound 35.5 was obtained analogously to compound 20.3 in 84% yield.

[0609] Synthesis of compound 35.6

[0610] Compound 35.6 was obtained analogously to compound 24.5 in 74% yield.

[0611] Synthesis of compound CDK7 999

[0612] Compound CDK7_999 was obtained similarly to compound CDK7_951 with a yield of 58%.

[0613] Similarly, compound CDK7_1102 was obtained using cyclopropylamine with an overall yield of 1%.

[0614] Example 36. Synthesis of compound CDK7_814.

[0615] Synthesis of compound CDK7 814

[0616] Compound 36.1 (0.152 g, 0.210 mmol), pyrimidine 1.4 (0.080 g, 0.210 mmol), ISfeCCh (0.067 g, 0.630 mmol), Pd(dppf)C12 (0.047 g, 0.060 mmol) in a mixture of 3 mL of 1,4-dioxane and 1.5 mL of water were stirred under nitrogen for 1 h at 100 °C. The volatiles were removed and the product was isolated by column chromatography. To the residue containing compound 36.2, 3 mL of TFA was added and the mixture was stirred at room temperature for 12 h. After standard workup, it was isolated by preparative chromatography. 0.023 g (30%) of compound CDK7_814 was obtained.

[0617] Synthesis of compound 37.2

[0618] To a solution of compound 37.1 (0.082 g, 0.340 mmol) in 4 mL of THF was added 1 M LiHMDS solution in tetrahydrofuran (0.405 mL, 0.410 mmol) at -10 °C and stirred for 1 h, methyl iodide (0.161 g, 1.12 mmol) was added and the mixture was stirred at 0 °C for 10 min, then at room temperature for 2 h. After standard workup, the product was isolated by column chromatography on silica gel. 0.067 g (79%) of compound 37.2 was obtained. Synthesis of compound CDK7 843

[0619] A mixture of compound 37.2 (0.085 g, 0.330 mmol), (BPin)2 (0.128 g, 0.490 mmol), [Ir(OMe)cod]2 (0.016 g, 0.020 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.013 g, 0.050 mmol) was mixed in 2 mL of THF and stirred at room temperature for 10 min, then a solution of compound 37.2 (0.085 g, 0.330 mmol) in 1 mL of THF was added and heated in a closed vessel at 70 °C for 2 h, then at room temperature for 12 h. After cooling, the mixture was filtered through a pad of silica gel, the solvent was removed in vacuo. Pyrimidine was added to the residue containing compound 37.3 1.4 (0.122 g, 0.320 mmol), ArCO3 (0.103 g, 0.960 mmol), Pd(dppf)Cl2 (0.072 g, 0.100 mmol) in a mixture of 3 mL of 1,4-dioxane and 1.5 mL of water. The resulting mixture was stirred under nitrogen for 4 h at 100 °C, the reaction mixture was filtered through a pad of silica gel and the solvent was removed in vacuo. The product was isolated by column chromatography on silica gel. Then the residue containing compound 37.4 was dissolved in 3 ml TFA and stirred at room temperature for 12 h. After standard workup, the product was isolated by preparative HPLC. 0.006 g (5%) of CDK7_843 was obtained.

[0620] Example 38. Synthesis of compound CDK7_1019.

[0621] Compound 16.5 (0.220 g, 0.350 mmol) was dissolved in 1 mL of TFA, stirred at room temperature for 32 h, and the solvent was removed in vacuo. The dry residue was then dissolved in 15 mL of dichloromethane, methyl iodide (0.024 mL, 0.390 mmol) and DIPEA (0.311 mL, 1.75 mmol) were added, and the mixture was stirred at room temperature for 12 h. After standard workup, the product was isolated by column chromatography. 0.160 g (85%) of compound 38.1 was obtained.

[0622] Synthesis of compound CDK7 1019

[0623] Compound 38.1 (0.160 g, 0.280 mmol), NaOH (0.226 g, 5.60 mmol) in 6 mL of ethanol and 6 mL of water were stirred at room temperature for 1 h. The solvent was removed in vacuo, and the product was isolated by preparative HPLC. 0.035 g (32%) of compound CDK7 1019 was obtained.

[0624] Example 39. Synthesis of compound CDK7_1020.

[0625] Synthesis of compound CDK7 1020

[0626] Compound 1.5 (0.050 g, 0.080 mmol), NaOH (0.065 g, 1.60 mmol) in 2 mL ethanol and 2 mL water was stirred at room temperature for 1 h. After standard workup, the residue was dissolved in 1.5 mL TFA and stirred at room temperature for 16 h. After standard workup, the product was isolated by preparative HPLC. 0.015 g (48%) of CDK7_1020 was obtained.

[0627] Example 40. Synthesis of compound 40.2.

[0628] 15.1 40.2

[0629] Synthesis of compound 40.2

[0630] Compound 40.2 was obtained analogously to compound 15.3 in 48% yield.

[0631] Example 41. Synthesis of compound CDK7 1199.

[0632] Synthesis of compound CDK7 1199

[0633] Compound 32.5 (0.053 g, 0.100 mmol), pyrimidine 40.2 (0.028 g, 0.090 mmol), XarCO3 (0.106 g, 0.270 mmol), Pd(dppf)Cl2 (0.020 g, 0.027 mmol) in a mixture of 1 mL 1,4-dioxane and 0.5 mL water were stirred under nitrogen at 100 °C for 2 h. After standard workup, intermediate 41.1 was used in the next step without further purification. To the residue containing compound 41.1 was added NaOH (0.032 g, 0.800 mmol), 4 mL ethanol and 4 mL water and stirred at room temperature for 1 h. After standard workup, the product was isolated by preparative HPLC. 0.001 g (3%) of compound CDK7_1199 was obtained.

[0634] Example 42. Synthesis of compound CDK7 1254.

[0635] Synthesis of compound 42.2

[0636] Compound 42.2 was obtained analogously to compound 29.1 in 97% yield.

[0637] Synthesis of compound 42.3 Compound 42.3 was obtained similarly to compound 29.2 with a yield of 62%.

[0638] Synthesis of compound 42.4

[0639] Compound 42.4 was obtained analogously to compound 29.3 in 72% yield.

[0640] Synthesis of compound 42.6

[0641] To a solution of compound 42.4 (0.220 g, 0.410 mmol) in 7 ml of ethanol was added NaBHi (0.062 g, 1.64 mmol) while cooling in an ice bath, the reaction mixture was stirred at 20 °C for 24 h. After standard work-up, the product was isolated by column chromatography on silica gel. The residue containing compound 42.5 was dissolved in 4 ml of dichloromethane and 0.57 ml of 4 N HCl solution in 1,4-dioxane was added and the mixture was stirred at 20 °C for 20 h. After standard work-up, the product was isolated by column chromatography. 0.077 g (79%) of compound 42.6 was obtained.

[0642] Synthesis of compound 42.7

[0643] Compound 42.7 was obtained analogously to compound 2.3 in 87% yield.

[0644] Synthesis of compound 42.8

[0645] Compound 42.8 was obtained similarly to compound 27.2 in 83% yield.

[0646] Synthesis of compound 42.9

[0647] Compound 42.9 was obtained similarly to compound 1.5 in 41% yield.

[0648] Synthesis of compound 42.10

[0649] Pd / C 5% (0.170 g, 0.080 mmol) was added to a solution of compound 42.9 (0.045 g, 0.080 mmol) in 5 ml of methanol. The mixture was hydrogenated at atmospheric pressure for 20 h, the reaction mixture was filtered through a layer of celite, and the solvent was removed in vacuo. 0.023 g (55%) of compound 42.10 was obtained.

[0650] Synthesis of compound CDK7 1254

[0651] Compound CDK7_1254 was obtained similarly to compound CDK7_836 with a yield of 29%.

[0652] Example 43. Synthesis of compound 43.1.

[0653] 29.4 43.1

[0654] Synthesis of compound 43.1

[0655] To a solution of compound 29.4 (1.00 g, 4.37 mmol) in 50 ml of tetrahydrofuran was added NaH (0.227 g, 5.68 mmol) at 0°C, the mixture was stirred for 30 min, 0.789 ml (4.37 mmol) of SEMC1 was added, and the mixture was stirred at room temperature for 3 h. After standard work-up, the reaction product was isolated by column chromatography. 0.927 g (59%) of compound 43.1 was obtained.

[0656] Example 44. Synthesis of compounds CDK7 1154, CDK7 1155, CDK7 1226,

[0657] CDK7 1227, CDK7 1229, CDK7 1259, CDK7 1268. Synthesis of compound 44.1

[0658] To a solution of compound 43.1 (0.300 g, 0.790 mmol) in 15 ml of DMF was added NaH (0.948 g, 23.7 mmol) at 0°C, the mixture was stirred for 10 min, bromocyclopentane (3.72 g, 23.7 mmol) was added, and the mixture was stirred at room temperature for 28 h. After standard work-up, the reaction product was isolated by column chromatography. 0.154 g (46%) of compound 44.1 was obtained.

[0659] Synthesis of compound 44.3

[0660] Compound 44.1 was dissolved in 5 mL TFA and stirred at room temperature for 1 h. Then, the volatiles were removed in vacuo and the dry residue was dissolved in 5 mL ethanol. 3 mL 3M NaOH solution was added, the mixture was stirred at room temperature for 1 h, and the volatiles were removed. After standard work-up, it was purified by column chromatography. Then, the residue containing compound 44.2 was dissolved in 5 mL DMF, NaH (0.029 g, 0.720 mmol) was added at 0 °C, the mixture was stirred for 30 min, then benzenesulfonyl chloride (0.134 g, 0.720 mmol) was added and the mixture was stirred at room temperature for 16 h. After standard work-up, the product was isolated by column chromatography. 0.054 g (34%) of compound 44.3 was obtained.

[0661] Synthesis of compound 44.4

[0662] Compound 44.4 was prepared analogously to compound 30.2.

[0663] Synthesis of compound 44.5

[0664] Compound 44.5 was prepared analogously to compound 32.6 using pyrimidine 31.1 in 54% yield. Synthesis of compound CDK7 1154

[0665] Compound CDK7_1154 was obtained similarly to compound CDK7_1122 with a yield of 12%.

[0666] The following compounds were obtained similarly:

[0667] Example 45. Synthesis of compound CDK7_1201, CDK7_1277.

[0668]

[0669] Compound 45.1 was prepared analogously to compound 44.1 using 2-iodopropane in 74% yield.

[0670] Synthesis of compound 45.2

[0671] Compound 45.2 was obtained similarly to compound 44.2 in 92% yield.

[0672] Synthesis of compound 45.3

[0673] Compound 45.3 was obtained analogously to compound 44.3 in 96% yield.

[0674] Synthesis of compound 45.4

[0675] Compound 45.4 was obtained similarly to compound 44.4 in 60% yield.

[0676] Synthesis of compound 45.6

[0677] Compound 45.6 was obtained analogously to compound 18.8 in 85% yield.

[0678] Synthesis of compound 45.7

[0679] Compound 45.6 (1.55 g, 2.65 mmol) was dissolved in 15 ml of 4 N HCl solution in 1,4-dioxane, the reaction mixture was stirred at 60°C for 30 min. After standard work-up, the product was filtered and the volatile components were removed in vacuo. 1.15 g (88%) of compound 45.7 were obtained.

[0680] Synthesis of compound 45.8

[0681] Compound 45.7 (0.470 g, 0.900 mmol) was dissolved in 6 ml of POO3 and stirred at 90°C for 30 min. After standard workup, the product was isolated by column chromatography. 0.367 g (79%) of compound 45.8 was obtained.

[0682] Synthesis of compound CDK7_1277

[0683] A suspension of compound 45.8 (0.534 g, 1.04 mmol), amine 40.1 (0.171 g, 1.35 mmol) and TEA (0.916 mL, 6.24 mmol) in 30 mL of absolute ethanol was stirred at room temperature for 60 h. To the resulting mixture, 2 mL of 3 M NaOH solution was added and the mixture was stirred at room temperature for 2 h. After standard work-up, the product was isolated by preparative HPLC. 0.170 g (35%) of the product CDK7 1277 was obtained.

[0684] Similarly, compound CDK7_1201 was obtained with a total yield of 3%.

[0685] Example 46. Synthesis of compound CDK7_1276.

[0686] Compound 46.1 was obtained analogously to compound 18.8 using pyrimidine 45.5 in 75% yield. Synthesis of compound 46.2 Compound 46.2 was obtained analogously to compound 45.7 using pyrimidine 45.5 in 75% yield. Synthesis of compound CDK7 1276 Compound 46.2 (0.075 g, 0.140 mmol) was dissolved in 0.5 ml ROSE and stirred at 90°C for 30 min. After standard work-up, it was isolated by column chromatography. The residue containing compound 46.3, amine 40.1 (0.083 g, 1.70 mmol) and TEA (0.117 mL, 0.840 mmol) in 8 mL of absolute ethanol was stirred at room temperature for 72 h. To the resulting mixture was added 2 mL of 3 M NaOH solution and stirred at room temperature for 4 h. After standard workup, the product was isolated by preparative HPLC. 0.012 g of the product CDK7 1276 (15%) was obtained.

[0687] Example 47. Analysis of the obtained compounds.

[0688] The purity and structure of the obtained compounds were confirmed by chromatography-mass spectrometry LC / MS-ESI and 'H NMR spectroscopy (Tables 3 and 4).

[0689] Equipment data:

[0690] Table 1. Chromato-mass spectrometry

[0691] Table 2. NMR spectrometer Table 3. Analytical data for example compounds Table 4. Analytical data for example compounds

[0692] Example 48. Inhibition of the enzymatic activity of CDK7-CycH, CDK2-CycA, CDK9-CycK, CDK13-CycK. Measurements were performed in a reaction volume of 5 μl using a 384-well plate (Coming Inc, cat. no. 4513). The analytes were titrated from 50 μM in steps of 4 at 11 concentration points in 1X kinase buffer A (Thermo Fisher Scientific Inc, cat. no. PV3189) with DTT (Sigma, cat. no. 646563-10X.5ML) prepared in water (Panrea, cat. 701074). The kinase was diluted in a similar buffer, mixed with the test compounds in the wells of the plate and preincubated for 10 minutes at 25 °C. After the incubation time, a mixture of the reaction substrate (CDKtide (SignalChem, cat. No. C06-58) or Histone Hl (SignalChem, cat. No. H10-54N) or PDKtide (SignalChem, cat. No. PYU-58) and ATP (SignalChem, cat. No. V915B), prepared in a single kinase buffer A, was added. A 1% solution of dimethyl sulfoxide (DMSO) (Sigma-Aldrich, cat. No. D2438) in the reaction volume was used as a negative control.The final concentrations of all reaction components are given in Table 5. The plate was spun at 400 ref in a centrifuge (Eppendorf, 5804 R) for one minute and incubated for 40-60 minutes at 25 °C. The amount of ATP consumed in the kinase reaction was then detected using the ADP-Glo™ detection system. The luminescence signal was measured on a Spark 20M multifunctional plate reader (Tecan Group Ltd, Switzerland). The IC50 value was determined using the Magellan 7.2 program (Tecan Group Ltd, Switzerland), approximating the experimental points using a four-parameter model with Levenberg-Marquardt optimization:. where A is the upper asymptote; D is the lower asymptote; C is the IC50, the concentration of inhibition of the kinase to half its activity, nM; B is the curvature parameter (slope).

[0693] Table 5. Final concentrations of kinase reaction components.

[0694] Table 6. Results of the biochemical test for inhibition of the activities of CDK7 / Cyclin H / MNAT1, CDK2 / Cyclin A, CDK9 / Cyclin K kinases. The IC50 parameter is presented as an average value obtained from data from several measurements, “A” for ICSO<5HM, “B” for 5HM <ICSO<5OHM, «С» для 5OHM<IC5O<2OOHM, И «D» для 1С5о> 2OOHN, and “N / A” means that the specified compound was not analyzed in the described test.

[0695]

[0696] Table 7. Results of the biochemical test for inhibition of the activity of kinases CDK7 / Cyclin H / MNAT1, CDK2 / Cyclin A, CDK9 / Cyclin K, CDK13 / Cyclin K. The parameter 1C5o is presented as an average value obtained from data from several experiments:

[0697] The results of these experiments indicate the production of high-affinity CDK7 inhibitors that are selective for CDK9, CDK13, and CDK2.

[0698] Example 49. Antiproliferative activity against sensitive cell lines in vitro.

[0699] The antiproliferative activity of the CDK7 inhibitors of the present invention was assessed in a cell-based assay on continuous cell cultures of MDA-MB-468 (triple-negative breast cancer, ATCC® HTB-132™) and NC1-H82 (small cell lung cancer, ATCC® HTB-175™) cells using the vital dye AlamarBlue (Thermo Fisher Scientific Inc, Cat. No. DALI 100). The cells were grown in DMEM (PanEco, Cat. No. C330n) and RPMI-1640 (PanEco, Cat. No. C330n), respectively. The basal growth medium was enriched with 2 mM L-glutamine (PanEco, cat. No. F032) and 10% fetal bovine serum (Gibco, cat. No. 16140-071). The night before the placement, the adherent MDA-MB-468 cells were removed from the plastic with a trypsin-EDTA solution (PanEco, cat. No. P039p), which was then inactivated with a complete DMEM medium, spun down at 1000 RPM in a centrifuge (Eppendorf, 5804 R), a cell suspension was prepared in a complete DMEM medium, added to 96-well culture plates (Corning Inc, cat. No. 3599) in an amount of 8 * 10 л3 cells in 100 μl of medium per well. The following day, the test compounds were dissolved in DMSO and diluted with complete DMEM medium to a final concentration in the range from 50 μM to 10 pM. The diluted compounds in a volume of 50 μl were added to the wells of the plate with cells in triplicates (the final concentration of DMSO was no more than 1%) and maintained at 37 °C in an incubator with 5% CO2 for 96 hours. The NC1-H82 cell line suspension was prepared on the day of the assay. 10 x 10 л3 cells in 100 μl of complete RPMI-1640 medium per well of a 96-well plate. The sample dilution procedure was as described above. Cells with the compounds under study were incubated at 37 °C in an incubator with 5% CO2 for 120 hours. Upon completion of the incubation, 15 μl of AlamarBlue reagent (Thermo Fisher Scientific Inc, cat. No. DALI 100) were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), and then additionally incubated for 5.5-6 hours at 37 °C in an incubator with 5% CO2. The number of living cells was detected using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland), measuring the fluorescent signal at an excitation wavelength (XEx) of 540 nm and an emission wavelength ( / Em) of 590 nm.

[0700] The IC50 value was determined using the Magellan program (Tecan Group Ltd, Switzerland), approximating the experimental points using a four-parameter model with optimization according to the Levenberg-Mark map.

[0701] Table 8. Results of the antiproliferative assay on MDA-MB-468 and NC1-H82 cell lines. The IC50 parameter is presented as the mean value obtained from several assays, “A” for ICSOMOHM, “B” for 10 nM<1C50<100 nM, “C” for 100 nM<1C50<1000 nM, and “D” for ICSOMOOOHM, and “N / A” means that the specified compound was not analyzed in the described assay.

[0702] The results of these experiments indicate the production of inhibitors capable of stopping the growth of triple-negative breast cancer and small cell lung cancer cells at nM concentrations.

[0703] Example 50. General cytotoxicity towards primary liver cells HepaRG in vitro.

[0704] General cytotoxicity studies of the CDK7 inhibitors of the present invention were performed on primary differentiated HepaRG cells (Biopredic Int, Cat. No. HPR101). One week prior to testing, cells were removed from freezing and maintained in Basal hepatic cell medium (Biopredic Int, Cat. No. MIL700079) supplemented with HepaRG maintenance / metabolism medium supplement with antibiotics (Biopredic Int, Cat. No. ADD620C). The medium in the cell flasks was changed every 2-3 days. The night before testing, cells were seeded in 96-well plates (Coming Inc, Cat. No. 3599) at a concentration of 25><10 л 3 cells in 100 μl of medium per well. The following day, the wells of the plates with cells were added with the analyzed compounds, titrated in the concentration range from 200 μM to 0.2 nM, and incubated for 72 hours. Cell viability was assessed using the method described above.

[0705] Table 9. Results of the general toxicity study on primary HepaRG cells. The CC50 parameter is presented as the average value obtained from several assays, “A” for CC50>2000NM, “B” for 2000nM> CC50>5000NM, “C” for 500nM> CC50>1000NM, and “D” for CC50<1000NM, and “N / A” means that the indicated compound was not analyzed in the described assay.

[0706] The results of these experiments indicate the production of CDK7 inhibitors that are non-toxic in the human hepatocyte model.

[0707] Example 51. Determination of bromodeoxyuridine incorporation into DNA When bromodeoxyuridine (BrdU) is added to dividing cells, Thymidine is replaced by its analogue BrdU and BrdU is incorporated into DNA. Thus, BrdU incorporated into DNA characterizes the intensity of DNA replication and the passage of cells through the S-phase of the cell cycle. A decrease in bromodeoxyuridine incorporation into DNA under the action of the compounds characterizes a slowdown in the cell cycle and DNA replication.

[0708] The ability of the CDK7 inhibitors of the present invention to inhibit BrdU incorporation into DNA was assessed in a cell-based assay on continuous cultures of MDA-MB-468 cells (triple negative breast cancer, ATCC® HTB-132™) using the BrdU Detection Kit (Roche, Cat. No. 11 669 915 001). The cells were grown in DMEM medium (PanEco, Cat. No. C330n). The basal growth medium was supplemented with 2 mM L-glutamine (PanEco, Cat. No. F032) and 10% fetal bovine serum (Gibco, Cat. No. 16140-071). Adherent MDA-MB-468 cells were removed from the plastic with trypsin-EDTA solution (PanEco, cat. No. P039p), which was then inactivated with complete DMEM medium, spun at 1000 RPM in a centrifuge (Eppendorf, 5804 R), a cell suspension was prepared in complete DMEM medium, added to 96-well culture plates (Corning Inc, cat. No. 3599) in an amount of 4x 10 л3 cells in 75 μl of medium per well. The compounds to be studied were dissolved in DMSO and diluted with complete DMEM medium to a final concentration in the range from 0.5 μM to 2 pM. Serum-free growth medium was removed from the wells of the plate and solutions containing diluted compounds in a volume of 100 μl in the basal growth medium were added. Candidates were added to the wells of the plate with cells in triplicate (the final concentration of DMSO was no more than 1%) and kept at 37 °C in an incubator with 5% CO2 for 24 hours. Upon completion of incubation, 10 μl of BrdU solution with a concentration of 10 μM were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia), and incubated for an additional 72 hours at 37 °C in an incubator with 5% CO2. Next, detection of incorporated BrdU was performed according to the kit manufacturer's recommendations. The medium containing BrdU was removed from the wells of the plate and the plate with cells was dried at 60 °C for 1 hour.To fix the cells, 200 μl of FixDenat solution were added to each well and incubated for 90 minutes at room temperature (+15-25 °C). The fixing solution was removed and 100 μl of anti-BrdU-POD working solution was added and incubated for 90 minutes at room temperature (+15-25 °C). The anti-BrdU-POD antibody solution was removed from the wells of the plate and the wells were washed 3 times with 200 μl of washing solution (10 minutes at room temperature (+15-25 °C)). 100 μl of substrate solution was added to each well to be analyzed and incubated for 3 minutes at room temperature (+15-25 °C) on an orbital shaker (Biosan, Latvia) and for another 5-7 minutes without mixing.

[0709] The amount of incorporated BrdU was detected using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring the luminescent signal. The IC50 value was determined using the Magellan software (Tecan Group Ltd, Switzerland) by fitting the experimental points using a four-parameter model with Levenberg-Markart optimization.

[0710] Table 10. Results of BrdU incorporation into DNA on MDA-MB-468 cell lines. The IC50 parameter is presented as an average value obtained from data from several experiments, IC50 , nM.

[0711] The results of these experiments indicate the production of CDK7 inhibitors whose antiproliferative effect in the MDA-MB-468 model (Example 49) is due to cell cycle arrest and slowing of DNA replication.

[0712] Example 52. Determination of passive membrane permeability through the artificial membrane “RAMRA”.

[0713] The passive membrane permeability of the compounds described in the present invention was determined using the PAMPA (parallel artificial membrane permeability assay) model at pH 7.4. A 96-well plate (Coming® BioCoat® Pre-coated PAMPA Plate System, Cat. No. 353015) was used, consisting of an acceptor and a donor part with a pre-coated lecithin-phospholipid bilayer on a PVDF filter simulating a cell membrane. The substance (at a concentration of 10 μmol) in 0.01 M phosphate buffer with pH 7.4 was added to the donor well of the plate, and pure buffer was added to the acceptor well, then both parts were combined and incubated for 20 hours at room temperature so that the compound was redistributed between the two wells and the membrane. Verapamil (USP, USA, Cat. No. 1711202) and propranolol (MCE LLC, USA, Cat. No. HY-B0573 / CS-2680) were used as control compounds with high and medium permeability.The samples were analyzed by reversed-phase HPLC with UV detection (Agilent 1260 chromatograph with UV detector), determining their peak areas in the donor and acceptor cells. Permeability (Pe, cm / s) and retention factor (R, %) in the lipid bilayer were calculated using the formula:.

[0714] Re=(-1P[1-C А (t) / CequiHbrium]) / (AX (1 / V D +1 / VA) X t)

[0715] R=l-[Co(t) x VD+ C A (t) x V A ] / (C0+VD), where

[0716] Co is the concentration of the substance in the donor cell at the initial moment of time t (μM); C А (t) — concentration of the substance in the acceptor cell at time t (μM);

[0717] Vd — volume of the donor cell (0.3 ml);

[0718] V a — volume of the acceptor cell (0.15 ml).

[0719] Cequilibrium=[CD(t) х V D + C A (t) х V A ] / (VD+V A ) A — filter area (0.3 cm 2); t — incubation time (72000 s);

[0720] Table 11. Results of the study of passive permeability through the lipid membrane model PAMPA. Parameter P е presented as an average value obtained from data from several productions, "A" for P е > 1-10 -5 cm / s, "B" for 10 -5 cm / s > P е > 5 - 10 -6 cm / s, "C" for 5 ■ 10 -6 cm / s > P е > 1-10 -6 cm / s, and "D" for Re <1- 10 -6 cm / s, and "N / A" indicates that the compound indicated was not analyzed in the assay described.

[0721] The results of these experiments indicate the production of CDK7 inhibitors that are able to passively penetrate the lipid membrane.

[0722] Example 53. In vitro assay for determining microsomal stability of compounds in human, rat and mouse microsomes.

[0723] The procedure for studying the metabolism of selected compounds was carried out in microsomal fractions of the liver (rats, mice, humans) in the presence of a cofactor of phase I metabolism (NADPH).

[0724] The rate of enzymatic degradation of the compound in liver microsomes in an in vitro assay was determined by incubating a reaction mixture containing 0.5 mg / ml pooled human, rat or mouse liver microsomes (XenoTech, USA, cat. no. H2610, cat. no. R1000, cat. no. M1000), 1 μM of the test compound, 1.5 mM β-nicotinamide adenine dinucleotide a (Carbosynth, UK, cat. no. NN108711101) and 1.5 mM magnesium chloride in 0.1 M sodium phosphate buffer (pH 7.4) in a solid-state thermostat at 37 °C. Incubation was performed in triplicate.

[0725] To determine the stability of the compounds under the conditions of sample preparation, an aliquot of the test compound and the microsomal fraction without the addition of the NADPH cofactor were prepared in two replicates and kept for 40 min at 37 °C.

[0726] Reactions were stopped at time points of 0, 10, 20, 30 and 40 min by adding ice-cold acetonitrile:methanol (3:1) containing internal standard.

[0727] The samples were then centrifuged to remove precipitated protein, and the supernatants were analyzed by HPLC-MS / MS to determine the in vitro clearance (CLint) of the compounds. An Agilent 6410 mass spectrometer (Agilent, USA) in combination with an Agilent 1260 Infinity II liquid chromatograph (Agilent, USA) and a refrigerated autosampler under the control of MassHunter software (Agilent, USA) was used as the HPLC-MS / MS system. Chromatographic analysis was performed on a C18 reversed-phase HPLC column (Agilent, Waters or equivalent) in gradient elution mode in a mobile phase system of 0.1% formic acid in water / 0.1% formic acid in acetonitrile, flow rate of 0.5 ml / min, Tcolumn = 35°C. Mass spectrometric detection was performed with electrospray ionization in multiple reaction monitoring mode. Precursor ions, fragment ions, and collision energies for each substance were selected experimentally.A graph of the dependence of the logarithm of the ratio of the peak area of ​​the substance to the peak area of ​​the internal standard on time was constructed. The dependent coefficient of this line corresponded to the elimination constant k, on the basis of which the in vitro clearance CLint was calculated:.

[0728] Elimination rate constant (k) = (—gradient)

[0729] 0.693

[0730] Half-life (C1 / 2)(min) = — - — incubation volume (µl) P(µl / mg) = — - - - - — - — protein in incubation (mg) V x 0.693 internal clearance CL int ) (µl ■ min ■ mg protein ) = - tl / 2

[0731] Based on the obtained in vitro clearance values ​​CLint, a conclusion was made about the microsomal stability of the selected compounds for humans, rats and mice.

[0732] The results are shown in Tables 12 and 13.

[0733] Table 12. In vitro human microsomal stability (HLM) results for selected compounds. Clint is presented as the mean value of several runs, “A” for Clint < 20 µL / (min-mg protein), “B” for 50 µL / (min-mg protein) > Clint > 20 µL / (min-mg protein), “C” for 100 µL / (min-mg protein) > Clint > 50 µL / (min-mg protein), and “L” for Clint > 100 µL / (min-mg protein).

[0734] Table 13. In vitro stability results of selected compounds in rat microsomes (RLM) and mice microsomes (MLM). Clint parameter is presented as the mean value obtained from several runs, “A” for Clint < 20 µL / (min-mg protein), “B” for 50 µL / (min-mg protein) > Clint > 20 µL / (min-mg protein), “C” for 100 µL / (min-mg protein) > Clint > 50 µL / (min-mg protein), and “D” for Clint > 100 µL / (min-mg protein), and “N / A” indicates that the specified compound was not analyzed in the described test. The results of these experiments indicate the production of CDK7 inhibitors that are resistant (B) and highly resistant (A) to the action of enzymes from human, mouse, and rat liver microsomes.

[0735] Example 54. Pharmacokinetic (PK) study.

[0736] Dosage and administration

[0737] Pharmacokinetic studies of the compounds were performed in CD-1 mice, male, approximately 8 weeks old, weighing 16-29 g. The animals were given a single oral (PO) administration (intragastric) at a dose of 10 mg / kg in a formulation of 0.2% hydroxypropyl methylcellulose (HPMC) in 5% aqueous glucose solution and a single IV bolus (intravenous) administration at a dose of 1.0 mg / kg for 1277 and at a dose of 2.0 mg / kg for CDK7_1187, CDK7_1225, CDK7_1229 and CDK7_1276 in a formulation containing 0.2% DMSO in 5% aqueous glucose solution.

[0738] For each compound, 21-30 animals were used for each dose of PO and IV administration. All mice were weighed and randomized prior to dosing.

[0739] For each time point, 3-5 animals were used. Each animal was selected at one time point. At least 12 hours before the start of the experiment, the animals were deprived of food, but had free access to water.

[0740] Animals from groups RO and IV had their blood collected before the administration of the substance and after 0.5, 2, 4, 8, 12 and 24 hours.

[0741] Blood samples

[0742] Blood was collected by closed cardiac puncture. Blood was collected in a volume of 0.2 ml in polypropylene tubes containing 20 μl of 5% EDTA. Blood plasma was separated by centrifugation at 10,000 rpm for 10 min at 4±2°C and placed in clean labeled tubes.

[0743] Blood plasma analysis

[0744] The studied blood plasma samples of mice from the experimental groups were collected in a volume of 50 μl. Then 200 μl of the internal standard solution (tolbutamide (Sigma, T0891)) prepared in acetonitrile, with a concentration of 50 ng / ml, pre-cooled in a refrigerator at 2-8°C, were added to the samples, mixed on a vortex (G560E, Scientific Industries) for 10 sec and kept at 4°C for 15 min to precipitate proteins. Then the samples were centrifuged (centrifuge 5417R, Eppendorf) at 1500 g for 10 min with cooling to 4°C. 150 μl of the supernatant was transferred to a 96-well plate for HPLC-MS / MS analysis. Quantitative determination of the studied compounds in blood plasma was performed by the absolute calibration method. The calibration curve was obtained by analyzing plasma samples with additions of known amounts of the standard of the compound being determined. The lower limit of quantitative determination of the compounds being studied in blood plasma was 1 ng / ml, the analytical range of the method was from 1 ng / ml to 2000 ng / ml.The method was partially validated in terms of selectivity, accuracy, precision, linearity, matrix effect, and stability.

[0745] A Qtrap 5500 mass spectrometer (AB Sciex) in combination with an Agilent 1290 Infinity II HPLC liquid chromatograph (Agilent) and a refrigerated multisampler (Agilent 1290 Infinity II Multisampler G7167B) was used as the HPLC-MS / MS system. Chromatographic analysis was performed on a C18 reversed-phase HPLC column (YMC-Triart C 18, 50*2 mm, 1.9 μm, YMC CO. Ltd). A mixture of deionized water and acetonitrile with the addition of 0.1% formic acid in gradient mode was used as the mobile phase, flow rate 0.5 ml / min, Tcolumn = 40 °C, Tautosampler = 8 °C, analysis time 2.8 min. Mass spectrometric detection was performed in the multiple reaction monitoring (MRM) mode. Precursor ions, fragment ions and collision energies for each substance were selected experimentally.MRM chromatograms of the analyte and internal standard were recorded for two transitions Q1 / Q3, one of which was used for quantitative calculations, the second served as confirmation that the exit time corresponded to the given substance. Based on the results of HPLC-MS / MS analysis of calibration samples, a calibration dependence of the areas of chromatographic peaks of the analyte, normalized to the signal of the internal standard, on the concentration of the analyte was constructed using the Analyst 1.6.3 software.

[0746] Pharmacokinetic analysis

[0747] Pharmacokinetic analysis was performed by a non-compartmental method using the Phoenix WinNonlin 6.3 software package. The main average PK parameters were determined: time to reach maximum concentration (Tmax), half-life (T1 / 2), maximum concentration (Cmax), area under the pharmacokinetic curve (AUClast) from the moment of administration to the last measured concentration, clearance (CL), standard distribution volume (Vss), and absolute systemic bioavailability (F). The pharmacokinetic parameters of the compounds of the present invention are presented in Tables 14-15.

[0748] Table 14. Pharmacokinetic parameters of compounds in mouse plasma after intravenous administration.

[0749] Table 15. Pharmacokinetic parameters of compounds in mouse plasma after oral administration.

[0750] The compounds of the present invention meet the target pharmacokinetic characteristics: the compounds are well absorbed and have a sufficient oral absorption effect. According to the average area under the curve (AUClast), the absolute bioavailability of the compounds was calculated to be more than 72.7%. In turn, this indicates the possibility of oral administration of these compounds to achieve pharmacodynamic effects.

[0751] Example 55. Permeability of the blood-brain barrier (BBB)

[0752] The ability of substances to penetrate the blood-brain barrier into the central nervous system (mouse brain) was assessed by the ratio of their areas under the pharmacokinetic curves in the brain and blood plasma of rats upon oral administration, characterizing tissue bioavailability to the rat brain, and was expressed as the AUCbrain / AUCplasma coefficient.

[0753] Dosage and administration

[0754] Pharmacokinetic studies of the compounds were performed on CD-1 mice, males, approximately 8 weeks old, weighing 16-29 g. The animals were given a single oral (PO) administration (intragastric) at a dose of 10 mg / kg in a formulation of 0.2% hydroxypropyl methylcellulose (HPMC) solution in 5% aqueous glucose solution.

[0755] For each compound, 21 animals were used. All mice were weighed and randomized before dosing.

[0756] Three animals were used for each time point. Biomaterials were collected from each animal at one time point. At least 12 hours before the start of the experiment, the animals were deprived of food, but had free access to water. Blood and brain samples were collected 0.5, 2, 4, 6, 8, 12, and 16 hours after the substance was administered.

[0757] Blood samples

[0758] All manipulations were carried out similarly to Example 54.

[0759] Brain samples

[0760] The mice brain was perfused with physiological solution through the circulatory system. For this purpose, the chest was opened, the right atrium was cut with microsurgical scissors, and a 10-ml syringe of physiological solution cooled to 4°C was injected into the left ventricle until the liver turned white. After washing, the skull was opened and the brain was taken out, weighed, and placed in 5-ml labeled test tubes.

[0761] Analysis of brain samples

[0762] A 4-fold volume of water was added to the brain sample and homogenized using a homogenizer (Omni Bead Ruptor 24) 2 times for 45 seconds. Brain homogenate of intact mice was prepared in a similar manner and then used to prepare calibration and QC samples. The calibration curve was obtained by analyzing brain homogenate samples with additions of known amounts of the standard of the compound being determined.

[0763] The samples were precipitated with chilled acetonitrile in a ratio of 1:4, containing the internal standard tolbutamide (Sigma, T0891) at a concentration of 50 ng / ml. The samples were mixed on a vortex (G560E, Scientific Industries) for 10 sec and kept at 4°C for 15 min to precipitate proteins, then centrifuged (centrifuge 5417R, Eppendorf) for 10 min at 1500 g. 150 μl of supernatants were collected and transferred to a 96-well plate for HPLC-MS / MS analysis. Quantitative determination of the studied compounds in brain homogenates was carried out similarly to the procedure described in Example 54. The lower limit of quantification of the studied compounds in brain homogenate was 0.3 ng / ml.

[0764] Pharmacokinetic analysis of the data was performed similar to the procedure described in Example 54. In addition to the main PK parameters, the ratio of brain and plasma concentrations at the studied time points (AUCbrain / AUCplasma) was calculated to assess bioavailability in the brain (permeability through the blood-brain barrier).

[0765] Table 16. Pharmacokinetic parameters of compounds in mouse brain homogenate after oral administration.

[0766] The data obtained indicate the ability of the compounds of the present invention to penetrate the BBB.

[0767] Example 56. Study of antitumor activity in vivo.

[0768] The antitumor activity of CDK7_1187 in vivo was assessed using a subcutaneous xenograft model of the NC1-H69 line (human small cell lung cancer, ATCC® HTB-119™) transplanted into BALB / c Nude mice.

[0769] The NC1-H69 cell line was cultured in RPMI-1640 medium (PanEco, Russia), with the basal growth medium enriched with 2 mM L-glutamine (PanEco, Russia) and 10% fetal bovine serum (Gibco, Thermo Fisher Scientific, USA).

[0770] The study used 20 mice (females) of the BALB / c Nude line, obtained from the Federal State Budgetary Scientific Institution “Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences” (ICG SB RAS).

[0771] BALB / c Nude mice were injected subcutaneously into the right lateral part of the body with 200 μl of a suspension containing 5* 10 6 NCI-H69 tumor cells and Matrigel (Corning® Matrigel® Basement Membrane Matrix) in a 1:1 ratio.

[0772] Determination of the linear dimensions of the tumor was performed using an electronic caliper. The volume of the tumor node was determined using formula (1):

[0773] V = LXW 2 / 2, (1) where L and W are the major and minor diameters of the tumor node, respectively.

[0774] The tumor growth inhibition index (TGI, %) was used as an indicator of the effectiveness of the drug under study, which was calculated using formula (2):

[0775] TPO(V)= x 100%, (2)

[0776] VK where VK and Vn are the average tumor node volume in the control group and the group of animals receiving the test substance, respectively.

[0777] After reaching an average tumor volume of 130 mm 3 The animals were divided into 2 groups of 10 animals each, with the tumor node volume used as a randomization criterion. The day of the first drug administration was designated as day 0.

[0778] The test substance CDK7_1187 was administered intragastrically at a dose of 6 mg / kg daily for 21 days. Before each administration, CDK7_1187 was diluted in 5% glucose solution (Solopharm, Russia) and 0.1% DMSO solution (Sigma, USA). The control group received 5% glucose solution and 0.1% DMSO solution in a similar volume.

[0779] Statistical analysis was performed using the GraphPad Prism 9 software package. The nonparametric Mann-Whitney test was used to assess the significance of differences when comparing tumor node volumes. Differences were defined as significant at p <0.05.

[0780] The dynamics of tumor growth are presented in Figure 1. The values ​​of the TPO indices, % are presented in Table 17.

[0781] Table 17. SRW index, %

[0782] The results of the study showed that when CDK7_1187 was administered to BALB / c Nude mice, the tumor volume was statistically significantly smaller than in the control group of animals on days 17 and 21 of the experiment. The tumor growth inhibition index at the end of the observation period was 48%.

Claims

Invention formula 1. Compound of formula I: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Ri is -C(Ha1)3, -CH(Ha1)2, -CH2Ha1, -Hal, -H, alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms alkyl unsubstituted or substituted by one or more atoms Hal R2, R3 each independently represents H, -(C-C6)alkyl; or R2, R3 together form -(C3-C6)cycloalkyl unsubstituted or unsubstituted by one or more -(C1-C6)alkyl; Li, L2 each independently represents a chemical bond, -NR5-, -O-, -S-, -S(O)-, - S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)ьз-, -(CH2)ьз- O-, -NR 5a -(CH2)i.3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH- C(O)-; A is a 6-10 membered aryl, unsubstituted or substituted by one or more R?; 6-10 membered aryl, unsubstituted or substituted by one or more R? a , condensed with -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs a ; 6-10 membered aryl, unsubstituted or substituted by one or more R-th, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; 6-10 membered aryl, unsubstituted or substituted by one or more R? c , fused with a 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more Rs c; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R?d; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R? e , condensed with (C3-C6)cycloalkyl, unsubstituted or substituted by one or more Rs e ; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R?f, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rsf; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R? g ; 5-6 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R?h, fused with 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rst; R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4aR4b, -P(O)(Ci-Ce alkyl)2, -S(O)2NH2, -S(O)2Ci-Ce alkyl, -(C -C6)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Bdg; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g; -C2-C6 alkenyl, unsubstituted or substituted by one or more R4h; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R41; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, condensed with phenyl, unsubstituted or substituted by one or more R4k; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R41, condensed with phenyl, unsubstituted or substituted by one or more R4m; R4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, -P(0)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl, R5, Rsa each independently represents -H, Ci-Ce alkyl, Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls; R7, R?a, R?b, R?c, R?d, R?e R?f R?g R?h each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(Ci-C6)alkyl, unsubstituted or substituted by one or more -Hal; Rsa, Rsb, Rsc, Rsd, Rse Rsf Rsh each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C -C6)alkyl, unsubstituted or substituted by one or more -Hal; Hal represents an atom of F, Cl, Br, I.

2. Connection according to I. 1, where -A-L2-R4 represents: 171 where k,m each independently represents 0, 1, 2 or 3, Xi, X2, X3, Xd, X5, X6 each independently represents C, N, CH, CH2, NH, S or O; Yi, Y2, Yz, Yd, Y5 each independently represents C, N or CH; Ь2 is a chemical bond, -NR.5-, -О-, -S-, -S(O)-, -S(O)2-, -С(О)-, -С(О)О-, - C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -Р(О)(СН3)-, -О-(СН2)Ьз-, -(СН2)Ьз-О-, -NR 5a -(CH2)i-3-, -(CH2)i.3-NR 5a -, -C(O)-(CH2)bz-, -(CH2)bz-C(O)-, -C(O)-NH- or -NH-C(O)-; R4 is -H -Hal, (=0), -OH, -C(O)OH, -NR4 a R4b, -P(O)(C1-C6 alkyl)2, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C -C6)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more R 4d ; phenyl, unsubstituted or substituted by one or more R4 e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more tf; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R4 g; -C2-C6 alkenyl, unsubstituted or substituted by one or more Rth; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more Rti; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more Rtj, fused with phenyl, unsubstituted or substituted by one or more R4k5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms, 172 selected from N, O or S, unsubstituted or substituted by one or more R41, condensed with phenyl, unsubstituted or substituted by one or more Вдпъ R4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R41, R4j, R4k, R41, R4m each independently represents -H, (=0), -OH -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)g, -P(0)(C1-Cb alkyl)g, morpholinyl, thiazolyl, phenyl, R5, Rsa each independently represents -H, Ci-Ce alkyl, Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls; R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C-C6)alkyl, unsubstituted or substituted by one or more -Hal; Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C -C6)alkyl, unsubstituted or substituted by one or more -Hal; Hal represents an atom of F, Cl, Br, I.

3. Connection according to pi. 1-2, where -A-L2-R4 represents 173 where k, w each independently represents 0, 1, 2 or 3, L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, - C(S)-, -C(=NH)-, -(CR6aR6b)i-3-, -P(O)(CH3)-, -O-(CH2)i-3-, -(CH2)i-3-O-, -NR 5a -(CH2)i.3-, -(CH2)i-3-NR 5a -, -C(O)-(CH2)i-3-, -(CH2)i-3-C(O)-, -C(O)-NH- or -NH-C(O)-; R4 represents -H -Hal, (=0), -OH, -C(O)OH, -NR4 aR4b, -P(O)(C1-C6 alkyl)r, -S(O)2NH2, -S(O)2CI-C6 alkyl, -(C -C6)alkyl, unsubstituted or substituted by one or more R4 C ; -O-Ci-Ce alkyl, unsubstituted or substituted by one or more 174 R 4d ; phenyl, unsubstituted or substituted by one or more R 4e ; 4-7 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R ; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more R 4g; -Cr-C6 alkenyl, unsubstituted or substituted by one or more R4h; 5-6 membered heteroaryl with 1,2,3 or 4 N atoms, unsubstituted or substituted by one or more R4i; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or more R4j, condensed with phenyl, unsubstituted or substituted by one or more R4k; 5-6 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R4I, condensed with phenyl, unsubstituted or substituted by one or more R 4m ; R 4a, R4b, R4C, R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, R4I, R4m each independently represents -H, (=0), -OH, -NH2, -Hal, -CN, -Ci-Ce alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl, -Ci-Ce alkyl; -O-Ci-C6 alkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl, unsubstituted or substituted by one or more radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -S(O)2Ci-C6 alkyl, -S(O)2NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)g, -P(0)(C1-Cb alkyl)g, morpholinyl, thiazolyl, phenyl, R5, Rsa each independently represents -H, Ci-Ce alkyl, Rea, Reb each independently represents -H, Ci-Ce alkyl, -Hal, or Rea and Reb together with the C atom to which they are attached form a C3-C6 cycloalkyl unsubstituted or unsubstituted by several -(C1-C6)alkyls; R7, R?b, R?d, R?f, each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; Rsb, Rsd, Rsf each independently represents -Hal, -OH, -NH2, -CN, (=0), -(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; -O(C1-C6)alkyl, unsubstituted or substituted by one or more -Hal; Hal represents an atom of F, Cl, Br, I.

4. Compounds according to paragraphs 1-3, where Li, L2 each independently represents a chemical bond, -C(O)-, -CH2-, -CH(CH3)-, -C(CH3)2-, -C(CH2)2-, -CF2-, -S-, -S(O)-, -S(O)2-, -O-, -NH-, -NCH3-, -P(O)(CH3)-, -C(O)O-, -C(O)NH- or -NHC(O)-.

5. Compounds according to paragraphs 1-3, where Ri is -H, -CF3, -CC13, -CHF2, -CH2F, -CHCh, -CH2Cl, -NO2.

6. Compounds according to paragraphs 1-3, where R2, R3 each independently represents -H, methyl, ethyl, propyl, or R2 and R3 together with the C atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl.

7. Compounds according to paragraphs 1-3, wherein R4 is -H, (=0), -OH, -F, -Cl, -Br, -P(O)(Ci-C6 alkyl)2; -S(O)2NH2; -S(O)2-(C1-C6)alkyl; -(C1-C6)alkyl, unsubstituted or substituted by one or more (=0), -Hal, -CN, -S(O)2-(C1-C6)alkyl; -O-(C1-C6)alkyl, unsubstituted or substituted by one or more (=0), -CN, -Hal; -(C3-C6)cycloalkyl, unsubstituted or substituted by one or more (=0), -OH, -Hal, -CN; phenyl, unsubstituted or substituted by one or more -Hal, -CN, morpholine, -P(O)(CH3)2; 5-6 membered heterocyclyl with 1, 2 or 3 heteroatoms, selected from N or O, unsubstituted or substituted by -(C1-C6)alkyl, (=O), -Hal, -CN; 5-6 membered heteroaryl with 1, 2, 3 or 4 heteroatoms selected from N, O or S, unsubstituted or substituted (=O), -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -Hal, -CN; 5-6 membered heteroaryl with 1 or 2 N atoms, unsubstituted or substituted by one or more (=O), -(C1-C6)alkyl, fused with phenyl; -NKdaBd, Bda, Bd each independently represents -H, (=0), morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

8. Compounds according to Article 7, where Kd is -H, -OH, (=0), -P(O)(CH3)2, -CH3, -CH2CH3, tert-butyl, -CH2CF3, -CH2CH2S(O)2CH3, -CF3, -Cl, -OCF3, -S(O)2NH2, -S(O)2CH3, phenyl, unsubstituted or substituted by one or more -Hal, -CN; methylpiperazinyl, piperazinyl, imidazolyl, thiazolyl, methylpyrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholine, oxanyl, oxolanyl, cyclohexyl, cyclopentyl, cyclopropyl, oxazolyl, methyloxazolyl, dimethyloxazolyl, dihydropyridinyl, methyldihydropyridinyl, -MBdaKd, Bda, Bd each independently represents -H, (=0), morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

9. Connections according to pi. 1-3,7, where Pd а , Vd, Vds, Vda, Kde, Idg, R-4g, Vd, R41, Vd], Vd, V 1, Vd шeach independently represents -H, (=0) -CH3, morpholinyl, -F, -8(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -Ci-C3 alkyl unsubstituted or substituted by phenyl, -P(O)(CH3)2.

10. Compounds according to paragraphs 1-3, where B5 is -H, -CH3.

11. Compounds according to paragraphs 1-3, where Rea and Bl each independently represent -H, -F, -CH3, or Rea and Bl together with the C atom to which they are attached represent cyclopropyl.

12. Compounds according to paragraphs 1-3, where R7, R?a, R?b, R?c, R?d, R?e, R?f, R?g, R?h each independently represents (=0), -Hal, -СНз; -ОСНз; -CHah; -OCHah.

13. Compounds according to points 1-3, where Rx a , Rsb, Rsc, Rsd, Rse RsfRsh each independently represents (=0), -Hal, -СНз; -ОСНз; -CHah; -OCHah.

14. The compound according to claim 1, which is: 4-(2-aminobenzoyl-N-[(3 S)-6, 6-dimethylpiperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 461); 4-(2-aminobenzoyl)-N-(6,6-dimethylpiperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 461 a); 4-(2-Aminobenzoyl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 549); 4-(2-aminobenzoyl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 549 a); 4-benzoyl-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_813); 4-benzoyl-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_ 813_a); 4-[(2-aminophenyl)methyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 540); 4-[(2-aminophenyl)methyl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 540 a); 4-[1-(2-aminophenyl)ethyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 541); 4-[1-(2-aminophenyl)ethyl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 541 a); 4-[(18)-1-(2-aminophenyl)ethyl]-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 541 b); 4-[(1 R)-1-(2-aminophenyl)ethyl]-N-[(38)-piperide in-3-yl]-5-(trifluoromethyl)pyrimidine indamine (CDK7 541 c); 4-[2-(2-aminophenyl)propan-2-yl]-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin- 2-amine (CDK7_542); 4-[2-(2-aminophenyl)propan-2-yl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 542 a); 4-[1-(2-aminophenyl)cyclopropyl]-N-[(38)-piperide in-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 543); 4-[1-(2-aminophenyl)cyclopropyl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 543 a); 4-[(2-aminophenyl)difluoromethyl]-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 544); 4-[(2-aminophenyl)difluoromethyl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 544 a); 4-[(2-aminophenyl)sulfanyl]-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 545); 4-[(2-aminophenyl)sulfanyl]-N-(piperidin-3-yl)-5-(triflomethyl)pyrimidin-2-amine (CDK7 545 a); 4-(2-aminobenzenesulfinyl)-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 546); 4-(2-aminobenzenesulfinyl)-M-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 546 a); 4-[(N)-2-aminobenzenesulfinyl]-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 546 b); 4-[(8)-2-aminobenzenesulfinyl]-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 546 c); 4-(2-aminobenzenesulfonyl)-M-[(38)-piperidin-3-yl]-5-trifluoromethyl1)pyrimidin-2-amine (CDK7_547); 4-(2-aminobenzenesulfonyl)-M-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_547_a); 4-(2-aminophenoxy)-]-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 548); 4-(2-aminophenoxy)-] -(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 548 a); N-(2-aminophenyl)-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2, 4-diamine (CDK7 550); N-(2-aminophenyl)-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 550 a); N-(2-aminophenyl)-N4-methyl-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 551); 177 N-(2-aminophenyl)-N4-methyl-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 551 a); №-phenyl-M2-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2, 4-diamine (CDK7 812); №-phenyl-M2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_812_a); 4-phenoxy-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_754); 4-phenoxy-]-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_754_a); 4-benzyl-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_766); 4-benzyl-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_766_a); 4-[(2-aminophenyl)(methyl)phosphoryl]-N-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_552); 4-[(2-aminophenyl)(methyl)phosphoryl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 552 a); 4-[(K)-(2-aminophenyl)(methyl)phosphoryl]-N-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_552_b); 4-[(8)-(2-aminophenyl)(methyl)phosphoryl]-N-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_552_c); №-[2-(Dimethylphosphoryl)phenyl]-M2-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_735); N4-[2-(dimethylphosphoryl)phenyl]-N2-( py peride n-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_735_a); 4-[2-(dimethylphosphoryl)phenoxy]-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin- 2-amine (CDK7 897); 4-[2-(dimethylphosphoryl)phenoxy]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 897 a); 4-[3-(dimethylphosphoryl)phenoxy]-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin- 2-amine (CDK7 892); 4-[3-(dimethylphosphoryl)phenoxy]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 892 a); N-[3-(dimethylphosphoryl)phenyl]-M2-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 888); N4-[3-(dimethylphosphoryl)phenyl]-N2-(pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 888 a); N4-[2-(d-methylphosphoryl)-5-methylphenyl]-N2-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_903); N4-[2-(dimethylphosphoryl)-5-methylphenyl]-N2-(n and per i n-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_903_a); N4-[2-(d-methylphosphoryl)-4-methylphenyl]-N2-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_904); N4-[2-(dimethylphosphoryl)-4-methylphenyl]-N2-(n and perid and n-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_904_a); N-[2-(dimethylphosphoryl)-5-(trifluoromethyl)phenyl]-M2-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_905); N4-[2-(dimethylphosphoryl)-5-(trifluoromethyl)phenyl]-N2-(trifluoromethyl)pyrimidine-3-yl)-5-(trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_905_a); 178 N-[2-(dimethylphosphoryl)-4-(trifluoromethyl)phenyl]-M2-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_906); N4-[2-(dimethylphosphoryl)-4-(trifluoromethyl)phenyl]-N2-(piperidin-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_906_a); M4-[5-chloro-2-(dimethylphosphoryl)phenyl]- -[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_907); M4-[5-chloro-2-(dimethylphosphoryl)phenyl]- -(piperidin-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_907_a); M4-[4-chloro-2-(dimethylphosphoryl)phenyl]- -[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_908); M4-[4-chloro-2-(dimethylphosphoryl)phenyl]- -(piperidin-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_908_a); N4-[2-(d i methylphosphoryl)-4-(trifluoromethoxy)phenyl]- N2-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_915); N-[2-(dimethylphosphoryl)-4-(trifluoromethoxy)phenyl]-N-(piperidin-3-yl)-5- (trifluoromethyl)pyrimidine-2, 4-diamine (CDK7_915_a); 2-[(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]benzene-1-sulfonamide (CDK7_889); 2-( { 2- [(piperidin-3 -yl)amino] -5 - (trifluoromethyl)pyrimidin -4-yl} amino)benzene- 1 - sulfonamide (CDK7_889_a); N4-(3-methylsulfonylphenyl)-N2-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin- 2, 4-diamine (CDK7 890); N-(3-methylsulfonylphenyl)-M2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7 890 a); 3 - [(2- { [(38)-piperidin-3-yl] amino} -5 - (trifluoromethyl) pyrimidin-4-yl) amino] benzene- 1 - sulfonamide (CDK7_891); 3 -( { 2- [(piperidin-3 -yl)amino] -5 - (trifluoromethyl)pyrimidin -4-yl} amino] benzene- 1 - sulfonamide (CDK7_891_a); 2-[(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)oxy]benzene-1-sulfonamide (CDK7_893); 2-( { 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} oxy)benzene- 1 - sulfonamide (CDK7_893_a); 4-(3-methylsulfonylphenoxy)-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 894); 4-(3-methylsulfonylphenoxy)-M-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 894 a); 3-[(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)oxy]benzene-1-sulfonamide (CDK7_895); 3 -( { 2- [(piperidin-3 -yl)amino] -5 - (trifluoromethyl)pyrimidin -4-yl} oxy)benzene- 1 - sulfonamide (CDK7_895_a); 4-(2,3-dihydro-1H-indol-7-yloxy)-M-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_827); 4-(2,3-dihydro-1H-indol-7-yloxy)-M-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_827_a); 4-(1 H- and indol-7-yloxy)-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 828); 179 4-(1 H-indol-7-yloxy)-T4-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 828 a); 4-(1,2,3,4-tetrahydrox and nol yn-8-yloxy)-] - [(38)-piperidin-3-yl] -5 - (trifluoromethyl)pyrimidin-2-amine (CDK7_829); 4-(1,2,3,4-tetrahydroquinolin-8-yloxy)-M-(piperidin-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_829_a); M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)-4-(quinolin-8-yloxy)pyrimidin-2-amine (CDK7 830); M-(piperidin-3-yl)-5-(trifluoromethyl)-4-(quinolin-8-yloxy)pyrimidin-2-amine (CDK7 830 a); N-{2-[(2-{ [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino] phenyl} acetamide (CDK7_898); N-[2-({ 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} amino)phenyl]acetamide (CDK7_898_a); N-{2-[(2-{ [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)oxy]phenyl} acetamide (CDK7_899); N-[2-({ 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} oxy)phenyl]acetamide (CDK7_899_a); ] -[(38)-6,6-dimethylpiperidin-3-yl]-4-(5-phenyl- 1 H-pyrrol-3 -yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_460); T4-(6,6-dimethylpiperidin-3-yl)-4-(5-phenyl-1H-pyrrol-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_460_a); T4-[(38)-piperidin-3-yl]-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 533); T4-(piperidin-3-yl)-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 533 a); 4-(4-phenyl-1 H-pyrrol-3-yl)-N-[(38)-piperidin-3-yl]-4-(4-phenyl- 1 H-pyrrol-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_534); 4-(4-phenyl-1 H-pyrrol-3-yl)-M-[piperidin-3-yl]-4-(4-phenyl- 1 H-pyrrol-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_534_a); 4-(5-benzoyl-1H-pyrrol-3-yl)-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 535); 4-(5-benzoyl-1 H-pyrrol-3-yl)-N-(n and perid and n-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 535 a); N,N-fl imethyl-4-(2- { [(38)-piperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)- 1 H-pyrrole-2-carboxamide (CDK7_536); N, N-methyl-4-{2-[(p i per i d i n-3 -yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H-pyrrole-2-carboxamide (CDK7_536_a); 4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H-pyrrole-2-carboxamide (CDK7_537); 4- { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_537_a); N-phenyl-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H-pyrrole-2-carboxamide (CDK7_538); N-phenyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H-pyrrole-2-carboxamide (CDK7_538_a); 180 4-[5-(4-methylpiperazine-1-carbonyl)- I H-pyrrol-3-yl]-1 -[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 539); 4-[5-(4-methylpiperazine-1-carbonyl)-1 H-pyrrol-3-yl]-N-(4-methylpiperazine-1-carbonyl)-1 H-pyrrol-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_539_a); 4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (CDK7_922); 4- { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxylic acid (CDK7_922_a); 4-[4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H-pyrrol-2-yl]benzoitrile (CDK7_695); 4-(4- { 2- [(piperidin-3-yl)amino]-5 - (trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrol-2-yl)benzonitrile (CDK7_695_a); 3-[4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H-pyrrol-2-yl]benzoitrile (CDK7_696); 3 -(4- { 2- [(piperidin-3-yl)amino]-5 - (trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrol-2-yl)benzonitrile (CDK7_696_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_814); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 5H,6H, 7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_814_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H-pyrrolo[3,2-c]pyridin-4-one (CDK7_815); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 5H,6H, 7H-pyrrolo[3,2-c]pyridin-4-one (CDK7_815_a); 6-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H,4H, 5H, 6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_843); 6-methyl-3-{ 2- [(piperidin-3-yl)amino]-5-(triftomethyl)pyrimidin-4-yl} - 1 H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_843_a); 3-(2-{[(38)-piperidine-3-yl]amino}-5-(trifluoromethyl)pyrimidine-4-yl)-1H,4H,5H,6H,7H- pyrrolo[2,3-c]pyridine-4-one (CDK7_844); 3 - { 2-[(piperide in-3 -yl)amino] -5 -(trifluoromethyl)pyrimide in -4-yl} - 1 H,4H, 5H,6H, 7H- pyrrolo[2,3-c]pyridine-4-one (CDK7_844_a); 6-methyl-Z -(2- { [(38)-piperide in-3 -yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridine-7-one (CDK7_845); 6-methyl-Z - { 2- [(piperidin-3 -yl)amino] -5 -(trifluoro methyl)pyrimide in -4-yl} - 1 H,6H, 7H- pyrrolo[2,3-c]pyridine-7-one (CDK7_845_a); N-( 1 H-imide azol-2-yl)-4-(2- { [(38)-piperidin-3 -yl] amino} -5 -(trifluoro methyl)pyrimide in - 4-yl)-1H-pyrrole-2-carboxamide (CDK7_833); N-( 1 H-imide azol-2-yl)-4- { 2-[(piperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidine-4-yl} - 1H-pyrrole-2-carboxamide (CDK7_833_a); 4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-N-(1,3-thiazol-2-yl)-1H-pyrrole-2-carboxamide (CDK7_834); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-N-(1,3-thiazol-2-yl)- 1H-pyrrole-2-carboxamide (CDK7_834_a); N-(1-methyl-1H-pyrazol-4-yl)-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimid in-4-yl)-1H-pyrrol-2-carboxamide (CDK7_835); 181 N-(1-methyl-1H-pyrazol-4-yl)-4-{2-[(piperidin-3-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_835_a); 4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-N-(pyridin-4-yl)- 1H-pyrrole-2-carboxamide (CDK7_836); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimid in-4-yl}-N-(n ir id i n-4- yl)- 1 H- pyrrole-2-carboxamide (CDK7_836_a); N-(4-cyanophenyl)-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_837); N-(4-cyanophenyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_837_a); N-[4-(morpholin-4-yl)phenyl]-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H-pyrrole-2-carboxamide (CDK7_838); N- [4-(morpholin-4-yl)phenyl] -4- { 2- [(piperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidine - 4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_838_a); N-methyl-4-(2-{ [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H-pyrrole-2-carboxamide (CDK7_846); N-methyl-4-{ 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_846_a); 4-(2-{ [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-M-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxamide (CDK7_847); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)- 1H-pyrrole-2-carboxamide (CDK7_847_a); N-(2-methanesulfonylethyl)-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-2-carboxamide (CDK7_848); T4-(2-methanesulfonylethyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_848_a); 4-[5-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-N-[(38)-piperidin-3-yl]-5- (trifluoromethyl1)pyrimidin-2-amine (CDK7_849); 4-[5-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-N-(n iperidin-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_849_a); N-(oKcaH-4-yl)-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrrole-2-carboxamide (CDK7_850); N-(oKcaH-4-yl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_850_a); N-(4-hydroxycyclohexyl)-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-2-carboxamide (CDK7_851); T4-(4-hydroxycyclohexyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidine- 4-yl}-1H-pyrrole-2-carboxamide (CDK7 851_a); N-(4-cyanocyclohexyl)-4-(2-{[(38)-piperidin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_852); N-(4-cyanocyclohexyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_852_a); N-cyclopropyl-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrrole-2-carboxamide (CDK7_951); N- ci cloprop il -4- { 2-[(piperide in-3 -yl)amino] -5 -(trifluoro methyl)pyrimidine-4-yl} - 1 H- pyrrole-2-carboxamide (CDK7_951_a); 182 6-(3 , 5 -dimethyl- 1 , 2-oxazole -4-yl)-3 -(2- { [(38)-piperide in-3 -yl] amino}-5- (trifluoromethyl)pyrimidine-4-yl)-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridine-7-one (CDK7 923); 6-(3 , 5 -dimethyl- 1 , 2-oxazole -4-yl)-3 - { 2- [(piperidine-3 -yl)amino]-5 -(trifluoro methyl) pyrimidine-4-yl}-1H,4H,5H,6H-7H-2npi,3pyrrhol-7 (CDK7_923_a); 6-(3 , 5 -dimethyl- 1 , 2-oxazole -4-yl)-3 -(2- { [(38)-piperide in-3 -yl] amino}-5- (trifluoromethyl)pyrimidine-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridine-7-one (CDK7_924); 6-(3 , 5 -dimethyl- 1 , 2-oxazole -4-yl)-3 - { 2- [(piperidin-3 -yl)amino]-5- (trifluoromethyl)pyrimidine-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridine-7-one (CDK7_924_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H,4H, 7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_925); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_925_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_926); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,6H, 7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_926_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_927); 3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} - 1 H, 8H-pyrrolo[2, 3 - c]azepin-8-one (CDK7_927_a); 7-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_928); 7-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H,4H, 7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_928_a); 7-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_929); 7-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H,6H, 7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_929_a); 7-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_930); 7-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_930_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7H, 8H-pyrrolo[2,3-c]azepin-8-one (CDK7_931); 3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} -7H, 8H-pyrrolo[2, 3 - c]azepin-8-one (CDK7_931_a); 3 -(2- { [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_932); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_932_a); 8-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_933); 8-methyl-3-{ 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_933_a); 183 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H,4H, 5H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_934); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 5H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_934_a); 8-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_935); 8-methyl-3-{ 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_935_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H,4H, 7H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_936); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 7H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_936_a); 8-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_937); 8-methyl-3-{ 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_937_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H,6H, 7H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_938); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,6H, 7H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_938_a); 8-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_939); 8-methyl-3-{ 2- [(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_939_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_940); 3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} - 1 H, 8H, 9H-pyrrolo[2,3 - c]azocin-9-one (CDK7_940_a); 8-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_941); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H, 8H, 9H-pyrrolo[2,3-c]azocin-9-one (CDK7_941_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-9H-pyrrolo[2,3-c]azocin-9-one (CDK7_942); 3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} -9H-pyrrolo[2,3 - c]azocin-9-one (CDK7_942_a); 3 -(2- { [(38)-piperidin-3-yl]amino}-5 -(trifluoromethyl)pyrimidin-4-yl)- 1H,4H, 5H,6H-pyrrolo[2,3-c]pyrrol-6-one (CDK7_943); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 5H,6H-pyrrolo[2,3-c]pyrrol-6-one (CDK7_943_a); 5-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (CDK7_944); 5-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (CDK7_944_a); ]-[(38)-piperidin-3-yl]-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 945); 184 (piperidin-3-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 945 a); 4-(1H-imide azol-4-yl)-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 946); 4-(1H-imidazol-4-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 946 a); T4-[(38)-piperidin-3-yl]-4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_947); T4-(piperidin-3-yl)-4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 947 a); N-[(38)-piperidin-3-yl]-4-(1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 948); N-(pyridin-3-yl)-4-(1 H- 1 ,2, 3 -triazol-4-yl)-5 -(trifluoromethyl)pyrimidin-2-amine (CDK7 948 a); T4-[(38)-piperidin-3-yl]-4-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 949); T4-(piperidin-3-yl)-4-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 949 a); T4-[(38)-piperidin-3-yl]-4-(2H-1,2,3,4-tetrazol-5-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 950); N-(pyridin-3-yl)-4-(2H-1,2,3,4-tetrazol-5-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 950 a); 4-(2-{ [(38)-piperidin-3-yl]amino} -5-(trifluoromethyl)pyrimidin-4-yl)- 1 ,2, 3 ,4-tetrahydroquinoxalin-2-one (CDK7_900); 4- {2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 ,2,3,4-tetrahydroquinoxalin-2-one (CDK7 900 a); 4-(2-{ [(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1,2- dihydroquinolin-2-one (CDK7_901); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1, 2- dihydroquinolin-2-one (CDK7 901 a); 4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1,2-d-hydroisoquinolin-1-one (CDK7 921); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1,2- d-hydroisoquinolin-1-one (CDK7 921 a); N- ci cloprop yl-N-methyl-4-(2- { [(38)-piperidin-3 -yl] amino} -5- (trifluoromethyl)pyrimidine (4-yl)- 1 H-pyrrole-2-carboxamide (CDK7_1001); M-cyclopropyl-M-methyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7 1001_a); ]8[-methyl-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-M-(1,3-thiazol-2-yl)-1H-pyrrol-2-carboxamide (CDK7_1003); N-methyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-N-(1,3-thiazol-2-yl)-1H-pyrrole-2-carboxamide (CDK7_1003_a); N-benzyl-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_997); N-benz yl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_997_a); 185 ]81-benzyl-N-methyl-4-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H-pyrrole-2-carboxamide (CDK7_998); N-benz yl-M-methyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7_998_a); 4-[5-(1-methyl-1H-13,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_999); 4- [5 -( 1 -methyl- 1 H- 1 ,2, 3 ,4-tetrazol-5 -yl)- 1 H-pyrrol-3 -yl] -N-(pyperidin-3 -yl)-5 - (trifluoromethyl)pyrimidin-2-amine (CDK7_999_a); 4- [5 -(2-methyl-2H- 1 ,2, 3 ,4-tetrazol-5 -yl)- 1 H-pyrrol-3 -yl] -N- [(38)-piperidin-3 -yl] -5 - (trifluoromethyl)pyrimidin-2-amine (CDK7 1 Ltd); 4-[5-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7 1000 a); 4-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrol-3-yl]-N-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7 1060); 4-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5- (trifluoromethyl)pyrimyridin-2-amine (CDK7_1060_a); 4-[5-(1-cyclopropyl-1H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-]81-[(38)-piperidin-3-yl]- 5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1102); 4-[5-(1-cyclopropyl-1H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 1102_a); 4-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1H-pyrrol-3-yl]-H-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_1103); 4-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1H-pyrrol-3-yl]-H-(piperidin-3-yl)-5- (trifluoromethyl)pyrimidin-2-amine (CDK7 1103_a); 4-[5-(1-methyl-1H-1,3-benzodiazol-2-yl)-1H-pyrrol-3-yl]-M-[(38)piperidin-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_1124); 4-[5 -(1-methyl-1H-1,3-benzodiazol-2-yl)-1H-pyrrol-3-yl]-M-(piperidin-3-yl)-5 - (trifluoromethyl)pyrimidin-2-amine (CDK7_1124_a); ethyl 4-(2-{ [(38)-piperidin-3-yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-2-carboxylate (CDK7_1020); ethyl 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxylate (CDK7_1020_a); N,N, 1 -trimethyl-4-(2-{ [(38)-piperidin-3-yl] amino} -5 -(trifluoromethyl)pyrimide in-4-yl)- 1 H-pyrrole-2-carboxamide (CDK7 1017); N,N, 1 -trimethyl-4- { 2- [(piperidin-3-yl)amino] -5 - (trifluoromethyl)pyrimidin-4-yl} - 1 H-pyrrole-2-carboxamide (CDK7 1017_a); H-[(38)-piperidin-3-yl]-4-[5-(pyridin-2-yl)-1H-pyrrol-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_1061); H-(piperidin-3-yl)-4-[5-(pyridin-2-yl)-1 H-pyrrol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 1061 a); H-[(38)-piperidin-3-yl]-4-[5-(pyrimidin-2-yl)-1H-pyrrol-3-yl]-5- (trifluoromethyl)pyrimide in-2-amine (CDK7 1062); H-(piperidin-3-yl)-4-[5-(pyrimidin-2-yl)-1H-pyrrol-3-yl]-5- (trifluoromethyl)pyrimidin-2-amine (CDK7_1062_a); 4-{5-[2-(dimethylphosphoryl)phenyl]-1H-pyrrol-3-yl}-H-[(38)-piperidin-3-yl]-5- (trifluoromethyl)pyrimide in-2-amine (CDK7_1057); 4- { 5 -[2-(dimethylphosphoryl)phenyl]-1 H-pyrrol-3-yl}-N-(pyridin-3-yl)-5 - (trifluoromethyl)pyrimidin-2-amine (CDK7_1057_a); 7-(1-methyl-1H-pyrazol-4-yl)-3-(2-{[(38)-piperidin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 955); 7-(1-methyl-1H-pyrazol-4-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_955_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7-( 1 - methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1122); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(1-methyl- 1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1122_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-6-( 1 - methyl-1H-pyrazol-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1123); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -6-( 1 -methyl- 1H-pyrazol-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1123_a); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-7-( 1 - methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine-8-one (CDK7_1136); 3 - [2-( { 4-azaspiro[2.5 ] octane-6-yl} amino)-5 -(trifluoromethyl)pyrimidine-4-yl]-7-( 1 -methyl- 1H-pyrazol-4-yl)-1H,4H,5H,6H,3p-H8-one[2H (CDK7_1136_a); 3 -(2- { [(7 S)-5 -azaspiro[3.5 ] nonan-7-yl]amino} -5 -(trifluoromethyl)pyrimidine-4-yl)-7-( 1 - methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine-8-one (CDK7_1137); 3 - [2-( { 5 -azaspiro[3.5 ] nonan-7-yl} amino)-5 -(trifluoromethyl)pyrimide in-4-yl]-7-( 1 -methyl- 1H-pyrazol-4-yl)-1H,4H,5H,6H,3p-p8,8 (CDK7_1137_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperide in-3 -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-7-( 1,3- thiazol-2-yl)-1H,4H,5H,6NepH,3p-8H, (CDK7_1138); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl}-7-(1,3- thiazol-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-18_18_CDK7-1); 7-(3 , 5 -dimethyl- 1 , 2-oxazol -4-yl)-3 -(2- { [(38)-6,6-d imethylpiperidin-3 -yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1139); 7-(3 , 5 -dimethyl- 1 , 2-oxazol -4-yl)-3 - { 2- [(6, 6-dimethylpiperidin-Z -yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1139 a); 5 - [3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-8- oxo- 1 H,4H, 5H, 6H,7H, 8H-pyrrolo[2, 3 -c]-methylase - -1 -1 ,2-dihydropyr id in -2-one (CDK7 1140); 5 -(3 - { 2- [(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimide in -4-yl} -8-oxo- 1 H,4H, 5H, 6H,7H, 8H-pyrrolo[2, 3 -s] azepin-7-yl)- 1 -methyl- 1 ,2-dihydropyridin-2-one (CDK7 1140 a); 3-(2-{[(3 S)-6, 6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(pyridin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1141); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(pyridin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1141_a); 3-(2-{[(3 S)-6, 6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(pyridin-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1142); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7- (pyridin-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1142_a); 3-(2-{[(3 S)-6, 6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(pyridin-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1143); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -7- (pyridin-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CD_7_13_1); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in-4-yl)-7-[( 1 - methyl-1H-pyrazol-4-yl)methyl]-1H,4H,5H,6H,7H,8H-rololo,38-pyr (CDK7 1144); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -7- [( 1 - methyl-1H-pyrazol-4-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolosonase[2,3H-K-78] 1144 a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-7- [(1,3 -thiazol-2-yl)methyl] - 1 H,4H, 5H, 6H, 7H, 8H-pyrolozone, 3-8-[8] (CDK7_1145); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -7- [( 1 , 3 - thiazol-2-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,-3-azepin-one] (CDK7_1145_a); 7- [(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)methyl] -3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} - 5 -(triftomethyl)pyrimidin-4-yl)- 1 H,4H, 5H, 6H, 7H, 8H-pyrrolo[2,3 -c] azepin-8-one (CDK7 1146); 7- [(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)methyl] -3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8-H-pyr-8-lonose[2,38] (CDK7 1146 a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-7-[ 1 - (1-methyl-1H-pyrazol-4-yl)ethyl]-1H,4H,5H,6H,7H-pyr-H-8,3-8[ (CDK7 1147); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(triformathyl)pyrimidin-4-yl} -7- [ 1 -(1 - methyl- 1 H-pyrazol-4-yl)ethyl] - 1 H,4H, 5H,6H, 7H, 8H-azeropine-2-[] 8-on (CDK7 1147 a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7 - [ 1 - (1,3-thiazol-2-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyr,38-p (CDK7_1148); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-[1-(1,3-thiazol-2-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1148_a); 7-[1-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-3-(2-{[(38)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1149); 7-[1-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1149 a); 3-(2-{[(3 S)-6, 6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(oxan-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1150); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(oxan-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1150_a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-3 -yl] amino} -5 -(trifluoromethyl)pyrimidin -4-yl)-7-[(oxan-4-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1151); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7- [(oxan-4-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1151_a); 188 3-(2-{[(3 S)-6, 6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(oxolan-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1152); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(oxolane- 3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1152_a); 3 - { 2-[(6, 6-dimethylpiperidin-3 -yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} -7-[(oxolan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1153); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7- [(oxolan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1153_a); 7-cyclopentyl-3-(2-{[(3 S)-6, 6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1154); 7-cyclopentyl-3-{2-[(6, 6-d imethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1154_a); 7-(cyclopentylmethyl)-3-(2-{[(3 S)-6, 6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1155); 7-(cyclopentylmethyl)-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 H,4H, 5H,6H, 7H, 8H-pyrrolo[2,3 -c]azepin-8-one (CDK7_1155_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7-[ 1 - (oxan-4-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1156); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7- [ 1 - (oxanil-4-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1156_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7-[ 1 - (oxolan-3-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1157); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7- [ 1 - (oxolan-3-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1157_a); 7-(1-cyclopentylethyl)-3-(2-{[(38)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1158); 7-( 1 -cyclopentylethyl)-3 - { 2- [(6, 6-d imethylpiperide in-3 -yl) amino] -5 - (trifluoromethyl) pyrimide in-4-yl} - 1 H,4H, 5H,6H, 7H, 8H-pyrrolo[2,3 -c] azepin-8-one (CDK7_1158_a); 7-tert-butyl-3-(2- { [(3 S)-6, 6-d imethylpiperidin-3 -yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1159); 7-tert-butyl-3-{2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(1-trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1159_a); 3-(2-{[(3 S)-6, 6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(2,2-dimethylpropyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1160); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(2,2-dimethylpropyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1160_a); 7-(3 ,3 -d imethylbutan-2-yl)-3 -(2- { [(3 S)-6, 6-dimethylpiperidin-3 -yl] amino} -5- (trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1161); 7-(3,3-d imethylbutan-2-yl)-3 - { 2-[(6,6-d imethylpiperidin-3-yl)amino] -5 -(trifluoromethyl) pyrimidin-4-yl} - 1 H,4H, 5H,6H, 7H, 8H-pyrrolo[2,3 -с] azepin-8-one (CDK7_1161_a); 8-(2-{[(3 S)-6, 6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-4-yl)-2H,3H,4H,5H,6H-pyrrolo[2,3-1 : [1,4]oxazepin-5-one (CDK7 1162); 189 8- { 2-[(6, 6-dimethylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -4-(1 -methyl-1H-pyrazol-4-yl)-2H,3H,4H,5H,6H-pyrrolo[2,3-^[1,4]oxazepin-5-one (CDK7_1162_a); (6 S)-3 -(2- { [(3 S)-6, 6-dimethylpiperidin-3 -yl] amino} -5 -(trifluoromethyl)pyrimide in-4-yl)-6-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1163); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -6-methyl-7- (1-methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrololosonase[2,38-pin-8] (CDK7 1163 a); (6R)-3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 6-methyl-7-(1 -methyl- 1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1164); 3 - { 2-[(6, 6-dimethylpiperidin-Z -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -6-methyl-7- (1-methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrololosonase[2,38-pin-8] (CDK7 1164 a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-6,6- d imethyl-7-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H,4H, 5H, 6H,7H, pyr, 38H -c] azepin-8-one (CDK7 1165); 3 - { 2-[(6, 6-dimethylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -6, 6- d imethyl-7-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H,4H, 5H, 6H,7H, 8H-pyrrolo[2, 3-с] azepin-8-one (CDK7 1165 a); 6-cyclopropyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1 H,6H,7H-pyrrolo[2, 3-c]pyridin-7-one (CDK7_1105); 6-cyclopropyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1 H,6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_1105_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-(1,3-thiazol-2-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1158); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6-(1,3-thiazol-2-yl)- 1 H,6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7 1058_a); 1-methyl-5-[7-oxo-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-6-yl]-1,2-dihydropyridin-2-one (CDK7_1052); 1-methyl-5-(7-oxo-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-6-yl)-1,2-dihydropyridin-2-one (CDK7_1052_a); T4-[(38)-piperidin-3-yl]-4-(1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_972); N -(piperidin-3 -yl)-4-(1H-pyrrol-3 -yl)-5 -(trifluoromethyl)pyrimidin-2-amine (CDK7_972_a); 7-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine-4, 8-dione (CDK7_1021); 7-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine-4, 8-dione (CDK7_1021_a); 6-(oxan-4-yl)-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1121); 6-(oxan-4-yl)-3 - { 2- [(piperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} - 1 H,6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_1121_a); 4-( 1 H-indol- 1 -yl )-N- [(38)-piperidin-3 -yl] -5 - (trifluoromethyl) pyrimidin-2-amine (CDK7 809); 190 4-(1 H-indol-1-yl)-N-(n and perid and n-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 809 a); 4-(1H-1,3-benzodiazol-1-yl)-M-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 810); 4-(1 H-1,3-benzodiazol-1-yl)-N-(and peridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 810 a); 4-(1H-1,2,3-benzotriazol-1-yl)-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 811); 4-(1H-1,2,3-benzotriazol-1-yl)-N-(pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7 811 a); 7-methyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-s]azepin-8-one (CDK7_953); 7-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-s]azepin-8-one (CDK7_953_a); 6-(1-methyl-1H-pyrazol-4-yl)-3-(2-{[(38)-piperidin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_959); 6-(1-methyl-1H-pyrazol-4-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_959_a); 6-benzyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,6H,7H-pyrrolo[2,3-s]pyridin-7-one (CDK7_961); 6-benzyl-3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} - 1 H, 6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_961_a); M,M-dimethyl-4-(2- { [(38)-piperidin-3-yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-carboxamide (CDK7_966); N, N-methyl-4-{2-[(pyridin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-imidazole-2-carboxamide (CDK7_966_a); M,M-dimethyl-4-(2- { [(38)-piperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)- 1 H-pyrrole-3-carboxamide (CDK7_991); N, N-methyl-4-{2-[(pyridin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1 H-pyrrole-3-carboxamide (CDK7 991_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(pyridin-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1176); 3 - { 2-[(piperide in-3 -yl)amino]-5 -(trifluoromethyl)pyrimide in-4-yl} -7-(pyridin-2-yl)- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]17CDK6_a(8); 3 -(2- { [(3 S)-6, 6-d imethylpiperide in-3 -yl] amino} -5 -(trifluoromethyl)pyrimidine-4-yl)-7 - methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[178,8K-8-c); 3 - { 2-[(6, 6-dimethylpiperidine-Z -yl)amino] -5 -(trifluoro methyl)pyrimidine-4-yl} -7-methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-a_18CDK7); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-6-( 1 - methyl- 1 H-pyrazol-4-yl)- 1 H,6pihydroH in-7H]- (CDK7_1199); 3 - [2-( { 4-azaspiro[2.5 ] octane-6-yl} amino)-5 -(trifluoromethyl)pyrimidine-4-yl]-6-( 1 -methyl- 1H-pyrazol-4-yl)-1H,6H,7H-pyrrolone-solon-[2,3-pyridine (CDK7_1199_a); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-6-methyl- 1H,6H,7H-pyrrolo[2,3-c]pyridine-7_-one (CD7_-one). 3 - [2-( { 4-azaspiro[2.5 ] octane -6-yl} amino)-5 -(trifluoromethyl)pyrimidine-4-yl] -6-methyl- 1H,6H,7H-pyrrolo[2,3-c]pyridin-712one (CD0_ane); 191 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino}-5-(trifluoromethyl)pyrimidine-4-yl)-7-methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-7-2]sonazepine (CD3-8-2]nazepine. 3 - [2-( { { 4-azaspiro[2.5 ] octane-6-yl} amino)-5-(trifluoromethyl)pyrimidine-4-yl]-7-methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin_1_a-8); 3 -(2- { [(38)-piperidin-3 -yl] amino} -5 -(trifluoromethyl)pyrimide in -4-yl)-6-( 1 , 3 -thiazol-4-yl)- 1 H, 6H,7H-pyrrolo[7_1, onpyridin-c20 -c); 3 - { 2-[(piperide in-3 -yl)amino] -5 -(trifluoromethyl)pyrimide in -4-yl} -6-( 1 ,3 -thiazol-4-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridine (1CD_7-one); 3 -(2- { [(38)-piperidin-3 -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-6-( 1 , 3 -thiazol-5 - yl)- 1 H, 6H,7H-pyrrolo-72] (CD20 -onpyridine); 3 - { 2-[(piperidin-3-yl)amino]-5 -(trifluoromethyl)pyrimidin-4-yl} -6-( 1 ,3 -thiazol-5-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1203_a); 6-(2-methyl- 1 , 3 -thiazol-4-yl)-3 -(2- { [(38)-piperidin-3 -yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1204); 6-(2-methyl- 1 , 3 -thiazol-4-yl)-3 - { 2-[(piperidin-3 -yl)amino]-5-(trifluoromethyl)pyrimidin- 4-yl} - 1 H, 6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_1204_a); 6-(2-methyl- 1 , 3 -thiazol-5 -yl)-3 -(2- { [(38)-piperidin-3 -yl] amino} -5 - (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1205); -(2-methyl-1,3-thiazol-5-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1205_a); 6-(4-methyl- 1 , 3 -thiazol-2-yl)-3 -(2- { [(38)-piperidin-3 -yl] amino} -5 - (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1206); 6-(4-methyl- 1 , 3 -thiazol-2-yl)-3 - { 2-[(piperidin-3 -yl)amino]-5-(trifluoromethyl)pyrimidin- 4-yl} - 1 H, 6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_1206_a); 6-(5-methyl-1,3-thiazol-2-yl)-3-(2-{[(38)-piperidin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1207); 6-(5-methyl-1,3-thiazol-2-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin- 4-yl} - 1 H, 6H,7H-pyrrolo[2, 3 -c]pyridin-7-one (CDK7_1207_a); 6-(cyclopropylmethyl)-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidine-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1208); 6-(cyclopropylmethyl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1208_a); 6-cyclobutyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1209); 6-cyclobutyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1209_a); 6-cyclopentyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1210); 6-cyclopentyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1210_a); 6-(1-methylcyclopropyl)-3-(2-{[(38)-piperidin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1211); 6-(1-methylcyclopropyl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1211_a); 6-cyclohexyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1212); 192 6-cyclohexyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1212_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-(pyridin-2-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1213); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -6-(pyridin-2-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1213_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-(pyridin-3-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1214); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -6-(pyridin-3-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1214_a); 3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-(pyridin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1215); 3 - { 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -6-(pyridin-4-yl)- 1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1215_a); 6-(3-methylpyridin-4-yl)-3-(2-{ [(38)-piperidin-3-yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1216); 6-(3-methylpyridin-4-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1216_a); 6-(2-methylpyridin-3-yl)-3-(2-{ [(38)-piperidin-3-yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1217); 6-(2-methylpyridin-3-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1217_a); 6-(4-methylpyridin-3-yl)-3-(2-{ [(38)-piperidin-3-yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1218); 6-(4-methylpyridin-3-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1218_a); 6-(3-methylpyridin-2-yl)-3-(2-{ [(38)-piperidin-3-yl] amino}-5- (trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1219); 6-(3-methylpyridin-2-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1219_a); 7-cyclopropyl-3-(2-{[(38)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1225); 7-cyclopropyl-3-{2-[(6, 6-d imethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1225_a); 7-cyclobutyl-3 -(2- { [(38)-6,6-dimethylpiperidin-3 -yl] amino} -5- (trifluoromethyl)pyrimide in-4-yl)- 1 H, 4 H, 5 H, 6 H, 7 H, 8 H-pyrrolo[2, 3 - с] azepin-8-one (CDK7 1226); 7-cyclobutyl-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1226_a); 7-(cyclopropylmethyl)-3-(2-{[(3S)-6,6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1227); 7-(cyclopropylmethyl)-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1227_a); 7-(cyclobutylmethyl)-3-(2-{[(3S)-6,6-d imethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1228); 193 7-(cyclobutylmethyl)-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1228_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7- (propan-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1229); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-(propan- 2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1229_a); 3 -(2- { [(3 S)-6, 6-d imethylpiperidin-3-yl]amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-7- (2,2,2-trifluoroethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1230); 3 - { 2-[(6, 6-dimethylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} -7-(2,2,2-trifluoroethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1230_a); 4-{5-methyl-3,4,6,13-tetraazatricyclo[8.3.0.0 2 , 6]trideca-1 (10),2,4, 11 -tetraen-11 -yl}-N- [(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1236); 4-{5-methyl-3 6D 3-tetraazatricyclo[83.0.0 2 , 6 ]trideca- 1(10), 2,4,11 -tetraen-11 -yl}-N- (piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1236_a); 4- { 5 -cyclopropyl-3 ,4, 6, 13 -tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-1(10),2,4,11-tetraen-11-yl}-N-[(38)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1237); 4- { 5 -cyclopropyl-3 ,4, 6, 13 -tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-1(10),2,4,11-tetraen-11-yl}-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1237_a); 3 -(2- { [(3 S)-6, 6-d imetilpiperidin-3 -yl] amino} -5 -(trifluoro methyl)pyrimidin-4-yl)-6,6, 7 - trimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3- c ]azepin-8-one (CDK7_1238); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6,6,7-trimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1238_a); (6 S )-3 -(2- { [(38)-6,6-dimethylpiperidin-3-yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)- 6,7-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1239); 3-{ 2-[(6, 6-dimethylpiperidin-3 -yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6,7-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-s]azepin-8-one (CDK7_1239_a); (6R)-3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 6,7-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1240); 3-{ 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6,7-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-s]azepin-8-one (CDK7_1240_a); 7-cyclopropyl-3-(2-{[(3 S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6,6-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7 1241); 7-cyclopropyl-3-{2-[(6, 6-d imethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6,6-dimethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1241_a); (68)-7-cyclopropyl-3-(2-{[(3S)-6,6-d-methylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1242); 7-cyclopropyl-3-{2-[(6, 6-d imethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6-methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1242_a); (6K)-7-cyclopropyl-3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(triflomethyl)pyrimidin-4-yl)-6-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1243); 7-cyclopropyl-3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1243_a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-3-yl] amino} -5 -(trifluoromethyl)pyrimidin-4-yl)-5 , 5,6- trimethyl-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1244); 194 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-5,5,6-trimethyl-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1244_a); 6,7-Dimethyl-3-(2-{[(38)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1254); 6,7-dimethyl-3-{ 2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1254_a); 3 -(2- { [(3 S )-6, 6-dimethylpiperidin-3 -yl] amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7- ethyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1259); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} -7-ethyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1259_a); 6-(2- { [(3 S)-6, 6-dimethylpiperidin-3 -yl]amino} -5 -(trifluoromethyl)pyrimidin -4-yl)- 1,4-diazatricyclo[7.1.1.0 3 , 7 ]undeca-3(7),5-dien-2-one (CDK7_1261); 6- { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl} - 1 ,4-diazatricyclo[7.1.1.0 3 , 7 ]undeca-3(7),5-dien-2-one (CDK7_1261_a); 7-methyl-3-(2-{[(3S,6S)-6-methylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1264); 7-methyl-3 - { 2-[(6-methylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4-yl} - 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1264_a); 3-(2-{[(3S,6S)-6-ethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1265); 3 - { 2-[(6-ethylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin -4-yl} -7-methyl- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1265_a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidin-3 -yl] amino} -5 -(trifluoromethyl)pyrimidin -4-yl)-7-(2-methoxyethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1268); 3 - { 2-[(6, 6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-(2-methoxyethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1268_a); 2-[3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-8-oxo-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-7-yl]acetonitrile (CDK7_1269); 2-(3 ​​- { 2- [(6, 6-dimethylpiperidin-3 -yl)amino] -5 -(trifluoromethyl)pyrimidin -4-yl} -8-oxo- 1 H,4H, 5H, 6H,7H, 8H-pyrrolo[2, 3 -c] azepin-7-yl)acetonitrile (CDK7_1269_a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidine-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-7- (oxetan-3-yl)-1H,4H,5H,6H,7H-8oneH[p3p-pyrrosone] (CDK7_1270); 3 - { 2-[(6, 6-dimethylpiperidine-Z -yl)amino] -5 -(trifluoromethyl)pyrimidine-4-yl} -7-(oxetan- 3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepine-8-one (CDK7_1270_a); 3 -(2- { [(3 S)-6, 6-dimethylpiperidine-Z -yl] amino} -5 -(trifluoro methyl)pyrimide in -4-yl)-7- [(oxetan-3-yl)methyl]-1H,4H,5H,6H,7p-H8[H,8H- (CDK7_1271); 3 - { 2-[(6, 6-dimethylpiperidine-Z -yl)amino] -5 -(trifluoromethyl)pyrimidine-4-yl} -7- [(oxetan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolone-az][2 (CDK7_1271_a); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-7-(2- methoxyethyl)-1H,4H,5H,6H,7H,8Hpyrrolo]one[2 (CDK7_1272); 3 - [2-( { { 4-azaspiro[2.5 ] octane-6-yl} amino)-5-(trifluoromethyl)pyrimidine-4-yl]-7-(2- methoxyethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,2CDin-K7-8]); 2-[3-(2-{{[(68)-4-azaspiro[2.5]octane-6-yl]amino}-5-(trifluoromethyl)pyrimidine-4-yl)-8- oxo-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-cytone_itryla]K7pine-7); 2-{3-[2-({4-azaspiro[2.5]octane-6-yl}amino)-5-(trifluoromethyl)pyrimidine-4-yl]-8-oxo- 1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepinton-7acetril_7itryl}a); 195 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoromethyl)pyrimidine-4-yl)-7- (oxetan-3-yl)-1H,4H,5H,6H,7H,8Az-onep-2pyrrolo] (CDK7_1274); 3 - [2-( { { 4-azaspiro[2.5 ] octane-6-yl} amino)-5 -(trifluoromethyl)pyrimidine-4-yl]-7-(oxetan-3 - yl)-1H,4H,5H,6H,7H,8H-pyrrolone-7_a[7CD_8-c); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-7- [(oxetan-3-yl)methyl]-1H,4H,5H,6H,7pr-8-one[p2H- (CDK7_1275); 3 - [2-( { 4-azaspiro[2.5 ] octane-6-yl} amino)-5-(trifluoromethyl)pyrimidine-4-yl]-7-[(oxetan- 3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolone-az][2, (CDK7_1275_a); 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-7- cyclopropyl-1H,4H,5H,6H,7H,8H-K7-pyrrolone-[2,3); 3 - [2-( { { 4-azaspiro[2.5 ] octane-6-yl} amino)-5-(trifluoromethyl)pyrimidine-4-yl]-7- cyclopropyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-a-1_](CD6-8_]2 3 -(2- { [(68)-4-azaspiro[2.5 ] octane-6-yl] amino} -5 -(trifluoro methyl)pyrimidine-4-yl)-7- (propane-2-yl)-1H,4H,5H,6H,7H,8H-az-pyrrolo]one[2 (CDK7_1277); 3 - [2-( { 4-azaspiro[2.5 ] octan-6-yl} amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-(propan-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1277_a).

15. A method for inhibiting the biological activity of cyclin-dependent protein kinases CDK7 in a subject, comprising contacting cyclin-dependent protein kinases CDK7 with a compound according to any one of paragraphs 1-14.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of paragraphs 1-14, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

17. A pharmaceutical composition according to claim 16, intended for the prevention or treatment of a disease or disorder associated with an increase in the activity of cyclin-dependent protein kinase CDK7.

18. A pharmaceutical composition according to claim 17, intended for the prevention or treatment of a disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7, wherein the disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7 is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

19. Pharmaceutical composition according to I. 18, wherein the oncological disease is selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing receptors for estrogens and / or progesterone HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, squamous cell cancer of the head and neck, oral cancer, oral squamous cell cancer, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer,thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell, 196 cellular lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitides (ANCA-associated vasculitides, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; autoinflammatory disease,selected from the group consisting of Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler's disease, Sweet's syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD),TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); an infectious inflammatory or non-infectious inflammatory disease selected from the group consisting of allergy (including but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthrostitis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis,Blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, 197 Acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

20. A method for treating a disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7, comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1-14 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to paragraph 16 to a subject in need of such treatment.

21. A method for treating a disease or disorder according to claim 20, wherein the disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7 is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

22. Method of treating a disease or disorder according to and. 21, wherein the oncological disease is selected from the group consisting of breast cancer, metastatic breast cancer, HEK2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer expressing receptors for estrogens and / or progesterone HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, squamous cell cancer of the head and neck, oral cancer, oral squamous cell cancer, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer,Castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome,Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), 198 Familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, Nomiable Infantile Multisystem Inflammatory Disease (NOMID), Chronic Infantile Neurologic Cutaneous Articular Syndrome (CINCA), Majid Syndrome, Mevalonate Kinase Deficiency (Hyperimmunoglobulinemia D Syndrome), PFAPA Syndrome (Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Lymphadenitis), PAPA Syndrome (Pyogenic Arthritis, Pyoderma Gangrenosum, Acne), Schnitzler Syndrome, Sweet Syndrome, Systemic Juvenile Idiopathic Arthritis, Still's Disease, Adult-Onset Still's Disease (AOSD), TRAPS Syndrome (Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome); infectious inflammatory or non-infectious inflammatory disease selected from the group including allergy (including, but not limited to: delayed hypersensitivity reactions, immediate hypersensitivity reactions, anaphylactic shock), allograft rejection,graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis,inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

23. The use of a compound according to any of paragraphs 1-14 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to paragraph 16 for the treatment of a disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7, in a subject in need of such treatment.

24. Use according to claim 23, wherein the disease or disorder associated with an increase in the activity of the cyclin-dependent protein kinase CDK7 is an oncological, infectious inflammatory or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

25. The use according to item 24, wherein the oncological disease is selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, breast cancer expressing estrogen receptors, breast cancer expressing progesterone receptors, triple-negative breast cancer (TNBC), HEK2-negative breast cancer, 199 estrogen receptor and / or progesterone receptor HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer, non-small cell lung cancer, ovarian cancer, metastatic ovarian cancer, glioma, astrocytoma, glioblastoma, pancreatic cancer, gastric cancer, colorectal cancer, head and neck cancer, head and neck squamous cell cancer, oral cancer, oral squamous cell cancer, hepatobiliary cancer, hepatocellular carcinoma, urothelial cancer, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma,multiple myeloma; an autoimmune disease selected from the group consisting of axial spondylitis, antiphospholipid syndrome, vasculitides (ANCA-associated vasculitides, including Wegener's granulomatosis and related forms of angiitis, temporal arteritis and polyarteritis nodosa, necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; an autoinflammatory disease selected from the group consisting of Behcet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, ostitis),cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory diseases, infantile multisystem inflammatory disease (NOMID), chronic infantile neurologic cutaneous-articular syndrome (CINCA), Majid syndrome, mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome), PFAPA syndrome (fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis), PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne), Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), TRAPS syndrome (tumor necrosis factor (TNF) receptor-associated periodic syndrome); infectious inflammatory or non-infectious inflammatory disease selected from the group including allergy (including, but not limited to: delayed-type hypersensitivity reactions,immediate hypersensitivity reactions, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, arthritis, adult respiratory distress syndrome, airway inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, 200 berylliosis, silicosis, talcosis, usual interstitial pneumonitis), tonsillitis, bursitis, phlegmon, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, lymphadenitis, hay fever, inflammatory bowel disease (including but not limited to: appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, inflammatory dermatoses), myelitis, myocarditis, nephritis, pyelonephritis, ostitis, osteomyelitis, optic neuritis, otitis, pancreatitis, Mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendinitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, testitis, transverse myelitis, urethritis, urocystitis,uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis., 201